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  Subjects -> BIOLOGY (Total: 3211 journals)
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    - BIOLOGY (1536 journals)
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BIOLOGY (1536 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: 25)
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: 28)
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: 11)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis     Open Access   (Followers: 1)
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: 26)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 13)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
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: 10)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 4)
Advances in Life Science and Technology     Open Access   (Followers: 18)
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: 2)
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: 21)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Hybrid Journal   (Followers: 18)
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: 15)
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: 16)
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)
Anadol University Journal of Science and Technology B : Theoritical Sciences     Open Access  
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: 13)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 24)
Annual Review of Cancer Biology     Full-text available via subscription   (Followers: 1)
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: 14)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 25)
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: 9)
Applied Biology     Open Access  
Applied Bionics and Biomechanics     Open Access   (Followers: 7)
Applied Vegetation Science     Full-text available via subscription   (Followers: 10)
Aquaculture Environment Interactions     Open Access   (Followers: 4)
Aquaculture International     Hybrid Journal   (Followers: 26)
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: 7)
Archives of Oral Biology     Hybrid Journal   (Followers: 3)
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: 7)
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: 5)
Biofilms     Full-text available via subscription   (Followers: 1)
Biogeosciences (BG)     Open Access   (Followers: 9)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 2)
Bioinformatics     Hybrid Journal   (Followers: 330)
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: 22)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 18)

        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: 28  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1742-7061
Published by Elsevier Homepage  [3161 journals]
  • Hypoxia impacts human MSC response to substrate stiffness during
           chondrogenic differentiation
    • Abstract: Publication date: Available online 4 March 2019Source: Acta BiomaterialiaAuthor(s): Daniel A. Foyt, Dheraj K. Taheem, Silvia A. Ferreira, Michael D.A. Norman, Jonna Petzold, Gavin Jell, Agamemnon E. Grigoriadis, Eileen Gentleman Tissue engineering strategies often aim to direct tissue formation by mimicking conditions progenitor cells experience within native tissues. For example, to create cartilage in vitro, researchers often aim to replicate the biochemical and mechanical milieu cells experience during cartilage formation in the developing limb bud. This includes stimulating progenitors with TGF-β1/3, culturing under hypoxic conditions, and regulating mechanosensory pathways using biomaterials that control substrate stiffness and/or cell shape. However, as progenitors differentiate down the chondrogenic lineage, the pathways that regulate their responses to mechanotransduction, hypoxia and TGF-β may not act independently, but rather also impact one another, influencing overall cell response. Here, to better understand hypoxia’s influence on mechanoregulatory-mediated chondrogenesis, we cultured human marrow stromal/mesenchymal stem cells (hMSC) on soft (0.167 kPa) or stiff (49.6 kPa) polyacrylamide hydrogels in chondrogenic medium containing TGF-β3. We then compared cell morphology, phosphorylated myosin light chain 2 staining, and chondrogenic gene expression under normoxic and hypoxic conditions, in the presence and absence of pharmacological inhibition of cytoskeletal tension. We show that on soft compared to stiff substrates, hypoxia prompts hMSC to adopt more spread morphologies, assemble in compact mesenchymal condensation-like colonies, and upregulate NCAM expression, and that inhibition of cytoskeletal tension negates hypoxia-mediated upregulation of molecular markers of chondrogenesis, including COL2A1 and SOX9. Taken together, our findings support a role for hypoxia in regulating hMSC morphology, cytoskeletal tension and chondrogenesis, and that hypoxia’s effects are modulated, at least in part, by mechanosensitive pathways. Our insights into how hypoxia impacts mechanoregulation of chondrogenesis in hMSC may improve strategies to develop tissue engineered cartilage.Graphical abstractGraphical abstract for this article
       
  • Culture of hybrid spheroids composed of calcium phosphate materials and
           mesenchymal stem cells on an oxygen-permeable culture device to predict in
           vivo bone forming capability
    • Abstract: Publication date: Available online 4 March 2019Source: Acta BiomaterialiaAuthor(s): Tomoya Sato, Takahisa Anada, Ryo Hamai, Yukari Shiwaku, Kaori Tsuchiya, Susumu Sakai, Kazuyoshi Baba, Keiichi Sasaki, Osamu Suzuki Three-dimensional (3-D) cell culture can better mimic physiological conditions in which cells interact with adjacent cells and the extracellular matrix than monolayer culture. We have developed a 3-D cell culture device, the Oxy chip, which can be used to generate and supply oxygen to cell spheroids to prevent hypoxia. Here, we used the Oxy chip to generate hybrid spheroids comprising calcium phosphate (CaP) particles (hydroxyapatite (HA), β-tricalcium phosphate (β-TCP) or octacalcium phosphate (OCP)) and mesenchymal stem cells (MSCs, C3H10T1/2 cells or D1 cells) that can be used to analyze cell differentiation mechanisms. We showed that the 3-D cell-cell and cell-material interactions and oxygenation offered by the Oxy chip promoted osteoblastic differentiation of MSCs. We also used histomorphometric analysis of hematoxylin and eosin staining, quality analyses by μCT and collagen orientation observation with picrosirius red staining in bone regeneration following implantation of three CaPs in a critical-sized defect in mouse calvaria. The in vivo bone formation capacity of the three tested CaP materials was OCP ≥ β-TCP> HA: the newly formed bone by OCP had a structure relatively close to that of the calvaria intact bone. When MSCs were 3-D cultured with the CaP materials using the Oxy chip, the in vitro osteogenic capacity of these materials was highly similar to trends observed in vivo. The in vitro alkaline phosphatase activity of D1 cells had the highest correlation with in vivo bone volume (R = 0.900). Chemical and FTIR spectroscopic analyses confirmed that differentiation of D1 cells could be associated with amorphous calcium phosphate precipitation concomitant with OCP hydrolysis. Taken together, hybrid spheroid cultures using the Oxy chip can be used to screen and predict bone forming potential of bone substitute materials.Statement of SignificanceAn oxygen permeable-culture chip (Oxy chip) can be used to induce formation of cell spheroids by mesenchymal stem cells (MSCs). Use of the Oxy chip avoids hypoxia in the spheroid core and enhances MSC osteoblastic differentiation relative to conventional spheroid culture methods. The present study showed that the Oxy chip mimics the in vivo environment associated with bone formation and can be used to generate hybrid spheroids consisting of calcium phosphates and MSCs that are useful for analyzing cell differentiation mechanisms. Bone formation analysis following implantation of calcium phosphate materials in mouse calvaria defects showed positive correlation with the in vitro results. We propose that hybrid spheroids cultured on the Oxy chip can be used to screen and predict the bone forming potential of bone substitute materials.Graphical abstractGraphical abstract for this article
       
  • Regulating substrate mechanics to achieve odontogenic differentiation for
           dental pulp stem cells on TiO2 filled and unfilled polyisoprene
    • Abstract: Publication date: Available online 2 March 2019Source: Acta BiomaterialiaAuthor(s): Ya-Chen Chuang, Yingjie Yu, Ming-Tzo Wei, Chung-Chueh Chang, Vincent Ricotta, Kuan-Che Feng, Likun Wang, Aneel K. Bherwani, H. Daniel Ou-Yang, Marcia Simon, Liudi Zhang, Miriam Rafailovich We have shown that materials other than hydrogels commonly used in tissue engineering can be effective in enabling differentiation of dental pulp stem cells (DPSC). Here we demonstrate that a hydrophobic elastomer, polyisoprene (PI), a component of Gutta-percha, normally used to obturate the tooth canal, can also be used to initiate differentiation of the pulp. We showed that PI substrates without additional coating promote cell adhesion and differentiation, while their moduli can be easily adjusted either by varying the coating thickness or incorporation of inorganic particles. DPSC plated on those PI substrates were shown, using SPM and hysitron indentation, to adjust their moduli to conform to differentially small changes in the substrate modulus. In addition, optical tweezers were used to separately measure the membrane and cytoplasm moduli of DPSC, with and without Rho kinase inhibitor. The results indicated that the changes in modulus were attributed predominantly to changes within the cytoplasm, rather than the cell membrane. CLSM was used to identify cell morphology. Differentiation, as determined by qRT-PCR, of the upregulation of OCN, and COL1α1 as well as biomineralization, characterized by SEM/EDAX, was observed on hard PI substrates in the absence of induction factors, i.e. dexamethasone, with moduli 3-4 MPa, regardless of preparation. SEM showed that even though biomineralization was deposited on both spun cast thin PI and filled thick PI substrates, the minerals were aggregated into large clusters on thin PI, and uniformly distributed on filled thick PI, where it was templated within banded collagen fibers.Statement of SignificanceThis manuscript demonstrates the potential of polyisoprene (PI), an elastomeric polymer, for use in tissue engineering. We show how dental pulp stem cells adjust their moduli continuously to match infinitesimally small changes in substrate mechanics, till a critical threshold is reached when they will differentiate. The lineage of differentiation then becomes a sensitive function of both mechanics and morphology for a given chemical composition. Since PI is a major component of Gutta-percha, the FDA approved material commonly used for obturating the root canal, this work suggests that it can easily be adapted for in vivo use in dental regeneration.Graphical abstractGraphical abstract for this article
       
  • Film Interface for Drug Testing for Delivery to Cells in Culture and in
           the Brain
    • Abstract: Publication date: Available online 2 March 2019Source: Acta BiomaterialiaAuthor(s): Min D. Tang-Schomer, David L. Kaplan, Michael Whalen Brain access remains a major challenge in drug testing. The nearly ‘impermeable’ blood-brain-barrier (BBB) prevents most drugs from gaining access to brain cells via systematic intravenous (IV) injection. In this study, silk fibroin films were used as drug carrier as well as cell culture substrate to simulate the in vivo interface between drug reservoir and brain cells for testing drug delivery in the brain. In in vitro studies, film-released arabinofuranosyl cytidine (AraC), a mitotic inhibitor, selectively killed glial cells in film-supported mixed neural cell cultures; with widened dosage windows for drug efficacy and tolerance compared to drugs in solution. In the brain, the presence of silk films was well tolerated with no signs of acute neuroinflammation, cell death, or altered brain function. Topical application of silk films on the cortical surface delivered Evans blue, a BBB-impenetrable fluorescent marker, through the intact dura matter into the parenchyma of the ipsilateral hemisphere as deep as the hippocampal region, but not the contralateral hemisphere. In a mouse traumatic brain injury (TBI) model, necrosis markers by film delivery accessed more cells in the lesion core than by con-current IV delivery; whereas the total coverage including the peri-lesional area appeared to be comparable between the two routes. The complementary distribution patterns of co-delivered markers provided direct evidence of the partial confinement of either route’s access to brain cells by a restrictive zone near the lesion border. Finally, film-delivered necrostatin-1 reduced overall cell necrosis by approximately 40% in the TBI model. These findings from representative small molecules of delivery route-dependent drug access are broadly applicable for evaluating drug actions both in vitro and in vivo. Combined with its demonstrated role of supporting neuron-electrode interfaces, the film system can be further developed for testing a range of neuromodulation approaches (i.e., drug delivery, electrical stimulation, cell graft) in the brain.Statement of SignificanceThis study demonstrated that silk fibroin films can be used to evaluate drug actions both in vitro and in vivo, partially overcoming the significant delivery barriers of the brain. This system can be adapted for efficient drug access to specific brain regions and/or cell types. The film system can be further developed for testing a range of interventions with drugs, electrical signals or cell graft for analysis of treatment outcomes including cell responses and brain function.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Photoluminescent and biodegradable
           polycitrate-polyethylene glycol-polyethyleneimine polymers as highly
           biocompatible and efficient vectors for bioimaging-guided siRNA and miRNA
           delivery” [Acta Biomaterial. 54 (2017) 69–80]
    • Abstract: Publication date: Available online 2 March 2019Source: Acta BiomaterialiaAuthor(s): Min Wang, Yi Guo, Meng Yu, Peter X. Ma, Cong Mao, Bo Lei
       
