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  Subjects -> BIOLOGY (Total: 3190 journals)
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BIOLOGY (1522 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 23)
Achievements in the Life Sciences     Open Access   (Followers: 5)
ACS Synthetic Biology     Hybrid Journal   (Followers: 24)
Acta Biologica Colombiana     Open Access   (Followers: 7)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access   (Followers: 2)
Acta Biologica Turcica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 27)
Acta Biotheoretica     Hybrid Journal   (Followers: 4)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Fytotechnica et Zootechnica     Open Access   (Followers: 1)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales     Open Access  
Acta Neurobiologiae Experimentalis     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 10)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis     Open Access  
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Journal of Graduate Research     Open Access  
Advanced Nonlinear Studies     Hybrid Journal  
Advanced Studies in Biology     Open Access  
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Bioinformatics     Open Access   (Followers: 17)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biology     Open Access   (Followers: 9)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 7)
Advances in Cell Biology/ Medical Journal of Cell Biology     Open Access   (Followers: 25)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 16)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Genome Biology     Full-text available via subscription   (Followers: 8)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 3)
Advances in Life Science and Technology     Open Access   (Followers: 16)
Advances in Life Sciences     Open Access   (Followers: 6)
Advances in Marine Biology     Full-text available via subscription   (Followers: 18)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Tropical Biodiversity and Environmental Sciences     Open Access  
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 8)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 1)
Ageing Research Reviews     Hybrid Journal   (Followers: 11)
Aging Cell     Open Access   (Followers: 18)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Hybrid Journal   (Followers: 15)
AJP Endocrinology and Metabolism     Hybrid Journal   (Followers: 24)
AJP Lung Cellular and Molecular Physiology     Hybrid Journal   (Followers: 3)
Al-Kauniyah : Jurnal Biologi     Open Access  
Alasbimn Journal     Open Access   (Followers: 1)
Alces : A Journal Devoted to the Biology and Management of Moose     Open Access  
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Biology Teacher     Full-text available via subscription   (Followers: 14)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 8)
American Journal of Bioethics     Hybrid Journal   (Followers: 13)
American Journal of Human Biology     Hybrid Journal   (Followers: 14)
American Journal of Medical and Biological Research     Open Access   (Followers: 8)
American Journal of Plant Sciences     Open Access   (Followers: 19)
American Journal of Primatology     Hybrid Journal   (Followers: 15)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 76)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anadolu University Journal of Science and Technology : C Life Sciences and Biotechnology     Open Access  
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 11)
Anatomical Science International     Hybrid Journal   (Followers: 3)
Animal Cells and Systems     Hybrid Journal   (Followers: 4)
Animal Models and Experimental Medicine     Open Access  
Annales de Limnologie - International Journal of Limnology     Hybrid Journal   (Followers: 1)
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3)
Annals of Applied Biology     Hybrid Journal   (Followers: 7)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 17)
Annals of Human Biology     Hybrid Journal   (Followers: 5)
Annals of Science and Technology     Open Access  
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 14)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 23)
Annual Review of Cancer Biology     Full-text available via subscription   (Followers: 2)
Annual Review of Cell and Developmental Biology     Full-text available via subscription   (Followers: 37)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 24)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 12)
Anthropological Review     Open Access   (Followers: 23)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antibiotics     Open Access   (Followers: 9)
Antioxidants     Open Access   (Followers: 4)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 8)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 4)
Apmis     Hybrid Journal   (Followers: 1)
APOPTOSIS     Hybrid Journal   (Followers: 8)
Applied Biology     Open Access  
Applied Bionics and Biomechanics     Open Access   (Followers: 8)
Applied Vegetation Science     Full-text available via subscription   (Followers: 10)
Aquaculture Environment Interactions     Open Access   (Followers: 4)
Aquaculture International     Hybrid Journal   (Followers: 25)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 7)
Aquatic Biology     Open Access   (Followers: 6)
Aquatic Ecology     Hybrid Journal   (Followers: 36)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 15)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 23)
Archaea     Open Access   (Followers: 3)
Archiv für Molluskenkunde: International Journal of Malacology     Full-text available via subscription   (Followers: 3)
Archives of Biological Sciences     Open Access  
Archives of Microbiology     Hybrid Journal   (Followers: 9)
Archives of Natural History     Hybrid Journal   (Followers: 6)
Archives of Oral Biology     Hybrid Journal   (Followers: 2)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 2)
Arquivos do Instituto Biológico     Open Access   (Followers: 1)
Arquivos do Museu Dinâmico Interdisciplinar     Open Access  
Arthropod Structure & Development     Hybrid Journal   (Followers: 2)
Arthropods     Open Access   (Followers: 1)
Artificial DNA: PNA & XNA     Hybrid Journal   (Followers: 3)
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Journal of Biodiversity     Open Access   (Followers: 4)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 4)
Asian Journal of Nematology     Open Access   (Followers: 4)
Asian Journal of Poultry Science     Open Access   (Followers: 4)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 6)
Autophagy     Hybrid Journal   (Followers: 3)
Avian Biology Research     Full-text available via subscription   (Followers: 4)
Avian Conservation and Ecology     Open Access   (Followers: 11)
Bacteriology Journal     Open Access   (Followers: 1)
Bacteriophage     Full-text available via subscription   (Followers: 3)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Plant Taxonomy     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Batman Üniversitesi Yaşam Bilimleri Dergisi     Open Access  
Berita Biologi     Open Access   (Followers: 1)
Between the Species     Open Access   (Followers: 1)
Bio Tribune Magazine     Hybrid Journal  
BIO Web of Conferences     Open Access  
BIO-Complexity     Open Access  
Bio-Grafía. Escritos sobre la Biología y su enseñanza     Open Access  
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
BioCentury Innovations     Full-text available via subscription   (Followers: 1)
Biochemistry and Cell Biology     Hybrid Journal   (Followers: 16)
Biochimie     Hybrid Journal   (Followers: 7)
BioControl     Hybrid Journal   (Followers: 5)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 5)
Biodemography and Social Biology     Hybrid Journal  
BioDiscovery     Open Access   (Followers: 2)
Biodiversidade e Conservação Marinha : Revista CEPSUL     Open Access  
Biodiversitas : Journal of Biological Diversity     Open Access  
Biodiversity Data Journal     Open Access   (Followers: 4)
Biodiversity Informatics     Open Access   (Followers: 1)
Biodiversity Information Science and Standards     Open Access  
Biodiversity: Research and Conservation     Open Access   (Followers: 27)
Bioedukasi : Jurnal Pendidikan Biologi FKIP UM Metro     Open Access  
Bioeksperimen : Jurnal Penelitian Biologi     Open Access  
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 1)
Bioenergy Research     Hybrid Journal   (Followers: 3)
Bioengineering and Bioscience     Open Access   (Followers: 1)
BioEssays     Hybrid Journal   (Followers: 10)
Bioethics     Hybrid Journal   (Followers: 15)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 4)
Biofilms     Full-text available via subscription   (Followers: 1)
Biogeosciences (BG)     Open Access   (Followers: 10)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 2)
Bioinformatics     Hybrid Journal   (Followers: 315)
Bioinformatics and Biology Insights     Open Access   (Followers: 11)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 7)
Biointerphases     Open Access   (Followers: 1)
Biojournal of Science and Technology     Open Access  
BioLink : Jurnal Biologi Lingkungan, Industri, Kesehatan     Open Access   (Followers: 1)
Biologia     Hybrid Journal  
Biologia on-line : Revista de divulgació de la Facultat de Biologia     Open Access  
Biological Bulletin     Partially Free   (Followers: 6)
Biological Control     Hybrid Journal   (Followers: 4)
Biological Invasions     Hybrid Journal   (Followers: 20)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 18)
Biological Letters     Open Access   (Followers: 5)

        1 2 3 4 5 6 7 8 | Last

Journal Cover
Acta Biomaterialia
Journal Prestige (SJR): 1.967
Citation Impact (citeScore): 7
Number of Followers: 27  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1742-7061
Published by Elsevier Homepage  [3155 journals]
  • Bioengineered bladder patches constructed from multilayered
           adipose-derived stem cell sheets for bladder regeneration
    • Abstract: Publication date: Available online 12 December 2018Source: Acta BiomaterialiaAuthor(s): Ying Wang, Shukui Zhou, Ranxing Yang, Qingsong Zou, Kaile Zhang, Qinghua Tian, Weixin Zhao, Lijuan Zong, Qiang Fu Cell-seeded scaffolds are a common route of cell transplantation for bladder repair and reconstruction. However, when cell suspensions are harvested, proteolytic enzymes often cause extracellular matrix damage and loss of intercellular junctions. To overcome this problem, we developed a bioengineered three-dimensional bladder patch comprising porous scaffolds and multilayered adipose-derived stem cell (ASC) sheets, and evaluated its feasibility for bladder regeneration in a rat model. Adipose-derived stem cells (ASCs) were labeled with ultrasmall super-paramagnetic iron oxide (USPIO) nanoparticles. ASC patches were constructed using multilayered USPIO-labeled ASC sheets and porous polyglycolic acid scaffolds. To monitor the distribution and localization of bioengineered bladder patches in live animals, magnetic resonance imaging (MRI) was performed 2 weeks, 4 weeks and 8 weeks after transplantation. The bladder regenerative potential of ASC patches was further evaluated by urodynamic and histological analysis. Scanning electron microscopy indicated that cell sheets adhered tightly to the scaffold. MRI showed hypointense signals that lasted up to 8 weeks at the site of USPIO-labeled ASC sheet transplants. Immunofluorescence demonstrated that these tissue-engineered bladder patches promoted regeneration of urothelium, smooth muscle, neural cells and blood vessels. Urodynamic testing revealed that the ASC patch restored bladder function with augmented capacity. The USPIO-labeled ASC patch provides a promising perspective on image-guided tissue engineering and holds great promise as a safe and effective therapeutic strategy for bladder regeneration.Statement of SignificanceAdipose-derived stem cell (ASC) sheets avoid enzymatic dissociation and preserve the cell-to-cell interactions and extracellular matrix (ECM) proteins, which exhibit great potential for tissue regeneration. In this study, we developed a bioengineered three-dimensional bladder patch comprising porous scaffolds and multilayered ASC sheets, and evaluated its feasibility for bladder regeneration in a rat model. Tissue-engineered bladder patches restored bladder function and promoted regeneration of urothelium, smooth muscle, neural cells and blood vessels. Moreover, ultrasmall super-paramagnetic iron oxide (USPIO)-labeled bladder patches can be dynamically monitored in vivo by noninvasive MRI for long periods of time. Therefore, The USPIO-labeled bladder patch provides a promising image-guided therapeutic strategy for bladder regeneration.Graphical abstractGraphical abstract for this article
       
  • Self-Assembled GFFYK Peptide Hydrogel Enhances the Therapeutic Efficacy of
           Mesenchymal Stem Cells in a Mouse Hindlimb Ischemia Model
    • Abstract: Publication date: Available online 11 December 2018Source: Acta BiomaterialiaAuthor(s): Anan Huang, Danni Liu, Xin Qi, Zhiwei Yue, Hongmei Cao, Kaiyue Zhang, Xudan Lei, Youzhi Wang, Deling Kong, Jie Gao, Zongjin Li, Na Liu, Yuebing Wang Mesenchymal stem cell (MSC) transplantation has emerged as a very promising strategy for the treatments of peripheral artery disease (PAD). However, MSC-based therapies are limited by low cell retention and survival rate in the ischemic zone. Small molecular (SM) hydrogels have shown attractive abilities to enhance the therapeutic effects of human MSCs via promoting their proliferation or maintaining their differentiation potential. Here, we designed and synthesized a new bioactive and biocompatible hydrogel, Nap-GFFYK-Thiol, using disulfide bonds as cleavable linkers to control the molecular self-assembly and we hypothesized this hydrogel could enhance the retention and engraftment of human placenta-derived MSCs (hP-MSCs) in a mouse ischemic hindlimb model. In vitro results demonstrated that the Nap-GFFYK-Thiol hydrogel increased cell viability through paracrine effects. Moreover, it enhanced the proangiogenic and anti-apoptotic effects of hP-MSCs. In vivo, Nap-GFFYK-Thiol hydrogel improved the hP-MSC retention in the murine ischemic hindlimb model as visualized by bioluminescence imaging. Furthermore, cotransplantation of hP-MSCs with hydrogel improved blood perfusion, leading to superior limb salvage. These therapeutic effects may attribute to reduced inflammatory cell infiltration, enhanced angiogenesis as well as suppressed collagen deposition. In conclusion, the Nap-GFFYK-Thiol hydrogel fabricated using disulfide bonds as cleavable linkers serves as an artificial niche for promoting hP-MSC survival and proangiogenic factor secretion in PAD therapy and thereby provide an alternative strategy for PAD therapy.Statement of SignificanceAlthough several phase I/II clinical trials of MSC-based treatments for critical limb ischemia (CLI) are ongoing, MSC-based therapies are still challenged by the low quality and quantity of cells in the ischemic zone, especially in cases of extensive or irreversible damage. Hydrogels have favorable biocompatibility and safety records in the medical field. In the current study, we engineered a new bioactive and biocompatible hydrogel, Nap-GFFYK-Thiol, using disulfide bonds as cleavable linkers to enhance the therapeutic efficacy of human placenta-derived MSCs (hP-MSCs) in mouse limb ischemia model. Notably, Nap-GFFYK-Thiol hydrogel acts as an artificial niche for promoting hP-MSC survival and proangiogenic factor secretion in PAD therapy, which further promoted the restoration of blood perfusion and regeneration of muscle cells. Considering the proangiogenic effect of Nap-GFFYK-Thiol on hP-MSCs, our results may provide a new strategy for the treatment of PAD.Graphical abstractGraphical abstract for this article
       
  • Looking deep into nature: A review of micro-computed tomography in
           biomimicry
    • Abstract: Publication date: Available online 10 December 2018Source: Acta BiomaterialiaAuthor(s): Anton du Plessis, Chris Broeckhoven Albert Einstein once said “look deep into nature, and then you will understand everything better”. Looking deep into nature has in the last few years become much more achievable through the use of high-resolution X-ray micro-computed tomography (microCT). The non-destructive nature of microCT, combined with three-dimensional visualization and analysis, allows for the most complete internal and external “view” of natural materials and structures at both macro- and micro-scale. This capability brings with it the possibility to learn from nature at an unprecedented level of detail in full three dimensions, allowing us to improve our current understanding of structures, learn from them and apply them to solve engineering problems. The use of microCT in the fields of biomimicry, biomimetic engineering and bioinspiration is growing rapidly and holds great promise. MicroCT images and three-dimensional data can be used as generic bio-inspiration, or may be interpreted as detailed blueprints for specific engineering applications, i.e., reverse-engineering nature. In this review, we show how microCT has been used in bioinspiration and biomimetic studies to date, including investigations of multifunctional structures, hierarchical structures and the growing use of additive manufacturing and mechanical testing of 3D printed models in combination with microCT. The latest microCT capabilities and developments which might support biomimetic studies are described and the unique synergy between microCT and biomimicry is demonstrated.Statement Of SignificanceThis review highlights the growing use of X-ray micro computed tomography in biomimetic research. We feel the timing of this paper is excellent as there is a significant growth and interest in biomimetic research, also coupled with additive manufacturing, but still no review of the use of microCT in this field. The use of microCT for structural biomimetic and biomaterials research has huge potential but is still under-utilized, partly due to lack of knowledge of the capabilities and how it can be used in this field. We hope this review fills this gap and fuels further advances in this field using microCT.Graphical abstractGraphical abstract for this article
       
  • Osteoblast responses to injectable bone substitutes of kappa-carrageenan
           and nano hydroxyapatite
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Jazmín I. González Ocampo, Mirian M. Machado de Paula, Nicole J. Bassous, Anderson O. Lobo, Claudia P. Ossa Orozco, Thomas J. Webster The combination of kappa-carrageenan (κ-CG) and hydroxyapatite (HA) to generate a bone substitute material has been underexplored to date. Carrageenans (CGs) have remarkable characteristics such as biocompatibility, hydrophilicity, and structural similarities with natural glycosaminoglycans (GAGs), and they have demonstrated the ability to stimulate cellular adhesion and proliferation. Hydroxyapatite nanoparticles have been one of the most investigated materials for bone regeneration due to their excellent biocompatibility, bioactivity and osteoconductivity. In particular, this study presents an approach for the preparation of new bioactive composites of κ-CG/nHA for numerous bone regeneration applications. We performed a set of in vitro experiments to evaluate the influence of the bone substitutes on human osteoblasts. Cell culture studies indicated that all samples tested were cytocompatible. Relative to control substrates, cellular attachment and proliferation were better on all the scaffold surfaces that were tested. The S2 and S3 samples, those permeated by 1.5 and 2.5 wt% of CG, respectively, exhibited an enhancement in cell spreading capacity compared to the S1 test materials which were comprised of 1 wt% of CG. Excellent osteoblast viability and adhesion were observed for each of the tested materials. Additionally, the bone substitutes developed for this study presented a distinct osteoconductive environment. Data supporting this claim were derived from alkaline phosphatase (ALP) and calcium deposition analyses, which indicated that, compared to the control species, ALP expression and calcium deposition were both improved on test κ-CG/nHA surfaces. In summary, the injectable bone substitute developed here demonstrated great potential for numerous bone regeneration applications, and thus, should be studied further.Statement of SignificanceThe novelty of this work lies in the determination of the in vitro cytocompatibility behavior of carrageenan and hydroxyapatite composite materials used as injectable bone substitutes. This injectable biomaterial can fill in geometric complex defects, and it displays bioactivity as well as high bone regeneration capacity. In this study, we evaluated the behaviors of osteoblast cells in contact with the scaffolds, including cellular adhesion and proliferation, cellular metabolism, and mineralization on the fabricated injectable bone substitutes. The results show than the carrageenan and hydroxyapatite substitutes provided a biomaterial with a great capacity for promoting cellular growth, adhesion, and proliferation, as well as contributing an osteoinductive environment for osteoblast differentiation and osteogenesis.Graphical abstractGraphical abstract for this article
       
  • Polydopamine-coated Au-Ag nanoparticle-guided photothermal colorectal
           cancer therapy through multiple cell death pathways
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Miao Hao, Chenfei Kong, Chengwei Jiang, Ruizhi Hou, Xiaoming Zhao, Jing Li, Yuqian Wang, Yiyao Gao, Hao Zhang, Bai Yang, Jinlan Jiang Nanoparticles are emerging as a new therapeutic modality due to their high stability, precise targeting, and high biocompatibility. Branched Au-Ag nanoparticles with polydopamine coating (Au-Ag@PDA) have strong near-infrared absorbance and no cytotoxicity but high photothermal conversion efficiency. However, the photothermal activity of Au-Ag@PDA in vivo and in vitro has not been reported yet, and the mechanism underlying the effects of photothermal nanomaterials is not clear. Therefore, in this study, the colorectal cancer cell line HCT-116 and nude mice xenografts were used to observe the photothermal effects of Au-Ag@PDA in vivo and in vitro. The results suggest that Au-Ag@PDA NPs significantly inhibited cell proliferation and induced apoptosis in colorectal cancer cells. Moreover, Au-Ag@PDA NP-mediated photothermal therapy inhibited the growth of tumors at doses of 50 and 100 μg in vivo. The mechanisms through which Au-Ag@PDA NPs induced colorectal cancer cell death involved multiple pathways, including caspase-dependent and -independent apoptosis, mitochondrial damage, lysosomal membrane permeability, and autophagy. Thus, our findings suggest that Au-Ag@PDA NPs could be used as potential antitumor agents for photothermal ablation of colorectal cancer cells.Graphical abstractGraphical abstract for this article
       
  • Nitroimidazole derivative incorporated liposomes for hypoxia-triggered
           drug delivery and enhanced therapeutic efficacy in patient-derived tumor
           xenografts
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Yi Li, Ailing Lu, Mengmeng Long, Lei Cui, Zhongping Chen, Li Zhu Hypoxia is not merely a tumor microenvironment byproduct, but rather an active participant in tumor development, invasion, and metastasis. Hypoxia contributes to poor outcomes in tumor treatment and has currently emerged as an important therapeutic target. In this work, a facile hypoxia-responsive liposomal drug delivery system was developed by incorporating derivatized nitroimidazole into liposome membranes. Under hypoxic conditions, hypoxia-induced reductive metabolism of the nitroimidazole derivative facilitated disassembly of the liposomes for triggered drug release. The liposomes showed high sensitivity to hypoxia, even at the cellular level, and could release payload in an oxygen-dependent manner, leading to high cytotoxicity in hypoxic conditions. In vivo fluorescence imaging revealed that there was a selective release of the liposomes at the hypoxic tumor site. As a result, the liposomes exhibited enhanced therapeutic efficacy in treating a hypoxic tumor in both cell line-derived and clinically relevant patient-derived xenograft models. Thus, hypoxia-responsive liposomes are a promising drug delivery system for hypoxia targeted tumor therapy.Statement of Significance1. A facile but smart hypoxia-responsive liposomal drug delivery system is developed by incorporating nitroimidazole derivative, one of representative hypoxia-responsive moieties, into phospholipid bilayer of the liposomes.2. The liposomes show extremely high sensitivity to hypoxia and can selectively release payload in hypoxic cells and hypoxic tumor.3. The liposomes show enhanced therapeutic efficacy not only in cell line-derived xenograft model but also in clinically relevant patient-derived xenograft model, indicating their promising prospect in clinical application.Graphical abstractGraphical abstract for this article
       
  • The multiscale structural and mechanical effects of mouse supraspinatus
           muscle unloading on the mature enthesis
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Alix C. Deymier, Andrea G. Schwartz, Zhounghou Cai, Tyrone L. Daulton, Jill D. Pasteris, Guy M. Genin, Stavros Thomopoulos The musculoskeletal system is sensitive to its loading environment; this is of particular concern under conditions such as disuse, paralysis, and extended-duration space flight. Although structural and mechanical changes to tendon and bone following paralysis and disuse are well understood, there is a pressing need to understand how this unloading affects the bone-tendon interface (enthesis); the location most prone to tears and injury. We therefore elucidated these effects of unloading in the entheses of adult mice shoulders that were paralyzed for 21 days by treatment with botulinum toxin A. Unloading significantly increased the extent of mechanical failure and was associated with structural changes across hierarchical scales. At the millimeter scale, unloading caused bone loss. At the micrometer scale, unloading decreased bioapatite crystal size and crystallographic alignment in the enthesis. At the nanometer scale, unloading induced compositional changes that stiffened the bioapatite/collagen composite tissue. Mathematical modeling and mechanical testing indicated that these factors combined to increase local elevations of stress while decreasing the ability of the tissue to absorb energy prior to failure, thereby increasing injury risk. These first observations of the multiscale effects of unloading on the adult enthesis provide new insight into the hierarchical features of structure and composition that endow the enthesis with increased resistance to failure.Statement of SignificanceThe musculoskeletal system is sensitive to its loading environment; this is of particular concern under conditions such as disuse, paralysis, and extended-duration space flight. Although changes to tendon and bone following paralysis are understood, there is a pressing need to clarify how unloading affects the bone-tendon interface (enthesis), which is the location most prone to tears and injury. We elucidated the effects of enthesis unloading in adult mice shoulders showing, for the first time, that unloading significantly increased the risk and extent of mechanical failure and was associated with structural changes across hierarchical scales. These observations provide new insight into the hierarchical features of structure and composition that endow the enthesis with resilience. This knowledge can be used to develop more targeted treatments to improve mobility and function.Graphical abstractGraphical abstract for this article
       
  • Nanofiber arrangement regulates peripheral nerve regeneration through
           differential modulation of macrophage phenotypes
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Yachao Jia, Weichao Yang, Kuihua Zhang, Shuo Qiu, Jia Xu, Chunyang Wang, Yimin Chai Topographical cues presented by aligned nanofibers have been demonstrated to stimulate peripheral nerve regeneration across long gaps, but the underlying mechanisms remain incompletely elucidated. Because macrophages play a crucial role in peripheral nerve regeneration and can be phenotypically modulated by topographical cues, we hypothesized that aligned nanofibers might induce the development of macrophage phenotypes that facilitate the regeneration of peripheral nerves. Here, macrophages were seeded on aligned and random poly(l-lactic acid-co-ε-caprolactone) nanofibers and their morphology and phenotypes were compared. Aligned nanofibers drastically stimulated macrophage elongation along the nanofibers, and, more importantly, induced the development of a pro-healing macrophage phenotype (M2 type), whereas random nanofibers induced a proinflammatory phenotype (M1 type). Notably, the macrophages polarized by aligned nanofibers potently promoted the proliferation and migration of Schwann cells in vitro. Thus, we constructed nerve-guidance conduits by using aligned and random nanofibers and evaluated their effects on macrophage polarization and nerve regeneration in a rat sciatic nerve defect model. Our in vivo results showed that the ratio of pro-healing macrophages was again higher in the aligned-nanofiber group, and further that Schwann cell infiltration and axon numbers were 2.0- and 2.84-fold higher in the aligned group than in the random group, respectively. This study demonstrates that nanofiber arrangement differentially regulates macrophage activation and that nerve-guidance conduits constructed from aligned nanofibers markedly facilitate peripheral nerve regeneration at least partly by promoting the pro-healing phenotype in macrophages.Statement of SignificanceThe effect of aligned nanofibers on peripheral nerve regeneration has been well established. However, the underlying mechanism remains unclear. Since macrophages play an important role in peripheral nerve regeneration, and can be phenotypically modulated by topographical cues, we hypothesized that aligned nanofibers may exert their beneficial effects via modulating macrophage phenotypes. This study demonstrates for the first time that nanofiber arrangement differentially modulates macrophage shape and polarization, and this subsequently influences the outcome of peripheral nerve regeneration. These findings reveals a novel relationship between biomaterial structure and macrophage activation, contributes to clarifying the mechanism of surface topography in tissue regeneration, and highlight the potential application prospect of aligned nanofiber scaffolds in nerve regeneration and wound healing.Graphical abstractGraphical abstract for this article
       
  • Identification of topographical architectures supporting the phenotype of
           rat tenocytes
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Steven Vermeulen, Aliaksei Vasilevich, Dimitrios Tsiapalis, Nadia Roumans, Pascal Vroemen, Nick R.M. Beijer, Aysegul Dede Eren, Dimitrios Zeugolis, Jan de Boer Tenocytes, the main cell type of the tendon, require mechanical stimuli for their proper function. When the tenocyte environment changes due to tissue damage or by transferring tenocytes from their native environment into cell culture, the signals from the tenocyte niche are lost, leading towards a decline of phenotypic markers. It is known that micro-topographies can influence cell fate by the physical cues they provide. To identify the optimal topography-induced biomechanical niche in vitro, we seeded tenocytes on the TopoChip, a micro-topographical screening platform, and measured expression of the tendon transcription factor Scleraxis. Through machine learning algorithms, we associated elevated Scleraxis levels with topological design parameters. Fabricating micro-topographies with optimal surface characteristics on larger surfaces allowed finding an improved expression of multiple tenogenic markers. However, long-term confluent culture conditions coincided with osteogenic marker expression and the loss of morphological characteristics. In contrast, passaging tenocytes which migrated from the tendon directly on the topography resulted in prolonged elongated morphology and elevated Scleraxis levels. This research provides new insights into how micro-topographies influence tenocyte cell fate, and supports the notion that micro-topographical design can be implemented in a new generation of tissue culture platforms for supporting the phenotype of tenocytes.Statement of SignificanceThe challenge in controlling in vitro cell behavior lies in controlling the complex culture environment. Here, we present for the first time the use of micro-topographies as a biomechanical niche to support the phenotype of tenocytes. For this, we applied the TopoChip platform, a screening tool with 2176 unique micro-topographies for identifying feature characteristics associated with elevated Scleraxis expression, a tendon related marker. Large area fabrication of micro-topographies with favorable characteristics allowed us to find a beneficial influence on other tenogenic markers as well. Furthermore, passaging cells is more beneficial for Scleraxis marker expression and tenocyte morphology compared to confluent conditions. This study presents important insights for the understanding of tenocyte behavior in vitro, a necessary step towards tendon engineering.Graphical abstractGraphical abstract for this article
       