  • A humanized bone microenvironment uncovers HIF2 alpha as a latent
           marker for osteosarcoma
    • Abstract: Publication date: Available online 2 March 2019Source: Acta BiomaterialiaAuthor(s): Ferdinand Wagner, Boris M. Holzapfel, Laure Martine, Jacqui McGovern, Christoph A. Lahr, Melanie Boxberg, Peter M. Prodinger, Susanne Grässel, Daniela Loessner, Dietmar W. Hutmacher The quest for predictive tumor markers for osteosarcoma (OS) has not well progressed over the last two decades due to a lack of preclinical models. The aim of this study was to investigate if microenvironmental modifications in an original humanized in vivo model alter the expression of OS tumor markers. Human bone micro-chips and bone marrow, harvested during hip arthroplasty, were implanted at the flanks of NOD/scid mice. We administered recombinant human bone morphogenetic protein 7 (rhBMP-7) in human bone micro-chips/bone marrow group I in order to modulate bone matrix and bone marrow humanization. Ten weeks post-implantation, human Luc-SAOS-2 OS cells were injected into the humanized tissue-engineered bone organs (hTEBOs). Tumors were harvested 5 weeks post-implantation to determine the expression of the previously described OS markers ezrin, periostin, VEGF, HIF1α and HIF2α. Representation of these proteins was analyzed in two different OS patient cohorts. Ezrin was downregulated in OS in hTEBOs with rhBMP-7, whereas HIF2α was significantly upregulated in comparison to hTEBOs without rhBMP-7. The expression of periostin, VEGF and HIF1α did not differ significantly between both groups. HIF2α was consistently present in OS patients and dependent on tumor site and clinical stage. OS patients post-chemotherapy had suppressed levels of HIF2α. In conclusion, we demonstrated the overall expression of OS-related factors in a preclinical model, which is based on a humanized bone organ. Our preclinical research results and analysis of two comprehensive patient cohorts imply that HIF2α is a potential prognostic marker and/or therapeutic target.Statement of Significance:This study demonstrates the clinical relevance of the humanized organ bone microenvironment in osteosarcoma research and validates the expression of tumor markers, especially HIF2α. The convergence of clinically proven bone engineering concepts for the development of humanized mice models is a new starting point for investigations of OS-related marker expression. The validation and first data set in such a model let one conclude that further clinical studies on the role of HIF2α as a prognostic marker and its potential as therapeutic target is a condition sine qua non.Graphical abstractGraphical abstract for this article
       
  • Preventing S. aureus biofilm formation on titanium surfaces by the release
           of antimicrobial β-peptides from polyelectrolyte multilayers
    • Abstract: Publication date: Available online 1 March 2019Source: Acta BiomaterialiaAuthor(s): Angélica de L. Rodríguez López, Myung-Ryul Lee, Benjamín J. Ortiz, Benjamin D. Gastfriend, Riley Whitehead, David M. Lynn, Sean P. Palecek Staphylococcus aureus infections represent the major cause of titanium based-orthopaedic implant failure. Current treatments for S. aureus infections involve the systemic delivery of antibiotics and additional surgeries, increasing health-care costs and affecting patient’s quality of life. As a step toward the development of new strategies that can prevent these infections, we build upon previous work demonstrating that the colonization of catheters by the fungal pathogen Candida albicans can be prevented by coating them with thin polymer multilayers composed of chitosan (CH) and hyaluronic acid (HA) designed to release a β-amino acid-based peptidomimetic of antimicrobial peptides (AMPs). We demonstrate here that this β-peptide is also potent against S. aureus (MBPC = 4 μg/mL) and characterize its selectivity toward S. aureus biofilms. We demonstrate further that β-peptide-containing CH/HA thin-films can be fabricated on the surfaces of rough planar titanium substrates in ways that allow mammalian cell attachment and permit the long-term release of β-peptide. β-Peptide loading on CH/HA thin-films was then adjusted to achieve release of β-peptide quantities that selectively prevent S. aureus biofilms on titanium substrates in vitro for up to 24 days and remained antimicrobial after being challenged sequentially five times with S. aureus inocula, while causing no significant MC3T3-E1 preosteoblast cytotoxicity compared to uncoated and film-coated controls lacking β-peptide. We conclude that these β-peptide-containing films offer a novel and promising localized delivery approach for preventing orthopaedic implant infections. The facile fabrication and loading of β-peptide-containing films reported here provides opportunities for coating other medical devices prone to biofilm-associated infections.Statement Of SignificanceTitanium (Ti) and its alloys are used widely in orthopaedic devices due to their mechanical strength and long-term biocompatibility. However, these devices are susceptible to bacterial colonization and the subsequent formation of biofilms. Here we report a chitosan and hyaluronic acid polyelectrolyte multilayer-based approach for the localized delivery of helical, cationic, globally amphiphilic β-peptide mimetics of antimicrobial peptides to inhibit S. aureus colonization and biofilm formation. Our results reveal that controlled release of this β-peptide can selectively kill S. aureus cells without exhibiting toxicity toward MC3T3-E1 preosteoblast cells. Further development of this polymer-based coating could result in new strategies for preventing orthopaedic implant-related infections, improving outcomes of these titanium implants.Graphical abstractGraphical abstract for this article
       
  • Polydispersity and negative charge are key modulators of extracellular
           matrix deposition under macromolecular crowding conditions
    • Abstract: Publication date: Available online 1 March 2019Source: Acta BiomaterialiaAuthor(s): Diana Gaspar, Kieran P. Fuller, Dimitrios I. Zeugolis Macromolecular crowding is a biophysical phenomenon that stems from the volume excluded by macromolecules, as they undergo steric repulsion and electrostatic interactions. The excluded volume depends on the shape, size, charge and polydispersity of the molecules. Although theoretical / computational models have been used to assess the influence of macromolecular crowding in biological media, real-time experiments are scarce. Herein, we evaluated the influence of hydrodynamic radius, charge and polydispersity of (a) various concentrations of different crowders (carrageenan, Ficoll™ and dextran sulphate); (b) various molecular weights of different crowders (70, 400 and 100 kDa of Ficoll™ and 10, 100 and 500 kDa of dextran sulphate) and (c) various cocktails of the same crowders (cocktails of various concentrations of different molecular weights Ficoll™ and dextran sulphate) on extracellular matrix deposition in human dermal fibroblast culture. The use of crowding cocktails with different molecular weight / concentrations of Ficoll™ or dextran sulphate molecules led to increased polydispersity and enhanced collagen type I deposition in comparison to their mono-domain counterparts. Carrageenan, however, induced the highest deposition of collagen type I due to its negative charge and inherent polydispersity. Our data contribute to a better understanding of the influence of the biophysical properties of the crowders on extracellular matrix deposition in vitro.Statement of SignificanceMacromolecular crowding is a biophysical phenomenon that accelerates and enhances extracellular matrix deposition in cell culture systems. Herein, we demonstrate that negatively charged and polydispersed macromolecules or cocktails of macromolecules, as opposed to neutral and monodomain macromolecules, induce highest extracellular matrix deposition in human dermal fibroblast cultures.Graphical abstractPolydispersed and negatively charged, as opposed to mono-domain and neutral, crowders are more effective in enhancing and accelerating extracellular matrix deposition in human dermal fibroblast culture.Graphical abstract for this article
       
  • 3D Bioprinting of Complex Channels within Cell-Laden Hydrogels
    • Abstract: Publication date: Available online 1 March 2019Source: Acta BiomaterialiaAuthor(s): Shen Ji, Emily Almeida, Murat Guvendiren 3D bioprinting is an emerging manufacturing approach to fabricate (cell-laden) hydrogel constructs with embedded microchannels, which are potentially useful for fundamental studies to understand vascularization and angiogenesis, and for developing organ-on-a-chip devices for disease modeling. Although numerous printing approaches have been developed, novel approaches are still needed that enable printing of channels with user-defined and tunable size, morphology, and complexity. Here, we report a novel bioprinting approach enabling printing of a sacrificial ink within commonly used photocurable hydrogels using a sequential printing approach. To achieve this, photocurable hydrogel is printed layer-by-layer as usual, but each layer is exposed to light briefly (seconds) to create partially crosslinked, self-supporting layers. At a desired thickness, immediately after the layer is printed (prior to partial crosslinking step), sacrificial hydrogel is directly printed within this viscous uncrosslinked layer. The layer was then exposed to light to confine and support the sacrificial hydrogel. After fully crosslinking the system, the sacrificial hydrogel is washed away, forming a channel. This approach allows bioprinting of cells with the matrix material and seeding of cells into channels after the sacrificial ink is removed. This approach can potentially provide a robust platform for fabricating vascularized tissues and studying cell behaviors on diverse channel surfaces.Statement of significance3D bioprinting is an emerging platform for the fabrication of hydrogel-based constructs for in vitro tissue/disease modelling or tissue and organ printing. Although several approaches have been developed to print channels within these constructs, it is still challenging to incorporate microchannels (for vascularization) within 3D bioprinted constructs. This study presents a novel bioprinting approach to create user-defined and tunable channels embedded within cell-laden hydrogel constructs. We report an important advance as our approach does not require complex device modifications for bioprinters or complex synthesis and processing hurdles for the inks. Since our approach does not require special chemistries, there are potentially a greater number of commercially available options for ink materials.Graphical abstractGraphical abstract for this article
       
  • Effect of grain orientation and magnesium doping on β-tricalcium
           phosphate resorption behavior
    • Abstract: Publication date: Available online 1 March 2019Source: Acta BiomaterialiaAuthor(s): Marta Gallo, Bastien Le Gars Santoni, Thierry Douillard, Fei Zhang, Laurent Gremillard, Silvia Dolder, Willy Hofstetter, Sylvain Meille, Marc Bohner, Jérôme Chevalier, Solène Tadier The efficiency of calcium phosphate (CaP) bone substitutes can be improved by tuning their resorption rate. The influence of both crystal orientation and ion doping on resorption is here investigated for beta-tricalcium phosphate (β-TCP). Non-doped and Mg-doped (1 and 6 mol.%) sintered β-TCP samples were immersed in acidic solution (pH 4.4) to mimic the environmental conditions found underneath active osteoclasts. The surfaces of β-TCP samples were observed after acid-etching and compared to surfaces after osteoclastic resorption assays. β-TCP grains exhibited similar patterns with characteristic intra-crystalline pillars after acid-etching and after cell-mediated resorption. Electron BackScatter Diffraction analyses, coupled with Scanning Electron Microscopy, Inductively Coupled Plasma - Mass Spectrometry and X-Ray Diffraction, demonstrated the influence of both grain orientation and doping on the process and kinetics of resorption. Grains with c-axis nearly perpendicular to the surface were preferentially etched in non-doped β-TCP samples, whereas all grains with simple axis (a, b or c) nearly normal to the surface were etched in 6 mol.% Mg-doped samples. In addition, both the dissolution rate and the percentage of etched surface were lower in Mg-doped specimens. Finally, the alignment direction of the intra-crystalline pillars was correlated with the preferential direction for dissolution.Statement of significanceThe present work focuses on the resorption behavior of calcium phosphate bioceramics. A simple and cost-effective alternative to osteoclast culture was implemented to identify which material features drive resorption. For the first time, it was demonstrated that crystal orientation, measured by Electron Backscatter Diffraction, is the discriminating factor between grains, which resorbed first, and grains, which resorbed slower. It also elucidated how resorption kinetics can be tuned by doping β-tricalcium phosphate with ions of interest. Doping with magnesium impacted lattice parameters. Therefore, the crystal orientations, which preferentially resorbed, changed, explaining the solubility decrease. These important findings pave the way for the design of optimized bone graft substitutes with tailored resorption kinetics.Graphical abstractGraphical abstract for this article
       
  • Synergistic interplay between human MSCs and HUVECs in 3D spheroids laden
           in collagen/fibrin hydrogels for bone tissue engineering
    • Abstract: Publication date: Available online 1 March 2019Source: Acta BiomaterialiaAuthor(s): Dong Nyoung Heo, Monika Hospodiuk, Ibrahim T. Ozbolat Stem cell encapsulation in hydrogels has been widely employed in tissue engineering, regenerative medicine, organ-on-a-chip devices and gene delivery; however, fabrication of native-like bone tissue using such a strategy has been a challenge, particularly in vitro, due to the limited cell loading densities resulting in weaker cell-cell interactions and lesser extra-cellular matrix deposition. In particular, scalable bone tissue constructs require vascular network to provide enough oxygen and nutrient supplies to encapsulated cells. To enhance stem cell function and generate pre-vascularized network, we here employed collagen/fibrin hydrogel as an encapsulation matrix for the incorporation of human mesenchymal stem cell/human umbilical vein endothelial cell (MSC/HUVEC) spheroids, and investigated their cellular behavior (including cell viability, morphology, proliferation, and gene expression profile) and compared to that of cell suspension- or MSC spheroids-laden hydrogels. MSC/HUVEC spheroids encapsulated in collagen/fibrin hydrogel showed better cell spreading and proliferation, and up-regulated osteogenic differentiation, and demonstrated pre-vascular network formation. Overall, MSC/HUVEC spheroids-laden hydrogels provided a highly suitable 3D microenvironment for bone tissue formation, which can be utilized in various applications, such as but not limited to tissue engineering, disease modeling and drug screening.Statement of SignificanceStem cell encapsulation in hydrogels has been widely used in various areas such as tissue engineering, regenerative medicine, organ-on-a-chip devices and gene delivery; however, fabrication of native-like bone tissue using such an approach has been a challenge, particularly in vitro, due to the limited cell loading densities resulting in weaker cell-cell interactions and lesser extra-cellular matrix deposition. Here in this work, we have encapsulated spheroids of human mesenchymal stems cells (MSCs) in collagen/fibrin hydrogel and evaluated their viability, proliferation, osteogenic differentiation, and bone formation potential in vitro with respect to cell suspension-laden hydrogel samples. We have further incorporated human umbilical vein endothelial cells (HUVECs) into MSC spheroids and demonstrated that the presence of HUVECs in 3D spheroid culture in collagen/fibrin gel induced the formation of pre-vascular network, improved cell viability and proliferation, enhanced the osteogenic differentiation of spheroids, and increased their bone mineral deposition. In sum, MSC/HUVEC spheroids laden hydrogels provided a highly suitable 3D microenvironment for bone tissue formation, which can be utilized in various applications, such as but not limited to tissue engineering and regenerative medicine, disease modeling and drug screening.Graphical abstractGraphical abstract for this article
       
  • Ultrasound-Triggered Antibiotic Release from PEEK Clips to Prevent Spinal
           Fusion Infection: Initial Evaluations
    • Abstract: Publication date: Available online 28 February 2019Source: Acta BiomaterialiaAuthor(s): Lauren J. Delaney, Daniel MacDonald, Jay Leung, Keith Fitzgerald, Alex M. Sevit, John R. Eisenbrey, Neil Patel, Flemming Forsberg, Christopher K. Kepler, Taolin Fang, Steven M. Kurtz, Noreen J. Hickok Despite aggressive peri-operative antibiotic treatments, up to 10% of patients undergoing instrumented spinal surgery develop an infection. Like most implant-associated infections, spinal infections persist through colonization and biofilm formation on spinal instrumentation, which can include metal screws and rods for fixation and an intervertebral cage commonly comprised of polyether ether ketone (PEEK). We have designed a PEEK antibiotic reservoir that would clip to the metal fixation rod and that would achieve slow antibiotic release over several days, followed by a bolus release of antibiotics triggered by ultrasound (US) rupture of a reservoir membrane. We have found using human physiological fluid (synovial fluid), that higher levels (100-500 μg) of vancomycin are required to achieve a marked reduction in adherent bacteria vs. that seen in the common bacterial medium, trypticase soy broth. To achieve these levels of release, we applied a polylactic acid coating to a porous PEEK puck, which exhibited both slow and US-triggered release. This design was further refined to a one-hole or two-hole cylindrical PEEK reservoir that can clip onto a spinal rod for clinical use. Short-term release of high levels of antibiotic (340 ± 168 μg), followed by US-triggered release was measured (7420 ± 2992 μg at 48 hr). These levels are sufficient to prevent adhesion of Staphylococcus aureus to implant materials. This study demonstrates the feasibility of an US-mediated antibiotic delivery device, which could be a potent weapon against spinal surgical site infection.Statement of SignificanceSpinal surgical sites are prone to bacterial colonization, due to presence of instrumentation, long surgical times, and the surgical creation of a dead space (≥ 5 cm3) that is filled with wound exudate. Accordingly, it is critical that new approaches are developed to prevent bacterial colonization of spinal implants, especially as neither bulk release systems nor controlled release systems are available for the spine. This new device uses non-invasive ultrasound (US) to trigger bulk release of supra-therapeutic doses of antibiotics from materials commonly used in existing surgical implants. Thus, our new delivery system satisfies this critical need to eradicate surviving bacteria, prevent resistance, and markedly lower spinal infection rates.Graphical abstractGraphical abstract for this article
       
  • Material stiffness influences the polarization state, function and
           migration mode of macrophages
    • Abstract: Publication date: Available online 28 February 2019Source: Acta BiomaterialiaAuthor(s): Rukmani Sridharan, Brenton Cavanagh, Andrew R. Cameron, Daniel J. Kelly, Fergal J. O'Brien Biomaterial implantation is followed by an inflammatory cascade dominated by macrophages, which determine implant acceptance or rejection through pro- and anti-inflammatory polarization states [1], [2]. It is known that chemical signals such as bacterial endotoxins and cytokines (IL4) can direct macrophage polarization [3]; however, recent evidence implicates biophysical cues in this process [4], [5]. Here we report that macrophages cultured on collagen-coated polyacrylamide gels of varying stiffness adapt their polarization state, functional roles and migration mode according to the stiffness of the underlying substrate. Through gene expression and protein secretion analysis, we show that stiff polyacrylamide gels (323kPa) prime macrophages towards a pro-inflammatory phenotype with impaired phagocytosis in THP1 derived macrophages, while soft (11kPa) and medium (88kPa) stiffness gels prime cells towards an anti-inflammatory, highly phagocytic phenotype. Furthermore, we show that stiffness dictates the migration mode of macrophages; on soft and medium stiffness gels, cells display Rho-A kinase (ROCK)-dependent, podosome-independent fast amoeboid migration and on stiff gels they adopt a ROCK-independent, podosome-dependent slow mesenchymal migration mode. We also provide a mechanistic insight into this process by showing that the anti-inflammatory property of macrophages on soft and medium gels is ROCK-dependent and independent of the ligand presented to them. Together, our results demonstrate that macrophages adapt their polarization, function and migration mode in response to the stiffness of the underlying substrate and suggest that biomaterial stiffness is capable of directing macrophage behaviour independent of the biochemical cues being presented to them. The results from this study establish an important role for substrate stiffness in directing macrophage behaviour, and will lead to the design of immuno-informed biomaterials that are capable of modulating the macrophage response after implantation.Statement of SignifianceBiomaterial implantation is followed by an inflammatory cascade dominated by macrophages, which determine implant acceptance or rejection through pro- and anti-inflammatory polarization states. It is known that chemical signals can direct macrophage polarization; however, recent evidence implicates biophysical cues in this process. Here we report that macrophages cultured on gels of varying stiffness adapt their polarization state, functional roles and migration mode according to the stiffness of the underlying substrate. The results from this study establish an important role for substrate stiffness in directing macrophage behaviour, and will lead to the design of immuno-informed biomaterials that are capable of modulating the macrophage response after implantation.Graphical abstractGraphical abstract for this article
       
  • Biodegradable water-based polyurethane scaffolds with a sequential release
           function for cell-free cartilage tissue engineering
    • Abstract: Publication date: Available online 27 February 2019Source: Acta BiomaterialiaAuthor(s): Yi-Ting Wen, Niann-Tzyy Dai, Shan-hui Hsu Three dimensional (3D) printing technology has rapidly developed as a promising technology for manufacturing tissue engineering scaffolds. Cells used in tissue engineering are subjected to the quality management and risk of contamination, while cell-free scaffolds may not have sufficient therapeutic efficacy. In this study, water-based 3D printing ink containing biodegradable polyurethane (PU), chemokine SDF-1, and Y27632 drug-embedding PU microspheres was printed at low temperature (-40 °C) to fabricate tissue engineering scaffolds with sequential drug release function. The scaffolds containing 200 ng/ml SDF-1 and 22 wt% Y27632-encapsulated microspheres (55 µg/ml Y27632 in microspheres) (abbreviated PU/SDF-1/MS_Y scaffolds) had the optimal performance. The structural design of the scaffolds allowed each of SDF-1 and Y27632 to be released sequentially in vitro and reach the effective concentration (∼100 ng/ml and 3.38 µg/ml, respectively) after the appropriate time (24 h and 62 h, respectively). Human mesenchymal stem cells (hMSCs) seeded in the scaffolds showed significant GAG deposition in 7 days. Besides, the gradual release of SDF-1 from the PU/SDF-1/MS_Y scaffolds could induce the migration of hMSCs. Implantation of the cell-free PU/SDF-1/MS_Y scaffolds in rabbit articular cartilage defects supported the potential of the scaffolds to promote cartilage regeneration. The 3D printed scaffolds with sequential releases of SDF-1 and Y27632 may have potential in cartilage tissue engineering.Statement of SignificanceThe clinical success of tissue engineering depends highly on the quality of externally supplied cells, while cell-free scaffolds may not have sufficient therapeutic efficacy. In this manuscript, water-based 3D printing ink containing biodegradable polyurethane (PU), chemokine SDF-1, and Y27632 drug-embedding PU microspheres was printed at low temperature to fabricate tissue engineering scaffolds with sequential drug release function. The structural design of the scaffolds allowed each of SDF-1 and Y27632 to be released sequentially in vitro. SDF-1 was released earlier from the scaffolds to promote cell migration. The drug Y27632 was released later from the microspheres into the matrix of the scaffolds to induce the chondrogenic differentiation of the attracted cells. Implantation of the cell-free PU/SDF-1/MS_Y scaffolds in rabbit articular cartilage defects supported the potential of the scaffolds to promote cartilage regeneration. We hypothesized that the cell-free scaffolds may improve the clinical applicability and convenience without the use of exogenous cells or growth factor.Graphical abstractGraphical abstract for this article
       
  • Hypoxia Mimicking Hydrogels to Regulate the Fate of Transplanted Stem
           Cells
    • Abstract: Publication date: Available online 27 February 2019Source: Acta BiomaterialiaAuthor(s): Binulal N. Sathy, Andrew Daly, Tomas Gonzalez-Fernandez, Dinorath Olvera, Grainne Cunniffe, Helen O. McCarthy, Nicholas Dunne, Oju Jeon, Eben Alsberg, Tammy H. Donahue, Daniel J. Kelly Controlling the phenotype of transplanted stem cells is integral to ensuring their therapeutic efficacy. Hypoxia is a known regulator of stem cell fate, the effects of which can be mimicked using hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors such as dimethyloxalylglycine (DMOG). By releasing DMOG from mesenchymal stem cell (MSC) laden alginate hydrogels, it is possible to stabilize HIF-1α and enhance its nuclear localization. This correlated with enhanced chondrogenesis and a reduction in the expression of markers associated with chondrocyte hypertrophy, as well as increased SMAD 2/3 nuclear localization in the encapsulated MSCs. In vivo, DMOG delivery significantly reduced mineralisation of the proteoglycan-rich cartilaginous tissue generated by MSCs within alginate hydrogels loaded with TGF-β3 and BMP-2. Together these findings point to the potential of hypoxia mimicking hydrogels to control the fate of stem cells following their implantation into the body.Statement of significanceThere are relatively few examples where in vivo delivery of adult stem cells has demonstrated a true therapeutic benefit. This may be attributed, at least in part, to a failure to control the fate of transplanted stem cells in vivo. In this paper we describe the development of hydrogels that mimic the effects of hypoxia on encapsulated stem cells. In vitro, these hydrogels enhance chondrogenesis of MSCs and suppress markers associated with chondrocyte hypertrophy. In an in vivo environment that otherwise supports progression along an endochondral pathway, we show that these hydrogels will instead direct mesenchymal stem cells (MSCs) to produce a more stable, cartilage-like tissue. In addition, we explore potential molecular mechanisms responsible for these phenotypic changes in MSCs.Graphical abstractGraphical abstract for this article
       