  • Assembly of histidine-rich protein materials controlled through divalent
           cations
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Hèctor López-Laguna, Ugutz Unzueta, Oscar Conchillo-Solé, Alejandro Sánchez-Chardi, Mireia Pesarrodona, Olivia Cano-Garrido, Eric Voltà, Laura Sánchez-García, Naroa Serna, Paolo Saccardo, Ramón Mangues, Antonio Villaverde, Esther Vázquez Nanostructured protein materials show exciting biomedical applications, since both structure and function can be genetically programmed. In particular, self-assembling histidine-rich proteins benefit from functional plasticity that allows the generation of protein-only nanoparticles for cell targeted drug delivery. However, the rational development of constructs with improved functions is limited by a poor control of the oligomerization process. By exploring cross-interactions between histidine-tagged building blocks, we have identified a critical architectonic role of divalent cations. The obtained data instruct about how histidine-rich protein materials can be assembled, disassembled and reassembled within the nanoscale through the stoichiometric manipulation of divalent ions, in a biochemical approach to biomaterials design.Statement of SignificanceDivalent metal and non-metal cations such as Ni2+, Cu2+ Ca2+ and Zn2+ have been identified as unexpected molecular tools to control the assembling, disassembling and reassembling of histidine-rich protein materials at the nanoscale. Their stoichiometric manipulation allows generating defined protein-protein cross-molecular contacts between building blocks, for a powerful nano-biochemical manipulation of the material’s architecture.Graphical abstractGraphical abstract for this article
       
  • Antibiofilm elastin-like polypeptide coatings: functionality,
           stability, and selectivity
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Saba Atefyekta, Maria Pihl, Chris Lindsay, Sarah C. Heilshorn, Martin Andersson Antimicrobial peptides (AMPs) are currently receiving interest as an alternative to conventional antibiotics to treat biomaterial-associated infection. However, the inherent instability of such peptides often limits their efficacy in intended clinical applications. Covalent immobilization of AMPs to surfaces is one strategy to increase the long-term stability and minimize the toxicity. In this work, an antimicrobial peptide, RRPRPRPRPWWWW-NH2 (RRP9W4N), was used to modify elastin-like polypeptide (ELP) surface coatings containing cell-adhesive peptide domains (RGD) using covalent chemistry. The AMP retained its antibacterial activity against Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa when covalently bonded to ELP surfaces. Simultaneously, the AMP functionalization had insignificant effect on the viability, function, and differentiation of human osteosarcoma MG63 cells and human mesenchymal stem cells (hMSCs). Furthermore, stability of the immobilized AMP in human blood serum was investigated, and the results suggested that the AMP preserved its antibacterial activity up to 24 h. Combined, the results show that covalently attached AMPs onto RGD-containing ELP are an excellent candidate as an antimicrobial coating for medical devices.Statement of SignificanceBiomaterial associated infection, caused by adherent biofilm, is usually difficult to treat. There is a high demand for new materials and treatments to decrease the infection rates, especially with increasing threats concerning resistant bacteria. Formation of biofilms on medical devices lowers the bacteria susceptibility towards traditional antibiotics and also circumvent our immune system often resulting in revisional surgery and extensive use of antibiotics. One promising strategy is to develop surfaces having low bacterial attractiveness or bacterial killing properties, but still retaining the main function of the device. In this study, we have developed an implant coating that demonstrates a high antimicrobial effect and at the same time showing no negative affect on human cells.Graphical abstractGraphical abstract for this article
       
  • An injectable platelet lysate-hyaluronic acid hydrogel supports cellular
           activities and induces chondrogenesis of encapsulated mesenchymal stem
           cells
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Elaheh Jooybar, Mohammad J. Abdekhodaie, Mansour Alvi, Abbas Mousavi, Marcel Karperien, Pieter J. Dijkstra Developing scaffolds that can provide cells and biological cues simultaneously in the defect site is of interest in tissue engineering field. In this study, platelet lysate (PL) as an autologous and inexpensive source of growth factors was incorporated into a cell-laden injectable hyaluronic acid-tyramine (HA-TA) hydrogel. Subsequently, the effect of platelet lysate on cell attachment, viability and differentiation of human mesenchymal stem cell (hMSCs) toward chondrocytes was investigated. HA-TA conjugates having a degree of substitution of 20 TA moieties per 100 disaccharide units were prepared and crosslinked in the presence of horseradish peroxidase and low concentrations of hydrogen peroxide. The storage moduli of the gels ranged from 500 to 2000 Pa and increased with increasing polymer concentration. In contrast to a retained round shape of the cells when using pure HA-TA hydrogel, the hMSCs attached and spread out in PL enriched matrix. The enrichment of hMSCs laden HA-TA hydrogels with PL induced a cartilage like extra cellular matrix deposition in vitro. The hMSCs increasingly deposited collagen type II and proteoglycans over time. The deposition of the new extracellular matrix (ECM) is simultaneous with gel degradation and resulted ultimately in the formation of a tough dense matrix. These findings demonstrate the potential of injectable HA-TA-PL hydrogel as a cell delivery system for cartilage regeneration.Statement of SignificanceCartilage tissue has limited ability to self-repair because of its avascular nature. To have an efficient cartilage tissue regeneration, we combined platelet lysate (PL), as an autologous and inexpensive source of growth factors, with an injectable hyaluronic acid tyramine (HA-TA) hydrogel scaffold. Platelet lysate had a vital role in supporting human mesenchymal stem cells (hMSCs) activities, like cell attachment, viability and proliferation in the 3D hydrogel structure. Also, the hMSCs encapsulated HA-TA induced hyaline cartilage generation when placed in chondrogenic differentiation medium. This study introduces a new system for cartilage tissue engineering, which can be injected in a minimally invasive manner and is rich with patient’s own growth factors and biological cues.Graphical abstractGraphical abstract for this article
       
  • Bioresorbable electrospun gelatin/polycaprolactone nanofibrous membrane as
           a barrier to prevent cardiac postoperative adhesion
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Bei Feng, Shoubao Wang, Dongjian Hu, Wei Fu, Jinglei Wu, Haifa Hong, Ibrahim J. Domian, Fen Li, Jinfen Liu Post-cardiac surgical sternal and epicardial adhesions increase the risk and complexity of cardiac re-operative surgeries, which represent a significant challenge for patients with the congenital cardiac disease. Bioresorbable membranes can serve as barriers to prevent postoperative adhesions. Herein, we fabricated a bioresorbable gelatin/polycaprolactone (GT/PCL) composite membrane via electrospinning. The membrane was characterized in terms of morphology, mechanical properties, and biocompatibility. We then evaluated its efficacy as a physical barrier to prevent cardiac operative adhesions in a rabbit model. Our results showed that the membrane had a nanofibrous structure and was sturdy enough to be handled for the surgical procedures. In vitro studies with rabbit cardiac fibroblasts demonstrated that the membrane was biocompatible and inhibited cell infiltration. Further application of the membrane in a rabbit cardiac adhesion model revealed that the membrane was resorbed gradually and effectively resisted the sternal and epicardial adhesions. Interestingly, six months after the operation, the GT/PCL membrane was completely resorbed with simultaneous ingrowth of host cells to form a natural barrier. Collectively, these results indicated that the GT/PCL membrane might be a suitable barrier to prevent sternal and epicardial adhesions and might be utilized as a novel pericardial substitute for cardiac surgery.Statement of SignificanceElectrospinning is a versatile method to prepare nanofibrous membranes for tissue engineering and regenerative medicine applications. However, with the micro-/nano-scale structure and high porosity, the electrospun membrane might be an excellent candidate as a barrier to prevent postoperative adhesion. Here we prepared an electropun GT/PCL nanofibrous membrane and applied it as a barrier to prevent sternal and epicardial adhesions. Our results showed that the membrane had sufficient mechanical strength, good biocompatibility, and effectively resisted the sternal and epicardial adhesions. What’s more, the membrane was bioresorbable and allowed simultaneous ingrowth of host cells to form a natural barrier. We believe that the current will inspire more research on nanomaterials to prevent postoperative adhesion applications.Graphical abstractGraphical abstract for this article
       
  • Matrix composition in 3-D collagenous bioscaffolds modulates the survival
           and angiogenic phenotype of human chronic wound dermal fibroblasts
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Pascal Morissette Martin, Aaron Grant, Douglas W. Hamilton, Lauren E. Flynn There is a substantial need for new strategies to stimulate cutaneous tissue repair in the treatment of chronic wounds. To address this challenge, our team is developing modular biomaterials termed “bead foams”, comprised of porous beads synthesized exclusively of extracellular matrix (ECM) and assembled into a cohesive three-dimensional (3-D) network. In the current study, bead foams were fabricated from human decellularized adipose tissue (DAT) or commercially-sourced bovine tendon collagen (COL) to explore the effects of ECM composition on human wound edge dermal fibroblasts (weDF) sourced from chronic wound tissues. The DAT and COL bead foams were shown to be structurally similar, but compositionally distinct, containing different levels of glycosaminoglycan content and collagen types IV, V, and VI. In vitro testing under conditions simulating stresses within the chronic wound microenvironment indicated that weDF survival and angiogenic marker expression were significantly enhanced in the DAT bead foams as compared to the COL bead foams. These findings were corroborated through in vivo assessment in a subcutaneous athymic mouse model. Taken together, the results demonstrate that weDF survival and paracrine function can be modulated by the matrix source applied in the design of ECM-derived scaffolds and that the DAT bead foams hold promise as cell-instructive biological wound dressings.Statement of SignificanceBiological wound dressings derived from the extracellular matrix (ECM) can be designed to promote the establishment of a more permissive microenvironment for healing in the treatment of chronic wounds. In the current work, we developed modular biomaterials comprised of fused networks of porous ECM-derived beads fabricated from human decellularized adipose tissue (DAT) or commercially-available bovine collagen. The bioscaffolds were designed to be structurally similar to provide a platform for investigating the effects of ECM composition on human dermal fibroblasts isolated from chronic wounds. Testing in in vitro and in vivo models demonstrated that cell survival and pro-angiogenic function were enhanced in the adipose-derived bioscaffolds, which contained higher levels of glycosaminoglycans and collagen types IV, V, and VI. Our findings support that the complex matrix composition within DAT can induce a more pro-regenerative cellular response for applications in wound healing.Graphical abstractGraphical abstract for this article
       
  • Investigation of the intrinsic permeability of ice-templated collagen
           scaffolds as a function of their structural and mechanical properties
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): L. Mohee, G.S. Offeddu, A. Husmann, M.L. Oyen, R.E. Cameron Collagen scaffolds are widely used in a range of tissue engineering applications, both in vitro and in vivo, where their permeability to fluid flow greatly affects their mechanical and biological functionality. This paper reports new insights into the interrelationships between permeability, scaffold structure, fluid pressure and deformation in collagen scaffolds, focussing in particular on the degree of closure and the alignment of the pores.Isotropic and aligned scaffolds of different occlusivity were produced by ice templating, and were characterised in terms of their structure and mechanical properties. Permeability studies were conducted using two experimental set-ups to cover a wide range of applied fluid pressures. The permeability was found to be constant at low pressures for a given scaffold with more open structures and aligned structures being more permeable. The deformation of scaffolds under high pressure led to a decrease in permeability. The aligned structures were more responsive to deformation than their isotropic equivalents with their permeability falling more quickly at low strain. For isotropic samples, a broad (1 − ɛ)2 dependence for permeability was observed with the constant of proportionality varying with collagen fraction as the starting structures became more occluded. Aligned scaffolds did not follow the same behaviour, with the pores apparently closing more quickly in response to early deformation. These results highlight the importance of scaffold structure in determining permeability to interstitial fluid, and provide an understanding of scaffold behaviour within the complex mechanical environment of the body.Statement of significanceCollagen scaffolds are widely used in tissue engineering applications, for instance to contribute with wound healing. Their permeability to fluid flow, such as water and blood, is important to ensure they perform efficiently when inside the body. The present study reports new insights into the relationships between permeability, scaffold structure, fluid pressure and deformation in collagen scaffolds. It presents in particular the experimental setups used to measure these properties and the result of comparisons between collagen scaffolds with different structures: aligned and isotropic (non-aligned). It indicates quantitative differences in terms of permeability, and the effects of compression on such permeability. The results contribute to the development and understanding of collagen scaffolds and their applications.Graphical abstractGraphical abstract for this article
       
  • Development of keratin-based membranes for potential use in skin repair
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Javier Navarro, Jay Swayambunathan, Max Lerman, Marco Santoro, John P. Fisher The layers in skin determine its protective and hemostasis functions. This layered microstructure cannot be naturally regenerated after severe burns; we aim to reconstruct it using guided tissue regeneration (GTR). In GTR, a membrane is used to regulate tissue growth by stopping fast-proliferating cells and allowing slower cells to migrate and reconstruct specialized microstructures. Here, we proposed the use of keratin membranes crosslinked via dityrosine bonding. Variables from the crosslinking process were grouped within an energy density (ED) parameter to manufacture and evaluate the membranes. Sol fraction, spectrographs, and thermograms were used to quantify the non-linear relation between ED and the resulting crosslinking degree (CD). Mechanical and swelling properties increased until an ED threshold was reached; at higher ED, the CD and properties of the membranes remained invariable indicating that all possible dityrosine bonds were formed. Transport assays showed that the membranes allow molecular diffusion; low ED membranes retain solutes within their structure while the high ED samples allow higher transport rates indicating that uncrosslinked proteins can be responsible of reducing transport. This was confirmed with lower transport of adipogenic growth factors to stem cells when using low ED membranes; high ED samples resulted in increased production of intracellular lipids. Overall, we can engineer keratin membranes with specific CD, a valuable tool to tune microstructural and transport properties.Graphical abstractGraphical abstract for this article
       
  • From microstructural design to surface engineering: A tailored approach
           for improving fatigue life of additively manufactured meta-biomaterials
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): S.M. Ahmadi, R. Kumar, E.V. Borisov, R. Petrov, S. Leeflang, Y. Li, N. Tümer, R. Huizenga, C. Ayas, A.A. Zadpoor, V.A. Popovich Recently, lattice titanium manufactured by additive manufacturing (AM) techniques has been utilized in various applications, including biomedical. The effects of topological design and processing parameters on the fatigue behaviour of such meta-biomaterials have been studied before. Most studies show that the fatigue life of additively manufactured lattice structures is limited. Post-processing techniques could play a major role in improving the fatigue of these promising biomaterials. This study aims to provide an in-depth investigation into the effects of heat treatments, hot isostatic pressing (HIP), sand blasting, and chemical etching on the microstructure, surface morphology, strength and fatigue resistance of selective laser melted titanium meta-biomaterials. It was found that the combination of microstructural design and surface engineering, induced by HIP and sand blasting respectively, allows to increase the endurance limit of these lattice meta-biomaterials by a factor of two. HIP treatment substantially decreased the internal porosity and transformed the microstructure to a more ductile mixture of α + β phases. Sand blasting allowed to eliminate surface imperfections and induced favourable compressive stress in the surface layer of the struts.Statement of SignificanceAdditively manufactured metallic meta-biomaterials are progressively being used as bone replacement orthopedic implants. While there is a great amount of research related to topological designs and their effect on mechanical (e.g. stiffness), physical (e.g. mass transport), and biological (e.g. osseointegration) properties, fatigue lifetime of such structures remains limited. This study provides fundamental investigation into the combined effect of microstructural design and surface engineering of titanium meta-biomaterial, enabled through various post treatment methods ranging from heat treatments to physical and chemical surface modifications. The findings show that fatigue life is significantly improved by applying developed herein novel method, which effortlessly can be used on other bone-mimicking metallic meta-biomaterials.Graphical abstractGraphical abstract for this article
       
  • New silyl-functionalized BisGMA provides autonomous strengthening without
           leaching for dental adhesives
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Linyong Song, Qiang Ye, Xueping Ge, Anil Misra, Candan Tamerler, Paulette Spencer Resin-based composite has overtaken dental amalgam as the most popular material for direct restorative dentistry. In spite of this popularity the clinical lifetime of composite restorations is threatened by recurrent decay. Degradation of the adhesive leads to gaps at the composite/tooth interface–bacteria, bacterial by-products and fluids infiltrate the gaps leading to recurrent decay and composite restoration failure. The durability of resin-dentin bonds is a major problem. We address this problem by synthesizing silyl-functionalized BisGMA (e.g., silyl-BisGMA), formulating dental adhesives with the new monomer and determining the physicochemical properties and leaching characteristics of the silyl-BisGMA adhesives. Silyl-BisGMA was synthesized by stoichiometric amounts of BisGMA and 3-isocyanatopropyl trimethoxysilane (IPTMS). The control adhesive was a mixture based on HEMA/BisGMA (45/55, w/w). In the experimental formulations, BisGMA was partially or completely replaced by silyl-BisGMA. Water miscibility, polymerization behavior (Fourier transform infrared spectroscopy, FTIR), thermal property (modulated differential scanning calorimetry, MDSC), mechanical properties in dry and wet conditions (dynamic mechanical analysis, DMA), and leached species (HPLC) were investigated. Data from all tests were submitted to appropriate statistical analysis (α = 0.05). Silyl-BisGMA-containing adhesives exhibited comparable water miscibility, lower viscosities, and significantly improved degree of conversion of CC bond as compared to the control. After 4 weeks aqueous aging, the glass transition temperature and rubbery moduli of the experimental copolymers were significantly greater than the control (p 
       
  • 3D-printed flexible polymer stents for potential applications in
           inoperable esophageal malignancies
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Maohua Lin, Negar Firoozi, Chi-Tay Tsai, Michael B. Wallace, Yunqing Kang Palliation therapy for dysphagia using esophageal stents is the current treatment of choice for those patients with inoperable esophageal malignancies. However, the metallic and plastic stents currently used in the clinical setting may cause complications, such as tumor ingrowth and stent migration into the stomach. To effectively reduce/overcome these complications, we designed a tubular, flexible polymer stent with spirals. The parameters of the spirals were computationally optimized by using a finite element analysis. The designed polymer stents with optimized spirals were then printed by a 3D printing technique. 3D-printed tubular polymer stents without spirals served as controls. The self-expansion and anti-migration properties of the printed stent were characterized in an ex vivo normal porcine esophagus. The biodegradability test of the stent was performed in a neutral buffer and acidic gastric buffer. The cytotoxicity of the new stent was examined through the viability test of human esophagus epithelial cells. Results showed the self-expansion force of the 3D-printed polymer stent with spirals was higher than the stent without spirals. The anti-migration force of the 3D-printed stent with spirals was significantly higher than that of the stent without spirals. Furthermore, the stent with spirals significantly decreased the migration distance compared to the non-spiral 3D-printed polymer stent. Degradation study showed that the polymer materials started to degrade after six weeks and the compressive strength of the stent was not significantly decreased with time. In vitro cell viability results further indicated that the polymer stent does not have any cytotoxicity. Together, these results showed that the 3D-printed stent with spirals has potential applications in the treatment of inoperable esophageal malignancies.Statement of significanceIn this study, we developed a new 3D-printed flexible tubular polymeric stent with spirals. The mechanical properties of the 3D-printed polymer stent are modulated by changing the ratios of PLA to TPU. The stent is flexible enough to be compressed in a clinically available stent delivery system, and can self-expand after it is released. The self-expansion force of the stent with spirals is higher than that of non-spiral stents. The spirals on the outside of the stent significantly increased the anti-migration force compared to non-spiral stents in an ex vivo normal pig esophagus. Together, the 3D-printed stent with spirals will bring promising potential in the treatment of inoperable esophagus malignancies or benign strictures.Graphical abstractGraphical abstract for this article
       
  • Biomimetic recyclable microgels for on-demand generation of hydrogen
           peroxide and antipathogenic application
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Hao Meng, Pegah Kord Forooshani, Pratik U. Joshi, Julie Osborne, Xue Mi, Christa Meingast, Rattapol Pinnaratip, Jonathan Kelley, Ameya Narkar, Weilue He, Megan C. Frost, Caryn L. Heldt, Bruce P. Lee Microgels that can generate antipathogenic levels of hydrogen peroxide (H2O2) through simple rehydration in solutions with physiological pH are described herein. H2O2 is a widely used disinfectant but the oxidant is hazardous to store and transport. Catechol, an adhesive moiety found in mussel adhesive proteins, was incorporated into microgels, which generated 1–5 mM of H2O2 for up to four days as catechol autoxidized. The sustained release of low concentrations of H2O2 was antimicrobial against both gram-positive (Staphylococcus epidermidis) and gram-negative (Escherichia coli) bacteria and antiviral against both non-enveloped porcine parvovirus (PPV) and enveloped bovine viral diarrhea virus (BVDV). The amount of released H2O2 is several orders of magnitude lower than H2O2 concentration previously reported for antipathogenic activity. Most notably, these microgels reduced the infectivity of the more biocide resistant non-envelope virus by 3 log reduction value (99.9% reduction in infectivity). By controlling the oxidation state of catechol, microgels can be repeatedly activated and deactivated for H2O2 generation. These microgels do not contain a reservoir for storing the reactive H2O2 and can potentially function as a lightweight and portable dried powder source for the disinfectant for a wide range of applications.Statement of SignificanceResearchers have designed bioadhesives and coatings using the adhesive moiety catechol to mimic the strong adhesion capability of mussel adhesive proteins. During catechol autoxidation, hydrogen peroxide (H2O2) is generated as a byproduct. Here, catechol was incorporated into microgels, which can generate millimolar levels of H2O2 by simply hydrating the microgels in a solution with physiological pH. The sustained release of H2O2 was both antimicrobial and antiviral, inactivating even the more biocide resistant non-enveloped virus. These microgels can be repeatedly activated and deactivated for H2O2 generation by incubating them in solutions with different pH. This simplicity and recyclability will enable this biomaterial to function as a lightweight and portable source for the disinfectant for a wide range of applications.Graphical abstractGraphical abstract for this article
       
  • Thermosensitive, fast gelling, photoluminescent, highly flexible, and
           degradable hydrogels for stem cell delivery
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Hong Niu, Xiaofei Li, Haichang Li, Zhaobo Fan, Jianjie Ma, Jianjun Guan Stem cell therapy is a promising approach to regenerate ischemic cardiovascular tissues yet experiences low efficacy. One of the major causes is inferior cell retention in tissues. Injectable cell carriers that can quickly solidify upon injection into tissues so as to immediately increase viscosity have potential to largely improve cell retention. A family of injectable, fast gelling, and thermosensitive hydrogels were developed for delivering stem cells into heart and skeletal muscle tissues. The hydrogels were also photoluminescent with low photobleaching, allowing for non-invasively tracking hydrogel biodistribution and retention by fluorescent imaging. The hydrogels were polymerized by N-isopropylacrylamide (NIPAAm), 2-hydroxyethyl methacrylate (HEMA), 1-vinyl-2-pyrrolidinone (VP), and acrylate-oligolactide (AOLA), followed by conjugation with hypericin (HYP). The hydrogel solutions had thermal transition temperatures around room temperature, and were readily injectable at 4 °C. The solutions were able to quickly solidify within 7 s at 37 °C. The formed gels were highly flexible possessing similar moduli as the heart and skeletal muscle tissues. In vitro, hydrogel fluorescence intensity decreased proportionally to weight loss. After being injected into thigh muscles, the hydrogel can be detected by an in vivo imaging system for 4 weeks. The hydrogels showed excellent biocompatibility in vitro and in vivo, and can stimulate mesenchymal stem cell (MSC) proliferation and paracrine effects. The fast gelling hydrogel remarkably increased MSC retention in thigh muscles compared to slow gelling collagen, and non-gelling PBS. These hydrogels have potential to efficiently deliver stem cells into tissues. Hydrogel degradation can be non-invasively and real-time tracked.Statement of SignificanceLow cell retention in tissues represents one of the major causes for limited therapeutic efficacy in stem cell therapy. A family of injectable, fast gelling, and thermosensitive hydrogels that can quickly solidify upon injection into tissues were developed to improve cell retention. The hydrogels were also photoluminescent, allowing for non-invasively and real-time tracking hydrogel biodistribution and retention by fluorescent imaging.Graphical abstractGraphical abstract for this article
       
  • Review of titanium surface modification techniques and coatings for
           antibacterial applications
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): H. Chouirfa, H. Bouloussa, V. Migonney, C. Falentin-Daudré Implanted biomaterials play a key role in the current success of orthopedic and dental procedures. Pure titanium and its alloys are the most commonly used materials for permanent implants in contact with bone. However, implant-related infections remain among the leading reasons for failure. The most critical pathogenic event in the development of infection on biomaterials is biofilm formation, which starts immediately after bacterial adhesion. In the last decade, numerous studies reported the ability of titanium surface modifications and coatings to minimize bacterial adhesion, inhibit biofilm formation and provide effective bacterial killing to protect implanted biomaterials. In the present review, the different strategies to prevent infection onto titanium surfaces are reported: surface modification and coatings by antibiotics, antimicrobial peptides, inorganic antibacterial metal elements and antibacterial polymers.Statement of SignificanceImplanted biomaterials play a key role in the current success of orthopedic and dental procedures. Pure titanium and its alloys are the most commonly used materials for permanent implants in contact with bone. Microbial infection is one of the main causes of implant failure. Currently, the global infection risk is 2–5% in orthopedic surgery. Numerous solutions exist to render titanium surfaces antibacterial. The LBPS team is an expert on the functionalization of titanium surfaces by using bioactive polymers to improve the biologiocal response. In this review, the different strategies to prevent infection are reported onto titanium and titanium alloy surfaces such as surface modification by antibiotics, antimicrobial peptides, inorganic antibacterial metal elements and antibacterial polymers.Graphical abstractGraphical abstract for this article
       
  • Bactericidal effects of nanopatterns: A systematic review
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Khashayar Modaresifar, Sara Azizian, Mahya Ganjian, Lidy E. Fratila-Apachitei, Amir A. Zadpoor We systematically reviewed the currently available evidence on how the design parameters of surface nanopatterns (e.g. height, diameter, and interspacing) relate to their bactericidal behavior. The systematic search of the literature resulted in 46 studies that satisfied the inclusion criteria of examining the bactericidal behavior of nanopatterns with known design parameters in absence of antibacterial agents. Twelve of the included studies also assessed the cytocompatibility of the nanopatterns. Natural and synthetic nanopatterns with a wide range of design parameters were reported in the included studies to exhibit bactericidal behavior. However, most design parameters were in the following ranges: heights of 100–1000 nm, diameters of 10–300 nm, and interspacings of  
       
  • The inflammasome in host response to biomaterials: Bridging inflammation
           and tissue regeneration
    • Abstract: Publication date: 1 January 2019Source: Acta Biomaterialia, Volume 83Author(s): Daniela P. Vasconcelos, Artur P. Águas, Mário A. Barbosa, Pablo Pelegrín, Judite N. Barbosa The development of new biomaterials to be used in tissue engineering applications is creating new solutions for a range of healthcare problems. The trend in biomaterials research has shifted from biocompatible “immune-evasive” biomaterials to “immune-interactive” materials that modulate the inflammatory response supporting implant integration as well as improving healing and tissue regeneration.Inflammasomes are large intracellular multiprotein complexes that are key players in host defence during innate immune responses and assemble after recognition of pathogens or danger signals. The process of biomaterial implantation causes injury to tissues that will consequently release danger signals that could be sensed by the inflammasome. There are increasing evidences that the inflammasome has a role in several inflammatory processes, from pathogen clearance to chronic inflammation or tissue repair. Thus, modulation of the inflammasome activity appears as an important target in the development of effective approaches in regenerative medicine.In this review, we discuss the main points of the current understanding on the host response to implanted biomaterials and how the paradigm of “immune-evasive” biomaterials has shifted over the last years; the significance of the inflammasome in the inflammatory response to biomaterials; and the growing idea that the immune system is of key importance in an effective tissue repair and regeneration.Statement of significanceWe herein discuss the main points of the current understanding on the host response to implanted biomaterials and how the paradigm of “immune-evasive” biomaterials has shifted to “immune-interactive” over the last years; the significance of the inflammasome in the inflammatory response to biomaterials; and the growing idea that the immune system is of key importance in an effective tissue repair and regeneration, supporting the emerging concept of Regenerative Immunology. The inflammasome is a recent and central concept in immunology research. Since the beginning of this century the inflammasome is viewed as key platform of the innate immune response. We believe that, successful modulation of the inflammasome activity will become a milestone in the fields of tissue engineering and regenerative medicine.Graphical abstractGraphical abstract for this article
       
  • Topological design, permeability and mechanical behavior of additively
           manufactured functionally graded porous metallic biomaterials
    • Abstract: Publication date: Available online 8 December 2018Source: Acta BiomaterialiaAuthor(s): Xiang-Yu Zhang, Gang Fang, Sander Leeflang, Amir A. Zadpoor, Jie Zhou Recent advances in additive manufacturing (AM) have enabled the fabrication of functionally graded porous biomaterials (FGPBs) for application as orthopedic implants and bone substitutes. Here, we present a step-wise topological design of FGPB based on diamond unit cells to mimic the structure of the femoral diaphysis. The FGPB was manufactured from Ti-6Al-4V powder using the selective laser melting (SLM) technique. The morphological parameters, permeability and mechanical properties of FGPB samples were measured and compared with those of the biomaterials with uniform porous structures based on the same type of the unit cell. The FGPB exhibited a low density (1.9 g/cm3), a moderate Young’s modulus (10.44 GPa), a high yield stress (170.6 MPa), a high maximum stress (201 MPa) and favorable ductility, being superior to the biomaterials with uniform porous structures in comprehensive mechanical properties. In addition, digital image correlation (DIC) and finite element (FE) simulation were used to unravel the mechanisms governing the deformation and yielding behavior of these biomaterials particularly at the strut junctions. Both DIC and FE simulations confirmed that the deformation and yielding of the FGPB occurred largely in the load-bearing layers but not at the interfaces between layers. Defect-coupled FE models based on solid elements provided further insights into the mechanical responses of the FGPB to compressive loads at both macro- and micro-scales. With the defect-coupled representative volume element model for the FGPB, the Young’s modulus and yield stress of the FGPBs were predicted with less than 2% deviations from the experimental data. The study clearly demonstrated the capabilities of combined experimental and computational methods to resolve the uncertainties of the mechanical behavior of FGPBs, which would open up the possibilities of applying various porosity variation strategies for the design of biomimetic AM porous biomaterials.Statement of SignificanceFunctionally graded bone scaffolds significantly promote the recovery of segmental bone defect. In the present study, we present a step-wise topological design of functionally graded porous biomaterial (FGPB) to mimic the structure of the femoral diaphysis. The Ti-6Al-4V FGPB exhibited a superior combination of low density, moderate Young’s modulus, high yield stress and maximum stress as well as favorable ductility. The biomechanical performance of FGPB was studied in both macro and micro perspectives. The defect-coupled model revealed the significant yielding in the load-bearing parts and the Young’s modulus and yield stress of the FGPBs were predicted with less than 2% deviations from the experimental data. The superiority of combined experimental and computational methods has been confirmed.Graphical abstractGraphical abstract for this article
       
  • Antiadhesion effect of the C17 glycerin ester of isoprenoid-type lipid
           forming a nonlamellar liquid crystal
    • Abstract: Publication date: Available online 6 December 2018Source: Acta BiomaterialiaAuthor(s): Takahide Murakami, Ichiro Hijikuro, Kota Yamashita, Shigeru Tsunoda, Kenjiro Hirai, Takahisa Suzuki, Yoshiharu Sakai, Yasuhiko Tabata Postoperative adhesion is a relevant clinical problem that causes a variety of clinical complications after abdominal surgery. The objective of this study is to develop a liquid-type antiadhesion agent and evaluate its efficacy in preventing tissue adhesion in a rat peritoneal adhesion model. The liquid-type agent was prepared by submicron-sized emulsification of C17 glycerin ester (C17GE), squalene, pluronic F127, ethanol, and water with a high-pressure homogenizer. The primary component was C17GE, which is an amphiphilic lipid of one isoprenoid-type hydrophobic chain and can form two phases of self-assembly nonlamellar liquid crystals. The C17GE agent consisted of nanoparticles with an internal inverted hexagonal phase when evaluated by small-angle X-ray scattering (SAXS) and cryo-transmission electron microscopy (cryo-TEM). Upon contact with the biological tissue, this agent formed a thin membrane with a bioadhesive property. After this agent was applied to a sidewall injury of rats, it showed a percentage average of adhesion significantly less than that obtained with the Seprafilm® antiadhesion membrane in a rat model. Additionally, the retention of the agent prolonged at the applied site in the peritoneal cavity of rats. In conclusion, the C17GE agent is promising as an antiadhesion material.Statement of SignificancePostoperative adhesion remains a common adverse effect. Although various materials have been investigated, there are few products commercially available to prevent adhesion. For the sheet-type agent, it is inconvenient to be applied through small laparotomy especially in laparoscopic surgery. Also, the liquid-type agent currently used requires complicated procedure to spray the targeted site.Our liquid-type anti-adhesion agent can form liquid crystal and act as a thin membrane like physical barrier between the peritoneum and tissues to prevent adhesion. Indeed, our agent prevent adhesion significantly compared with the anti-adhesion membrane clinically most used. Moreover, our agent is highly stable by itself and easy to use in laparoscopic surgery, leading to a promising new candidate as an anti-adhesion material.Graphical abstractGraphical abstract for this article
       
  • Nanotopographical Regulation of Pancreatic Islet-like Cluster Formation
           from Human Pluripotent Stem Cells using a Gradient-Pattern Chip
    • Abstract: Publication date: Available online 6 December 2018Source: Acta BiomaterialiaAuthor(s): Jong hyun Kim, Bo Gi Park, Suel-Kee Kim, Dong-Hyun Lee, Gyung Gyu Lee, Deok-Ho Kim, Byung-Ok Choi, Kyu Back Lee, Jong-Hoon Kim Bioengineering approaches to regulate stem cell fates aim to recapitulate the in vivo microenvironment. In recent years, manipulating the micro- and nano-scale topography of the stem cell niche has gained considerable interest for the purposes of controlling extrinsic mechanical cues to regulate stem cell fate and behavior in vitro. Here, we established an optimal nanotopographical system to improve 3-dimensional (3D) differentiation of pancreatic cells from human pluripotent stem cells (hPSCs) by testing gradient-pattern chips of nano-scale polystyrene surface structures with varying sizes and shapes. The optimal conditions for 3D differentiation of pancreatic cells were identified by assessing the expression of developmental regulators that are required for pancreatic islet development and maturation. Our results showed that the gradient chip of pore-part 2 (Po-2, 200∼300 nm diameter) pattern was the most efficient setting to generate clusters of pancreatic endocrine progenitors (PDX1+ and NGN3+) compared to those of other pore diameters (Po-1, 100∼200 or Po-3, 300∼400 nm) tested across a range of pillar patterns and flat surfaces. Furthermore, the Po-2 gradient pattern-derived clusters generated islet-like 3D spheroids and tested positive for the zinc-chelating dye dithizone. The spheroids consisted of more than 30% CD200+ endocrine cells and also expressed NKX6.1 and NKX2.2. In addition, pancreatic β- cells expressing insulin and polyhormonal cells expressing both insulin and glucagon were obtained at the final stage of pancreatic differentiation. In conclusion, our data suggest that an optimal topographical structure for differentiation to specific cell types from hPSCs can be tested efficiently by using gradient-pattern chips designed with varying sizes and surfaces.Statement of SignificanceOur study provides demonstrates of using gradient nanopatterned chips for differentiation of pancreatic islet-like clusters.Gradient nanopatterned chips are consisted of two different shapes (nanopillar and nanopore) in three different ranges of nano sizes (100∼200, 200∼300, 300∼400nm). We found that optimal nanostructures for differentiation of pancreatic islet-like clusters were 200∼300 nm nano pores.Cell transplantation is one of the major therapeutic option for type 1 diabetes mellitus (DM) using stem cell-derived β-like cells. We generated 50 um pancreatic islet-like clusters in size, which would be an optimal size for cell transplantation. Futuremore, the small clusters provide a powerful source for cell therapy.Our findings suggest gradient nanopatterned chip provides a powerful tool to generate specific functional cell types of a high purity for potential uses in cell therapy development.Graphical abstractGraphical abstract for this article
       
  • Mixed-charge pseudo-zwitterionic mesoporous silica nanoparticles with
           low-fouling and reduced cell uptake properties
    • Abstract: Publication date: Available online 6 December 2018Source: Acta BiomaterialiaAuthor(s): Noemí Encinas, Mercedes Angulo, Carlos Astorga, Montserrat Colilla, Isabel Izquierdo-Barba, María Vallet-Regí The design of drug delivery systems needs to consider biocompatibility and host body recognition for an adequate actuation. In this work, mesoporous silica nanoparticles (MSNs) surfaces were successfully modified with two silane molecules to provide mixed-charge brushes (-NH3⊕/-PO3⊝) and well evaluated in terms of surface properties, low-fouling capability and cell uptake in comparison to PEGylated MSNs. The modification process consists in the simultaneous direct-grafting of hydrolysable short chain amino (aminopropyl silanetriol, APST) and phosphonate-based (trihydroxy-silyl-propyl-methyl-phosphonate, THSPMP) silane molecules able to provide a pseudo-zwitterionic nature under physiological pH conditions. Results confirmed that both mixed-charge pseudo-zwitterionic MSNs (ZMSN) and PEG-MSN display a significant reduction of serum protein adhesion and macrophages uptake with respect to pristine MSNs. In the case of ZMSNs, his reduction is up to a 70-90% for protein adsorption and c.a. 60% for cellular uptake. This pseudo-zwitterionic modification has been focused on the aim of local treatment of bacterial infections through the synergistic effect between the inherent antimicrobial effect of mixed-charge system and the levofloxacin antibiotic release profile. These findings open promising future expectations for the effective treatment of bacterial infections through the use mixed-charge pseudo-zwitterionic MSNs furtive to macrophages and with antimicrobial properties.Statement of significanceHerein a novel antimicrobial mixed-charge pseudo-zwitterionic MSNs based system with low-fouling and reduced cell uptake behavior has been developed. This chemical modification has been performed by the simultaneous grafting of short chain organosilanes, containing amino and phosphonate groups, respectively. This nanocarrier has been tested for local infection treatment thought the synergistic effect between the inherent antimicrobial effect of mixed-charge brushes and the levofloxacin antibiotic release profile.Graphical abstractGraphical abstract for this article
       
  • Cartilage Penetrating Cationic Peptide Carriers for Applications in Drug
           Delivery to Avascular Negatively Charged Tissues
    • Abstract: Publication date: Available online 6 December 2018Source: Acta BiomaterialiaAuthor(s): Armin Vedadghavami, Erica K. Wagner, Shikhar Mehta, Tengfei He, Chenzhen Zhang, Ambika G. Bajpayee Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148x showing that intra-tissue long-range charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues.Statement of significance:Osteoarthritis (OA) remains an untreatable disease partly due to short joint residence time of drugs and a lack of delivery methods that can effectively target the dense, avascular, highly negatively charged cartilage tissue. In this study, we designed cartilage penetrating and binding cationic peptide carriers (CPCs) that, due to their optimal charge provide adequate electrical driving force to rapidly transport OA drugs into cartilage and reach their cell and matrix targets in therapeutic doses before drugs exit the joint space. This way cartilage is converted from being a barrier to drug entry into a drug depot that can provide sustained drug release for several weeks. This study also investigates synergistic effects of short-range H-bond and hydrophobic interactions in combination with long-range electrostatic interactions on intra-cartilage solute transport. The work provides rules for rational design of cartilage penetrating charge-based carriers depending on the net charge of tissue (normal versus arthritic), macromolecule to be delivered and whether the application is in drug delivery or tissue imaging.Graphical abstractGraphical abstract for this article
       
  • Co-delivery of cisplatin and doxorubicin by covalently conjugating with
           polyamidoamine dendrimer for enhanced synergistic cancer therapy
    • Abstract: Publication date: Available online 5 December 2018Source: Acta BiomaterialiaAuthor(s): Xue-Ling Guo, Xiao-Xuan Kang, Yue-Qi Wang, Xiao-Jie Zhang, Chang-Jian Li, Yang Liu, Li-Bo Du Because of the synergistic effects of drugs and minimal drug dose for cancer therapy, combination chemotherapy is frequently used in the clinic. In this study, hyaluronic acid-modified amine-terminated fourth-generation polyamidoamine dendrimer nanoparticles were synthesized for systemic co-delivery of cisplatin and doxorubicin (HA@PAMAM-Pt-Dox). In vitro data showed that HA@PAMAM-Pt-Dox can enter the cells through the lysosome mediated-pathway in a time-dependent manner. Cell viability studies indicated that HA@PAMAM-Pt-Dox exhibited a higher anticancer activity on MCF-7 and MDA-MB-231 breast cancer cells at a relative low concentration. HA@PAMAM-Pt-Dox not only efficiently inhibited tumor growth but also significantly reduced the toxicity of Dox. Moreover, intravenous administration of HA@PAMAM-Pt-Dox to MDA-MB-231 tumor-bearing BALB/c nude mice resulted in the accumulation of HA@PAMAM-Pt-Dox at the tumor site, thereby significantly inhibiting tumor growth without apparent toxicity. These results suggested that HA@PAMAM-Pt-Dox has great potential to improve the chemotherapeutic efficacy of cisplatin and doxorubicin in breast cancer.Statement of SignificanceOne of the main problems in cancer treatment is the development of drug resistance. To date, it is believed that combination chemotherapy might be an effective strategy for the above problem. However, for two completely different drugs, combination chemotherapy faces huge difficulties including the antagonistic nature of drugs, variations in drugs in terms of solubility, and limited tumor targeting. Recent developments in nanoscience and nanotechnology provide an effective approach for such disadvantages. Considering the advantages of dendrimers such as control of size and molecular weight, bioavailability, and biosafety, we used fourth-generation dendrimers modified by HA as drug vectors by covalently conjugating them with anticancer drugs (cisplatin and doxorubicin) to form a nanodrug delivery system, named HA@PAMAM-Pt-Dox. We observed that the HA@PAMAM-Pt-Dox system can effectively kill breast cancer cells both in vitro and in vivo, which showed a favorable synergistic effect. This strategy can be extended to other drugs, thus providing a highly effective strategy for cancer treatment.Graphical abstractGraphical abstract for this article
       
  • Antimicrobial coatings prepared from Dhvar-5-click-grafted chitosan
           powders
    • Abstract: Publication date: Available online 5 December 2018Source: Acta BiomaterialiaAuthor(s): Mariana Barbosa, Fabíola Costa, Cláudia Monteiro, Filipa Duarte, M. Cristina L. Martins, Paula Gomes Antimicrobial peptides (AMP) are powerful components of the innate immune system, as they display wide activity spectrum and low tendency to induce pathogen resistance. Hence, the development of AMP-based coatings is a very promising strategy to prevent biomaterials-associated infections. This work aims to investigate if Dhvar-5-chitosan conjugates, previously synthesized by us via azide-alkyne “click” reaction, can be applied as antimicrobial coatings. Ultrathin coatings were prepared by spin coater after dissolving Dhvar-5-chitosan conjugate powder in aqueous acetic acid. Peptide orientation and exposure from the surface was confirmed by ellipsometry and contact angle measurements. Bactericidal activity was evaluated against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, the most prevalent pathogens in implant-associated infections. Results showed that Dhvar-5-chitosan coatings displayed bactericidal effect. Moreover, since Dhvar-5 has head-to-tail amphipathicity, it was clear that the bactericidal potency was dependent on which domain of the peptide (cationic or hydrophobic) was exposed. In this context, Dhvar-5 immobilized through its C-terminus (exposing its hydrophobic end) presented higher antimicrobial activity against Gram-positive bacteria and reduced adhesion of Gram-negative bacteria. This orientation-dependent antimicrobial activity was further corroborated by the anti-biofilm assay, as covalent immobilization of Dhvar-5 through its C-terminus provided anti-biofilm properties to the chitosan thin film. Immobilization of Dhvar-5 showed no cytotoxic effect against HFF-1 cells, as both metabolic activity and cell morphology were similar to control. In conclusion, Dhvar-5-chitosan coatings are promising antimicrobial surfaces without cytotoxic effects against human cells.Statement of significanceAMP-tethering onto ground biomaterial is still a poorly explored strategy in research. In this work, AMP-tethered onto ground chitosan is used to produce highly antibacterial ultrathin films. Powdered AMP-tethered chitosan appears as an alternative solution for antimicrobial devices production, as it is suitable for large scale production, being easier to handle for fabrication of different coatings and materials with antimicrobial properties and without inducing toxicity.Graphical abstractGraphical abstract for this article
       
  • Behavior of valvular interstitial cells on trilayered nanofibrous
           substrate mimicking morphologies of heart valve leaflet
    • Abstract: Publication date: Available online 5 December 2018Source: Acta BiomaterialiaAuthor(s): Soumen Jana, Amir Lerman Heart valve tissue engineering could be an alternative to the current bioprosthetic heart valves and their limitations, especially for pediatric patients. However, heart valve tissue engineering remains challenging because leaflets — the primary component of a heart valve — have three diversely oriented layers — circumferential, random and radial. In order to mimic the orientations, we first designed three novel collectors to fabricate three nanofibrous layers with those orientations from a polymeric biomaterial in an electrospinning system. Then, we devised a novel direct electrospinning technique to develop a unified trilayered nanofibrous (TN) substrate comprising those oriented layers. The TN substrate supported the growth and orientations of seeded porcine valvular interstitial cells (PVICs) and their deposited collagen fibrils. After one month culture, the obtained trilayered tissue construct (TC) exhibited increased tensile properties over its TN substrate. Most importantly, the developed TC did not show any sign of shrinkage. Gene expression pattern of the PVICs indicated the developing stage of the TC. Their protein expression pattern was quite similar to that of leaflets.Statement of SignificanceThis manuscript mainly talks about development of a novel trilayered nanofibrous substrate mimicking the morphologies of a heart valve leaflet. Then it describes the culturing of valvular interstitial cells that reside in the leaflet, in the substrate and compares the behavior of the cultured cells with that in the native leaflets in terms cell morphology, protein deposition and its orientation, and molecular signature. This study builds the groundwork for our future trilayered, tissue-engineered leaflet development. This research article would be of great interest to investigators and researchers in cardiovascular tissue engineering especially in cardiac valve tissue engineering through biomaterial-based tissue engineering.Graphical abstractGraphical abstract for this article
       
  • Repurposing suramin for the treatment of breast cancer lung metastasis
           with glycol chitosan-based nanoparticles
    • Abstract: Publication date: Available online 5 December 2018Source: Acta BiomaterialiaAuthor(s): Bei Cheng, Feng Gao, Erica Maissy, Peisheng Xu Suramin (SM), a drug for African sleeping sickness and river blindness therapy, has been investigated in various clinical trials for cancer therapy. However, SM was eventually withdrawn from the market because of its narrow therapeutic window and the side effects associated with multiple targets. In this work, we developed a simple but effective system based on a nontoxic dose of SM combined with a chemotherapeutic agent for the treatment of metastatic triple-negative breast cancer (TNBC). SM and glycol chitosan (GCS) formed nanogels because of the electrostatic effect, whereas doxorubicin (DOX) was incorporated into the system through the hydrophilic and hydrophobic interactions between DOX and GCS as well as the ionic interactions between DOX and SM to yield GCS-SM/DOX nanoparticles (NPs). GCS-SM/DOX NPs have a size of approximately 186 nm and a spherical morphology. In vitro experiments showed that GCS-SM NPs could effectively inhibit cancer cell migration and invasion, as well as angiogenesis. Furthermore, in a TNBC lung metastasis animal model, GCS-SM/DOX NPs significantly reduced tumor burden and extended the lifespan of animals, while not inducing cardio and renal toxicities associated with the DOX and SM, respectively. As all the components used in this system are biocompatible and easy for large-scale fabrication, the GCS-SM/DOX system is highly translatable for the metastatic breast cancer treatment.Statement of SignificanceThe doxorubicin-loaded glycol chitosan-suramin nanoparticle (GCS-SM/DOX) is novel in the following aspects: SM acts as not only a gelator for the first time in the preparation of the nanoparticle but also an active pharmaceutical agent in the dosage form. GCS-SM/DOX NP significantly reduced tumor burden and extended the lifespan of animals with triple-negative breast cancer lung metastasis. GCS-SM/DOX NPs attenuate cardio and renal toxicities associated with the DOX and SM. The GCS-SM/DOX system is highly translatable because of its simple, one-pot, and easy-to-scale-up preparation protocol.Graphical abstractGraphical abstract for this article
       
  • Micro-scaled topographies direct differentiation of human epidermal stem
           cells
    • Abstract: Publication date: Available online 5 December 2018Source: Acta BiomaterialiaAuthor(s): Sebastiaan Zijl, Aliaksei S. Vasilevich, Priyalakshmi Viswanathan, Ayelen Luna Helling, Nick R.M. Beijer, Gernot Walko, Ciro Chiappini, Jan de Boer, Fiona M. Watt Human epidermal stem cells initiate terminal differentiation when spreading is restricted on ECM-coated micropatterned islands, soft hydrogels or hydrogel-nanoparticle composites with high nanoparticle spacing. The effect of substrate topography, however, is incompletely understood. To explore this, primary human keratinocytes enriched for stem cells were seeded on a topographical library with over 2000 different topographies in the micrometre range. Twenty-four hours later the proportion of cells expressing the differentiation marker Transglutaminase-1 was determined by high content imaging. As predicted, topographies that prevented spreading promoted differentiation. However, we also identified topographies that supported differentiation of highly spread cells. Topographies supporting differentiation of spread cells were more irregular than those supporting differentiation of round cells. Low topography coverage promoted differentiation of spread cells, whereas high coverage promoted differentiation of round cells. Based on these observations we fabricated a topography in 6-well plate format that supported differentiation of spread cells, enabling us to examine cell responses at higher resolution. We found that differentiated spread cells did not assemble significant numbers of hemidesmosomes, focal adhesions, adherens junctions, desmosomes or tight junctions. They did, however, organise the actin cytoskeleton in response to the topographies. Rho kinase inhibition and blebbistatin treatment blocked the differentiation of spread cells, whereas SRF inhibition did not. These observations suggest a potential role for actin polymerization and actomyosin contraction in the topography-induced differentiation of spread cells.Statement of significanceThe epidermis is the outer covering of the skin. It is formed by layers of cells called keratinocytes. The basal cell layer contains stem cells, which divide to replace cells in the outermost layers that are lost through a process known as differentiation. In this manuscript we have developed surfaces that promote the differentiation of epidermal stem cells in order to understand the signals that control differentiation. The experimental tools we have developed have the potential to help us to devise new treatments that control diseases such as psoriasis and eczema in which epidermal stem cell proliferation and differentiation are disturbed.Graphical abstractGraphical abstract for this article
       
  • Degradable conductive self-healing hydrogels based on
           dextran-graft-tetraaniline and N-carboxyethyl chitosan as injectable
           carrier for myoblast cell therapy and muscle regeneration
    • Abstract: Publication date: Available online 5 December 2018Source: Acta BiomaterialiaAuthor(s): Baolin Guo, Jin Qu, Xin Zhao, Mengyao Zhang Injectable conductive hydrogels have great potential as tissue engineering scaffolds and delivery vehicles for electrical signal-sensitive cell therapy. In this work, we present the synthesis of a series of injectable electroactive degradable hydrogels with rapid self-healing ability and their potential application as cell delivery vehicles for skeletal muscle regeneration. Self-healable conductive injectable hydrogels based on dextran-graft-aniline tetramer-graft-4-formylbenzoic acid and N-carboxyethyl chitosan were synthesized under physiological conditions. The dynamic Schiff base bonds between the formylbenzoic acid and the amine group of N-carboxyethyl chitosan endowed the hydrogels with rapid self-healing ability, which was verified by the rheological test. Equilibrated swelling ratio, morphology, mechanical strength, electrochemistry, and conductivity of the injectable hydrogels were fully investigated. The self-healable conductive hydrogels showed an in vivo injectability and a linear-like degradation behavior. Two different kinds of cells (C2C12 myoblasts and human umbilical vein endothelial cells (HUVECs)) were encapsulated in the hydrogels by the self-healing effect. The L929 fibroblast cell culture results indicated the biocompatibility of the hydrogels. Moreover, the C2C12 myoblast cells were released from the conductive hydrogels with a linear-like profile. The in vivo skeletal muscle regeneration was also studied in a volumetric muscle loss injury model. All these data indicated that these biodegradable self-healing conductive hydrogels are potential candidates as cell delivery vehicles and scaffolds for skeletal muscle repair.Statement of SignificanceInjectable hydrogels with self-healing and electrical conductivity are excellent candidates for skeletal muscle tissue engineering scaffolds and myoblast cell therapy. Self-healing property of the hydrogels can prolong their life-time. However, most of the reported conductive hydrogels are not degradable or do not have self-healing ability. We synthesized anti-bacterial conductive self-healing hydrogels as delivery carrier for cardiac cell therapy based on chitosan-grafted-tetraaniline in our previous work. However, acid solution was used to dissolve the polymers that may induce toxicity to cells. In this work, we have synthesized a series of injectable electroactive biodegradable hydrogels with rapid self-healing ability composed of N-carboxyethyl chitosan (CECS) and dextran-graft-aniline oligomers which can dissolve in pH 7.4 PBS solution, and we further demonstrated their potential application as cell delivery vehicles for skeletal muscle regeneration.Graphical abstractGraphical abstract for this article
       