  • Osteocytes respond to particles of clinically-relevant conventional and
           cross-linked polyethylene and metal alloys by up-regulation of resorptive
           and inflammatory pathways
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Renee T. Ormsby, Lucian B. Solomon, Dongqing Yang, Tania N. Crotti, David R. Haynes, David M. Findlay, Gerald J. Atkins Periprosthetic osteolysis is a major cause of implant failure in total hip replacements. Aseptic loosening caused by osteolytic lesions is associated with the production of bioactive wear particles from the articulations of implants. Wear particles infiltrate the surrounding tissue of implants, promoting inflammation as well as bone resorption. Osteocytes have been shown to both regulate physiological osteoclastogenesis and directly remodel their perilacunar bone matrix by the process of osteocytic osteolysis. We hypothesise that osteocytes respond to wear debris of orthopaedic implant materials by adopting a pro-catabolic phenotype and thus contribute to periprosthetic osteolysis through the known pathways of bone loss. Osteocyte responses to particles derived from clinically relevant materials, ultra-high molecular weight polyethylene (UHMWPE), highly cross-linked polyethylene (XLPE) and metal alloys, Ti6Al4V and CoCrMo, were examined in vitro in human primary osteocyte-like cultures. Osteocyte-like cells exposed to both polyethylene and metal wear particle types showed upregulated expression of catabolic markers associated with osteocytic osteolysis, MMP13, carbonic anhydrase 2 (CA2) and cathepsin K (CTSK). In addition, pro-osteoclastogenesis markers RANKL and M-CSF were induced, as well as the expression of pro-inflammatory cytokines, IL-6 and TNFα, albeit with different kinetics. These findings suggest a previously unrecognised action of wear particles of multiple orthopaedic materials on osteocytes, and suggest a multifaceted role for osteocytes in periprosthetic osteolysis.Statement of SignificanceThis study addresses periprosthetic osteolysis, a major clinical problem leading to aseptic loosening of orthopaedic implants. It is well accepted that wear particles of polyethylene and of other implant materials stimulate the activity of bone resorbing osteoclasts. Our recent work provided evidence that commercial particles of ultra-high molecular weight polyethylene (UHMWPE) stimulated osteocytes to adopt a bone catabolic state. In this study we demonstrate for the first time that particles derived from materials in clinical use, conventional UHMWPE, highly cross-linked polyethylene (XLPE), and Ti6Al4V and CoCrMo metal alloys, all stimulate human osteocyte activities of osteocyte-regulated osteoclastogenesis, osteocytic osteolysis, proinflammatory responses, osteocyte apoptosis, albeit to varying extents. This study provides further mechanistic insight into orthopaedic wear particle mediated bone disease in terms of the osteocyte, the most abundant and key controlling cell type in bone.Graphical abstractGraphical abstract for this article
       
  • Tuning the tribofilm nanostructures of polymer-on-metal joint replacements
           for simultaneously enhancing anti-wear performance and corrosion
           resistance
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Gen Liu, Ligang Zhang, Guitao Li, Fuyan Zhao, Qinglun Che, Chao Wang, Ga Zhang Total joint replacement is currently the most successful clinical treatment for improving the life quality of individuals afflicted with end-stage osteoarthritis of knee or hip joints. However, release of wear and corrosion products from the prostheses is a critical issue causing adverse physiological responses of local issues. β-SiC nanoparticles were dispersed into polyetheretherketone (PEEK) materials and their role in tribocorrosion performance of PEEK-steel joints exposed to simulated body fluid was investigated. It is demonstrated that β-SiC nanoparticles increase greatly the wear resistance of the PEEK materials, and meanwhile mitigate significantly corrosion of the steel counterpart. It is revealed that tribochemical reactions of β-SiC nanoparticles promoted formation of a robust tribofilm having complex structures providing protection and shielding effects. The present work proposes a strategy for developing high-performance polymer-on-metal joint replacement materials of enhanced lifespan and biocompatibility via tuning interface nanostructures.Statement of SignificanceAdverse tissue responses to metal wear and corrosion products from metal base implants remain a challenge to surgeons and patients. We demonstrated that leaching of metal ions and release of metallic debris are well decreased via tuning interface nanostructures of metal-polymer joint bearings by dispersing β-SiC nanoparticles into polyetheretherketone (PEEK). It is identified that the addition of β-SiC greatly improves the tribological performances of the PEEK materials and mitigated corrosion of the steel. Tribo-chemistry reactions of SiC induce the formation of complex structures which provide protection and shielding effects. Nanostructures of the tribofilm were also comprehensively investigated. These novel findings proposed a potential route for designing high performance metal-polymer joint replacement materials.Graphical abstractGraphical abstract for this article
       
  • Robocasting of Cu2+ & La3+ doped sol–gel glass scaffolds with greatly
           enhanced mechanical properties: Compressive strength up to 14 MPa
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Basam A.E. Ben–Arfa, Sofia Neto, Isabel M. Miranda Salvado, Robert C. Pullar, José M.F. Ferreira This research details the successful fabrication of scaffolds by robocasting from high silica sol–gel glass doped with Cu2+ or La3+. The parent HSSGG composition within the system SiO2–CaO–Na2O–P2O5 [67% Si – 24% Ca – 5% Na – 4% P (mol%)] was doped with 5 wt% Cu2+ or La3+ (Cu5 and La5). The paper sheds light on the importance of copper and lanthanum in improving the mechanical properties of the 3–D printed scaffolds. 1 h wet milling was sufficient to obtain a bioglass powder ready to be used in the preparation of a 40 vol% solid loading paste suitable for printing. Moreover, Cu addition showed a small reduction in the mean particle size, while La exhibited a greater reduction, compared with the parent glass. Scaffolds with macroporosity between 300 and 500 µm were successfully printed by robocasting, and then sintered at 800 °C. A small improvement in the compressive strength (7–18%) over the parent glass accompanied the addition of La. However, a much greater improvement in the compressive strength was observed with Cu addition, up to 221% greater than the parent glass, with compressive strength values of up to ∼14 MPa. This enhancement in compressive strength, around the upper limit registered for human cancellous bones, supports the potential use of this material in biomedical applications.Statement of Significance3D porous bioactive glass scaffolds with greatly improved compressive strength were fabricated by robocasting from a high silica sol–gel glasses doped with Cu2+ or La3+. In comparison to the parent glass, the mechanical performance of scaffolds was greatly improved by copper-doping (>220%), while a modest increase of ∼9% was registered for lanthanum-doping. Doping ions (particularly La3+) acted as glass modifiers leading to less extents of silica polymerisation. This favoured the milling of the glass powders and the obtaining of smaller mean particle sizes. Pastes with a high solid loading (40 vol%) and with suitable rheological properties for robocasting were prepared from all glass powders. Scaffolds with dimensions of 3 × 3 × 4 mm and macro-pore sizes between 300 and 500 µm were fabricated.Graphical abstractGraphical abstract for this article
       
  • Patterning of human epidermal stem cells on undulating elastomer
           substrates reflects differences in cell stiffness
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Seyedeh Atefeh Mobasseri, Sebastiaan Zijl, Vasiliki Salameti, Gernot Walko, Andrew Stannard, Sergi Garcia-Manyes, Fiona M. Watt In human skin the junction between epidermis and dermis undulates, the width and depth of the undulations varying with age and disease. When primary human epidermal keratinocytes are seeded on collagen-coated polydimethylsiloxane (PDMS) elastomer substrates that mimic the epidermal-dermal interface, the stem cells become patterned by 24 h, resembling their organisation in living skin. We found that cell density and nuclear height were higher at the base than the tips of the PDMS features. Cells on the tips not only expressed higher levels of the stem cell marker β1 integrin but also had elevated E-cadherin, Desmoglein 3 and F-actin than cells at the base. In contrast, levels of the transcriptional cofactor MAL were higher at the base. AFM measurements established that the Young’s modulus of cells on the tips was lower than on the base or cells on flat substrates. The differences in cell stiffness were dependent on Rho kinase activity and intercellular adhesion. On flat substrates the Young’s modulus of calcium-dependent intercellular junctions was higher than that of the cell body, again dependent on Rho kinase. Cell patterning was influenced by the angle of the slope on undulating substrates. Our observations are consistent with the concept that epidermal stem cell patterning is dependent on mechanical forces exerted at intercellular junctions in response to undulations in the epidermal-dermal interface.Statement of significanceIn human skin the epidermal-dermal junction undulates and epidermal stem cells are patterned according to their position. We previously created collagen-coated polydimethylsiloxane (PDMS) elastomer substrates that mimic the undulations and provide sufficient topographical information for stem cells to cluster on the tips. Here we show that the stiffness of cells on the tips is lower than cells on the base. The differences in cell stiffness depend on Rho kinase activity and intercellular adhesion. We propose that epidermal stem cell patterning is determined by mechanical forces exerted at intercellular junctions in response to the slope of the undulations.Graphical abstractGraphical abstract for this article
       
  • Emergent structure-dependent relaxation spectra in viscoelastic fiber
           networks in extension
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Rohit Y. Dhume, Victor H. Barocas Viscoelasticity plays an important role in the mechanical behavior of biological tissues undergoing dynamic loading. Exploring viscoelastic relaxation spectra of the tissue is essential for predicting its mechanical response. Most load-bearing tissues, however, are also composed of networks of intertwined fibers and filaments of, e.g., collagen, elastin. In this work, we show how non-affine deformations within fiber networks affect the relaxation behavior of the material leading to the emergence of structure-dependent time scales in the relaxation spectra. In particular, we see two different contributions to the network relaxation process: a material contribution due to the intrinsic viscoelasticity of the fibers, and a kinematic contribution due to non-affine rearrangement of the network when different fibers relax at different rates. We also present a computational model to simulate viscoelastic relaxation of networks, demonstrating the emergent time scales and a pronounced dependence of the network relaxation behavior on whether components with different relaxation times percolate the network. Finally, we observe that the simulated relaxation spectrum for Delaunay networks is comparable to that measured experimentally for reconstituted collagen gels by others.Statement of SignificanceViscoelasticty plays an important role in the mechanical behavior of biological tissues undergoing dynamic loading. Stress relaxation tests provide a convenient way to explore the viscoelastic behavior of the material, while providing an advantage of interrogating multiple time scales in a single experiment. Most load bearing tissues, however, are composed of networks of intertwined fibers and filaments. In the present study, we analyze how the network structure can affect the viscoelastic relaxation behavior of a tissue leading to the emergence of structure-based time scales in the relaxation spectra.Graphical abstractGraphical abstract for this article
       
  • Structure-function relationships of fetal ovine articular cartilage
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Wendy E. Brown, Grayson D. DuRaine, Jerry C. Hu, Kyriacos A. Athanasiou It is crucial that the properties of engineered neocartilage match healthy native cartilage to promote the functional restoration of damaged cartilage. To accurately assess the quality of neocartilage and the degree of biomimicry achieved, its properties must be evaluated against native cartilage and tissue from which the cells for neocartilage formation were sourced. Fetal ovine cartilage is a promising and translationally relevant cell source with which to engineer neocartilage, yet, it is largely non-characterized. The influence of biomechanics during cartilage development, as well as their potential impact on structure-function relationships in utero motivates additional study of fetal cartilage. Toward providing tissue engineering design criteria and elucidating structure-function relationships, 11 locations across four regions of the fetal ovine stifle were characterized. Locational and regional differences were found to exist. Although differences in GAG content were observed, compressive stiffness did not vary or correlate with any biochemical component. Patellar cartilage tensile stiffness and strength were significantly greater than those of the medial condyle. Tensile modulus and UTS significantly correlated with pyridinoline content. More advanced zonal organization, more intense collagen II staining, and greater collagen and pyridinoline contents in the trochlear groove and patella suggest these regions exhibit a more advanced maturational state than others. Regional differences in functional properties and their correlations suggest that structure-function relationships emerge in utero. These data address the dearth of information of the fetal ovine stifle, may serve as a repository of information for cartilage engineering strategies, and may help elucidate functional adaptation in fetal articular cartilage.Statement of SignificanceEngineered neocartilage must be evaluated against healthy native cartilage and cell source tissue to determine its quality and degree of biomimicry. While fetal ovine cartilage has emerged as a promising and translationally relevant cell source with which to engineer neocartilage, it is largely non-characterized. Therefore, 11 locations across four regions (medial condyle, lateral condyle, trochlear groove, and patella) of the fetal ovine stifle were characterized. Importantly, locational and regional differences in functional properties were observed, and significant correlations of tensile properties to collagen and crosslink contents were detected, suggesting that functional adaptation begins in utero. This study provides a repository of quantitative information, clarifies the developmental order of cartilage functional properties, and informs future cartilage engineering efforts.Graphical abstractGraphical abstract for this article
       
  • Neuroblastoma-targeting triangular gadolinium oxide nanoplates for precise
           excision of cancer
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Yushen Jin, Yanyan Li, Xin Yang, Jie Tian Neuroblastoma accounts for 8–10% of malignancies in infants and children. It is urgent to develop an appropriate theranostic agent for effective diagnosis and therapy of neuroblastoma. Herein, we constructed RVG peptide and IRDye800-conjugated bovine serum albumin-coated triangular gadolinium oxide nanoplates (RVG&IRDye800-Gd2O3 TNs) as a targeting MRI agent for the diagnosis of neuroblastoma preoperation and a fluorescence imaging agent for the guidance of the precise excision of the neuroblastoma in surgery. RVG&IRDye800-Gd2O3 TNs have uniform edge length. The RVG&IRDye800-Gd2O3 TNs show remarkably enhanced affinity to both mouse- and human-derived neuroblastoma cells compared with IRDye800-Gd2O3 TNs (3.07-fold and 3.02-fold, respectively). Because of the increased accumulation in tumor cells, RVG&IRDye800-Gd2O3 TNs exhibit signals threefold to fivefold higher than the surrounding normal tissues, which is propitious to the diagnosis of neuroblastoma preoperation and provides real-time visual guidance of the precise excision of the neuroblastoma. Most importantly, with the guidance of the fluorescence imaging agent, the survival rate increased from 0% to 80% 42 days after surgery compared with that in conventional surgery. These findings indicated that the RVG peptide combined with IRDye800-Gd2O3 TNs has the potential to improve the diagnosis and treatment of patients with neuroblastoma.Statement of significanceIn this study, we prepared RVG peptide and IRDye800-conjugated bovine serum albumin-coated triangular gadolinium oxide nanoplates (RVG&IRDye800-Gd2O3 TNs) as a targeting MRI agent for the diagnosis of neuroblastoma preoperation and a fluorescence imaging agent for the guidance of the precise excision of the neuroblastoma during surgery.Neuroblastoma was accurately located by MRI imaging, and the tumor margin could be real-time monitored through near-infrared fluorescence imaging.The RVG&IRDye800-Gd2O3 TNs exhibit signals threefold to fivefold higher than those in the surrounding normal tissues, which is propitious to the diagnosis of the neuroblastoma preoperation and provides real-time visual guidance of the precise excision of the neuroblastoma.With the guidance of the fluorescence imaging agent in surgery, the survival rate increased from 0% to 80% 42 days after surgery compared with that in conventional surgery.Graphical abstractGraphical abstract for this article
       
  • Optimized liposomes with transactivator of transcription peptide and
           anti-apoptotic drugs to target hippocampal neurons and prevent
           tau-hyperphosphorylated neurodegeneration
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Yung-Chih Kuo, Chang-Li Chen, Rajendiran Rajesh Liposomes (lip) carrying pharmaceuticals have shown promise in their ability to advance the therapy for neurodegenerative diseases. However, the low nerve-targeting capacity and poor penetration rate of lip through the blood–brain barrier (BBB) are major hurdles to achieving successful treatment. Herein, we developed lip incorporating cardiolipin (CL) and phosphatidic acid (PA) to promote their capability against hyperphosphorylation of tau protein, and a transactivator of transcription (TAT) peptide to permeate the BBB for delivering nerve growth factor (NGF), rosmarinic acid (RA), curcumin (CURC) and quercetin (QU). We derived an optimization method to assess a better composition of phospholipids in the lip loaded with the four medicines. Experimental results revealed that this optimized lip increased the viability of SK-N-MC cells insulted with β-amyloid peptide (Aβ) fibrils and prevented Wistar rat brain from producing hyperphosphorylated tau. CL and PA and the grafted TAT peptide on the carrier surface improved the rescue efficiency by inhibiting Aβ deposition and reducing the expressions of phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), c-Jun N-terminal protein kinase, p38, tau at serine 202 and caspase-3. The lip also enhanced the expressions of p-ERK5 and p-cyclic adenosine monophosphate response element-binding protein. The amalgamated activity of NGF, RA, CURC and QU, and the effect of charged CL/PA on Aβ deposits supported the therapeutic efficacy of lip. The optimized TAT-NGF-RA-CURC-QU-CL/PA-lip can be a capable drug delivery system to cross the BBB and protect Alzheimer’s disease brains from tau hyperphosphorylation.Statements of SignificanceThe therapeutic efficiency of liposomes (lip) against neurodegenerative disorder depends on their nerve-targeting capacity and ability to permeate the blood–brain barrier (BBB). Lip was developed incorporating cardiolipin (CL) and phosphatidic acid (PA) to promote their target specificity against hyperphosphorylation of tau protein, and a transactivator of transcription (TAT) peptide to permeate the BBB. We have successfully derived an optimization method using a new mathematical expression for the first time to assess a better composition of phospholipids in lip loaded with nerve growth factor (NGF), rosmarinic acid (RA), curcumin (CURC) and quercetin (QU). The optimized TAT-NGF-RA-CURC-QU-CL/PA-lip efficaciously down-regulated the expressions of phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), c-Jun N-terminal protein kinase, p38, tau at serine 202 and caspase-3, and up-regulated the expressions of p-ERK5 and p-cyclic adenosine monophosphate response element-binding protein in Alzheimer’s disease Wistar rat model.Graphical abstractGraphical abstract for this article
       
  • Highly-branched poly(N-isopropyl acrylamide) functionalised with pendant
           Nile red and chain end vancomycin for the detection of Gram-positive
           bacteria
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Thomas Swift, Maria Katsikogianni, Richard Hoskins, Pavintorn Teratarantorn, Ian Douglas, Sheila MacNeil, Stephen Rimmer This study shows how highly branched poly(N-isopropyl acrylamide) (HB-PNIPAM) with a chain pendant solvatochromic dye (Nile red) could provide a fluorescence signal, as end groups bind to bacteria and chain segments become desolvated, indicating the presence of bacteria. Vancomycin was attached to chain ends of HB-PNIPAM or as pendant groups on linear polymers each containing Nile red. Location of the dye was varied between placement in the core of the branched polymer coil or the outer domains. Both calorimetric and fluorescence data showed that branched polymers responded to binding of both the peptide target (D-Ala-D-Aa) and bacteria in a different manner than analogous linear polymers; binding and response was more extensive in the branched variant. The fluorescence data showed that only segments located in the outer domains of branched polymers responded to binding of Gram-positive bacteria with little response when linear analogous polymer or branched polymer with the dye in the inner core was exposed to Staphylococcus aureus.Graphical abstractGraphical abstract for this article
       
  • Micropatterning of a 2-methacryloyloxyethyl phosphorylcholine polymer
           surface by hydrogenated amorphous carbon thin films for endothelialization
           and antithrombogenicity
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Kenta Bito, Terumitsu Hasebe, Shunto Maegawa, Tomoya Kitagawa, Tomohiro Matsumoto, Tetsuya Suzuki, Atsushi Hotta The existing first-generation drug-eluting stent (DES) has caused late and very late stent thrombosis related to incomplete stent endothelialization. Hence, biomaterials that possess sufficient anti-thrombogenicity and endothelialization with the controlled drug release system have been highly required. In this work, we have developed a newly designed drug-release platform composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer, a non-thrombogenic polymer, and micropatterned hydrogenated amorphous carbon (a-C:H), a cell-compatible thin film. The platelet adhesion and the endothelial cell adhesion behavior on the micropatterned substrates were investigated in vitro. The results indicated that the micropatterned a-C:H/MPC polymer substrates effectively supported the human umbilical vein endothelial cell (HUVEC) proliferation, while suppressing the platelet adhesion. Interestingly, the HUVEC exhibited different shape and behavior by changing the island size of the micropatterned a-C:H. By introducing both a non-thrombogenic polymer and cell-compatible thin films through a simple patterning method, we demonstrated that the platform had the potential to be utilized as a base material for DES with cell controllability.Statement of significanceThe current first-generation drug-eluting stents (DES) would cause late and very late stent thrombosis due to the incomplete endothelialization of the metal stent material. In this work, we have developed a new DES platform composed of a 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer micropatterned by hydrogenated amorphous carbon (a-C:H). Two types of differently micropatterned a-C:H stent surface were made. Our studies revealed that the micropatterned a-C:H/MPC polymer substrates could effectively enhance the endothelial cell (EC) proliferation, simultaneously suppressing the platelet adhesion, becoming a highly biocompatible material especially for indwelling devices including a drug-release device. The new drug-release platform could be utilized as a base material for cell-controllable coating on DES.Graphical abstractGraphical abstract for this article
       
  • Biodegradable Pickering emulsions of Lipiodol for liver trans-arterial
           chemo-embolization
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Frédéric Deschamps, Thomas Isoardo, Stéphanie Denis, Nicolas Tsapis, Lambros Tselikas, Valérie Nicolas, Angélo Paci, Elias Fattal, Thierry de Baere, Nicolas Huang, Laurence Moine Water-in-oil (W/O) Lipiodol emulsions remain the preferable choice for local delivery of chemotherapy in the treatment of hepatocellular carcinoma. However, their low stability severely hampers their efficiency. Here, remarkably stable W/O Lipiodol emulsion stabilized by biodegradable particles was developed thanks to Pickering technology. The addition of poly(lactide-co-glycolide) nanoparticles (NPs) into the aqueous-phase of the formulation led to W/O Pickering emulsion by a simple emulsification process through two connected syringes. Influence of nanoparticles concentration and water/oil ratio on emulsion stability and droplet size were studied. All formulated Pickering emulsions were W/O type, stable for at least one month and water droplets size could be tuned by controlling nanoparticle concentration from 24 µm at 25 mg/mL to 69 µm at 5 mg/mL. The potential of these emulsions to efficiently encapsulate chemotherapy was studied through the internalization of doxorubicin (DOX) into the aqueous phase with a water/oil ratio of 1/3 as recommended by the medical community. Loaded-doxorubicin was released from conventional emulsion within a few hours whereas doxorubicin from stable Pickering emulsion took up to 10 days to be completely released. In addition, in vitro cell viability evaluations performed on the components of the emulsion and the Pickering emulsion have shown no significant toxicity up to relatively high concentrations of NPs (3 mg/mL) on two different cell lines: HUVEC and HepG2.Statement of SignificanceWe present an original experimental research in the field of nanotechnology for biomedical applications. In particular, we have formulated, thanks to Pickering technology, a new therapeutic emulsion stabilized with biodegradable PLGA nanoparticles. As far as we know, this is the first therapeutic Pickering emulsion reported in the literature for hepatocellular carcinoma. Such a new emulsion allows to easily prepare a predictable and stable lipiodolized emulsion having all the required characteristics for optimum tumor uptake. As demonstrated throughout our manuscript, emulsions stabilized with these nanoparticles have the advantage of being biodegradable, biocompatible and less toxic compared to usual emulsions stabilized with synthetic surfactants.These findings demonstrate the plausibility of the use of Pickering emulsions for chemoembolization as a therapeutic agent in extended release formulations.Graphical abstractGraphical abstract for this article
       