  • Extracellular matrix derived from chondrocytes promotes rapid expansion of
           human primary chondrocytes in vitro with reduced dedifferentiation
    • Abstract: Publication date: Available online 5 December 2018Source: Acta BiomaterialiaAuthor(s): Yong Mao, Travis Block, Anya Singh-Varma, Anne Sheldrake, Rachel Leeth, Sy Griffey, Joachim Kohn A significant expansion of autologous chondrocytes in vitro is required for cell-based cartilage repair. However, the in vitro expansion of chondrocytes under standard culture conditions inevitably leads to the dedifferentiation of chondrocytes and contributes to suboptimal clinical outcomes. To address this challenge, we focused our efforts on developing an improved in vitro expansion protocol, which shortens the expansion time with decreased dedifferentiation. It is known that the tissue microenvironment plays a critical role in regulating the cellular functions of resident cells and provides guidance in tissue-specific regeneration. We hypothesized that chondrocyte extracellular matrix (ECM) mimics a native microenvironment and that it may support chondrocyte expansion in vitro. To test this hypothesis, we prepared decellularized ECMs from allogeneic human articular chondrocytes (HAC) (AC-ECM) and bone marrow stromal cells (BM-ECM) and studied their effects on the in vitro expansion of primary HAC. The differential composition and physical properties of these two ECMs were revealed by mass spectrometry and atomic force microscopy. Compared with standard tissue culture polystyrene (TCP) or BM-ECM, HAC cultured on AC-ECM proliferated faster and maintained the highest ratio of COL2A1/COL1A1. Furthermore, a pellet culture study demonstrated that cells expanded on AC-ECM produced a more cartilage-like ECM than cells expanded on BM-ECM or TCP. This is the first report on modulating chondrocyte expansion and dedifferentiation using cell type-specific ECM and on identifying AC-ECM as a preferred substrate for in vitro expansion of HAC cell-based therapies.Statement of SignificanceTo reduce the dedifferentiation of chondrocytes during in vitro expansion, cell-type specific extracellular matrix (ECM), which mimics a native microenvironment, was prepared from human articular chondrocytes (AC-ECM) or bone marrow stromal cells (BM-ECM). As demonstrated by mass spectrometry and atomic force microscopy, AC-ECM and BM-ECM have differential ECM compositions and physical characteristics. Human articular chondrocytes (HAC) expanded faster and maintained a better chondrocyte phenotype on AC-ECM than on BM-ECM or a standard culture surface. AC-ECM has potential to be developed for expanding HAC for cell-based therapies.Graphical abstractGraphical abstract for this article
       
  • Guided wave elastography of layered soft tissues
    • Abstract: Publication date: Available online 5 December 2018Source: Acta BiomaterialiaAuthor(s): Guo-Yang Li, Yang Zheng, Yu-Xuan Jiang, Zhaoyi Zhang, Yanping Cao In vivo mechanical characterization of soft biological tissues has broad applications ranging from disease diagnosis to tissue engineering. Shear wave elastography based on the bulk wave theory has been widely used to measure the mechanical properties of soft tissues. Given that most soft tissues basically have layered structures, the dispersive feature of elastic waves should be considered when the thickness of the interested layer is comparable to or smaller than the wavelength. Bearing this fundamental issue in mind, we propose an ultrasound-based guided wave elastography (GWE) method to characterize the mechanical properties of layered soft tissues. The dispersion relations of guided waves in layered structures were derived first, and its explicit expression was achieved. An inverse approach based on the dispersion relation to characterize the mechanical properties of layered soft tissues was then established. Both finite element analysis (FEA) and phantom experiments were carried out to validate the new method. In vivo experiments on forearm skin demonstrate the usefulness of the present method in characterizing layered soft tissues.Statement of SignificanceLayered soft tissues and artificial soft materials are ubiquitous in both nature and engineering. Imaging their in vivo/in situ mechanical properties finds important applications and remains a great challenge to date. Here, we propose an ultrasound-based guided wave elastography method to in vivo characterize the elastic properties of layered soft materials. We validate the method via finite element analysis and phantom experiments and further demonstrate its usefulness in practice by performing in vivo measurements on forearm skins. Given that the dispersive feature of elastic waves in layered soft media is considered in our method, it provides the opportunity to assess the intrinsic elastic properties of an individual layer in a non-destructive manner as shown in our experiments.Graphical abstractGraphical abstract for this article
       
  • Functionalization of hyaluronic acid hydrogels with ECM-derived peptides
           to control myoblast behavior
    • Abstract: Publication date: Available online 1 December 2018Source: Acta BiomaterialiaAuthor(s): Juan Martin Silva Garcia, Alyssa Panitch, Sarah Calve Volumetric muscle loss (VML) occurs when skeletal muscle injury is too large for the body to fully self-repair. Typically, fibrotic tissue fills the void, which reduces muscle functionality and limb movement. Although a wide variety of natural and synthetic scaffolds have been studied with the purpose of providing the appropriate structural support, to date no scaffold has significantly restored muscle functionality after VML. Satellite cells, adult stem cells within the muscle capable of restoring smaller injuries, are sensitive to the stiffness and composition of the surrounding environment. Scaffolds that only address structural support are not sufficient to restore functionality and instead need to be designed to both promote satellite cell activation and prevent excessive fibroblast recruitment. The objective of this study was to design a scaffold that mimicked the regenerative environment and determine how the biomechanical properties differentially influence myogenic precursor and connective tissue cells. One of the main extracellular matrix (ECM) molecules upregulated during regeneration is hyaluronic acid (HA). Therefore, thiol-modified HA and poly(ethylene glycol) diacrylate hydrogels were generated and functionalized with peptides based on ECM known to influence regeneration, including fibronectin, laminin and tenascin-C. Scaffolds with different stiffness were created by varying HA content. The influence of HA stiffness and peptide functionalization on myogenic precursor and connective tissue cell proliferation, migration and gene expression was quantified. Our results indicated that HA hydrogels functionalized with the laminin peptide, IKVAV, show potential due to the enhanced promotion of myogenic cell behaviors including migration, proliferation and an increase in relevant transcription factors.Statement of SignificanceThe goal of this study was to identify hyaluronic acid (HA) hydrogels with peptide and stiffness combinations that will direct muscle-derived cells towards regenerating phenotypes. While the interaction of skeletal muscle with RGD-functionalized HA hydrogels has been investigated, none of the other peptides described in this study had been used in the context of HA-based scaffolds and skeletal muscle-derived cells. Notably, the response of cells to variations in mechanics was dependent on ECM coating and lineage. The 3% HA functionalized with the laminin peptide, IKVAV, showed the most promise for future in vivo studies, as these hydrogels best promoted myoblast cell proliferation, attachment and spreading, enhanced migration over connective tissue cells and upregulated transcription factors associated with activated satellite cells.Graphical abstractGraphical abstract for this article
       
  • Osteoclasts in Bone Regeneration under Type 2 Diabetes Mellitus
    • Abstract: Publication date: Available online 30 November 2018Source: Acta BiomaterialiaAuthor(s): Zhiai Hu, Chi Ma, Yongxi Liang, Shujuan Zou, Xiaohua Liu Diabetes mellitus (DM) affects hundreds of million people worldwide and the impaired bone healing is an important DM-related complication. Understanding how DM affects the activities of osteoclasts and the underlying mechanisms is crucial to the development of effective approaches for accelerating bone healing in DM condition. To date, however, the influence of DM on osteoclasts remains obscure and controversial. In this study, we established a type 2 DM (T2DM) alveolar bone defect model, which closely simulates the pathogenesis of human T2DM, to explore the diabetic osteoclast activity during bone regeneration. We found that a high glucose concentration diminished the formation of osteoclasts, and the differentiation and function of osteoclasts from T2DM rats were suppressed. The degradation of matrix by osteoclasts was significantly reduced at a high glucose concentration. In vivo experiments further indicated that T2DM inhibited osteoclastogenesis and osteoclast activity, and delayed the degradation of matrix during the alveolar bone regeneration in T2DM rats. Our work clarifies the influence of T2DM on osteoclasts, and provides valuable insights for the design of novel scaffolding materials that target on osteoclasts for T2DM bone regeneration.Statement of SignificanceImpaired bone healing is one of the diabetes mellitus (DM)-related complications. Understanding how DM affects osteoclast activity and scaffolding matrix degradation is pivotal to the development of effective approaches for accelerating bone healing in DM condition. Currently, the influences of DM on osteoclast activity and matrix degradation in bone defect areas, however, remain controversial and obscure. Herein, we established a type 2 DM (T2DM) alveolar bone defect model and our results show that T2DM inhibited osteoclastogenesis and osteoclast activity, and delayed the degradation of scaffolding matrix. Our work clarifies the influence of T2DM on osteoclasts and matrix degradation, and provides insights for the design of novel scaffolding materials that target on osteoclasts for T2DM bone regeneration.Graphical abstractGraphical abstract for this article
       
  • Biodegradable amino acid-based poly(ester amine) with tunable
           immunomodulating properties and their in vitro and in vivo wound healing
           studies in diabetic rats’ wounds
    • Abstract: Publication date: Available online 30 November 2018Source: Acta BiomaterialiaAuthor(s): Mingyu He, Luyao Sun, Xiaoling Fu, Sean P. McDonough, Chih-Chang Chu The objective of this study is to design a new family of biodegradable synthetic polymeric biomaterials for providing a tunable inhibition of macrophage’s nitric oxide synthase (NOS) pathway. L-Arginine (Arg) is the common substrate for NOS and arginase. Both two metabolic pathways participate in the wound healing process. An impaired wound healing, such as diabetic or other chronic wounds is usually associated with an overproduction of NO by macrophages via the NOS pathway. In this study, a new family of L-nitroarginine (NOArg) based polyester amide (NOArg-PEA) and NOArg-Arg PEA copolymers (co-PEA) were designed and synthesized with different composition ratios. The NOArg-PEA and NOArg-Arg co-PEAs are biodegradable (more than 50% degradation in vitro in 4 days at 37 °C), biocompatible and did not activate the resting macrophage immune response per se. When classically activated or alternatively activated macrophages (CAM/AAM) were incubated with NOArg-PEA and NOArg-Arg co-PEAs, the treatments decreased the NO production of CAM, increased the arginase activity in both CAM and AAM, increased TGF-β1 production of CAM to various degrees and had no significant effect on TNF-α production. Diabetic rat models were used to evaluate the efficacy of NOArg-PEA and NOArg-Arg co-PEAs on wound healing. Diabetic rats treated with 2-NOArg-4 PEA, 2-NOArg-4-Arg-4 20/80, and 2-NOArg-4-Arg-4 50/50 biomaterials achieved 40%∼80% faster-wound healing when compared with the control on day 7. The data from the histological and immunohistochemical analysis showed that the 2-NOArg-4-Arg-4 20/80 and 2-NOArg-4-Arg-4 50/50 treatments led to more AAM phenotypes (CD206) and arginase I production in wound tissue than the control during the first 7 days, i.e., suggesting pro-healing wound microenvironment with improved re-epithelialization of wound healing. A similar trend was retained until Day 14. The 2-NOArg-4-Arg-4 20/80 and 2-NOArg-4-Arg-4 50/50 treatments also increased the collagen deposition and angiogenesis in the healing wound between day 7 to day 14. Both in vitro and in vivo data of this study showed that this new family of NOArg-Arg co-PEA biomaterials have the potential as viable alternatives for treating impaired wound healing, such as diabetic or other types of chronic wounds.Statement of significanceDiabetic or other chronic wounds is usually associated with an overproduction of NO and pro-inflammatory signals by macrophages. Arginine supplement or NOS inhibitors administration failed to achieve an expected improved wound healing because of the dynamic complexity of arginine catabolism, the difficulty in transition from pro-inflammatory to pro-healing, and the short-term efficacy. We designed and synthesized a new family of water-soluble and degradable nitroarginine-arginine polyester amides to rebalance NOS/arginase metabolism pathways of macrophages. They showed tunable immunomodulating properties in vitro. The in vivo studies were performed to evaluate their efficacy in accelerating the healing. These new biomaterials have the potential as viable alternatives for treating impaired wound healing. The general audience of Acta Biomaterialia should be interested in these findings.Graphical abstractGraphical abstract for this article
       
  • A versatile strategy to create active tumor-targeted chemo-photothermal
           therapy nanoplatform: a case of IR-780 derivative co-assembled with
           camptothecin prodrug
    • Abstract: Publication date: Available online 29 November 2018Source: Acta BiomaterialiaAuthor(s): Wenxiu He, Yue Jiang, Qian Li, Di Zhang, Zhonghao Li, Yuxia Luan Self-assembled nanovehicles of chemotherapy drug with photothermal agent are regarded as intriguing chemo-photothermal therapy nanoplatform. However, most of the drugs and photothermal agents have poor water solubility and poor interactions to drive the formation of self-assembled nanovehicles, which is a bottleneck of co-assembled drug/photothermal agent for cancer therapy. Here, we proposed a versatile strategy to create self-assembled chemo-photothermal therapy nanoplatform based on the chemical modification of photothermal agent and drug. The IR-780 and camptothecin (CPT) were chosen as the studied models since they are important photothermal agent and anticancer drug, both of which have such poor water solubility with strong itself molecular interactions that they cannot co-assemble together. IR-780 was modified with an active targeting ligand lactobionic acid (LA) to result in amphiphilic IR780-LA while CPT was modified into redox-sensitive prodrug CPT-ss-CPT through a disulfide linkage to realize its assembly. Well-defined nanoparticles (NPs) could be created through the co-assembling of IR780-LA and CPT-ss-CPT. The IR780-LA/CPT-ss-CPT nanoparticles were demonstrated to be an excellent fluorescence imaging-guided, redox-responsive and enhanced synergistic chemo-photothermal therapy nanoplatform against tumors. Specifically, our chemical modification strategy offers a universal way to create self-assembled chemo-photothermal therapy nanoplatform, which solves the bottleneck of co-assembled drug/photothermal agent for cancer therapy.Statement of SignificanceSelf-assembled nanoparticles of chemotherapeutics with photothermic drugs are regarded as intriguing chemo-photothermal therapy nanoplatform. However, most drugs have too poor solubility and interactions to form into self-assembled nanoparticles. We proposed a versatile strategy to create co-assembled chemo-photothermal therapy nanoparticles based on the chemical modification of common drugs. The IR-780 was modified with an active targeting ligand LA to result in amphiphilic IR780-LA molecules, while CPT was modified into redox-sensitive prodrug CPT-ss-CPT through disulfide linkage. Well-defined IR780-LA/CPT-ss-CPT nanoparticles were created through the co-assembling of IR780-LA and CPT-ss-CPT. The nanoparticles were demonstrated to be an excellent fluorescence imaging-guided, redox-responsive, active targeting chemo-photothermal therapy nanoplatform against tumors. Our strategy offers a versatile way to construct smart chemo-photothermal therapy nanoplatform from common drugs.Graphical abstractGraphical abstract for this article
       
  • Calcium phosphate nanoparticle-mediated transfection in 2D and 3D mono-
           and co-culture cell models
    • Abstract: Publication date: Available online 29 November 2018Source: Acta BiomaterialiaAuthor(s): Viktoriya Sokolova, Leonardo Rojas-Sánchez, Nataniel Białas, Nina Schulze, Matthias Epple The transfer of nucleic acids into living cells, i.e. transfection, is a major technique in current molecular biology and medicine. As nucleic acids alone are not able to penetrate the cell membrane, an efficient carrier is needed. Calcium phosphate nanoparticles can serve as carrier due to their biocompatibility, biodegradability and high affinity to nucleic acids like DNA or RNA. Their application was extended here from two-dimensional (2D) to three-dimensional (3D) cell culture models, including co-cultures. Compared to 2D monolayer cell cultures, a 3D culture system represents a more realistic spatial, biochemical and cellular environment. The uptake of fluorescent calcium phosphate nanoparticles (diameter 40 to 70 nm; cationic) was studied in 2D and 3D cell culture models by confocal laser scanning microscopy. The transfection of eGFP by calcium phosphate nanoparticles was compared in 2D and 3D cell culture, including co-cultures of green fluorescing HeLa-eGFP cells and MG-63 cells in 2D and in 3D models with the red fluorescent protein mCherry. This permitted a cell-specific assessment of the local transfection efficiency. In general, the penetration of nanoparticles into the spheroids was significantly higher than that of a model oligonucleotide carried by Lipofectamine. The transfection efficiency was comparable in 3D cell cultures with 2D cell cultures, but it occurred preferentially at the surface of the spheroids, following the uptake pathway of the nanoparticles.Statement of significanceThree-dimensional cell culture models can serve as a bridge between the in-vitro cell cultures and the in-vivo situation, especially when mass transfer effects have to be considered. This is the case for nanoparticles where the incubation effect in a two-dimensional cell culture strongly differs from a three-dimensional cell culture or a living tissue. We have compared the uptake of nanoparticles and a subsequent transfection of fluorescent proteins in two-dimensional and three-dimensional cell culture models. An elegant model to investigate the transfection in co-cultures was developed using HeLa-eGFP cells (green fluorescent) together with MG-63 cells (non-fluorescent) that were transfected with the red-fluorescing protein mCherry. Thereby, the transfection of both cell types in the co-culture was easily distinguished.Graphical abstractGraphical abstract for this article
       
  • Stimuli-Responsive Polymer-Doxorubicin Conjugate: Antitumor Mechanism and
           Potential as Nano-Prodrug
    • Abstract: Publication date: Available online 29 November 2018Source: Acta BiomaterialiaAuthor(s): Kai Chen, Hao Cai, Hu Zhang, Hongyan Zhu, Zhongwei Gu, Qiyong Gong, Kui Luo Polymer-drug conjugates has significantly improved the anti-tumor efficacy of chemotherapeutic drugs and alleviated their side effects. N-(1,3-dihydroxypropan-2-yl) methacrylamide (DHPMA) copolymer was synthesized via RAFT polymerization and polymer-doxorubicin (DOX) (diblock pDHPMA-DOX) were formed by conjugation, resulting in a self-aggregation-induced nanoprodrug with a favorable size of 21 nm and great stability. The nanoprodrug with a molecular weight (MW) of 95 kDa released drugs in response to tumor microenvironmental pH variations and they were enzymatically hydrolyzed into low MW segments (45 kDa). The nanoprodrug was transported through the endolysosomal pathway, released the drug into the cytoplasm and some was localized in the mitochondria, resulting in disruption of the cellular actin cytoskeleton. Cellular apoptosis was also associated with reduction in the mitochondrial potential caused by the nanoprodrug. Notably, the nanoprodrug had a significantly prolonged blood circulation time with an elimination half time of 9.8 h, displayed high accumulation within tumors, and improved the in vivo therapeutic efficacy against 4T1 xenograft tumors compared to free DOX. The tumor xenograft immunohistochemistry study clearly indicated tumor inhibition was through the inhibition of cell proliferation and antiangiogenic effects. Our studies demonstrated that the diblock pDHPMA-DOX nanoprodrug with a controlled molecular structure is promising to alleviate adverse effects of free DOX and have a great potential as an efficient anticancer agent.Statement of significanceIn this work, we prepared a biodegradable diblock DHPMA polymer-doxorubicin conjugate via one-pot of RAFT polymerization and conjugate chemistry. The conjugate-based nanoprodrug was internalized by endocytosis to intracellularly release DOX and further induce disruption of mitochondrial functions, actin cytoskeleton alterations and cellular apoptosis. The nanoprodrug with a high molecular weight (MW) (95 kDa) showed a long blood circulation time and achieved high accumulation into tumors. The nanoprodrug was degraded into low MW (∼45 kDa) products below the renal threshold, which ensured its biosafety. Additionally, the multi-stimuli-responsive nanoprodrug demonstrated an enhanced antitumor efficacy against 4T1 breast tumors and alleviated side effects, showing a great potential as an efficient and safe anticancer agent.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Enhanced oxygen permeability in membrane-bottomed
           concave microwells for the formation of pancreatic islet spheroids”
           [Acta Biomater. 65 (2018) 185–196]
    • Abstract: Publication date: Available online 28 November 2018Source: Acta BiomaterialiaAuthor(s): GeonHui Lee, Yesl Jun, HeeYeong Jang, Junghyo Yoon, JaeSeo Lee, MinHyung Hong, Seok Chung, Dong-Hwee Kim, SangHoon Lee
       
  • 3D collagen microfibers stimulate the functionality of preadipocytes and
           maintain the phenotype of mature adipocytes for long term cultures
    • Abstract: Publication date: Available online 28 November 2018Source: Acta BiomaterialiaAuthor(s): Fiona Louis, Shiro Kitano, João F. Mano, Michiya Matsusaki Although adipose tissue is one of the most abundant tissues of the human body, its reconstruction remains a competitive challenge. The conventional in vitro two or three-dimensional (2D or 3D) models of mature adipocytes unfortunately lead to their quick dedifferentiation after one week, and complete differentiation of adipose derived stem cells (ADSC) usually requires more than one month. In this context, we developed biomimetic 3D adipose tissues with high density collagen by mixing type I collagen microfibers with primary mouse mature adipocytes or human ADSC in transwells. These 3D-tissues ensured a better long-term maintained phenotype of unilocular mature adipocytes, compared to 2D, with a viability of 96 ± 2% at day 14 and a good perilipin immunostaining,- the protein necessary for stabilizing the fat vesicles. For comparison, in 2D culture, mature adipocytes released their fat until splitting their single adipose vesicle into several ones with significantly 4 times smaller size. Concerning ADSC, the adipogenic genes expression in 3D-tissues was found at least doubled throughout the differentiation (over 8 times higher for GLUT4 at day 21), along with it, almost 4 times larger fat vesicles were observed (10 ± 4 µm at day 14). Perilipin immunostaining and leptin secretion, the satiety protein, attested the significantly doubled better functionality of ADSC in 3D adipose tissues. These obtained long-term maintained phenotype and fast adipogenesis make this model relevant for either cosmetic/pharmaceutical assays or plastic surgery purposes.Statement of significanceAdipose tissue has important roles in our organism, providing energy from its lipids storage and secreting many vital proteins. However, its reconstruction in a functional in vitro adipose tissue is still a challenge. Mature adipocytes directly extracted from surgery liposuctions quickly lose their lipids after a week in vitro and the use of differentiated adipose stem cells is too time-consuming. We developed a new artificial fat tissue using collagen microfibers. These tissues allowed the maintenance of viable big unilocular mature adipocytes up to two weeks and the faster adipogenic differentiation of adipose stem cells. Moreover, the adipose functionality confirmed by perilipin and leptin assessments makes this model suitable for further applications in cosmetic/pharmaceutical drug assays or for tissue reconstruction.Graphical abstractGraphical abstract for this article
       
  • Multifunctional nanotheranostic gold nanocages for photoacoustic imaging
           guided radio/photodynamic/photothermal synergistic therapy
    • Abstract: Publication date: Available online 27 November 2018Source: Acta BiomaterialiaAuthor(s): Xiaoyu Xu, Yu Chong, Xiaoyun Liu, Han Fu, Chenggong Yu, Jie Huang, Zhijun Zhang In this work, we developed a novel multifunctional nanoplatform based on hyaluronic acid modified Au nanocages (AuNCs-HA). The rational design of AuNCs-HA renders the nanoplatform three functionalities: (1) AuNCs-HA with excellent LSPR peak in the NIR region act as contrast agent for enhanced photoacoustic (PA) imaging and photothermal therapy (PTT); (2) the nanoplatform with high-energy rays (X-ray) absorption and auger electrons generation acts as a radiosensitizer for radiotherapy; (3) good photocatalytic property and large surface area make AuNCs-HA a photosensitive agent for photodynamic therapy (PDT). In vivo results demonstrated that AuNCs-HA presented excellent PA imaging performance after intravenous injection, which provided contour, size, and location information of the tumor. Moreover, because AuNCs-HA could combine radiotherapy and phototherapy together, the tumors treated with AuNCs-HA showed complete growth inhibition, comparing to that with each therapy alone. Taken together, our present study demonstrates that AuNCs-HA is of great potential as a multifunctional nanoplatform for PA imaging-guided radio- and photo-therapy of tumor.Statement of SignificanceIn this study, a commendable theranostic nanoplatform based on hyaluronic acid modified AuNCs (AuNCs-HA) was developed. In our approach, the dilute solution of Gold(III) chloride is slowly dripped into Ag nanocubes solution, then the Au nanocages were obtained by redox reaction, and followed by HA modification. We explored them, simultaneously, as radiosensitizers for RT, photosensitizers for PDT, and therapeutic agents for PTT. Compared to that of each therapies alone, the combination of radio-therapy and photo-therapy results in a considerably improved tumor eliminating effect and efficiently inhibited tumor growth. In addition, AuNCs-HA exhibited remarkably strong PA signals for precise identification of the location, size, and boundary of the tumor, thereby facilitating imaging-guided therapy. In brief, our design of AuNCs-HA represents a general and versatile strategy for building up cancer-targeted nanotheranostics with desired synergistic imaging and therapy functionalities.Graphical abstractAuNCs-HA exhibited PA imaging guided combined radiotherapy, PDT and PTT trimodalites, leading to effectively synergistic anticancer efficacy.Graphical abstract for this article
       
  • Meshes in a mess: Mesenchymal stem cell-based therapies for soft tissue
           reinforcement
    • Abstract: Publication date: Available online 27 November 2018Source: Acta BiomaterialiaAuthor(s): F. Marinaro, F.M. Sánchez-Margallo, V. Álvarez, E. López, R. Tarazona, M.V. Brun, R. Blázquez, J.G. Casado Surgical meshes are frequently used for the treatment of abdominal hernias, pelvic organ prolapse, and stress urinary incontinence. Though these meshes are designed for tissue reinforcement, many complications have been reported. Both differentiated cell- and mesenchymal stem cell-based therapies have become attractive tools to improve their biocompatibility and tissue integration, minimizing adverse inflammatory reactions. However, current studies are highly heterogeneous, making it difficult to establish comparisons between cell types or cell coating methodologies. Moreover, only a few studies have been performed in clinically relevant animal models, leading to contradictory results. Finally, a thorough understanding of the biological mechanisms of mesenchymal stem cells in the context of foreign body reaction is lacking. This review aims to summarize in vitro and in vivo studies involving the use of differentiated and mesenchymal stem cells in combination with surgical meshes. According to preclinical and clinical studies and considering the therapeutic potential of mesenchymal stem cells, it is expected that these cells will become valuable tools in the treatment of pathologies requiring tissue reinforcement.Statement of SignificanceThe implantation of surgical meshes is the standard procedure to reinforce tissue defects such as hernias. However, an adverse inflammatory response secondary to this implantation is frequently observed, leading to a strong discomfort and chronic pain in the patients. In many cases, an additional surgical intervention is needed to remove the mesh.Both differentiated cell- and stem cell-based therapies have become attractive tools to improve biocompatibility and tissue integration, minimizing adverse inflammatory reactions. However, current studies are incredibly heterogeneous and it is difficult to establish a comparison between cell types or cell coating methodologies. This review aims to summarize in vitro and in vivo studies where differentiated and stem cells have been combined with surgical meshes.Graphical abstractGraphical abstract for this article
       
  • Early stage mechanical remodeling of collagen surrounding head and neck
           squamous cell carcinoma spheroids correlates strongly with their invasion
           capability
    • Abstract: Publication date: Available online 27 November 2018Source: Acta BiomaterialiaAuthor(s): Yin-Quan Chen, Jean-Cheng Kuo, Ming-Tzo Wei, Yen-Chih Chen, Muh-Hwa Yang, Arthur Chiou Mechanical remodeling of stromal collagen, such as reorientation and deformation of collagen matrix, generated by invading cancer cells, plays an important role in the progression of cancer invasion and metastasis. In this study, we applied time-lapse microscopy in conjunction with particle displacement mapping to analyze time-dependent contraction and expansion deformations of collagen surrounding individual spheroids of head and neck squamous cell carcinoma cells (HNSCC), OECM-1 & SAS, as the cancer cells detached from the spheroid and invaded into the surrounding 3D collagen matrix. Our results revealed that highly-invasive HNSCC spheroids, stimulated by epidermal growth factor (EGF), generated a strong contraction deformation of the surrounding collagen in the very early stage, and aligned the collagen fibers radially with respect to the center of the spheroid. This initial collagen contraction deformation generated by the HNSCC spheroid bears a strong positive correlation with the overall extent of subsequent cancer cells invasion; hence, it may serve as an early indicator of the invasion capability of the HNSCC spheroids.Statement of significanceMechanical remodeling of extracellular matrix (ECM) generated by cancer cells plays an important role in the progression of cancer invasion and metastasis. We observed that the extent of collagen initial contraction deformation surrounding a head and neck squamous cell carcinoma cell (HNSCC) spheroid play an indispensable role in early stage to promote cancer cells invasion into the surrounding ECM. Our results revealed that more invasive HNSCC spheroids generated a larger extent of initial collagen contraction to align the surrounding collagen and to promote cancer cells invasion. This initial collagen contraction deformation generated by the HNSCC spheroids bears a strong positive correlation with the overall extent of cancer cells invasion; hence, it may serve as an early indicator of the invasion capability of the HNSCC spheroids.Graphical abstractGraphical abstract for this article
       
  • Compositionally Graded Doped Hydroxyapatite Coating using Laser and Plasma
           Spray Deposition
    • Abstract: Publication date: Available online 27 November 2018Source: Acta BiomaterialiaAuthor(s): Dongxu Ke, Ashley A. Vu, Amit Bandyopadhyay, Susmita Bose Plasma sprayed hydroxyapatite (HA) coating is known to improve the osteoconductivity of metallic implants. However, the adhesive bond strength of the coating is affected due to a mismatch in coefficients of thermal expansion (CTE) between the metal and the HA ceramic. In this study, a gradient HA coating was prepared on Ti6Al4V by laser engineered net shaping (LENSTM) followed by plasma spray deposition. In addition, 1 wt.% MgO and 2 wt.% Ag2O were mixed with HA to improve the biological and antibacterial properties of the coated implant. Results showed that the presence of an interfacial layer by LENSTM enhanced adhesive bond strength from 26 ± 2 MPa for just plasma spray coating to 39 ± 4 MPa for LENSTM and plasma spray coatings. Presence of MgO and Ag2O did not influence the adhesive bond strength. Also, Ag+ ions release dropped by 70% less with a gradient HA LENSTM layer due to enhanced crystallization of the HA layer. In vitro human osteoblast cell culture revealed presence of Ag2O had no deleterious effect on proliferation and differentiation when compared to pure HA as control and provided antibacterial properties against E. coli and S. aureus bacterial strands. This study presents an innovative way to improve interfacial mechanical properties of plasma sprayed HA coating for load-bearing orthopedic implants.Statement of SignificanceImplants are commonly composed of metals that lack osteoconductivity. Osteoconductivity is a propriety where bone grows on the surface meaning the material is compatible with the surrounding bone tissue. Plasma sprayed hydroxyapatite (HA) coating improves the osteoconductivity of metallic implants however the adhesive bond strength can be weak. This study incorporates a gradient HA coating by using an additive manufacturing technique, laser engineered net shaping (LENSTM), followed by plasma spray deposition to enhance the adhesive bond strength by incorporating a thermal barrier. The proposed system has not been well studied in the current literature and the results presented bring forth an innovative way to improve the interfacial mechanical properties of plasma sprayed HA coating for load-bearing orthopedic implants.Graphical abstractGraphical abstract for this article
       
  • Bone-like features in skate suggest a novel elasmobranch synapomorphy and
           deep homology of trabecular mineralization patterns
    • Abstract: Publication date: Available online 27 November 2018Source: Acta BiomaterialiaAuthor(s): Oghenevwogaga J. Atake, David M.L. Cooper, B. Frank Eames Bone is a defining characteristic of the vertebrate skeleton, and while chondrichthyans (sharks, skates, and other cartilaginous fishes) are vertebrates, they are hypothesized to have lost the ability to make bone during their evolution. Multiple descriptions of a bone-like tissue in neural arches of vertebrae in various shark species (selachians), however, challenge this hypothesis. Here, we extend this argument by analyzing vertebrae of two members of the batoids (the little skate Leucoraja erinacea and Eaton’s skate Bathyraja eatonii), the sister group to selachians within elasmobranchs. Micro-CT images showed a bone-like mineralization pattern in neural arches of each skate species, and histological analyses confirmed that this bone-like tissue surrounded a cartilage core, exactly as described in sharks. Another mineralization pattern identified in skate vertebrae was distinct from the polygonal tesseral and areolar patterns that classically are associated with the chondrichthyan endoskeleton. Many regions of the vertebrae, including the neural spine and transverse processes, showed this perichondral mineralization pattern, termed here trabecular tesseral. Other than the cartilage core of the neural arch, all mineralized tissues in skate vertebrae had flattened cells surrounded by matrix with bone-like histology. Analyses of quantitative microstructural parameters revealed that, compared to rat vertebrae, the bone-like mineralization pattern in the neural arches of skate vertebrae was more similar to compact bone than trabecular bone. In contrast, the thickness of the trabecular tesseral pattern was more similar to trabecular bone than compact bone of rat vertebrae. In conclusion, a bone-like tissue in neural arches of skate vertebrae appears to be a novel elasmobranch synapomorphy. We propose that the trabecular tesseral mineralization pattern in the skate might have deep homology to the mineralization pattern utilized in trabecular bone.Statement of SignificanceMineralization patterns of skeletal tissues have not been investigated thoroughly in all vertebrate clades. Despite their designation as ‘cartilaginous fish’, chondrichthyans clearly evolved from ancestral vertebrates that made bone. The consensus that chondrichthyans lost the ability to make bone during their evolution, however, is challenged by reports of bone and bone-like tissues in the neural arches of vertebrae in extant sharks (selachians). Here, we provide evidence from micro-CT imaging and histological analyses to support our hypothesis that a bone-like tissue is present in the neural arches of batoids (the sister group to selachians within elasmobranchs). These results argue strongly that the neural arch bone-like tissue is a previously unknown synapomorphy of elasmobranchs. In addition to the bone-like mineralization pattern identified in the neural arches, micro-CT images also showed a novel mineralization pattern which we described as trabecular tesseral. Quantitative microstructural features shared between trabecular tesseral pattern and trabecular bone (from homologous rat vertebrae) suggest that both patterns might derive from an ancestral gene network driving trabecular mineralization (i.e., deep homology).Graphical abstractGraphical abstract for this article
       
  • Tissue engineered hydrogels supporting 3D neural networks
    • Abstract: Publication date: Available online 27 November 2018Source: Acta BiomaterialiaAuthor(s): Ulises A. Aregueta-Robles, Penny J. Martens, Laura A. Poole-Warren, Rylie A. Green Promoting nerve regeneration requires engineering cellular carriers to physically and biochemically support neuronal growth into a long lasting functional tissue. This study systematically evaluated the capacity of a biosynthetic poly(vinyl alcohol) (PVA) hydrogel to support growth and differentiation of co-encapsulated neurons and glia. A significant challenge is to understand the role of the dynamic degradable hydrogel mechanical properties on expression of relevant cellular morphologies and function. It was hypothesised that a carrier with mechanical properties akin to neural tissue will provide glia with conditions to thrive, and that glia in turn will support neuronal survival and development. PVA co-polymerised with biological macromolecules sericin and gelatin (PVA-SG) and with tailored nerve tissue-like mechanical properties were used to encapsulate Schwann cells (SCs) alone and subsequently a co-culture of SCs and neural-like PC12s. SCs were encapsulated within two PVA-SG gel variants with initial compressive moduli of 16 kPa and 2 kPa, spanning a range of reported mechanical properties for neural tissues. Both hydrogels were shown to support cell viability and expression of extracellular matrix proteins, however, SCs grown within the PVA-SG with a higher initial modulus were observed to present with greater physiologically relevant morphologies and increased expression of extracellular matrix proteins. The higher modulus PVA-SG was subsequently shown to support development of neuronal networks when SCs were co-encapsulated with PC12s. The lower modulus hydrogel was unable to support effective development of neural networks. This study demonstrates the critical link between hydrogel properties and glial cell phenotype on development of functional neural tissues.Statement of SignificanceHydrogels as platforms for tissue regeneration must provide encapsulated cellular progenitors with physical and biochemical cues for initial survival and to support ongoing tissue formation as the artificial network degrades. While most research focuses on tailoring scaffold properties to suit neurons, this work aims to support glia SCs as the key cellular component that physically and biochemically supports the neuronal network. The challenge is to modify hydrogel properties to support growth and development of multiple cell types into a neuronal network. Given SCs ability to respond to substrate mechanical properties, the significance of this work lies in understanding the relationship between dynamic hydrogel mechanical properties and glia SCs development as the element that enables formation of mature, differentiated neural networks.Graphical abstractGraphical abstract for this article
       
  • Biomimetic porous Mg with tunable mechanical properties and biodegradation
           rates for bone regeneration
    • Abstract: Publication date: Available online 27 November 2018Source: Acta BiomaterialiaAuthor(s): Min-Ho Kang, Hyun Lee, Tae-Sik Jang, Yun-Jeong Seong, Hyoun-Ee Kim, Young-Hag Koh, Juha Song, Hyun-Do Jung The medical applications of porous Mg scaffolds are limited owing to its rapid corrosion, which dramatically decreases the mechanical strength of the scaffold. Mimicking the bone structure and composition can improve the mechanical and biological properties of porous Mg scaffolds. The Mg structure can also be coated with HA by an aqueous precipitation coating method to enhance both the corrosion resistance and the biocompatibility. However, due to the brittleness of HA coating layer, cracks tend to form in the HA coating layer, which may influence the corrosion and biological functionality of the scaffold. Consequently, in this study, hybrid poly(ether imide) (PEI)–SiO2 layers were applied to the HA-coated biomimetic porous Mg to impart the structure with the high corrosion resistance associated with PEI and excellent bioactivity with SiO2. The porosity of the Mg was controlled by adjusting the concentration of the sodium chloride (NaCl) particles used in the fabrication via the space-holder method. The mechanical measurements showed that the compressive strength and stiffness of the biomimetic porous Mg increased as the portion of the dense region increased. In addition, following results show that HA/(PEI–SiO2) hybrid-coated biomimetic Mg is a promising biodegradable scaffold for orthopedic applications. In-vitro testing revealed that the proposed hybrid coating reduced the degradation rate and facilitated osteoblast spreading compared to HA- and HA/PEI-coating scaffolds. Moreover, in-vivo testing with a rabbit femoropatellar groove model showed improved tissue formation, reduced corrosion and degradation, and improved bone formation on the scaffold.Statement of significancePorous Mg is a promising biodegradable scaffold for orthopedic applications. However, there are limitations in applying porous Mg for an orthopedic biomaterial due to its poor mechanical properties and susceptibility to rapid corrosion. Here, we strategically designed the structure and coating layer of porous Mg to overcome these limitations. First, porous Mg was fabricated by mimicking the bone structure which has a combined structure of dense and porous regions, thus resulting in an enhancement of mechanical properties. Furthermore, the biomimetic porous Mg was coated with HA/(PEI-SiO2) hybrid layer to improve both corrosion resistance and biocompatibility. As the final outcome, with tunable mechanical and biodegradable properties, HA/(PEI-SiO2)-coated biomimetic porous Mg could be a promising candidate material for load-bearing orthopedic applications.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Metal-organic frameworks, NH2-MIL-88(Fe), as carriers
           for ophthalmic delivery of brimonidine” [Acta Biomater. 79 (2018)
           344–353]
    • Abstract: Publication date: Available online 26 November 2018Source: Acta BiomaterialiaAuthor(s): Se-Na Kim, Chun Gwon Park, Beom Kang Huh, Seung Ho Lee, Chang Hee Min, Yun Young Lee, Young Kook Kim, Ki Ho Park, Young Bin Choy
       
  • Characterization of a Cell-Assembled extracellular Matrix and the effect
           of the devitalization process
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Laure Magnan, Gaëlle Labrunie, Sébastien Marais, Sylvie Rey, Nathalie Dusserre, Marc Bonneu, Sabrina Lacomme, Etienne Gontier, Nicolas L'Heureux We have previously shown that the Cell-Assembled extracellular Matrix (CAM) synthesized by normal, human, skin fibroblasts in vitro can be assembled in a completely biological vascular graft that was successfully tested in the clinic. The goal of this study was to perform a detailed analysis of the composition and the organization of this truly bio-material. In addition, we investigated whether the devitalization process (dehydration) used to store the CAM, and thus, make the material available “off-the-shelf,” could negatively affect its organization and mechanical properties. We demonstrated that neither the thickness nor the mechanical strength of CAM sheets were significantly changed by the dehydration/freezing/rehydration cycle. The identification of over 50 extracellular matrix proteins highlighted the complex composition of the CAM. Histology showed intense collagen and glycosaminoglycan staining throughout the CAM sheet. The distribution of collagen I, collagen VI, thrombospondin-1, fibronectin-1, fibrillin-1, biglycan, decorin, lumican and versican showed various patterns that were not affected by the devitalization process. Transmission electron microscopy analysis revealed that the remarkably dense collagen network was oriented in the plane of the sheet and that neither fibril density nor diameter was changed by devitalization. Second harmonic generation microscopy revealed an intricate, multi-scale, native-like collagen fiber orientation. In conclusion, this bio-material displayed many tissue-like properties that could support normal cell-ECM interactions and allow implantation without triggering degradative responses from the host's innate immune system. This is consistent with its success in vivo. In addition, the CAM can be devitalized without affecting its mechanical or unique biological architecture.Statement of SignificanceThe extracellular matrix (ECM) defines biological function and mechanical properties of tissues and organs. A number of promising tissue engineering approaches have used processed ECM from cadaver/animal tissues or cell-assembled ECM in vitro combined with scaffolds. We have shown the clinical potential of a scaffold-free approach based on an entirely biological material produced by human cells in culture without chemical processing. Here, we perform a comprehensive analysis of the properties of what can truly be called a bio-material. We also demonstrate that this material can be stored dried without losing its remarkable biological architecture.Graphical abstractGraphical abstract for this article
       
  • Acta Awards 2019
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s):
       
  • PEGylated hydrazided gold nanorods for pH-triggered
           chemo/photodynamic/photothermal triple therapy of breast cancer
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Weijun Xu, Junmin Qian, Guanghui Hou, Yaping Wang, Jinlei Wang, Tiantian Sun, Lijie Ji, Aili Suo, Yu Yao Integration of multimodal therapies into one nanoplatform holds great promise to overcome the drawbacks of conventional single-modal therapy and pursues enhanced anticancer efficacy. Herein, we developed a PEGylated gold nanorods (GNRs)-based nanoplatform (GNRs-MPH-ALA/DOX-PEG) with pH-responsive drug release property for triple-combined chemotherapy (CT), photodynamic therapy (PDT) and photothermal therapy (PTT) of breast cancer. GNRs were first decorated with mercaptopropionylhydrazide (MPH) and thiol-terminated monomethoxyl poly(ethylene glycol) (mPEG-SH) via Au-thiol linkage, and subsequently conjugated with chemotherapeutant doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (ALA) through acid-liable hydrazone bonds between drugs and MPH molecules. The resulting nanoplatform GNRs-MPH-ALA/DOX-PEG exhibited excellent stability in physiological solutions and pH-responsive DOX and ALA release behaviors. In vitro studies showed that GNRs-MPH-ALA/DOX-PEG could efficiently enter human breast cancer MCF-7 cells and release DOX and ALA into cytoplasm. Furthermore, DOX could locate in the cell nucleus and ALA was productively metabolized into protoporphyrin IX (PpIX). Upon near-infrared (NIR) irradiation, PpIX produced enough reactive oxygen species for PDT and meanwhile GNRs could efficiently induce hyperthermia for PTT. Compared with single CT and dual-modal CT/PDT or CT/PTT treatment, the triple-combined CT/PDT/PTT treatment could more efficiently kill MCF-7 cells via a superadditive antitumor effect. Furthermore, the circulation half-life of GNRs-MPH-ALA/DOX-PEG in the blood was as long as approximately 52 min and it exhibited a tumor accumulation of 3.3%. The triple-combined CT/PDT/PTT treatment could completely suppress tumor growth without obvious systemic toxicity. Our study paves a new avenue for multimodal therapy of breast cancer.Statement of significanceThe development of a simple but effective strategy to construct a versatile nanoplatform for multi-combined therapy still remains an enormous challenge. In this work, we developed a novel and simple nanoplatform GNRs-MPH-ALA/DOX-PEG with pH-responsive drug release for triple-combined chemotherapy (CT), photodynamic therapy (PDT) and photothermal therapy (PTT) of breast cancer. The nanoplatform could be efficiently internalized by MCF-7 cells. The intracellular GNRs-MPH-ALA/DOX-PEG could release DOX for CT, induce hyperthermia for PTT and generate high levels of ROS for PTT. Compared with single CT and dual-modal CT/PDT or CT/PTT treatments, the triple-combined CT/PDT/PTT treatment could more efficiently kill MCF-7 cells via a superadditive antitumor effect. Furthermore, upon triple-combined CT/PDT/PTT treatment, the tumor growth was completely suppressed without obvious systemic toxicity.Graphical abstractGraphical abstract for this article
       
  • Transferrin/aptamer conjugated mesoporous ruthenium nanosystem for
           redox-controlled and targeted chemo-photodynamic therapy of glioma
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Xufeng Zhu, Hui Zhou, Yanan Liu, Yayu Wen, Chunfang Wei, Qianqian Yu, Jie Liu The blood-brain barrier (BBB) and low targeting are major obstacles for the treatment of gliomas. Accordingly, overcoming the BBB and enhancing the targeting of drugs to the glioma area are key to achieving a good therapeutic effect. Here, we have developed the mesoporous ruthenium nanosystem RBT@MRN-SS-Tf/Apt with dual targeting function. Transferrin (Tf) and aptamer AS1411 (Apt) are grafted on the surfaces of mesoporous ruthenium nanoparticles (MRN) with high loading capacity. This is achieved via redox-cleavable disulfide bonds, serving as both a capping agent and a targeting ligand, enabling the effective penetration of the blood-brain barrier and targeting the glioma. In addition, RBT@MRN-SS-Tf/Apt can specifically kill glioma cells in vitro and in vivo. Moreover, anti-tumor drugs [Ru(bpy)2(tip)]2+ (RBT) will produce reactive oxygen species and induce apoptosis of tumor cells under laser irradiation, providing photodynamic therapy (PDT) for the treatment of gliomas, and further prolonging the median survival period. The study shows that this chemical photodynamic therapy nanosystem can be used as an efficient and powerful synergistic system for the treatment of brain tumors and other brain diseases of the central nervous system.Statement of SignificanceIn order to overcome the blood-brain barrier and low targeting, and enhance the anti-glioma activities of nanodrugs. We have developed RBT@MRN-SS-Tf/Apt with dual targeting function. It is achieved release drug via redox-cleavable disulfide bonds, and enable the effective penetration of the blood-brain barrier and targeting the glioma. Moreover, anti-tumor drugs RBT will produce reactive oxygen species and induce apoptosis of tumor cells under laser irradiation, providing photodynamic therapy (PDT) for the treatment of gliomas, and further prolonging the median survival period. Therefore, this chemical photodynamic therapy nanosystem can be used as an efficient and powerful synergistic system for the treatment of brain tumors and other brain diseases of the central nervous system.Graphical abstractGraphical abstract for this article
       
  • Colistin nanoparticle assembly by coacervate complexation with polyanionic
           peptides for treating drug-resistant gram-negative bacteria
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Yu-Han Liu, Shu-Chen Kuo, Bing-Yu Yao, Zih-Syun Fang, Yi-Tzu Lee, Yuan-Chih Chang, Te-Li Chen, Che-Ming Jack Hu Amidst the ever-rising threat of antibiotics resistance, colistin, a decade-old antibiotic with lingering toxicity concern, is increasingly prescribed to treat many drug-resistant, gram-negative bacteria. With the aim of improving the safety profile while preserving the antimicrobial activity of colistin, a nanoformulation is herein developed through coacervate complexation with polyanionic peptides. Upon controlled mixing of cationic colistin with polyglutamic acids, formation of liquid coacervates was demonstrated. Subsequent stabilization by DSPE-PEG and homogenization through micro-fluidization of the liquid coacervates yielded nanoparticles 8 nm in diameter. In vitro assessment showed that the colistin antimicrobial activity against multiple drug-resistant bacterial strains was retained and, in some cases, enhanced following the nanoparticle assembly. In vivo administration in mice demonstrated improved safety of the colistin nanoparticle, which has a maximal tolerated dose of 12.5 mg/kg compared to 10 mg/kg of free colistin. Upon administration over a 7-day period, colistin nanoparticles also exhibited reduced hepatotoxicity as compared to free colistin. In mouse models of Klebsiella pneumoniae bacteremia and Acinetobacter baumannii pneumonia, treatment with colistin nanoparticles showed equivalent efficacy to free colistin. These results demonstrate coacervation-induced nanoparticle assembly as a promising approach towards improving colistin treatments against bacterial infections.Statement of SignificanceImproving the safety of colistin while retaining its antimicrobial activity has been a highly sought-after objective toward enhancing antibacterial treatments. Herein, we demonstrate formation of stabilized colistin nanocomplexes in the presence of anionic polypeptides and DSPE-PEG stabilizer. The nanocomplexes retain colistin’s antimicrobial activity while demonstrating improved safety upon in vivo administration. The supramolecular nanoparticle assembly of colistin presents a unique approach towards designing antimicrobial nanoparticles.Graphical abstractGraphical abstract for this article
       
  • Effects of bisphosphonate ligands and PEGylation on targeted delivery of
           gold nanoparticles for contrast-enhanced radiographic detection of breast
           microcalcifications
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Lisa E. Cole, Tracie L. McGinnity, Lisa E. Irimata, Tracy Vargo-Gogola, Ryan K. Roeder A preclinical murine model of hydroxyapatite (HA) breast microcalcifications (µcals), which are an important clinical biomarker for breast cancer detection, was used to investigate the independent effects of high affinity bisphosphonate (BP) ligands and a polyethylene glycol (PEG) spacer on targeted delivery of gold nanoparticles (Au NPs) for contrast-enhanced radiographic detection. The addition of BP ligands to PEGylated Au NPs (BP-PEG-Au NPs) resulted in five-fold greater binding affinity for targeting HA µcals, as expected, due to the strong binding affinity of BP ligands for calcium. Therefore, BP-PEG-Au NPs were able to target HA µcals in vivo after intramammary delivery, which enabled contrast-enhanced radiographic detection of µcals in both normal and radiographically dense mammary tissues similar to previous results for BP-Au NPs, while PEG-Au NPs did not. The addition of a PEG spacer between the BP targeting ligand and Au NP surface enabled improved in vivo clearance. PEG-Au NPs and BP-PEG-Au NPs were cleared from all mammary glands (MGs) and control MGs, respectively, within 24–48 h after intramammary delivery, while BP-Au NPs were not. PEGylated Au NPs were slowly cleared from MGs by lymphatic drainage and accumulated in the spleen. Histopathology revealed uptake of PEG-Au NPs and BP-PEG-Au NPs by macrophages in the spleen, liver, and MGs; there was no evidence of toxicity due to the accumulation of NPs in organs and tissues compared with untreated controls for up to 28 days after delivery.Statement of SignificanceAu NP imaging probes and therapeutics are commonly surface functionalized with PEG and/or high affinity targeting ligands for delivery. However, direct comparisons of PEGylated Au NPs with and without a targeting ligand, or ligand-targeted Au NPs with and without a PEG spacer, on in vivo targeting efficiency, biodistribution, and clearance are limited. Therefore, the results of this study are important for the rationale design of targeted NP imaging probes and therapeutics, including the translation of BP-PEG-Au NPs which enable improved sensitivity and specificity for the radiographic detection of abnormalities (e.g., µcals) in women with dense breast tissue.Graphical abstractGraphical abstract for this article
       
  • Early angiogenesis detected by PET imaging with 64Cu-NODAGA-RGD is
           predictive of bone critical defect repair
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Anne-Margaux Collignon, Julie Lesieur, Nadège Anizan, Rana Ben Azzouna, Anne Poliard, Caroline Gorin, Didier Letourneur, Catherine Chaussain, Francois Rouzet, Gael Y. Rochefort Therapies using stem cells may be applicable to all fields of regenerative medicine, including craniomaxillofacial surgery. Dental pulp stem cells (DPSCs) have demonstrated in vitro and in vivo osteogenic and proangiogenic properties. The aim of the study was to evaluate whether early angiogenesis investigated by nuclear imaging can predict bone formation within a mouse critical bone defect. Two symmetrical calvarial critical-sized defects were created. Defects were left empty or filled with i) DPSC-containing dense collagen scaffold, ii) 5% hypoxia-primed DPSC-containing dense collagen scaffold, iii) acellular dense collagen scaffold, or iv) left empty. Early angiogenesis assessed by PET using 64Cu-NODAGA-RGD as a tracer was found to be correlated with bone formation determined by micro-CT within the defects from day 30, and to be correlated to the late calcium apposition observed at day 90 using 18F-Na PET. These results suggest that nuclear imaging of angiogenesis, a technique applicable in clinical practice, is a promising approach for early prediction of bone grafting outcome, thus potentially allowing to anticipate alternative regenerative strategies.Statement of SignificanceBone defects are a major concern in medicine. As life expectancy increases, the number of bone lesions grows, and occurring complications lead to a delay or even lack of consolidation. Therefore, to be able to predict healing or the absence of scarring at early times would be very interesting. This would not “waste time” for the patient.We report here that early nuclear imaging of angiogenesis, using 64Cu-NODAGA-RGD as a tracer, associated with nuclear imaging of mineralization, using 18F-Na as a tracer, is correlated to late bone healing objectivized by classical histology and microtomography.This nuclear imaging represents a promising approach for early prediction of bone grafting outcome in clinical practice, thus potentially allowing to anticipate alternative regenerative strategies.Graphical abstractGraphical abstract for this article
       
  • Development of an innervated tissue-engineered skin with human sensory
           neurons and Schwann cells differentiated from iPS cells
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Quentin Muller, Marie-Josée Beaudet, Thiéry De Serres-Bérard, Sabrina Bellenfant, Vincent Flacher, François Berthod Cutaneous innervation is increasingly recognized as a major element of skin physiopathology through the neurogenic inflammation driven by neuropeptides that are sensed by endothelial cells and the immune system. To investigate this process in vitro, models of innervated tissue-engineered skin (TES) were developed, yet exclusively with murine sensory neurons extracted from dorsal root ganglions. In order to build a fully human model of innervated TES, we used induced pluripotent stem cells (iPSC) generated from human skin fibroblasts. Nearly 100% of the iPSC differentiated into sensory neurons were shown to express the neuronal markers BRN3A and β3-tubulin after 19 days of maturation. In addition, these cells were also positive to TRPV1 and neurofilament M, and some of them expressed Substance P, TrkA and TRPA1. When stimulated with molecules inducing neuropeptide release, iPSC-derived neurons released Substance P and CGRP, both in conventional monolayer culture and after seeding in a 3D fibroblast-populated collagen sponge model. Schwann cells, the essential partners of neurons for function and axonal migration, were also successfully differentiated from human iPSC as shown by their expression of the markers S100, GFAP, p75 and SOX10. When cultured for one additional month in the TES model, iPSC-derived neurons seeded at the bottom of the sponge formed a network of neurites spanning the whole TES up to the epidermis, but only when combined with mouse or iPSC-derived Schwann cells. This unique model of human innervated TES should be highly useful for the study of cutaneous neuroinflammation.Statement of SignificanceThe purpose of this work was to develop in vitro an innovative fully human tissue-engineered skin enabling the investigation of the influence of cutaneous innervation on skin pathophysiology. To reach that aim, neurons were differentiated from human induced pluripotent stem cells (iPSCs) generated from normal human skin fibroblasts. This innervated tissue-engineered skin model will be the first one to show iPSC-derived neurons can be successfully used to build a 3D nerve network in vitro. Since innervation has been recently recognized to play a central role in many human skin diseases, such as psoriasis and atopic dermatitis, this construct promises to be at the forefront to model these diseases while using patient-derived cells.Graphical abstractGraphical abstract for this article
       