  • Refined assessment of the impact of cell shape on human mesenchymal stem
           cell differentiation in 3D contexts
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Andrea C. Jimenez-Vergara, Rodrigo Zurita, Abigail Jones, Patricia Diaz-Rodriguez, Xin Qu, Kenneth L. Kusima, Mariah S. Hahn, Dany J. Munoz-Pinto Numerous studies have demonstrated that the differentiation potential of human mesenchymal stem cells (hMSCs) can be modulated by chemical and physical cues. In 2D contexts, inducing different cell morphologies, by varying the shape, area and/or curvature of adhesive islands on patterned surfaces, has significant effects on hMSC multipotency and the onset of differentiation. In contrast, in vitro studies in 3D contexts have suggested that hMSC differentiation does not directly correlate with cell shape. However, in 3D, the effects of cell morphology on hMSC differentiation have not yet been clearly established due to the chemical and physical properties being intertwined in 3D matrices. In this work, we studied the effects of round or elongated cell morphologies on hMSC differentiation independently of scaffold composition, modulus, crosslink density and cell-mediated matrix remodeling. The effects of cell shape on hMSC lineage progression were studied using three different cell culture media compositions and two values of scaffold rigidity. Differences in cell shape were achieved using interpenetrating polymer networks (IPNs). The mechanical and diffusional properties of the scaffolds and cell-matrix interactions were characterized. In addition, cell responses were evaluated in terms of cell spreading via gene and protein expression of differentiation markers. Cumulative results support, and extend upon previous work indicating that cell shape alone in 3D contexts does not significantly modulate hMSC differentiation, at least for the scaffold chemistry, range of modulus and culture conditions explored in this study.Statement of SignificanceIn 2D contexts, inducing different cell shapes, by varying the curvature, area size and shape of a patterned surface, has significant effects on hMSC multipotency and the onset of cell differentiation. In contrast, in vitro studies in 3D contexts have suggested that hMSC differentiation does not directly correlate with cell shape. However, in 3D, the effects of cell morphology on hMSC differentiation have not yet been clearly established due to the chemical and physical properties being intertwined in 3D matrices. In this work, we studied the effects of round or elongated cell morphologies on the differentiation of hMSCs independently of scaffold composition, modulus, crosslink density and cell mediated matrix remodeling. Cumulative results support, and extend upon previous work indicating that cell shape alone in 3D contexts does not significantly modulate hMSCs differentiation commitment.Graphical abstractGraphical abstract for this article
       
  • Cross-linked cellulose nanocrystal aerogels as viable bone tissue
           scaffolds
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Daniel A. Osorio, Bryan E.J. Lee, Jacek M. Kwiecien, Xiaoyue Wang, Iflah Shahid, Ariana L. Hurley, Emily D. Cranston, Kathryn Grandfield Chemically cross-linked cellulose nanocrystal (CNC) aerogels possess many properties beneficial for bone tissue scaffolding applications. CNCs were extracted using sulfuric acid or phosphoric acid, to produce CNCs with sulfate and phosphate half-ester surface groups, respectively. Hydrazone cross-linked aerogels fabricated from the two types of CNCs were investigated using scanning electron microscopy, X-ray micro-computed tomography, X-ray photoelectron spectroscopy, nitrogen sorption isotherms, and compression testing. CNC aerogels were evaluated in vitro with osteoblast-like Saos-2 cells and showed an increase in cell metabolism up to 7 days while alkaline phosphatase assays revealed that cells maintained their phenotype. All aerogels demonstrated hydroxyapatite growth over 14 days while submerged in simulated body fluid solution with a 0.1 M CaCl2 pre-treatment. Sulfated CNC aerogels slightly outperformed phosphated CNC aerogels in terms of compressive strength and long-term stability in liquid environments, and were implanted into the calvarian bone of adult male Long Evans rats. Compared to controls at 3 and 12 week time points, sulfated CNC aerogels showed increased bone volume fraction of 33% and 50%, respectively, compared to controls, and evidence of osteoconductivity. These results demonstrate that cross-linked CNC aerogels are flexible, porous and effectively facilitate bone growth after they are implanted in bone defects.Statement of SignificanceDue to the potential complications associated with autografts, there is a need for synthetic bone tissue scaffolds. Here, we report a new naturally-based aerogel material for bone regeneration made solely from chemically cross-linked cellulose nanocrystals (CNC). These highly porous CNC aerogels were shown to promote the proliferation of bone-like cells and support the growth of hydroxyapatite on their surface in vitro. The first in vivo study on these materials was conducted in rats and showed their osteconductive properties and an increase in bone volume up to 50% compared to sham sites. This study demonstrates the potential of using functionalized cellulose nanocrystals as the basis for aerogel scaffolds for bone tissue engineering.Graphical abstractGraphical abstract for this article
       
  • Decellularized neonatal cardiac extracellular matrix prevents widespread
           ventricular remodeling in adult mammals after myocardial infarction
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Zhouguang Wang, Daniel W. Long, Yan Huang, William C.W. Chen, Kang Kim, Yadong Wang Heart disease remains a leading killer in western society and irreversibly impacts the lives of millions of patients annually. While adult mammals do not possess the ability to regenerate functional cardiac tissue, neonatal mammals are capable of robust cardiomyocyte proliferation and regeneration within a week of birth. Given this change in regenerative function through development, the extracellular matrix (ECM) from adult tissues may not be conducive to promoting cardiac regeneration, although conventional ECM therapies rely exclusively on adult-derived tissues. Therefore the potential of ECM derived from neonatal mouse hearts (nmECM) to prevent adverse ventricular remodeling in adults was investigated using an in vivo model of acute myocardial infarction (MI). Following a single administration of nmECM, we observed a significant improvement in heart function while adult heart-derived ECM (amECM) did not improve these parameters. Treatment with nmECM limits scar expansion in the left ventricle and promotes revascularization of the injured region. Furthermore, nmECM induced expression of the ErbB2 receptor, simulating a neonatal-like environment and promoting neuregulin-1 associated cardiac function. Inhibition of the ErbB2 receptor effectively prevents these actions, suggesting its role in the context of nmECM as a therapy. This study shows the potential of a neonatal-derived biological material in vivo, diverting from the conventional use of adult-derived ECM therapies in research and the clinic.Statement of significanceThe of use extracellular matrix biomaterials to aid tissue repair has been previously reported in many forms of injury. The majority of ECM studies to date utilized ECM derived from adult tissues that are not able to fully regenerate functional tissue. In contrast, this study tests the ability of ECM derived from a regenerative organ, the neonatal heart, to stimulate functional cardiac repair after MI. This study is the first to test its potential in vivo. Our results indicate that extracellular factors present in the neonatal environment can be used to alter the healing response in adults, and we have identified the role of ErbB2 in neonatal ECM-based cardiac repair.Graphical abstractGraphical abstract for this article
       
  • Syndiotactic peptides for targeted delivery
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Gaurav Jerath, Ruchika Goyal, Vishal Trivedi, T.R. Santhoshkumar, Vibin Ramakrishnan Lack of cell-type specificity and proteolytic susceptibility have long been the major bottlenecks for the development of peptide-based biomaterials for targeted drug delivery. Though a poly-l backbone provides the adaptability to re-conform the peptide structure to bind to a receptor, it also makes the peptide more susceptible to proteolytic cleavage. We have attempted to address this issue by designing a set of syndiotactic peptides de novo, with alternating l- and d-amino acids in succession. The designed peptides have higher rates of cellular uptake than the Tat (48–60) peptide in breast and cervical cancer cells. The uptake is independent of concentration, temperature and endocytosis (clathrin mediated). Importantly, the peptides are stable in both human plasma and bovine serum. The peptide-drug conjugates are much less toxic to the non-cancerous cells than cancer cells. The designed peptides are a step forward towards the development of targeted drug delivery vectors on peptide templates.Statement of SignificancePresent options in chemotherapy have multiple side effects arising from the lack of cell-type specificity, which makes them synonymous with “a Pyrrhic victory”. Proteolytic susceptibility and non-specificity towards cancer cells has stunted the development of peptide-based biomaterials for targeted drug delivery. We have designed a set of peptides, addressing the above-mentioned roadblocks at an in vitro level. The peptides were designed on the template of a naturally existing peptide antibiotic from Bacillus brevis. The designed peptides have higher rates of cellular transduction than the model peptide (Tat), and is majorly membrane based. The peptides are stable in serum and selective towards cancer cells. Observations presented in this work can potentially take the discipline of de novo design of biomaterial conjugates forward.Graphical abstractGraphical abstract for this article
       
  • Intervertebral disc regeneration with an adipose mesenchymal stem
           cell-derived tissue-engineered construct in a rat nucleotomy model
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Hiroyuki Ishiguro, Takashi Kaito, Seido Yarimitsu, Kunihiko Hashimoto, Rintaro Okada, Junichi Kushioka, Ryota Chijimatsu, Shota Takenaka, Takahiro Makino, Yusuke Sakai, Yu Moriguchi, Satoru Otsuru, David A. Hart, Hiromichi Fujie, Norimasa Nakamura, Hideki Yoshikawa Low back pain results in more global disabilities than any other condition, and intervertebral disc (IVD) degeneration is commonly involved in the etiology. Supplementation of IVDs with reparative cells is a rational strategy to address such clinical problems. We have previously developed a scaffold-free tissue-engineered construct (TEC) as a novel cell therapy system for repair of articular cartilage and meniscus. We now show the regenerative potential of adipose mesenchymal stem cells derived TEC (ADSC-TEC) for IVD degeneration using a rat tail model of total nucleotomy. The regenerative efficacy of ASDC-TEC was investigated structurally and biomechanically up to 6 months after implantation. ADSC-TEC implantation into IVDs preserved the disc height, endplate, and annulus fibrosus structure, and showed similar biomechanical characteristics to the sham group at postoperative 6 weeks. The structure of regenerated IVD was maintained until 6 months. Furthermore, ADSC-TEC implantation attenuated the impact of age-related biomechanical deterioration when assessed at 6 months post-implantation. These results demonstrate that use of ADSC-TECs can be an effective treatment for IVD degeneration.Statement of significanceWe developed adipose mesenchymal stem cell-derived scaffold-free tissue engineered construct (ADSC-TEC) as a novel cell therapy system. The ADSC-TEC implantation into a rat total-nucleotomized disc space regenerated intervertebral discs (IVDs) histologically and biomechanically. The regenerative capacity of the ADSC-TEC was exerted by its trophic effects on annulus fibrosus cells and the load-sharing effect at intervertebral space. Interestingly, the regenerated IVDs by the ADSC-TEC was less susceptible to the age-related deterioration than the IVDs of normal rats. Thus, the application of ADSC-TEC into the degenerated disc can be an alternative therapy for various disease associated with structural and functional failure of IVDs.Graphical abstractGraphical abstract for this article
       
  • Bioinspired baroplastic glycosaminoglycan sealants for soft tissues
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Rui R. Costa, Diana Soares da Costa, Rui L. Reis, Iva Pashkuleva We describe biomimetic adhesives inspired by the marine glues fabricated by the sandcastle worm. The formation of stable polyelectrolyte complexes between poly-L-lysine (PLL) and glycosaminoglycans (GAGs) with different sulfation degree – heparin (HEP), chondroitin sulfate (CS) and hyaluronic acid (HA) – is optimized by zeta-potential titrations. These PLL/GAG complexes are transformed into compact polyelectrolyte complexes (coPECs) with controlled water contents and densities via baroplastic processing. Rotational shear tests demonstrate that coPECs containing sulfated GAGs (HEP or CS) have solid-like properties, whereas HA-based complexes form highly hydrated viscous-like networks. The adhesiveness of the generated coPECs (normalized lap shear strength) is tested in dry and wet states using polystyrene and rabbit skin, respectively. In dry state, the adhesives exhibit lap shear strengths in the order of hundreds of kPa, with coPLL/HEP and coPLL/CS being about 1.5 times stronger than coPLL/HA. In wet state, all coPECs seal rabbit skin and recover over 60% of the elongation capacity of intact skin with coPLL/HA providing the sturdiest adhesion (∼85% elongation recovery). We demonstrate that this is due to the higher water fraction that improves the bonding between the wet specimens, showcasing the potential superior mechanical recovery on injured tissues.Statement of SignificanceThe development of medical sealants with sufficient adhesive strength in the presence of water and moist remains a huge challenge. We present glycosaminoglycans (GAGs) as biomaterials for the assembly of baroplastics with strong adhesive strength to soft tissues at physiological conditions. Baroplastics with tacky properties were generated by a mild assembly process based on polyelectrolyte complexation and compaction. These materials behave as versatile sealants: their adhesiveness can be adjusted to either dry or wet specimens because of the different sulfation degree of GAGs. These sealants were noncytotoxic towards L929 cells and allowed the damaged skin to recover a great deal of its native elasticity: they preserved the J-shaped stress/strain mechanical response that is typical of biological soft tissues.Graphical abstractGraphical abstract for this article
       