  • Multi-cellular transitional organotypic models to investigate liver
           fibrosis
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Sophia M. Orbach, Andrew J. Ford, Scott-Eugene Saverot, Padmavathy Rajagopalan Hepatic fibrosis is the result of wound healing and inflammation resulting in organ dysfunction. Hepatocytes, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs) play critical roles in fibrogenesis. As the liver undergoes fibrosis, there are populations of cells that are healthy, fibrotic as well as those undergoing fibrosis. We investigated how a varying mechanical environment could induce changes in hepatic cells. In this study, a gradient in the mechanical properties of the microenvironment resulted in transitioning phenotypes in hepatic cells. We have designed detachable polyelectrolyte multilayers (PEMs) whose elastic moduli ranged from 21 to 43 kPa to serve as Space of Disse mimics. We assembled novel 3D organotypic liver models comprised of hepatocytes, LSECs, HSCs, KCs, and the Space of Disse mimic. We demonstrate how cells in contact with a mechanical gradient exhibit different properties compared to cells cultured using non-gradient PEMs. Significant differences were observed in HSC and KC proliferation between 3D cultures assembled with gradient and non-gradient PEMs. While HSCs on the stiffer regions of the gradient PEMs expressed both GFAP and α-SMA, cells in cultures assembled with homogeneous 43 kPa multilayers primarily expressed α-SMA. Over an 8-day culture, the elastic modulus in the 21 and 43 kPa regions of the gradient PEMs increased by 1.6 and 3.7-fold, respectively. This was accompanied by a 4-fold increase in hydroxyproline. Such in vitro tissues can be used to investigate the effects of liver fibrosis.Statement of SignificanceWe have assembled a liver model assembled with four major primary hepatic cell types to investigate how a varying mechanical environment induces changes in hepatic cells. In this study, a gradient in the mechanical properties of the microenvironment results in transitioning phenotypes in hepatic cells. Our goal was to investigate the interplay between mechanical properties and a multi-cellular engineered liver tissue. In these models, Kupffer cell proliferation and hepatic stellate cell activation occurred due to mechanical cues and inter-cellular signaling across a distance of 2000 μm. These models are unique, in that, fibrosis was initiated purely through changes to the microenvironment. These models were not exposed to fibrogenic factors nor were the models assembled with cells from fibrotic rats. To the best of our knowledge, these are the first liver models that capture how a gradient microenvironment can result in transitioning cellular phenotypes.Graphical abstractGraphical abstract for this article
       
  • Bioengineering a novel 3D in vitro model of gastric mucosa for
           stomach permeability studies
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Bianca N. Lourenço, Tiago dos Santos, Carla Oliveira, Cristina C. Barrias, Pedro L. Granja The field of stomach-directed therapeutics and diagnosis is still hampered by the lack of reliable in vitro models that closely mimic the gastric mucosa where gastric cancer cells are generally confined. Here we propose a rapid, complex, and innovative 3D in vitro model of the gastric mucosa, by extending a conventional gastric monolayer model to an inner stratum of the mucosa – the lamina propria. The developed model comprises normal stomach fibroblasts embedded in a 3D RGD-modified alginate hydrogel prepared on the basolateral side of a Transwell® insert, mimicking the extracellular matrix and cellular component of the lamina propria, onto which a moderately differentiated adenocarcinoma stomach cell line (MKN74) was seeded, reproducing the physiological conditions of the gastric barrier. The integrity and functionality of the in vitro model was evaluated through permeability studies of FITC-dextran and 200 nm fluorescent polystyrene nanoparticles at gastric conditions. Nanoparticle transport was pH-dependent and strongly impacted by the biomimetic lamina propria, highlighting that a gastric extracellular matrix (ECM)-like microenvironment should be integrated in an in vitro permeability model to be adopted as a reliable evaluation tool of innovative therapeutics and diagnosis of gastric diseases.Statement of SignificanceCurrent in vitro models of the gastric mucosa are limited to simplistic 2D cell culture systems, which ignore the dimensionality of the stomach wall and make it difficult to reliably test new therapeutic approaches to gastric pathologies. By combining stomach fibroblasts embedded within a 3D RGD-modified alginate hydrogel and epithelial gastric cancer cells in a Transwell® system, we established a new biomimetic model of the stomach mucosa. Epithelial cells recreate the gastric epithelium, while the cell-laden 3D hydrogel recapitulates both the cellular composition and dimensionality of the extracellular matrix of gastric lamina propria. This cellularized 3D model stands as a promising evaluation platform to assist the development of new strategies for the treatment and diagnosis of gastric diseases.Graphical abstractGraphical abstract for this article
       
  • Bioactive effects of silica nanoparticles on bone cells are size, surface,
           and composition dependent
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Shin-Woo Ha, Manjula Viggeswarapu, Mark M. Habib, George R. Beck Silica based nanoparticles have been demonstrated to have intrinsic biologic activity towards the skeleton and to function by promoting the differentiation of bone forming osteoblasts while inhibiting the differentiation of bone resorbing osteoclasts. The excitement surrounding nanomedicine in part revolves around the almost unlimited possibilities for varying the physicochemical properties including size, composition, and surface charge. To date few studies have attempted to manipulate these characteristics in concert to optimize a complex biologic outcome. Towards this end, spherical silica nanoparticles of various sizes (50–450 nm), of different surface properties (OH, CO2H, NR4+, mNH2), and of different composition (silica, gold, and polystyrene) were synthesized and evaluated for biological activity toward skeletal cells. Osteoblast activity was most influenced by composition and size variables, whereas osteoclasts were most affected by surface property variation. The study also establishes nanoparticle mediated suppression of Nfatc1, a key transcriptional regulator for osteoclast differentiation, identifying a novel mechanism of action. Collectively, the study highlights how during the design of bioactive nanoparticles, it is vital to consider not only the myriad of physical properties that can be manipulated, but also that the characteristics of the target cell plays an equally integral role in determining biological outcome.Statement of significanceSilica nanomaterials represent a promising biomaterial for beneficial effects on bone mass and quality as well as regenerative tissue engineering and are currently being investigated for intrinsic bioactivity towards the primary cells responsible for skeletal homeostasis; osteoblasts and osteoclasts. The goal of the current study was to assess the physical properties of silica nanoparticles that impart intrinsic bioactivity by evaluating size, surface charge, and composition. Results reveal differential influences of the physical properties of nanoparticles towards osteoblasts and osteoclasts. This study provides new insights into the design of nanoparticles to specifically target different aspects of bone metabolism and highlights the opportunities provided by nanotechnology to modulate a range of cell specific biological responses for therapeutic benefit.Graphical abstractGraphical abstract for this article
       
  • Radical polymerization-crosslinking method for improving extracellular
           matrix stability in bioprosthetic heart valves with reduced potential for
           calcification and inflammatory response
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Gaoyang Guo, Linhe Jin, Wanyu Jin, Liang Chen, Yang Lei, Yunbing Wang In recent years, the number of heart valve replacements has multiplied with valve diseases because of aging populations and the surge in rheumatic heart disease in young people. Among them, bioprosthetic heart valves (BHVs) have become increasingly popular. Transcatheter aortic valve implantation (TAVI) valve as an emerging BHV has been increasingly applied to patients. However, the current commercially used BHVs treated with glutaraldehyde (Glut) still face the problem of durability. BHVs derived from Glut-treated xenogenetic tissues would undergo structural degeneration and calcification sometimes even as short as less than 10 years. This issue has already become a big challenge considering more and more young patients at the age of 50–60 s are receiving the BHV replacement. In our study, an approach that is totally different from the previous techniques named by us as the radical polymerization-crosslinking (RPC) method was developed to improve extracellular matrix stability, prevent calcification, and reduce inflammatory response in BHVs. The porcine pericardium (PP) tissue was decellularized, functionalized with methacryloyl groups, and subsequently crosslinked by radical polymerization. We found that high-density RPC treatment remarkably improved the stability of collagen and elastin of PP, enhanced its endothelialization potential, and provided reliable biomechanical performance as compared to Glut treatment. The in vivo rat model also confirmed the increased componential stability and the reduced inflammatory response of RPC-treated PP. Moreover, the RPC-treated PP showed better in vivo anticalcification potential than Glut-treated PP.Statement of significanceBioprosthetic heart valves (BHVs) manufactured from glutaraldehyde (Glut)-treated xenogeneic tissues have been used to treat valve-related diseases for several decades. However, the durability of BHVs remains unresolved and becomes more pronounced particularly in younger patients. Although a number of new alternative methods for Glut crosslinking have been proposed, their overall performance is still far from ready to use in humans. In this study, radical polymerization was investigated for crosslinking the porcine pericardium (PP). This treatment was found to have advantages compared to Glut-treated PP in terms of stability, biocompatibility, and anticalcification potential with the hope of addressing the needs of more robust biomaterials for the fabrication of BHVs.Graphical abstractGraphical abstract for this article
       
  • Vitronectin promotes the vascularization of porous polyethylene
           biomaterials
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Maximilian E.T. Hessenauer, Kirsten Lauber, Gabriele Zuchtriegel, Bernd Uhl, Timon Hussain, Martin Canis, Sebastian Strieth, Alexander Berghaus, Christoph A. Reichel Rapid implant vascularization is a prerequisite for successful biomaterial engraftment. Vitronectin (VN) is a matricellular glycoprotein well known for its capability to interact with growth factors, proteases, and protease inhibitors/receptors. Since such proteins are highly relevant for angiogenic processes, we hypothesized that VN contributes to the tissue integration of biomaterials. Employing different in vivo and ex vivo microscopy techniques, engraftment of porous polyethylene (PPE) implants was analyzed in the dorsal skinfold chamber model in wild-type (WT) and VN−/− mice. Upon PPE implantation, vascularization of this biomaterial was severely compromised in animals lacking this matricellular protein. Proteome profiling revealed that VN deficiency does not cause major changes in angiogenic protein composition in the implants suggesting that VN promotes PPE vascularization via mechanisms modulating the activity of angiogenic factors rather than by directly enriching them in the implant. Consequently, surface coating with recombinant VN (embedded in Matrigel®) accelerated implant vascularization in WT mice by enhancing the maturation of a vascular network. Thus, VN contributes to the engraftment of PPE implants by promoting the vascularization of this biomaterial. Surface coating with VN might provide a promising strategy to improve the vascularization of PPE implants without affecting the host’s integrity.Statement of SignificancePorous polyethylene (PPE) is a biomaterial frequently used in reconstructive surgery. The proper vascularization of PPE implants is a fundamental prerequisite for its successful engraftment in host tissue. Although the overall biocompatibility of PPE is good, there are less favorable application sites for its use in tissue reconstruction mostly characterized by low blood supply. Employing advanced in vivo microscopy methods and proteomic analyses in genetically engineered mice, we here describe a previously unrecognized function of vitronectin (VN) that enables this abundantly present glycoprotein to particularly promote the vascularization of PPE biomaterial. These properties of VN specifically facilitate the formation of a dense vessel network within the implant which relies on modulating the activity of angiogenic mediators rather than on the enrichment of these factors in the implant. Consequently, surface coating with this matricellular protein effectively accelerated and intensified implant vascularization which might be beneficial for its implementation at unfavorable sites for implantation without affecting the host’s integrity.Graphical abstractEndogenous vitronectin (VN) promotes the vascularization of PPE biomaterial (left, mid). Additional surface coating with recombinant VN accelerates and intensifies this process (right).Graphical abstract for this article
       
  • Design and development of pH-responsive polyurethane membranes for
           intravaginal release of nanomedicines
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Seungil Kim, Yannick Leandre Traore, Emmanuel A. Ho, Muhammad Shafiq, Soo Hyun Kim, Song Liu The objective of this study was to develop and characterize a novel intravaginal membrane platform for pH-triggered release of nanoparticles (NPs), which is essential for efficient intravaginal delivery of certain effective but acid-labile therapeutic agents for sexually transmitted infections, such as small interfering RNA (siRNA). A pH-responsive polyurethane (PU) was electrospun into a porous nanofibrous membrane. The diameters of the fibers, as well as the thickness and pore sizes of the membrane under dry and wet conditions (pH 4.5 and 7.0), were determined from scanning electron microscopy (SEM) micrographs. pH-dependent zeta-potential (ζ) of the membrane was evaluated using a SurPASS electrokinetic analyzer. Visiblex™ color-dyed polystyrene NPs (PSNs, 200 nm, COOH) and CCR5 siRNA-encapsulated solid lipid NPs (SLNs) were used for in vitro NP release studies in a vaginal fluid simulant (VFS) at pH 4.5 (normal physiological vaginal pH) and 7.0 (vaginal pH neutralization by semen). During 24 h of incubation in VFS, close-to-zero PSNs (2 ± 1%) and 28 ± 4% SLNs were released through the PU membrane at pH 4.5, whereas the release of PSNs and SLNs significantly increased to 60 ± 6% and 59 ± 8% at pH 7.0, respectively. The pH-responsive release of NPs hinged on the electrostatic interaction between the pH-responsive membrane and the anionic NPs, and the change in pH-responsive morphology of the membrane. In vitro biocompatibility studies of the membrane showed no significant cytotoxicity to VK2/E6E7 human epithelial cells and Sup-T1 human T-cells and no significant changes in the expression of pro-inflammatory cytokines (IL-6, IL-8, and IL-1β). Overall, the porous pH-responsive PU membrane demonstrated its potential in serving as a “window” membrane in reservoir-type intravaginal rings (IVRs) for pH-responsive intravaginal release of NPs.Statement of SignificanceStimuli-responsive intravaginal nanoparticle release is achieved for the first time through a new electrospun pH-responsive polyurethane (PU) semi-permeable membrane, which can serve as a “window” membrane in the reservoir-type IVR for the prevention of human immunodeficiency virus (HIV) transmission. Almost no release of nanoparticles was observed at normal pH in the female genital tract (in vaginal fluid simulant [VFS], at pH 4.5); however, a continuous release of NPs was observed at elevated pH in the female genital tract (in VFS, at pH 7.0). This pH-responsive intravaginal release can reduce side effect and drug resistance by avoiding unnecessary exposure. The PU semi-permeable membrane demonstrated potential use as biomaterials for “smart” intravaginal nanoparticle release and has great potential to protect women from HIV.Graphical abstractGraphical abstract for this article
       
  • Pore size directs bone marrow stromal cell fate and tissue regeneration in
           nanofibrous macroporous scaffolds by mediating vascularization
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Melanie J. Gupte, W. Benton Swanson, Jiang Hu, Xiaobing Jin, Haiyun Ma, Zhanpeng Zhang, Zhongning Liu, Kai Feng, Ganjun Feng, Guiyong Xiao, Nan Hatch, Yuji Mishina, Peter X. Ma In the U.S., 30% of adults suffer joint pain, most commonly in the knee, which severely limits mobility and is often attributed to injury of cartilage and underlying bone in the joint. Current treatment methods such as microfracture result in less resilient fibrocartilage with eventual failure; autografting can cause donor site morbidity and poor integration. To overcome drawbacks in treatment, tissue engineers can design cell-instructive biomimetic scaffolds using biocompatible materials as alternate therapies for osteochondral defects. Nanofibrous poly (l-lactic acid) (PLLA) scaffolds of uniform, spherical, interconnected and well-defined pore sizes that are fabricated using a thermally-induced phase separation and sugar porogen template method create an extracellular matrix-like environment which facilitates cell adhesion and proliferation. Herein we report that chondrogenesis and endochondral ossification of rabbit and human bone marrow stromal cells (BMSCs) can be controlled by scaffold pore architecture, particularly pore size. Small-pore scaffolds support enhanced chondrogenic differentiation in vitro and cartilage formation in vivo compared to large-pore scaffolds. Endochondral ossification is prevented in scaffolds with very small pore sizes; pore interconnectivity is critical to promote capillary ingrowth for mature bone formation. These results provide a novel strategy to control tissue regenerative processes by tunable architecture of macroporous nanofibrous scaffolds.Statement of significanceProgress in understanding the relationship between cell fate and architectural features of tissue engineering scaffolds is critical for engineering physiologically functional tissues. Sugar porogen template scaffolds have uniform, spherical, highly interconnected macropores. Tunable pore-size guides the fate of bone marrow stromal cells (BMSCs) towards chondrogenesis and endochondral ossification, and is a critical design parameter to mediate neotissue vascularization. Preventing vascularization favors a chondrogenic cell fate while allowing vascularization results in endochondral ossification and mineralized bone formation. These results provide a novel strategy to control tissue regenerative processes by tunable architecture of macroporous nanofibrous scaffolds.Graphical abstractGraphical abstract for this article
       
  • Microstructure, mechanical properties, biocompatibility, and in vitro
           corrosion and degradation behavior of a new Zn–5Ge alloy for
           biodegradable implant materials
    • Abstract: Publication date: December 2018Source: Acta Biomaterialia, Volume 82Author(s): Xian Tong, Dechuang Zhang, Xiaotuan Zhang, Yingchao Su, Zimu Shi, Kun Wang, Jianguo Lin, Yuncang Li, Jixing Lin, Cuie Wen Zinc (Zn)-based alloys are considered a new class of biodegradable implant materials due to their superior chemical stability and processability compared to biodegradable magnesium (Mg) alloys. In this study, we report a new biodegradable Zn–5Ge alloy with highly desirable mechanical, corrosion, and biological properties. Microstructural characterization revealed the effective grain-refining effect of germanium (Ge) on the Zn alloy. Tensile test results indicated that the hot-rolled Zn–5Ge alloy showed an ultimate tensile strength of 237.0 MPa, a yield strength of 175.1 MPa, and an elongation of 21.6%; while as-cast pure Zn showed an ultimate tensile strength of 33.6 MPa, a yield strength of 29.3 MPa, and an elongation of 1.2%. The corrosion rates measured by potentiodynamic polarization tests in Hank’s solution in ascending order are: as-cast Zn–5Ge (0.1272 mm/y) 
       
  • Cell Armor for Protection Against Environmental Stress: Advances,
           Challenges and Applications in Micro- and Nanoencapsulation of Mammalian
           Cells
    • Abstract: Publication date: Available online 24 November 2018Source: Acta BiomaterialiaAuthor(s): Onur Hasturk, David L. Kaplan Unlike unicellular organisms and plant cells surrounded with a cell wall, naked plasma membranes of mammalian cells make them more susceptible to environmental stresses encountered during in vitro biofabrication and in vivo cell therapy applications. Recent advances in micro- and nanoencapsulation of single mammalian cells provide an effective strategy to isolate cells from their surroundings and protect them against harsh environmental conditions. Microemulsification and droplet-based microfluidics have enabled researchers to encapsulate single cells within a variety of microscale hydrogel materials with a range of biochemical and mechanical properties and functionalities including enhanced cell-matrix interactions or on-demand degradation. In addition to microcapsules, nanocoatings of various organic and inorganic substances on mammalian cells have allowed for the formation of protective shells. A wide range of synthetic and natural polymers, minerals and supramolecular metal-organic complexes have been deposited as nanolayers on the cells via electrostatic interactions, receptor-ligand binding, non-specific interactions, and in situ polymerization/crosslinking. Here, current strategies in encapsulation of single mammalian cells along with challenges and advances are reviewed. Protection of encapsulated stem cells, fibroblasts, red and white blood cells and cancer cells against harsh in vitro and in vivo conditions including anoikis, UV radiation, physical forces, proteolytic enzymes and immune clearance are discussed.Statement of SignificanceThe mechanical fragility of the plasma membrane and susceptibility to extracellular biochemical factors due to the lack of a physical barrier like a tough cell wall or exoskeleton make mammalian cells extra sensitive to harsh environmental conditions. This sensitively, in turn, limits the ex vivo storage, handling and manipulation of mammalian cells, as well as their in vivo applications. Environmental stresses such as exposure to UV, reactive chemicals and mechanical stress during biofabrication processes like 3D bioprinting can often compromise cell viability and function. Micro- and nanoencapsulation of single mammalian cells in protective shells have emerged as promising approaches to isolate cells from their surroundings and enhance resistance against perturbations in conditions during regenerative medicine and tissue engineering applications. In this review, the current state of art of single cell encapsulation strategies and the challenges associated with these technologies are discussed in detail. This is followed by the review of the protection provided by cell armor against a range of harsh in vitro and in vivo conditions.Graphical abstractGraphical abstract for this article
       
  • Three-dimensional (3D) Printed Scaffold and Material Selection for Bone
           Repair
    • Abstract: Publication date: Available online 24 November 2018Source: Acta BiomaterialiaAuthor(s): Lei Zhang, Guojing Yang, Blake N. Johnson, Xiaofeng Jia Critical-sized bone defect remains a substantial challenge in clinical settings and requires bone grafts or bone substitute materials. However, existing biomaterials often do not meet the clinical requirements of structural support, osteoinductive property, and controllable biodegradability. To treat large-scale bone defects, the development of three-dimensional (3D) porous scaffolds has received considerable focus within bone engineering. A variety of biomaterials and manufacturing methods including 3D printing have emerged to fabricate patient-specific bioactive scaffolds that possess controlled micro-architectures for bridging bone defects in complex configurations. During the last decade, with the development of the 3D printing industry, a large number of tissue-engineered scaffolds have been created for preclinical or clinical applications using novel materials and innovated technologies. Thus, this review provides a brief overview of current advances in existing biomaterials and tissue engineering scaffolds prepared by 3D printing technologies, with an emphasis on the material selection, scaffold design optimization, and their preclinical or clinical applications in the repair of critical-sized bone defects. Furthermore, it will elaborate the current limitations and potential future prospects of 3D printing technology.Statement of Significance3D printing has emerged as a critical fabrication process for bone engineering due to its ability to control bulk geometry and internal structure of tissue scaffolds. The advancement of bioprinting methods and compatible ink materials for bone engineering have been a major focus to develop optimal 3D scaffolds for bone defect repair. Achieving a successful balance between the properties of a scaffold favorable to cellular function, cellular viability, and mechanical integrity under load-bearing conditions is critical. Hybridization of natural and synthetic polymer-based materials is a promising approach to create novel tissue engineered scaffolds that combines the advantages of both materials and meets various requirements, including biological activity, mechanical strength, easy fabrication and controllable degradation. 3D printing is linked to the future of bone grafts to create on-demand patient-specific grafts.Graphical abstractGraphical abstract for this article
       
  • Porous Scaffolds from Droplet Microfluidics for Prevention of Intrauterine
           Adhesion
    • Abstract: Publication date: Available online 23 November 2018Source: Acta BiomaterialiaAuthor(s): Yunlang Cai, Fangyuan Wu, Yunru Yu, Yuxiao Liu, Changmin Shao, Hongcheng Gu, Minli Li, Yuanjin Zhao Severe intrauterine adhesions (IUAs) have a great negative impact on women's psychological and reproductive health. It remains a significant challenge to prevent postoperative IUAs because of the complications of various clinical preventive measures and incompatibility of uterine cavity morphology. Herein, we present a new drug-loaded porous scaffold based on a microfluidic droplet template, which combines the characteristics of the artificial biocompatible material GelMA and the natural polysaccharide material Na-alginate. By changing the containers that collect the microfluidic droplets, the porous scaffold conforming to the shape of the uterine cavity could be obtained. The porous structure, mechanical property, and flexibility impart the scaffold with compressibility and send it to the uterus through the vagina. In addition, the external–internal connected open structures could load and control the release of drugs to repair the damaged region continuously in vivo. To verify the antiadhesion and repair of drug-loaded porous scaffolds, we tested the system in the rat model of IUAs, and it was demonstrated that the system had the ability to improve neovascularization, cellularize the damaged tissue, and repair the endometrium. These features provide the drug-loaded porous scaffolds with new options for the improvement of postoperative IUAs.Statement of SignificanceIntrauterine adhesions are caused by various causes of damage to the endometrial basal layer, thus leading to part or entire adhesions in the cervical or uterine cavity. Clinically, various preventive measures reach the barrier effect through the physical barrier, which are difficult to further promote the repair of the damaged endometrium, and most of them have apparent side effects. This study aims to prepare compressible and biodegradable three-dimensional porous drug-loading biological scaffolds. GelMA and Na-alginate have desirable biocompatibility. The interconnect porous scaffolds, which were prepared through the combination of biomaterials and single emulsion microfluidics, not only have compressibility but also provide space for drug delivery and release. This system can further promote the repair of the endometrium while preventing adhesion.Graphical abstractGraphical abstract for this article
       
  • Characterization of a tissue-engineered choroid
    • Abstract: Publication date: Available online 23 November 2018Source: Acta BiomaterialiaAuthor(s): Aïcha Dede Djigo, Julie Bérubé, Solange Landreville, Stéphanie Proulx The choroid of the eye is a vascularized and pigmented connective tissue lying between the retina and the sclera. Increasing evidence demonstrates that, beyond supplying nutrients to the outer retina, the different choroidal cells contribute to the retina’s homeostasis, especially by paracrine signaling. However, the precise role of each cell type is currently unclear. Here, we developed a choroidal substitute using the self-assembly approach of tissue engineering. Retinal pigment epithelial (RPE) cells, as well as choroidal stromal fibroblasts, vascular endothelial cells and melanocytes, were isolated from human eye bank donor eyes. Fibroblasts were cultured in a medium containing serum and ascorbic acid. After six weeks, cells formed sheets of extracellular matrix (ECM), which were stacked to produce a tissue-engineered choroidal stroma (TECS). These stromal substitutes were then characterized and compared to the native choroid. Their ECM composition (collagens and proteoglycans) and biomechanical properties (ultimate tensile strength, strain and elasticity) were similar. Furthermore, RPE cells, human umbilical vein endothelial cells and choroidal melanocytes successfully repopulated the stromas. Physiological structures were established, such as a confluent monolayer of RPE cells, vascular-like structures and a pigmentation of the stroma. Our TECS thus recaptured the biophysical environment of the native choroid, and can serve as study models to understand the normal interactions between the RPE and choroidal cells, as well as their reciprocal exchanges with the ECM. This will consequently pave the way to derive accurate insight in the pathophysiological mechanisms of diseases affecting the choroid.Statement of significanceThe choroid is traditionally known for supplying blood to the avascular outer retina. There has been a renewed attention directed towards the choroid partly due to its implication in the development of age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries. Since AMD involves the dysfunction of the choroid/retinal pigment epithelium (RPE) complex, a three-dimensional (3D) model of RPE comprising the choroid layer is warranted. We used human choroidal cells to engineer a choroidal substitute. Our approach takes advantage of the ability of cells to recreate their own environment, without exogenous materials. Our model could help to better understand the role of each choroidal cell type as well as to advance the development of new therapeutics for AMD.Graphical abstractGraphical abstract for this article
       