  • Incorporation of types I and III collagen in tunable hyaluronan hydrogels
           for vocal fold tissue engineering
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Tanaya Walimbe, Sarah Calve, Alyssa Panitch, M. Preeti Sivasankar Vocal fold scarring is the fibrotic manifestation of a variety of voice disorders, and is difficult to treat. Tissue engineering therapies provide a potential strategy to regenerate the native tissue microenvironment in order to restore vocal fold functionality. However, major challenges remain in capturing the complexity of the native tissue and sustaining regeneration. We hypothesized that hydrogels with tunable viscoelastic properties that present relevant biological cues to cells might be better suited as therapeutics. Herein, we characterized the response of human vocal fold fibroblasts to four different biomimetic hydrogels: thiolated hyaluronan (HA) crosslinked with poly(ethylene glycol) diacrylate (PEGDA), HA-PEGDA with type I collagen (HA-Col I), HA-PEGDA with type III collagen (HA-Col III) and HA-PEGDA with type I and III collagen (HA-Col I-Col III). Collagen incorporation allowed for interpenetrating fibrils of collagen within the non-fibrillar HA network, which increased the mechanical properties of the hydrogels. The addition of collagen fibrils also reduced hyaluronidase degradation of HA and hydrogel swelling ratio. Fibroblasts encapsulated in the HA-Col gels adopted a spindle shaped fibroblastic morphology by day 7 and exhibited extensive cytoskeletal networks by day 21, suggesting that the incorporation of collagen was essential for cell adhesion and spreading. Cells remained viable and synthesized new DNA throughout 21 days of culture. Gene expression levels significantly differed between the cells encapsulated in the different hydrogels. Relative fold changes in gene expression of MMP1, COL1A1, fibronectin and decorin suggest higher degrees of remodeling in HA-Col I-Col III gels in comparison to HA-Col I or HA-Col III hydrogels, suggesting that the former may better serve as a natural biomimetic hydrogel for tissue engineering applications.Statement of SignificanceVoice disorders affect about 1/3rd of the US population and significantly reduce quality of life. Patients with vocal fold fibrosis have few treatment options. Tissue engineering therapies provide a potential strategy to regenerate the native tissue microenvironment in order to restore vocal fold functionality. Various studies have used collagen or thiolated hyaluronan (HA) with gelatin as potential tissue engineering therapies. However, there is room for improvement in providing cells with more relevant biological cues that mimic the native tissue microenvironment and sustain regeneration. The present study introduces the use of type I collagen and type III collagen along with thiolated HA as a natural biomimetic hydrogel for vocal fold tissue engineering applications.Graphical abstractGraphical abstract for this article
       
  • Selective stiffening of fibrin hydrogels with micron resolution via
           photocrosslinking
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Mark Keating, Micah Lim, Qingda Hu, Elliot Botvinick Fibrin hydrogels are used as a model system for studying cell-ECM biophysical interactions. Bulk mechanical stiffness of these hydrogels has been correlated to mechanotransduction and downstream signaling. However, stiffness values proximal to cells can vary by orders of magnitude at the length scale of microns. Patterning of matrix stiffness at this spatial scale can be useful in studying such interactions. Here we present and evaluate a technique to selectively stiffen defined regions within a fibrin hydrogel. Laser scanning illumination activates ruthenium-catalyzed crosslinking of fibrin tyrosine residues, resulting in tunable stiffness changes spanning distances as small as a few microns and a localized compaction of the material. As probed by active microrheology, stiffness increases by as much as 25X, similar to previously observed stiffness changes around single cells in 3D culture. In summary, our method allows for selective modification of fibrin stiffness at the micron scale with the potential to create complex patterns, which could be valuable for the investigation of mechanotransduction in a biologically meaningful way.Statement of SignificanceFibrin hydrogels are used as a naturally derived model to study interactions between cells and their surrounding extracellular matrix (ECM). ECM stiffness influences cell state. Cells in 3D culture considerably modify the stiffness of their pericellular space, which can be quite heterogeneous at the micron-scale. Here we present and evaluate a method to pattern stiffness within fibrin hydrogels using a laser scanning confocal microscope and selective photo crosslinking. We believe that this technique can aid future studies of cell-ECM interactions by enabling researchers to modify the pericellular distribution of stiffness.Graphical abstractGraphical abstract for this article
       
  • Platelet rich plasma hydrogels promote in vitro and in vivo angiogenic
           potential of adipose-derived stem cells
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Meghan Samberg, Randolph Stone, Shanmugasundaram Natesan, Andrew Kowalczewski, Sandra Becerra, Nicole Wrice, Andrew Cap, Robert Christy Despite great advances in skin wound care utilizing grafting techniques, the resulting severe scarring, deformity and ineffective vascularization remains a challenge. Alternatively, tissue engineering of new skin using patient-derived stem cells and scaffolding materials promises to greatly increase the functional and aesthetic outcome of skin wound healing. This work focused on the optimization of a polyethylene glycol modified (PEGylated) platelet-rich plasma (PRP) hydrogel for the protracted release of cytokines, growth factors, and signaling molecules and also the delivery of a provisional physical framework for stem cell angiogenesis. Freshly collected whole blood was utilized to synthesize PEGylated PRP hydrogels containing platelet concentrations ranging from 0 to 200,000 platelets/µl. Hydrogels were characterized using thromboelastography and impedance aggregometry for platelet function and were visualized using scanning electron microscopy. To assess the effects of PEGylated PRP hydrogels on cells, PRP solutions were seeded with human adipose-derived stem cells (ASCs) prior to gelation. Following 14 days of incubation in vitro, increased platelet concentrations resulted in higher ASC proliferation and vascular gene and protein expression (assessed via RT-PCR, ELISA, and immunochemistry). Using a rat skin excision model, wounds treated with PRP + ASC hydrogels increased the number of vessels in the wound by day 8 (80.2 vs. 62.6 vessels/mm2) compared to controls. In conclusion, the proposed PEGylated PRP hydrogel promoted both in vitro and transient in vivo angiogenesis of ASCs for improved wound healing.Statement of SignificanceOur findings support an innovative means of cellular therapy intervention to improve surgical wound healing in a normal wound model. ASCs seeded within PEGylated PRP could be an efficacious and completely autologous therapy for treating patients who have poorly healing wounds caused by vascular insufficiency, previous irradiation, or full-thickness burns. Because wound healing is a dynamic and complex process, the application of more than one growth factor with ASCs demonstrates an advantageous way of improving healing.Graphical abstractGraphical abstract for this article
       
  • Tissue-mimicking gelatin scaffolds by alginate sacrificial templates for
           adipose tissue engineering
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Nicola Contessi Negrini, Mathilde Bonnetier, Giorgio Giatsidis, Dennis P. Orgill, Silvia Farè, Benedetto Marelli When adipose tissue (AT) is impaired by trauma or disease, AT engineering could provide a shelf-ready structural and functional restoration as alternative to current clinical treatments, which mainly aim at aesthetic replacement. Yet, the lack of an efficient vascular network within the scaffolds represents a major limitation to their translation application in patients. Here, we propose the use of microstructured crosslinked gelatin hydrogels with an embedded prevascular channel as scaffolding materials for AT engineering. The scaffolds are fabricated using – simultaneously – alginate-based microbeads and 3D printed filaments as sacrificial material encapsulated in gelatin at the point of material fabrication and removed post-crosslinking. This method yields the formation of microstructures that resemble the micro-architecture of physiological human fat tissue and of microvessels that can facilitate vascularization through anastomosis with patients’ own blood vessels. The cytocompatible method used to prepare the gelatin scaffolds showed structural stability over time while allowing for cell infiltration and protease-based remodeling/degradation. Scaffolds’ mechanical properties were also designed to mimic the one of natural breast adipose tissue, a key parameter for AT regeneration. Scaffold’s embedded channel (∅ = 300–400 µm) allowed for cell infiltration and enabled blood flow in vitro when an anastomosis with a rat blood artery was performed using surgical glue. In vitro tests with human mesenchymal stem cells (hMSC) showed colonization of the porous structure of the gelatin hydrogels, differentiation into adipocytes and accumulation of lipid droplets, as shown by Oil Red O staining.Statement of SignificanceThe potential clinical use of scaffolds for adipose tissue (AT) regeneration is currently limited by an unmet simultaneous achievement of adequate structural/morphological properties together with a promoted scaffold vascularization. Sacrificial materials, currently used either to obtain a tissue-mimicking structure or hollow channels to promote scaffold’ vascularization, are powerful versatile tools for the fabrication of scaffolds with desired features. However, an integrated approach by means of sacrificial templates aiming at simultaneously achieving an adequate AT-mimicking structure and hollow channels for vascularization is missing. Here, we prove the suitability of crosslinked gelatin scaffolds obtained by using sacrificial alginate microbeads and 3D printed strands to achieve proper features and hollow channels useful for scaffolds vascularization.Graphical abstractGraphical abstract for this article
       
  • The influence of alloying and fabrication techniques on the mechanical
           properties, biodegradability and biocompatibility of zinc: A comprehensive
           review
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): J. Venezuela, M.S. Dargusch Zinc has been identified as one of the most promising biodegradable metals along with magnesium and iron. Zinc appears to address some of the core engineering problems associated with magnesium and iron when applied to biomedical implant applications; hence the increase in the amount of research investigations on the metal in the last few years. In this review, the current state-of-the-art on biodegradable Zn, including recent developments, current opportunities and future directions of research are discussed. The discussions are presented with a specific focus on reviewing the relationships that exist between mechanical properties, biodegradability, and biocompatibility of zinc with alloying and fabrication techniques. This work hopes to guide future studies on biodegradable Zn that will help in advancing this field of research.Statement of Significance(i) The review offers an up-to-date and comprehensive review of the influence of alloying and fabrication technique on mechanical properties, biodegradability and biocompatibility of Zn; (ii) the work cites the most relevant biodegradable Zn fabrication processes including additive manufacturing techniques; (iii) the review includes a listing of research gap and future research directions for the field of biodegradable Zn.Graphical abstractGraphical abstract for this article
       