  • Dual-ion delivery for synergistic angiogenesis and bactericidal capacity
           with silica-based microsphere
    • Abstract: Publication date: Available online 19 November 2018Source: Acta BiomaterialiaAuthor(s): Khaliun Boldbaatar, Khandmaa Dashnyam, Jonathan C. Knowles, Hae-Hyoung Lee, Jung-Hwan Lee, Hae-Won Kim Inhibition of bacterial growth with the simultaneous promotion of angiogenesis has been challenging in the repair and regeneration of infected tissues. Here, we aim to tackle this issue through the use of cobalt-doped silicate microspheres that can sustainably release dual ions (silicate and cobalt) at therapeutically-relevant doses. The cobalt was doped up to 2.5 wt% within a sol-gel silicate glass network, and microspheres with the size of ∼300 μm were generated by an emulsification method. The cobalt and silicate ions released were shown to synergistically upregulate key angiogenic genes, such as HIF1-α, VEGF and the receptor KDR. Moreover, the incorporation of ions promoted the polarization, migration, homing and sprouting angiogenesis of endothelial cells. Neo-vascular formation was significantly higher in the dual-ion delivered microspheres, as evidenced in a chicken chorioallantoic membrane model. When cultured with bacterial species, the cobalt-doped microspheres effectively inhibited bacteria growth in both indirect or direct contacts. Of note, the bacteria/endothelial cell coculture model proved the efficacy of dual-ion releasing microcarriers for maintaining the endothelial survivability against bacterial contamination and their cell-cell junction. The current study demonstrates the multiple actions (proangiogenic and antibacterial) of silicate and cobalt ions released from microspheres, and the concept provided here can be extensively applied to repair and regenerate infected tissues as a growth factor- or drug-free delivery system.Statement of significanceWhile several ions have been introduced to biomaterials for therapeutic purposes, relaying the effects of antibacterial into tissue regenerative (e.g., angiogenesis) has been a significant challenge. In this study, we aim to develop a biomaterial platform that has the capacity of both ‘antibacterial’ and ‘proangiogenic’ from a microsphere sustainably releasing multiple ions (herein cobalt and silicate). Here, dual-actions of the microspheres revealed the stimulated endothelial functions as well as the inhibited growth of different bacterial species. In particular, protecting endothelial survivability against bacterial contamination was reported using the bacterial/endothelial co-culture model. The current concept of drug-free yet multiple-ion delivery biomaterials can be applicable for the repair and regeneration of infected tissues with dual actions of angiogenesis and suppressing bacterial activity.Graphical abstractDual ions (silicate and cobalt ions) released from microspheres promote angiogenesis while simultaneously inhibiting bacteria growth, as demonstrated by the salvaged survivability of endothelial cells against bacterial contamination. The multiple ion-delivery microspheres can be potentially useful for the repair and regeneration of infected tissues as a drug-free biomaterial platform.Graphical abstract for this article
       
  • A dual-targeted hyaluronic acid-gold nanorod platform with triple-stimuli
           responsiveness for photodynamic/photothermal therapy of breast cancer
    • Abstract: Publication date: Available online 19 November 2018Source: Acta BiomaterialiaAuthor(s): Weijun Xu, Junmin Qian, Guanghui Hou, Yaping Wang, Jinlei Wang, Tiantian Sun, Lijie Ji, Aili Suo, Yu Yao Multi-stimuli-responsive theranostic nanoplatform integrating functions of both imaging and multimodal therapeutics holds great promise for improving diagnosis and therapeutic efficacy. In this study, we reported a pH, glutathione (GSH) and hyaluronidase (HAase) triple-responsive nanoplatform for HER2 and CD44 dual-targeted and fluorescence imaging-guided PDT/PTT dual-therapy against HER2-overexpressed breast cancer. The nanoplatform was fabricated by functionalizing gold nanorods (GNRs) with hyaluronic acid (HA) bearing pendant hydrazide and thiol groups via Au-S bonds, and subsequently chemically conjugating 5-aminolevulinic acid (ALA), Cy7.5 and anti-HER2 antibody onto HA moiety for PDT, fluorescence imaging and active targeting, respectively. The resulting versatile nanoplatform GNR-HA-ALA/Cy7.5-HER2 had uniform sizes, favorable dispersibility, as well as pH, GSH and HAase triple-responsive drug release manner. In vitro studies demonstrated that HER2 and CD44 receptor-mediated dual-targeting strategy could significantly enhance the cellular uptake of GNR-HA-ALA/Cy7.5-HER2. Under near-infrared (NIR) irradiation, MCF-7 cells could efficiently generate reactive oxygen species (ROS) and heat, and be more efficiently killed by a combination of PDT and PTT as compared with individual therapy. Pharmacokinetic and biodistribution studies showed that the nanoplatform possessed a circulation half-life of 1.9 h and could be specifically delivered to tumor tissues with an accumulation ratio of 12.8%. Upon the fluorescence imaging-guided PDT/PTT treatments, the tumors were completely eliminated without obvious side effects. The results suggest that the GNR-HA-ALA/Cy7.5-HER2 hold great potential for breast cancer therapy.Statement of significanceA combination of photodynamic therapy (PDT) and photothermal therapy (PTT) is emerging as a promising cancer treatment strategy. However, its therapeutic efficacy is compromised by the nonspecific delivery and unintended release of photo-responsive agents. Herein, we developed a multifunctional theranostic nanoplatform GNR-HA-ALA/Cy7.5-HER2 with pH, glutathione and hyaluronidase triple-responsive drug release for HER2 and CD44 dual-targeted and fluorescence imaging-guided PDT/PTT therapy against breast cancer. We demonstrated that HER2 and CD44 receptors-mediated dual-targeting strategy significantly enhanced the cellular uptake of GNR-HA-ALA/Cy7.5-HER2. We also demonstrated that the combined PDT/PTT treatment had significantly superior antitumor effect than PDT or PTT alone both in vitro and in vivo. Therefore, GNRs-HA-ALA//Cy7.5-HER2 could serve as a promising nanoplatform for HER2-postive breast cancer therapy.Graphical abstractGraphical abstract for this article
       
  • Enhancing Chondrogenesis and Mechanical Strength Retention in
           Physiologically Relevant Hydrogels with Incorporation of Hyaluronic Acid
           and Direct Loading of TGF-β
    • Abstract: Publication date: Available online 17 November 2018Source: Acta BiomaterialiaAuthor(s): Yuhao Deng, Aaron X. Sun, Kalon J. Overholt, Gary Z. Yu, Madalyn R. Fritch, Peter G. Alexander, He Shen, Rocky S. Tuan, Hang Lin Cell-loaded hydrogels are frequently applied in cartilage tissue engineering for their biocompatibility, ease of application, and ability to conform to various defect sites. As a bioactive adjunct to the biomaterial, transforming growth factor beta (TGF-β) has been shown to be essential for cell differentiation into a chondrocyte phenotype and maintenance thereof, but the low amounts of endogenous TGF-β in the in vivo joint microenvironment necessitate a mechanism for controlled delivery and release of this growth factor. In this study, TGF-β3 was directly loaded with human bone marrow-derived mesenchymal stem cells (MSCs) into poly-D,L-lactic acid/polyethylene glycol/poly-D,L-lactic acid (PDLLA-PEG) hydrogel, or PDLLA-PEG with the addition of hyaluronic acid (PDLLA/HA), and cultured in vitro. We hypothesize that the inclusion of HA within PDLLA-PEG would result in a controlled release of the loaded TGF-β3 and lead to a robust cartilage formation without the use of TGF-β3 in the culture medium. ELISA analysis showed that TGF-β3 release was effectively slowed by HA incorporation, and retention of TGF-β3 in the PDLLA/HA scaffold was detected by immunohistochemistry for up to 3 weeks. By means of both in vitro culture and in vivo implantation, we found that sulfated glycosaminoglycan production was higher in PDLLA/HA groups with homogenous distribution throughout the scaffold than PDLLA groups. Finally, with an optimal loading of TGF-β3 at 10 μg/mL, as determined by RT-PCR and glycosaminoglycan production, an almost twofold increase in Young’s modulus of the construct was seen over a 4-week period compared to TGF-β3 delivery in the culture medium. Taken together, our results indicate that the direct loading of TGF-β3 and stem cells in PDLLA/HA has the potential to be a one-step point-of-care treatment for cartilage injury.Statement of SignificanceStem cell-seeded hydrogels are commonly used in cell-based cartilage tissue engineering, but they generally fail to possess physiologically relevant mechanical properties suitable for loading. Moreover, degradation of the hydrogel in vivo with time further decreases mechanical suitability of the hydrogel due in part to the lack of TGF-β3 signaling. In this study, we demonstrated that incorporation of hyaluronic acid (HA) into a physiologically stiff PDLLA-PEG hydrogel allowed for slow release of one-time preloaded TGFβ3, and when loaded with adult mesenchymal stem cells and cultured in vitro, it resulted in higher chondrogenic gene expression and constructs of significantly higher mechanical strength than constructs cultured in conventional TGFβ3-supplemented medium. Similar effects were also observed in constructs implanted in vivo. Our results indicate that direct loading of TGF-β3 combined with HA in the physiologically stiff PDLLA-PEG hydrogel has the potential to be used for one-step point-of-care treatment of cartilage injury.Graphical abstractGraphical abstract for this article
       
  • Study on the effectiveness of ligand reversible shielding strategy in
           targeted delivery and tumor therapy
    • Abstract: Publication date: Available online 15 November 2018Source: Acta BiomaterialiaAuthor(s): Zhenpeng Hu, Xiaomin Li, Ming Yuan, Xinyu Wang, Yapei Zhang, Wei Wang, Zhi Yuan We previously proved the superiority of the ligand reversible shielding strategy based on the pH-responsive self-assembly/disassembly of gold nanoparticles through computed tomography imaging in vivo. Herein, the practicality of this strategy in tumor therapy was investigated by a ligand reversible shielding system based on a temperature-responsive polymer. The ligand biotin, cisplatin-loaded chain poly(acrylic acid)-Pt, and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm)) were co-modified onto the surface of gold nanostars. In the blood circulation (37 °C), the ligand was shielded by the extension of P(NIPAAm-co-AAm), whose lower critical solution temperature (LCST) is approximately 39 °C. After the nanoparticles accumulate at the tumor site by the enhanced permeability and retention (EPR) effect, the heat generated from gold nanostars upon near-infrared light irradiation would trigger the contraction of P(NIPAAm-co-AAm), thus deshielding the ligand for enhanced tumor cellular uptake. Owing to the reversible extension–contraction transformation change of P(NIPAAm-co-AAm), the reversible shielding effect on the ligand could be accomplished even if the nanoparticles return to the blood circulation. The results indicated that the system could extend blood circulation (1.6-fold at 24 h), reduce immune system clearance (28% lower), and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. This strategy showed significantly superior tumor inhibition (11% higher) than the irreversible system. All these results make clear that the ligand reversible shielding strategy is effective and offers important references for the design of nanomaterials for improving tumor accumulation.Statement of significanceHerein, the practicality of the ligand reversible shielding strategy in tumor therapy was investigated. The ligand biotin, cisplatin loaded chain poly(acrylic acid)-Pt and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm) which LCST is about 39 °C) were co-modified onto the surface of gold nanostars. This well-designed NPs could shield target ligand in blood circulation (37 °C) and deshield it at tumor site (40 - 41 °C) reversibly. The results indicated that the system could extend blood circulation (1.6-fold at 24 h), reduce immune system clearance (28% lower) and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. Significantly, the strategy showed superior tumor inhibition than the irreversible system (11% higher).Graphical abstractGraphical abstract for this article
       
  • Alum-functionalized graphene oxide nanocomplexes for effective anticancer
           vaccination
    • Abstract: Publication date: Available online 15 November 2018Source: Acta BiomaterialiaAuthor(s): Xiaoli Wang, Fengqiang Cao, Mengmeng Yan, Yijia Liu, Xianghui Zhu, Hongfan Sun, Guilei Ma Aluminum-based adjuvant (e.g., aluminum oxyhydroxide (AlO(OH), known as the commercial Alhydrogel® (Alum)) is the first adjuvant to be used in human vaccines. Although Alum shows a robust induction of antibody-mediated immunity, its weak stimulation of cell-mediated immunity makes it a questionable adjuvant for cancer immunotherapy. Herein, we described a novel formulation of Alum-based adjuvant by preparing AlO(OH)-modified graphene oxide (GO) nanosheets (GO-AlO(OH)), which, in addition to maintaining the induction of humoral immune response by AlO(OH), could further elicit the cellular immune response by GO. Similar to Alum, GO-AlO(OH) vaccine formulation could be constructed by the incorporation of antigen using a facile mixing/adsorption approach. Antigen-loaded GO-AlO(OH) nanocomplexes facilitated cellular uptake and cytosolic release of antigens and promoted DC maturation, thereby eliciting higher antigen-specific IgG titers, inducing robust CD4+ and CD8+ T lymphocyte response, and inhibiting tumor growth in vivo. Furthermore, by employing tumor cell lysate-based cancer vaccines, GO-AlO(OH) nanocomplexes led to significant inhibition of tumor growth and can be implemented as a personalized treatment strategy for cancer vaccine development. Overall, GO-AlO(OH) nanocomplexes described herein may serve as a facile and efficient approach for effective anticancer vaccination.Statement of significanceHerein, we described a novel formulation of aluminum-based adjuvant by preparing aluminum oxyhydroxide (AlO(OH)) (known as “Alum”)-modified graphene oxide (GO) nanocomplexes (GO-AlO(OH)), which, in addition to maintaining the induction of humoral immune response by AlO(OH), could further elicit the cellular immune response by GO. GO-AlO(OH) nanocomplexes can be prepared easily and in large scale by a chemical precipitation method. Similar to “Alum,” antigen-loaded GO-AlO(OH) vaccine formulation could be constructed by the incorporation of antigen using a facile mixing/adsorption approach. The very simple and reproductive preparation process of vaccines and the powerful ability to raise both humoral and cellular immune responses provide a novel approach for improving cancer immunotherapy efficacy.Graphical abstractGraphical abstract for this article
       
  • Synergistic effect of Si-hydroxyapatite coating and VEGF adsorption on
           Ti6Al4V-ELI scaffolds for bone regeneration in an osteoporotic bone
           environment
    • Abstract: Publication date: Available online 13 November 2018Source: Acta BiomaterialiaAuthor(s): I. Izquierdo-Barba, L. Santos-Ruiz, J. Becerra, M.J. Feito, D. Fernández-Villa, M.C. Serrano, I. Díaz-Güemes, B. Fernández-Tomé, S. Enciso, F.M. Sánchez-Margallo, D. Monopoli, H. Afonso, M.T. Portolés, D. Arcos, M. Vallet-Regí The osteogenic and angiogenic responses to metal macroporous scaffolds coated with silicon substituted hydroxyapatite (SiHA) and decorated with vascular endothelial growth factor (VEGF) have been evaluated in vitro and in vivo. Ti6Al4V-ELI scaffolds were prepared by electron beam melting and subsequently coated with Ca10(PO4)5.6(SiO4)0.4(OH)1.6 following a dip coating method. In vitro studies demonstrated that SiHA stimulates the proliferation of MC3T3-E1 pre-osteoblastic cells, whereas the adsorption of VEGF stimulates the proliferation of EC2 mature endothelial cells. In vivo studies were carried out in an osteoporotic sheep model, evidencing that only the simultaneous presence of both components led to a significant increase of new tissue formation in osteoporotic bone.Statement of significanceReconstruction of bones after severe trauma or tumors extirpation is one of the most challenging tasks in the field of orthopedic surgery. This scenario is even more complicated in the case of osteoporotic patients, since their bone regeneration capability is decreased. In this work we present a porous implant that promotes bone regeneration even in osteoporotic bone. By coating the implant with an osteogenic bioceramics such as silicon substituted hydroxyapatite and subsequent adsorption of vascular endothelial growth factor, these implants stimulate the bone ingrowth when they are implanted in osteoporotic sheepGraphical abstractGraphical abstract for this article
       
  • Effect of stress on corrosion of high-purity magnesium in vitro
           and in vivo
    • Abstract: Publication date: Available online 13 November 2018Source: Acta BiomaterialiaAuthor(s): Yuanming Gao, Lizhen Wang, Linhao Li, Xuenan Gu, Kuo Zhang, Jie Xia, Yubo Fan Magnesium-based implants are subjected to complicated stresses during implantation in the human body. The stress effects on corrosion of magnesium (Mg) in vitro were investigated in previous studies, whereas in this study, the corrosion behaviors of high-purity (HP) Mg under stress were comparatively studied in vitro in Hank’s solution and in vivo in the subcutaneous environment of rats. Loading devices were designed to apply compressive stress (15.1±0.5 MPa) and tensile stress (13.2±0.2 MPa) on HP Mg specimens both in vitro and in vivo. Corrosion rates of HP Mg were characterized by mass and volume losses. It was shown that the applied compressive stress had no effect on in vitro corrosion behaviors and the applied tensile stress accelerated the in vitro corrosion, thereby causing severe pitting corrosions and stress corrosion cracking (SCC). However, there was no significant change for corrosion behaviors in vivo under neither compressive stress nor tensile stress. Severe pitting corrosion and SCC did not occur in vivo. Histological evaluation revealed that a fibrotic capsule induced by foreign body reaction was formed on the corrosion surfaces of HP Mg in the subcutaneous environment. It was proposed that the fibrotic capsule suppressed the effects of stress in vivo by protecting the corrosion surfaces. These results provided new insights into understanding the stress effects on the corrosion of Mg both in vitro and in vivo.Statement of SignificanceMg and Mg alloys have shown potential as biodegradable metallic materials. During implantation, Mg is subjected to various mechanical environments in human body. It is necessary to clear different stress effect on Mg corrosion. However, few studies were performed in vivo. It is important to analyze the effect of quantitative stress on Mg corrosion in vivo. In this study, quantitative stresses were applied on Mg both in vitro and in vivo. The effects of stress on in vitro and in vivo corrosions of Mg were investigated and compared.Graphical abstractGraphical abstract for this article
       
  • Erratum to “Responsive antimicrobial dental adhesive based on
           drug-silica co-assembled particles” [Acta Biomater. 76 (2018) 283–294]
           
    • Abstract: Publication date: Available online 13 November 2018Source: Acta BiomaterialiaAuthor(s): Cameron A. Stewart, Jenny H. Hong, Benjamin D. Hatton, Yoav Finer
       
  • Hydrazone covalent adaptable networks modulate extracellular matrix
           deposition for cartilage tissue engineering
    • Abstract: Publication date: Available online 10 November 2018Source: Acta BiomaterialiaAuthor(s): Benjamin M. Richardson, Daniel G. Wilcox, Mark A. Randolph, Kristi S. Anseth Cartilage tissue engineering strategies often rely on hydrogels with fixed covalent crosslinks for chondrocyte encapsulation; yet the resulting material properties are largely elastic and can impede matrix deposition. To address this limitation, hydrazone crosslinked poly(ethylene glycol) hydrogels were formulated to achieve tunable viscoelastic properties and to study how chondrocyte proliferation and matrix deposition vary with the time-dependent material properties of covalent adaptable networks. Hydrazone equilibrium differences were leveraged to produce average stress relaxation times from hours (4.01x103s) to months (2.78x106s) by varying the percentage of alkyl-hydrazone (aHz) to benzyl-hydrazone (bHz) crosslinks. Swelling behavior and degradation associated with adaptability was characterized to quantify temporal network changes that can influence the behavior of encapsulated chondrocytes. After four weeks, mass swelling ratios varied from 36±3 to 17±0.4 and polymer retention ranged from 46±4% to 92±5%, with higher aHz content leading to loss of network connectivity with time. Hydrogels were formulated near the Flory-Stockmayer bHz percolation threshold (17% bHz) to investigate chondrocyte response to distinct levels of covalent architecture adaptability. Four weeks post-encapsulation, formulations with average relaxation times of 3 days (2.6x105s) revealed increased cellularity and an interconnected articular cartilage-specific matrix. Chondrocytes embedded in this adaptable formulation (22% bHz) deposited 190±30% more collagen and 140±20% more sulfated glycosaminoglycans compared to the 100% bHz control, which constrained matrix deposition to pericellular space. Collectively, these findings indicate that incorporating highly adaptable aHz crosslinks enhanced regenerative outcomes. However, connected networks containing more stable bHz bonds were required to achieve the highest quality neocartilaginous tissue.Statement of SignificanceCovalently crosslinked hydrogels provide robust mechanical support for cartilage tissue engineering applications in articulating joints. However, these materials traditionally demonstrate purely elastic responses to deformation despite the dynamic viscoelastic properties of native cartilage tissue. Here, we present hydrazone poly(ethylene glycol) hydrogels with tunable viscoelastic properties and study covalent adaptable networks for cartilage tissue engineering. Using hydrazone equilibrium and Flory-Stockmayer theory we identified average relaxation times leading to enhanced regenerative outcomes and showed that extracellular matrix deposition was biphasic as a function of the hydrazone covalent adaptability. We also showed that the incorporation of highly adaptable covalent crosslinks could improve cellularity of neotissue, but that a percolating network of more stable bonds was required to maintain scaffold integrity and form the highest quality neocartilaginous tissue.Graphical abstractGraphical abstract for this article
       
  • Lipid-hyaluronan synergy strongly reduces intrasynovial tissue boundary
           friction
    • Abstract: Publication date: Available online 10 November 2018Source: Acta BiomaterialiaAuthor(s): Weifeng Lin, Reut Mashiah, Jasmine Seror, Assaf Kadar, Oleg Dolkart, Tamir Pritsch, Ronit Goldberg, Jacob Klein Hyaluronan (HA)-lipid layers on model (mica) surfaces massively reduce friction as the surfaces slide past each other, and have been proposed, together with lubricin, as the boundary layers accounting for the extreme lubrication of articular cartilage. The ability of such HA-lipid complexes to lubricate sliding biological tissues has not however been demonstrated. Here we show that HA-lipid layers on the surface of an intrasynovial tendon can strongly reduce the friction as the tendon slides within its sheath. We find a marked lubrication synergy when combining both HA and lipids at the tendon surface, relative to each component alone, further enhanced when the polysaccharide is functionalized to attach specifically to the tissue. Our results shed light on the lubricity of sliding biological tissues, and indicate a novel approach for lubricating surfaces such as tendons and, possibly, articular cartilage, important, respectively, for alleviating function impairment following tendon injury and repair, or in the context of osteoarthritis.Statement of SignificanceLubrication breakdown between sliding biological tissues is responsible for pathologies ranging from dry eye syndrome to tendon-injury repair impairment and osteoarthtritis. These are increasing with human longevity and impose a huge economic and societal burden. Here we show that synergy of hyaluronan and lipids, molecules which are central components of synovial joints and of the tendon/sheath system, can strongly reduce friction between sliding biological tissues (the extrasynovial tendon sliding in its sheath), relative to untreated tissue or to either component on its own. Our results point to the molecular origins of the very low friction in healthy tendons and synovial joints, as well as to novel treatments of lubrication breakdown in these organs.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Surface modifications and oxidative degradation in
           MPC-grafted highly cross-linked polyethylene liners retrieved from
           
    • Abstract: Publication date: Available online 10 November 2018Source: Acta BiomaterialiaAuthor(s): Shine Tone, Masahiro Hasegawa, Leonardo Puppulin, Giuseppe Pezzotti, Akihiro Sudo
       
  • Glass-ceramics for cancer treatment: So close, or yet so far'
    • Abstract: Publication date: Available online 9 November 2018Source: Acta BiomaterialiaAuthor(s): Marta Miola, Yousef Pakzad, Sara Banijamali, Saeid Kargozar, Chiara Vitale-Brovarone, Abolfazl Yazdanpanah, Oana Bretcanu, Arash Ramedani, Enrica Vernè, Masoud Mozafari After years of research on the ability of glass-ceramics in bone regeneration, this family of biomaterials has shown revolutionary potentials in a couple of emerging applications such as cancer treatment. Although glass-ceramics have not yet reached their actual potential in cancer therapy, the relevant research activity is significantly growing in this field. It has been projected that this idea and the advent of magnetic bioactive glass-ceramics and mesoporous bioactive glasses could result in major future developments in the field of cancer. Undoubtedly, this strategy needs further developments to better answer the critical questions essential for the clinical usage. This review aims to address the existing research developments on glass-ceramics for cancer treatment, starting with the current status and moving to the future advances.Statement of SignificanceAlthough glass-ceramics have not yet reached their potential in cancer therapy, research activity is significantly growing. It has been speculated that this idea and the advent of modern glass-ceramics could result in significant future advances. Undoubtedly, this strategy needs further investigations and many critical questions have to be answered before it can be successfully applied for cancer treatment. This paper reviews the current state-of-the-art, starting with current products and moving onto recent developments in this field. . According to our knowledge, there is a lack of a systematic review on the importance and developments of magnetic bioactive glass-ceramics and mesoporous bioactive glasses for cancer treatment, and it is expected that this review will be of interest to those working in this area.Graphical abstractGraphical abstract for this article
       
  • Dynamic control of hydrogel crosslinking via sortase-mediated reversible
           transpeptidation
    • Abstract: Publication date: Available online 8 November 2018Source: Acta BiomaterialiaAuthor(s): Matthew R. Arkenberg, Dustin M. Moore, Chien-Chi Lin Cell-laden hydrogels whose crosslinking density can be dynamically and reversibly tuned are highly sought-after for studying pathophysiological cellular fate processes, including embryogenesis, fibrosis, and tumorigenesis. Special efforts have focused on controlling network crosslinking in poly(ethylene glycol) (PEG) based hydrogels to evaluate the impact of matrix mechanics on cell proliferation, morphogenesis, and differentiation. In this study, we sought to design dynamic PEG-peptide hydrogels that permit cyclic/reversible stiffening and softening. This was achieved by utilizing reversible enzymatic reactions that afford specificity, biorthogonality, and predictable reaction kinetics. To that end, we prepared PEG-peptide conjugates to enable sortase A (SrtA) induced tunable hydrogel crosslinking independent of macromer contents. Uniquely, these hydrogels can be completely degraded by the same enzymatic reactions and the degradation rate can be tuned from hours to days. We further synthesized SrtA-sensitive peptide linker (i.e., KCLPRTGCK) for crosslinking with 8-arm PEG-norbornene (PEG8NB) via thiol-norbornene photocrosslinking. These hydrogels afford diverse softening paradigms through control of network structures during crosslinking or by adjusting enzymatic parameters during on-demand softening. Importantly, user-controlled hydrogel softening promoted spreading of human mesenchymal stem cells (hMSCs) in 3D. Finally, we designed a bis-cysteine-bearing linear peptide flanked with SrtA substrates at the peptide’s N- and C-termini (i.e., NH2-GGGCKGGGKCLPRTG-CONH2) to enable cyclic/reversible hydrogel stiffening/softening. We show that matrix stiffening and softening play a crucial role in growth and chemoresistance in pancreatic cancer cells. These results represent the first dynamic hydrogel platform that affords cyclic gel stiffening/softening based on reversible enzymatic reactions. More importantly, the chemical motifs that affords such reversible crosslinking were built-in on the linear peptide crosslinker without any post-synthesis modification.Statement of SignificanceCell-laden ‘dynamic’ hydrogels are typically designed to enable externally stimulated stiffening or softening of the hydrogel network. However, no enzymatic reaction has been used to reversibly control matrix crosslinking. The application of SrtA-mediated transpeptidation in crosslinking and post-gelation modification of biomimetic hydrogels is innovative because of the specificity of the reaction and reversible tunability of crosslinking kinetics. While SrtA has been previously used to crosslink and fully degrade hydrogels, matrix softening and reversible stiffening of cell-laden hydrogels has not been reported. By designing simple peptide substrates, this unique enzymatic reaction can be employed to form a primary network, to gradually soften hydrogels, or to reversibly stiffen hydrogels. As a result, this dynamic hydrogel platform can be used to answer important matrix-related biological questions that are otherwise difficult to address.Graphical abstractGraphical abstract for this article
       
  • Construction of a biodegradable, versatile nanocarrier for optional
           combination cancer therapy
    • Abstract: Publication date: Available online 7 November 2018Source: Acta BiomaterialiaAuthor(s): Jia Wen, Yinghua Lv, Yongqian Xu, Pengfei Zhang, Hongjuan Li, Xiaoxu Chen, Xueliang Li, Lingkai Zhang, Fengyu Liu, Wenxian Zeng, Shiguo Sun A novel biodegradable versatile nanocarrier (FA-CM) was fabricated based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2) for optional combination cancer therapy. Biodegradation, versatility, targeting, bioimaging, in vitro cytotoxicity and in vivo antitumor efficacy were evaluated. The results showed that FA-CM could not only be effectively degraded into Co2+, Al3+ and Mn2+ to overcome the long-term toxic side effects, but also successfully load any positive-charged, negative-charged, hydrophilic, and hydrophobic drug, meeting the critical requirement of versatile nanocarrier. Meanwhile, the presence of FA led to the higher uptake efficiency, cytotoxicity, and excellent fluorescence imaging of FA-CM toward cancerous cells. In particular, FA-CM exhibited glutathione and pH dual-response drug release, avoiding any premature leakage and side effects. The applicability of the FA-CM was determined by co-loading hydrophilic (doxorubicin (DOX)) and hydrophobic drug (paclitaxel (PTX)) for synergistic combination chemotherapy. In vitro cytotoxicity evaluation and a xenograft tumor model of hepatoma showed that this combination exhibited more efficient anticancer effects compared with either free drug alone or the corresponding cocktail solutions. Especially, the ratios of DOX and PTX loaded on FA-CM could be tuned as needed. A powerful approach is provided for the design and preparation of a biodegradable versatile nanocarrier with targeted ability and excellent biocompatibility, which can be potentially applied in clinical practice and medical imaging.Statement of SignificanceDrug delivery nanocarriers that can transport an effective dosage of drug molecules to targeted cells and tissues have been extensively designed to overcome the adverse side effects and low effectiveness of conventional chemotherapy. However, lack of biodegradability and versatility existing in majority of nanocarriers limit their further clinical applications. Thus, constructing a novel biodegradable versatile nanocarrier that can carry various types of drugs, is in urgent need and more suitable for commercial production and clinical use. In this study, we developed a novel biodegradable versatile nanocarrier (FA-CM) based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2) for optional combination cancer therapy. This work provides a new strategy for constructing versatile biodegradable platform for targeted drug delivery, which would have broad applications in cancer theranostics.Graphical abstractGraphical abstract for this article
       
  • Mammary Fibroblasts Remodel Fibrillar Collagen Microstructure in a
           Biomimetic Nanocomposite Hydrogel
    • Abstract: Publication date: Available online 7 November 2018Source: Acta BiomaterialiaAuthor(s): Chun Liu, Benjamin Chiang, Daniela Lewin Mejia, Kathryn E. Luker, Gary D. Luker, Andre Lee Architecture and microstructure of type I collagen fibers constitute central regulators of tumor invasion with aligned fibers providing a route for migration of stromal and cancer cells. Several different aspects of fibrillar collagen, such as stiffness, density, thickness, and pore size, may regulate migration of cancer cells, but determining effects of any one parameter requires clear decoupling of physical properties of collagen networks. The objective of this work is to develop and apply an in vitro three-dimensional (3D) tumor-extra cellular matrix (ECM) model with tunable physical parameters to define how stromal fibroblasts modulate collagen microstructure to control migration of breast cancer cells. We incorporated two different types of polyhedral oligomeric silsesquioxane (POSS) nano-molecules into a collagen/alginate matrix to induce different mechanisms of gelling. The resultant biomimetic, nanocomposite hydrogels show different collagen fibrillar microstructures while maintaining constant overall matrix stiffness, density, and porosimetry. Spheroids of human mammary fibroblasts embedded in these 3D matrices remodel the collagen network to varying extents based on differences in underlying matrix microstructures. The remodeled collagen matrix shows oriented, thicker fibrillar tracks, facilitating invasion of tumor cells. By decoupling effects of matrix stiffness and architecture, our nanocomposite hydrogels serve as robust platforms to investigate how biophysical properties of tumor environments control key processes regulating tumor progression in breast cancer and other malignancies.Statement of SignificanceOur manuscript demonstrates a new type of nanocomposite hydrogel with two different gelling mechanisms, produced by incorporating two types of Polyhedral oligomeric silsesquioxane (POSS) nano-molecules into a collagen/alginate matrix. The resultant biomimetic hydrogels show different fibrillar collagen microstructures while maintaining constant overall matrix stiffness, density, and porosimetry. These gels allow us to uncouple effects of matrix stiffness versus architecture on migration and invasion of breast cancer cells and stromal fibroblasts. Upon embedding spheroids of human mammary fibroblasts (HMFs) and dissociated 231 breast cancer cells, we showed that HMFs remodeled the collagen network to differing extents dependent on starting matrix microstructures in each hydrogel. The remodeled collagen matrix showed aligned collagen fibers perpendicular to the surface of a spheroid with migrating HMFs following these fibers as occurs in tumors in vivo. To our knowledge, this is the first study showing significant different fibrillar collagen microstructures with constant collagen density and gel stiffness. This study establishes a new type of nanocomposite 3D hydrogels for studies of biophysical and cellular interactions in engineered tumor environments.Graphical abstractGraphical abstract for this article
       
  • Suicide-Gene Transfection of Tumor-tropic Placental Stem Cells employing
           Ultrasound-Responsive Nanoparticles
    • Abstract: Publication date: Available online 7 November 2018Source: Acta BiomaterialiaAuthor(s): Juan L. Paris, Paz de la Torre, M. Victoria Cabañas, Miguel Manzano, Ana I. Flores, María Vallet-Regí A Trojan-horse strategy for cancer therapy employing tumor-tropic mesenchymal stem cells transfected with a non-viral nanovector is here presented. In this sense, ultrasound-responsive mesoporous silica nanoparticles were coated with a polycation (using two different molecular weights), providing them with gene transfection capabilities that were evaluated using two different plasmids. First, the expression of Green Fluorescent Protein was analyzed in Decidua-derived Mesenchymal Stem Cells after incubation with the silica nanoparticles. The most successful nanoparticle was then employed to induce the expression of two suicide genes: cytosine deaminase and uracil phosphoribosyl transferase, which allow the cells to convert a non-toxic pro-drug (5-fluorocytosine) into a toxic drug (5-Fluorouridine monophosphate). The effect of the production of the toxic final product was also evaluated in a cancer cell line (NMU cells) co-cultured with the transfected vehicle cells, Decidua-derived Mesenchymal Stem Cells.Statement of SignificanceCell-mediated cancer therapy has recently attracted great interest. Tumor-homing cells can exert anticancer effects through innate capacities, via transfection with a therapeutic gene or acting as vehicles of therapeutic nanoparticles. In this work, an ultrasound-responsive mesoporous silica nanoparticle (capable of carrying an anticancer drug) is engineered to act as a non-viral transfection agent for tumor-tropic human placental mesenchymal stem cells. The successful transfection of the vehicle cells is evaluated employing different expression plasmids. After transfection with two suicide genes, the vehicle cells are capable of converting a non-toxic pro-drug into a highly toxic molecule, which can also kill surrounding cancer cells in an in vitro co-culture model. This work opens the gate for a plethora of strategies in which both genes and drug-loaded nanoparticles can be transported towards tumor tissues by easily available human mesenchymal stem cells.Graphical abstractGraphical abstract for this article
       
  • Isocyanate-terminated urethane-based dental adhesive bridges dentinal
           matrix collagen with adhesive resin
    • Abstract: Publication date: Available online 7 November 2018Source: Acta BiomaterialiaAuthor(s): Rongchen Xu, Fan Yu, Li Huang, Wei Zhou, Yan Wang, Fu Wang, Xiang Sun, Gang Chang, Ming Fang, Ling Zhang, Fang Li, Franklin Tay, Lina Niu, Jihua Chen Commercially available dental adhesives fail to chemically unite the demineralized collagen matrix with resinous materials within the resin-dentin interface. Sub-micron separations between the collagen fibrils and polymerized resin provide the backdrop for bond deterioration. Here, novel isocyanate-terminated urethane methacrylate precursors (UMP) were synthesized with the capacity to bond chemically to dentin collagen via covalent and hydrogen bonds. Collagen grafted with UMP also copolymerized with other methacrylate resin monomers, thereby producing a monoblock of chemically-linked biocomposite. The viscosity, degree of conversion and biocompatibility of UMP are comparable with commercially available resin monomers. An experimental adhesive containing 40% UMP demonstrated co-polymerization capability, good infiltration capacity and achieved higher immediate bond strength to dentin than the control commercially available adhesive. Improvement of dentin bonding by incorporation of UMP into dentin adhesives justifies future evaluation of the potential of these UMP-based adhesives in extending the longevity of resin-dentin bonds.Statement of SignificanceComposite-adhesive restorations have become an indispensable treatment modality in contemporary restorative dentistry. While the inability of these adhesives to bond chemically with collagen undermines the bond quality. This study describes a novel isocyanate-terminated urethane-multi-methacrylate precursors (UMP) which can bridge dentinal matrix collagen with adhesive resin by covalent and hydrogen bonds. Furthermore, an experimental UMP-based adhesive shows better co-polymerization capability, good infiltration capacity and higher immediate bond strength than the putatively effective adhesive Single Bond 2. The new chemical bonding mechanism based on UMP would theoretically produce more stable bonding interface that are more resistant to degradation.Graphical abstractGraphical abstract for this article
       
  • Biomaterials and Glia: Progress on Designs to Modulate Neuroinflammation
    • Abstract: Publication date: Available online 7 November 2018Source: Acta BiomaterialiaAuthor(s): C. Tsui, K. Koss, M.A. Churchward, K.G. Todd Microglia are multi-functional cells that play a vital role in establishing and maintaining the function of the nervous system and determining the fate of neurons following injury or neuropathology. The roles of microglia are diverse and essential to the capacity of the nervous system to recover from injury, however sustained inflammation can limit recovery and drive chronic disease processes such as neurodegenerative disorders. When assessing implantable therapeutic devices in the central nervous system, an improved lifetime of the implant is considered achievable through the attenuation of microglial inflammation. Consequently, there is a tremendous underexplored potential in biomaterial and engineered design to modulate neuroinflammation for therapeutic benefit. Several strategies for improving device compatibility reviewed here include: biocompatible coatings, improved designs in finer and flexible shapes to reduce tissue shear-related scarring, and loading of anti-inflammatory drugs. Studies about microglial cell cultures in 3D hydrogels and nanoscaffolds to assess various injuries and disorders are also discussed. A variety of other microglia-targeting treatments are also reviewed, including nanoparticulate systems, cellular backpacks, and gold plinths, with the intention of delivering anti-inflammatory drugs by targeting the phagocytic nature of microglia. Overall, this review highlights recent advances in biomaterials targeting microglia and inflammatory function with the potential for improving implant rejection and biocompatibility studies.Statement of SignificanceMicroglia are the resident immune cells of the central nervous system, and thus play a central role in the neuroinflammatory response against conditions than span acute injuries, neuropsychiatric disorders, and neurodegenerative disorders. This review article presents a summary of biomaterials research that target microglia and other glial cells in order to attenuate neuroinflammation, including but not limited to: design of mechanically compliant and biocompatible stimulation electrodes, hydrogels for high-throughput 3D modelling of nervous tissue, and uptake of nanoparticle drug delivery systems. The goal of this paper is to identify strengths and gaps in the relevant literature, and to promote further consideration of microglia behaviour and neuroinflammation in biomaterial design.Graphical abstractGraphical abstract for this article
       
  • Backside wear in acetabular hip joint replacement
    • Abstract: Publication date: Available online 5 November 2018Source: Acta BiomaterialiaAuthor(s): Steffen Braun, Robert Sonntag, Stefan Schroeder, Ulrike Mueller, Sebastian Jaeger, Jan Philippe Kretzer IntroductionBesides head-insert articulation in hip joint replacements, micro-motions between the backside of assembled polyethylene acetabular liners and the metal cup may cause additional wear. Pelvic osteolysis frequently occurs in the region of screw holes, and cup loosening hints to clinically relevant amounts of polyethylene backside wear. It has yet to be confirmed whether backside wear particles differ in size and morphology compared to articulating wear. Previous methods have been limited to subjective assessment of backside surface damages without consideration of wear debris. The aim of this study was to develop and validate a method for quantitative in vitro measurements of polyethylene backside wear in artificial hip cups and to characterize these wear particles for the first time.MethodsTitanium cup-systems (Plasmafit®Plus7, Aesculap, UHMWPE liner) were sinusoidally loaded (2.5kN) and a torque of 5Nm was simultaneously applied. The front and rear side of the cup were separated to isolate backside wear. After 2 x 106 cycles the surrounding fluid was filtered and a particle analysis was performed.ResultsBackside wear had a particles size of 64.1 ± 1.9 nm and was verified as round and oval particles with partly rough outlines. An estimated total number of particles of 1.26 x 109 ± 1.67 x 108 per 106 cycles was determined.ConclusionBackside wear was estimated to be several times lower than published values of articulating wear. However, polyethylene backside wear particles represented significantly smaller particles with partly roughened outlines than articulating wear particles and may therefore cause higher biological response in macrophage-mediated bone resorption compared to articulated particles.Graphical abstractGraphical abstract for this article
       
  • Mineralization in Micropores of Calcium Phosphate Scaffolds
    • Abstract: Publication date: Available online 5 November 2018Source: Acta BiomaterialiaAuthor(s): Laurence E. Rustom, Michael J. Poellmann, Amy J. Wagoner Johnson With the increasing demand for novel bone repair solutions that overcome the drawbacks of current grafting techniques, the design of artificial bone scaffolds is a central focus in bone regeneration research. Calcium phosphate scaffolds are interesting given their compositional similarity with bone mineral. The majority of studies focus on bone growth in the macropores (> 100 microns) of implanted calcium phosphate scaffolds where bone structures such as osteons and trabeculae can form. However, a growing body of research shows that micropores (< 50 microns) play an important role not only in improving bone growth in the macropores, but also in providing additional space for bone growth. Bone growth in the micropores of calcium phosphate scaffolds offers major mechanical advantages as it improves the mechanical properties of the otherwise brittle materials, further stabilizes the implant, improves load transfer, and generally enhances osteointegration. In this paper, we review evidence in the literature of bone growth into micropores, emphasizing on identification techniques and conditions under which bone components are observed in the micropores. We also review theories on mineralization and propose mechanisms, mediated by cells or not, by which mineralization may occur in the confined micropore space of calcium phosphate scaffolds. Understanding and validating these mechanisms will allow to better control and enhance mineralization in micropores to improve the design and efficiency of bone implants.Statement of SignificanceThe design of synthetic bone scaffolds remains a major focus for engineering solutions to repair damaged and diseased bone. Most studies focus design of and growth in macropores (> 100 microns), however research increasingly shows the importance of microporosity (< 50 microns). Micropores provide an additional space for bone growth, which provides multiple mechanical advantages to the scaffold/bone composite. Here, we review evidence in of bone growth into micropores in calcium phosphate scaffolds and conditions under which growth occurs in micropores, and propose mechanisms that enable or facilitate growth in these pores. Understanding these mechanisms will allow researchers to exploit them and improve the design and efficiency of bone implants.Graphical abstractGraphical abstract for this article
       
  • In vivo self-assembly of small diameter pulmonary visceral pleura artery
           graft
    • Abstract: Publication date: Available online 3 November 2018Source: Acta BiomaterialiaAuthor(s): Xiao Lu, Ling Han, Ghassan S. Kassab BackgroundThere is a significant clinical need for small vascular grafts < 1 mm in diameter.Materials and MethodsThe structure and composition of swine pulmonary visceral pleura (PVP) were investigated. Two processes, glutaraldehyde (GA) crosslink and decellularization (dc) plus GA crosslink, were used to inhibit the immune response. The thrombosis-resistance of the GA-crosslinked PVP (GA-PVP) was determined with in vitro and in vivo studies. Small vessel grafts with 0.7 diameter mm were constructed using the GA-PVP and surgically interposed in the femoral artery of rats for up to 24 weeks. Blood flow in the GA-PVP grafts were measured and ex vivo vascular reactivity of the prostheses were evaluated along with immuno-histological analysis.ResultsThe GA-PVP mesothelium contains abundant glycocalyx-like substance and a smooth surface. The mechanical properties of the GA-PVP were similar to the femoral artery of rat in the range of physiological pressures. The in vitro and in vivo studies confirmed poor platelet adhesion on the GA-PVP mesothelial surface in comparison with dc processed PVP (dc-PVP). Patency of the GA-PVP prostheses in femoral arteries of rats was 86% in the 24 weeks postoperative period while patency of dc-PVP in femoral arteries of rats was 33% at 1week postoperative period. Blood flow in the GA-PVP prostheses were not statistically different than the contralateral femoral artery. Biomarkers of neo-endothelial cells, neo-media smooth muscle cells, and extracellular matrices were observed in the GA-PVP prostheses. The significant agonists-induced vasoconstriction and endothelium-dependent vasodilation were apparent at 12 weeks and further amplified in the 24 weeks postoperative, which suggests self-assembly of functional neo-endothelium and neo-media.ConclusionsThe high patency and functionality of the small grafts suggest that the GA-PVP is a promising prosthetic biomaterial for vascular reconstructions.Statement of SignificanceSmall artery graft (diameter < 1 mm) in the peripheral circulation that functionally arterializes has not been possible primarily due to thrombosis. Our findings indicate that lung visceral pleura may address thrombogenicity as the major pitfall in small diameter grafts. Here, grafts of 0.7 mm diameter were constructed from swine pulmonary visceral pleura (PVP) and implanted into femoral artery position of rats up to 24 weeks. The total patency of grafts in femoral arteries of rats was 86% in the 24-week period. The neo-endothelial and –medial layers were assembled in the grafts as evidenced by robust biomarkers of endothelial cells, smooth muscle cells, and extracellular matrices observed in the grafts. Agonists-induced vasoconstriction and endothelium-dependent vasodilation were apparent at 12 weeks and were amplified at 24 weeks. The high patency of the small grafts suggests that the PVP is a promising prosthetic biomaterial for vascular reconstructions.Graphical abstractGraphical abstract for this article
       
  • A stabilized retro-inverso peptide ligand of transferrin receptor for
           enhanced liposome-based hepatocellular carcinoma-targeted drug delivery
    • Abstract: Publication date: Available online 3 November 2018Source: Acta BiomaterialiaAuthor(s): Jiajing Tang, Qiantao Wang, Qianwen Yu, Yue Qiu, Ling Mei, Dandan Wan, Xuhui Wang, Man Li, Qin He The application of tumor targeting ligands to the treatment of cancer holds promise for improving efficacy and reducing toxicity. LT7 (L(HAIYPRH)) peptide, a phage display-selected peptide, exhibited high binding affinity to transferrin receptor (TfR) overexpressed on tumor cells. However, its in vivo tumor targeting efficiency was impaired due to enzymatic degradation in blood circulation. To improve the stability and targeting ability, a retro-inverso analogue of LT7 peptide, named DT7 peptide (D(HRPYIAH)), was designed for targeted therapy of hepatocellular carcinoma. The result of computer simulation predicted that DT7 bound to TfR protein more efficiently than LT7, and this prediction was confirmed experimentally by surface plasmon resonance (SPR). Ex vivo stability experiment demonstrated that DT7 possessed stronger ability against proteolysis than LT7 in fresh mouse serum. We further prepared DT7-, LT7-, and transferrin (Tf)-modified liposomes (DT7-LIP, LT7-LIP, and Tf-LIP, respectively). DT7-LIP showed a significantly stronger in vitro targeting ability than LT7-LIP and Tf-LIP under normal condition and simulated biological condition. In addition, the in vitro antitumor effect of DTX-loaded DT7-LIP was markedly enhanced in comparison to DTX-loaded LT7-LIP and DTX-loaded Tf-LIP. In vivo imaging indicated that DT7-LIP had better tumor accumulation than LT7-LIP and Tf-LIP. For in vivo antitumor studies, the tumor growth rate of mice treated with DTX-loaded DT7-LIP was significantly inhibited compared to that in mice treated with DTX-loaded LT7-LIP and DTX-loaded Tf-LIP. Overall, this study verified the potential of the stable DT7 peptide in improving the efficacy of docetaxel in the treatment of hepatocellular carcinoma.Statement of significanceA phage display library-selected LT7 (L(HAIYPRH)) peptide exhibited high affinity to transferrin receptor (TfR). However, its bioactivity was impaired in vivo as L-peptides are susceptible to degradation by proteolytic enzymes. Here, we designed a retro-inverso peptide DT7(D(HRPYIAH)) and demonstrated its increased serum stability and higher binding affinity to TfR. A stabilized targeted drug delivery system was further constructed by modified DT7 peptide on the surface of liposomes. The data indicated that DT7 peptide-modified liposomes exhibited higher targeting ability in vitro and in vivo. More importantly, DT7-modified liposomes demonstrated positive preclinical significance in enhancing the therapeutic effects against hepatocellular carcinoma.Graphical abstractGraphical abstract for this article
       
  • Chitosan-based Sleeves Loaded with Silver and Chlorhexidine in a
           Percutaneous Rabbit Tibia Model with Repeated Bacterial Challenge
    • Abstract: Publication date: Available online 17 October 2018Source: Acta BiomaterialiaAuthor(s): Jinlong Shao, Bing Wang, Carla J.M. Bartels, Ewald M. Bronkhorst, John A. Jansen, X. Frank Walboomers, Fang Yang Various strategies have been explored to prevent pin tract infections (PTI), including the use of antibacterial sleeves. However, an ideal animal model to evaluate the efficacy of antibacterial strategies is still lacking. This study aimed to construct an animal model with a consistent induction of infection after bacterial challenge. Further, the efficacy of silver and chlorhexidine loaded chitosan sleeves was evaluated to prevent PTI around a percutaneous implant. Titanium pins wrapped with sleeves were implanted in anterior lateral rabbit tibia. After two weeks, Staphylococcus aureus suspensions (1 × 106 CFU) were injected weekly to the exit site, and the clinical infection status was recorded. After six weeks, all rabbits were euthanized to evaluate the bacterial colonization microbiologically and histomorphometrically. Results showed that the implant screw bilaterally penetrated the tibia and kept the implant stable. A rod length of twice the thickness of the soft-tissue layer was necessary to maintain the percutaneous penetration of the implants. A 100% infection rate was obtained by the bacterial inoculation. Silver loaded sleeves reduced significantly the bacterial density and reduced the inflammatory symptoms of the percutaneous pin tract. However, the addition of chlorhexidine to the sleeves had no added value in terms of further reduction of bacteria and inflammation. In conclusion, a consistent animal model was designed to evaluate strategies to prevent PTI. In addition, the use of silver loaded chitosan sleeves can be pursued for further (pre-)clinical exploration for the prevention of PTI.Statement of SignificanceThis study constructed a bacterial challenged percutaneous rabbit tibia model to evaluate the potential of antibacterial strategies for the prevention of pin tract infections. The model was applied to evaluate a silver and chlorhexidine loaded membranes as an antibacterial sleeve. Our results demonstrate that the rabbit tibia model is suitable to evaluate antibacterial strategies for the prevention of pin tract infection as evidenced by the stable, bone fixed percutaneous implant and a 100% infection rate of the percutaneous pin tract. Silver loaded sleeves can lower the bacterial density of the percutaneous pin tract, but the addition of chlorhexidine to the silver-loaded sleeves does not contribute to an enhanced antibacterial effect. Such experiments are of considerable interest to those in the research community, industry, and clinicians involved the occurrence of infection of skin penetrating medical devices.Graphical abstractGraphical abstract for this article
       
  • Effect of working environment and procedural strategies on mechanical
           performance of bioresorbable vascular scaffolds
    • Abstract: Publication date: Available online 17 October 2018Source: Acta BiomaterialiaAuthor(s): Pei-Jiang Wang, Farhad Rikhtegar Nezami, Maysam B. Gorji, Francesca Berti, Lorenza Petrini, Tomasz Wierzbicki, Francesco Migliavacca, Elazer R. Edelman Polymeric bioresorbable scaffolds (BRS), at their early stages of invention, were considered as a promising revolution in interventional cardiology. However, they failed dramatically compared to metal stents showing substantially higher incidence of device failure and clinical events, especially thrombosis. One problem is that use of paradigms inherited from metal stents ignores dependency of polymer material properties on working environment and manufacturing/deployment steps. Unlike metals, polymeric material characterization experiments cannot be considered identical under dry and submerged conditions at varying rates of operation.We demonstrated different material behaviors associated with variable testing environment and parameters. We, then, have employed extracted material models, which are verified by computational methods, to assess the performance of a full-scale BRS in different working condition and under varying procedural strategies. Our results confirm the accepted notion that slower rate of crimping and inflation can potentially reduce stress concentrations and thus reduce localized damages. However, we reveal that using a universal set of material properties derived from a benchtop experiment conducted regardless of working environment and procedural variability may lead to a significant error in estimation of stress-induced damages and overestimation of benefits procedural updates might offer.We conclude that, for polymeric devices, microstructural damages and localized loss of structural integrity should complement former macroscopic performance-assessment measures (fracture and recoil). Though, to precisely capture localized stress concentration and microstructural damages, context-related testing environment and clinically-relevant procedural scenarios should be devised in preliminary experiments of polymeric resorbable devices to enhance their efficacy and avoid unpredicted clinical events.Statement of SignificanceBioresorbable scaffolds (BRS) with the hope to become the next cardiovascular interventional revolution failed in comparison to metal stents. When BRS were characterized using methods for metal stents, designers were misled to seek problem sources at erroneous timeframe and use inefficient indicators, and thus no signal of concern emerged. We demonstrated fundamental flaws associated with applying a universal set of material properties to study device performances in different phases of manufacturing/implantation, and these may be responsible for failure in predicting performance in first-generation BRS. We introduced new criterion for the assessment of structural integrity and device efficacy in next-generation BRS, and indeed all devices using polymeric materials which evolve with the environment they reside in.Graphical abstractGraphical abstract for this article
       
  • Pharmacokinetics and efficacy of orally administered polymeric chloroquine
           as macromolecular drug in the treatment of inflammatory bowel disease
    • Abstract: Publication date: Available online 17 October 2018Source: Acta BiomaterialiaAuthor(s): Shrey Kanvinde, Yashpal Singh Chhonker, Rizwan Ahmad, Fei Yu, Richard Sleightholm, Weimin Tang, Lee Jaramillo, Yi Chen, Yuri Sheinin, Jing Li, Daryl J. Murry, Amar B. Singh, David Oupický Inflammatory bowel disease is a chronic inflammation of the gastrointestinal tract with poor understanding of its pathogenesis and no effective cure. The goal of this study was to evaluate the feasibility of orally administered non-degradable polymeric chloroquine (pCQ) to locally reduce colon inflammation. The pCQ was synthesized by radical copolymerization of N-(2-hydroxypropyl)methacrylamide with methacryloylated hydroxychloroquine (HCQ). The anti-inflammatory activity of orally administered pCQ versus HCQ was tested in a mouse model of colitis induced by Citrobacter rodentium (C. rodentium). Single-dose pharmacokinetic and biodistribution studies performed in the colitis model indicated negligible systemic absorption (p ≤ 0.001) and localization of pCQ in the gastrointestinal tract. A multi-dose therapeutic study demonstrated that the localized pCQ treatment resulted in significant reduction in the colon inflammation (p ≤ 0.05). Enhanced suppression of pro-inflammatory cytokines IL-6 (p ≤ 0.01) and IL1-β and opposing upregulation of IL-2 (p ≤ 0.05) recently reported to be involved in downstream anti-inflammatory events suggested that the anti-inflammatory effects of the pCQ are mediated by altering mucosal immune homeostasis. Overall, the reported findings demonstrate a potential of pCQ as a novel polymer therapeutic option in inflammatory bowel disease with the potential of local effects and minimized systemic toxicity.Statement of SignificanceInflammatory bowel disease is a chronic localized inflammation of the gastrointestinal tract with no effective cure. Despite being widely researched in anti-inflammatory studies, chloroquine has limited application in inflammatory bowel disease due to its limitations in chronic administration setting due to high systemic absorption related side effects. Various studies have shown that the local gastrointestinal accumulation can be improved by using polymeric drugs. The reported study provides quantitative data relating to the applicability of non-degradable polymeric chloroquine as a local therapy of inflammatory bowel disease. The main significance of this study is in the design of novel macromolecular agents for oral, locally acting anti-inflammatory therapies.Graphical abstractGraphical abstract for this article
       
 
 
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