  • Novel β-Ti35Zr28Nb alloy scaffolds manufactured using selective laser
           melting for bone implant applications
    • Abstract: Publication date: 15 March 2019Source: Acta Biomaterialia, Volume 87Author(s): Yuncang Li, Yunfei Ding, Khurram Munir, Jinxing Lin, Milan Brandt, Andrej Atrens, Yin Xiao, Jagat Rakesh Kanwar, Cuie Wen Titanium (Ti) based tissue engineering scaffolds can be used to repair damaged bone. However, successful orthopedic applications of these scaffolds rely on their ability to mimic the mechanical properties of trabecular bone. Selective laser melting (SLM) was used to manufacture scaffolds of a new β-Ti35Zr28Nb alloy for biomedical applications. Porosity values of the scaffolds were 83% for the FCCZ structure (face centered cubic unit cell with longitudinal struts) and 50% for the FBCCZ structure (face and body centered cubic unit cell with longitudinal struts). The scaffolds had an elastic modulus of ∼1 GPa and a plateau strength of 8–58 MPa, which fall within the values of trabecular bone (0.2–5 GPa for elastic modulus and 4–70 MPa for compressive strength). The SLM-manufactured β-Ti35Zr28Nb alloy showed good corrosion properties. MTS assay revealed that both the FCCZ and FBCCZ scaffolds had a cell viability similar to the control. SEM observation indicated that the osteoblast-like cells adhered, spread and grew healthily on the surface of both scaffolds after culture for 7, 14 and 28 d, demonstrating good biocompatibility. Overall, the SLM-manufactured Ti35Zr28Nb scaffolds possess promising potential as hard-tissue implant materials due to their appropriate mechanical properties, good corrosion behavior and biocompatibility.Statement of SignificanceNovel β Ti35Zr28Nb alloy scaffolds with FCCZ and FBCCZ structures were successfully fabricated by selective laser melting (SLM) for biomedical applications. The scaffolds showed values of elastic modulus of ∼1 GPa and plateau strength of 8–58 MPa, which fall within the ranges of the mechanical properties of trabecular bone. The SLM-manufactured β Ti35Zr28Nb alloy showed good corrosion properties. Both SLM-manufactured FCCZ and FBCCZ scaffolds exhibited good biocompatibility, with osteoblast-like cells attaching, growing, and spreading in a healthy way on their surfaces after culturing for different periods up to 28 d.Graphical abstractGraphical abstract for this article
       
  • Aerosol technique-based carbon-encapsulated hollow mesoporous silica
           nanoparticles for synergistic chemo-photothermal therapy
    • Abstract: Publication date: Available online 26 February 2019Source: Acta BiomaterialiaAuthor(s): Milan Gautam, Raj Kumar Thapa, Bijay Kumar Poudel, Biki Gupta, Hima Bindu Ruttala, Hanh Thuy Nguyen, Zar Chi Soe, Wenquan Ou, Kishwor Poudel, Han-Gon Choi, Sae Kwang Ku, Chul Soon Yong, Jong Oh Kim Near-infrared (NIR)-responsive drug delivery systems have enhanced tumor ablative efficiency through permeation and retention effects. Graphene oxide (GO) has shown great potential both in photothermal therapy and in drug delivery. Thus, in this study, we designed an ambient spark-generated GO, wrapped on topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSN-NH2-TPT-CGO), to function as an efficient platform for pH-dependent sustained release of TPT. HMSN-NH2-TPT-CGO also exhibited a combined chemo-photothermal effect within a single carrier system. This developed system was stable with a uniform particle size (∼190 nm) and was demonstrated to possess a sufficient heat-absorbing capacity to induce tumor cell ablation. We performed the ablation of tumor cells both in vitro and in vivo in combination with photothermal therapy and chemotherapy using the spark-generated functional GO and HMSN. The prepared nanocarriers demonstrated high cellular uptake, apoptosis, and G0/G1 cell cycle arrest. In vivo study using the MDA-MB-231 xenograft model revealed the ultraefficient tumor ablative performance of HMSN-NH2-TPT-CGO compared with that of free TPT, with no toxic effect on vital organs. Altogether, the optimized nanocarriers presented a significant potential to act as a vehicle for cancer treatment.Statement of significanceThis is the first study that uses spark-generated graphene oxide nanoflakes to cover the topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSNs) to treat breast cancer. Dense silica was used as a hard template to prepare the HMSNs attributing to a high drug payload. The concentration of Na2CO3 was precisely controlled to minimize the silica etching time within 70 min. The use of the nanographene flakes served a dual purpose, first, by acting as a capping agent to prevent the premature release of drug and, second, by serving as a nano heater that significantly ablates the tumor cells. The prepared nanocarriers (NCs) exhibited effective and enhanced in vitro and in vivo apoptosis, as well as significant tumor growth inhibition even after 15 days of treatment time, with toxic effect to the vital organs. The NCs enhanced in vitro tumor cell killing effects and served as an effective carrier for in vivo tumor regression, thereby highlighting the enormous potential of this system for breast cancer therapy.Graphical abstractGraphical abstract for this article
       
  • A Genetically Engineered Fc-binding Amphiphilic Polypeptide for
           Congregating Antibodies in vivo
    • Abstract: Publication date: Available online 26 February 2019Source: Acta BiomaterialiaAuthor(s): Wen Liu, Stephanie Wong-Noonan, Ngoc B. Pham, Isha Pradhan, Amy Spigelmyer, Riley Funk, Justin Nedzesky, Henry Cohen, Ellen S. Gawaltd, Yong Fan, Wilson S. Meng We report herein an affinity-based hydrogel used in creating subcutaneous depots of antibodies in vivo. The biomaterials design centered on pG_EAK, a polypeptide we designed and expressed in E.coli. The sequence consists of a truncated protein G (pG) genetically fused with repeats of the amphiphilic sequence AEAEAKAK (“EAK”). Capture of IgG was demonstrated in vitro in gels prepared from admixing pG_EAK and EAK (“pG_EAK/EAK gel”). The binding affinities and kinetics of pG for IgG were recapitulated in the pG_EAK polypeptide. Injecting IgG antibodies formulated with pG_EAK/EAK gel into subcutaneous space resulted in retention of the antibodies at the site for at least six days, whereas only signal at background levels was detected in grafts injected with IgG formulated in saline or diffusion-driven gel. The local retention of IgG in pG_EAK/EAK gel was correlated with limited distribution of the antibody in liver, spleen and lymph nodes, in contrast to those injected with antibodies formulated in saline or non-Fc binding EAK gel. In addition, antibodies formulated with pG_EAK/EAK gel and injected in mouse footpads were found to retain at the site for 19 days. As a demonstration of potential bioengineering applications, thymic epithelial cells (TECs), the primary population of thymic stromal cells that are critical for the development of T-lymphocytes, were mixed with pG_EAK/EAK gel formulated with TEC-specific anti-EpCAM antibodies and injected subcutaneously into athymic nude mice. The injected TECs congregated into functional thymic units in vivo, supporting the development of both CD4+ and CD8+ T cells as well as Foxp3+ regulatory T cells in the mice. In conclusion, pG_EAK/EAK gel can be used to retain IgG locally in vivo, and can be tailored as scaffolds for controlling deposition of molecular and/or cellular therapeutics.Statement of significanceThe unique concept of the work centers on the genetic fusion of an Fc-binding domain and a self-assembling domain into a single polypeptide. To our knowledge, such bi-functional peptide has not been reported in the literature. The impact of the work lies in the ability to display IgG antibodies and Fc-fusion proteins of any specificity. The data shown demonstrate the platform can be used to localize IgG in vivo, and can be tailored for controlling deposition of primary thymic epithelial cells (TECs). The results support a biomaterials-based strategy by which TECs can be delivered as functional units to support T-lymphocyte development in vivo. The platform described in the study may serve as an important tool for immune engineering.Graphical abstractGraphical abstract for this article
       
  • Synthesis and assessment of drug-eluting microspheres for transcatheter
           arterial chemoembolization
    • Abstract: Publication date: Available online 26 February 2019Source: Acta BiomaterialiaAuthor(s): Lingran Du, Yugang Huang, Qiang Zhang, Yi Zhou, Jianwen Huang, Libiao Yan, Zongjun Yu, Aiping Qin, Hainan Yang, Mianrong Chen, Lu Liang, Biyun Bian, Xufeng Li, Jijun Fu Transcatheter arterial chemoembolization (TACE) is well known as an effective treatment for inoperable hepatocellular carcinoma (HCC). In this study, a novel embolic agent of ion-exchange poly(hydroxyethyl methacrylate-acrylic acid) microspheres (HAMs) was successfully synthesized by the inverse suspension polymerization method. Then, HAMs were assessed for their activity as an embolic agent by investigating morphology, particle size, water retention capability, elasticity and viscoelasticity, microcatheter/catheter deliverability, cytotoxicity, renal arterial embolization to rabbits and histopathological examinations. The ability of drug loading and drug eluting of HAMs was also investigated by using doxorubicin (Dox) as the model drug. HAMs showed to be feasible and effective for vascular embolization and to be as a drug vehicle for loading positively charged molecules and potential use in the clinical interventional chemoembolization therapy.Statement of SignificanceA novel embolic agent of ion-exchange poly(hydroxyethyl methacrylate-acrylic acid) microspheres (HAMs) was successfully synthesized by the inverse suspension polymerization method and was used as a drug vehicle to load positively charged molecules by ion absorption. Then, a series of assessments including physicochemical properties, mechanical properties, drug-loading capability, and embolic efficacy were performed. Surface and cross-section morphology and pore size of fully hydrated HAMs were first investigated by Phenom ProX SEM, which intuitively disclosed the “honeycomb” network morphology. HAMs also showed to be feasible and effective for vascular occlusion and have potential use in clinical interventional embolization therapy.Graphical abstractGraphical abstract for this article
       
  • A polymeric micelle with an endosomal pH-sensitivity for intracellular
           delivery and enhanced antitumor efficacy of hydroxycamptothecin
    • Abstract: Publication date: Available online 26 February 2019Source: Acta BiomaterialiaAuthor(s): Xiaohui Pu, Luling Zhao, Jia Li, Rufeng Song, Yanling Wang, Keke Yu, Xianqiao Hou, Peng Qiao, Lanlan Zong, Sheng Chang Amphiphilic poly(ethylene glycol)-imino-poly(benzyl-L-aspartate) (PIPA) and poly(ethylene glycol)-poly(benzyl-L-aspartate) (PPA) block copolymers were synthesized as pH-responsive and pH-nonresponsive copolymers, respectively. Polymer micelles were fabricated by the film dispersion method, and hydroxycamptothecin (HCPT) was physically encapsulated into the micelles. The average diameter of the HCPT-loaded PIPA micelles (PIPAH micelles) was approximately 230 nm, which was slightly smaller than that of the HCPT-loaded PPA micelles (PPAH micelles, approximately 260 nm). The drug-loading content and encapsulation efficiency of the PIPAH micelles (3.33% and 68.89%, respectively) were slightly higher than those of the PPAH micelles (2.90% and 59.68%, respectively). The PIPAH micelles exhibited better colloid stability, storage stability, and plasma stability than the PPAH micelles. Drug release from the PIPAH micelles with imino groups was pH dependent, and more than 75% or 65% of the loaded HCPT was released within 24 h in weakly acidic media (pH 5.0 or 6.0, respectively). An in vitro cell assay demonstrated that the pH-sensitive micelles exhibited potent suppression of cancer cell proliferation and little cytotoxicity on normal cells. Additionally, these micelles could be efficiently internalized by the tumor cells through macropinocytosis- and caveolin-mediated endocytotic pathways. HCPT-loaded micelles had longer circulation time than the HCPT solution in a pharmacokinetic study. In vivo antitumor experiments indicate that the PIPAH micelles had better antitumor efficacy than the pH-insensitive PPAH micelles and the HCPT solution. Therefore, the pH-responsive PIPAH micelles have great potential for high-efficiency delivery of HCPT.Statement of significanceIn this study, a new type of pH-responsive amphiphilic copolymer, poly(ethylene glycol)-imino-poly(benzyl-L-aspartate) (PIPA) block copolymer, was synthesized. This copolymer had then self-assembled to form nanomicelles for tumor intracellular delivery of hydroxycamptothecin (HCPT) for the first time. In in vitro test, the PIPAH micelles exhibited adequate stability and pH-dependent drug release. To one's excitement, the PIPAH micelles exhibited better antitumor efficacy and biosafety than the pH-insensitive micelles (PPAH) and the HCPT solution in in vitro and in vivo antitumor experiments. Therefore, the pH-responsive micelles in this study have significant potential to be used for high-performance delivery of HCPT and potentially for the targeted delivery of other cancer therapeutic agents. The polymer designed in this study can be used as a carrier of poorly soluble drugs or other active ingredients.Graphical abstractGraphical abstract for this article
       
  • Release of methylene blue from graphene oxide-coated electrospun
           nanofibrous scaffolds to modulate functions of neural progenitor cells
    • Abstract: Publication date: Available online 26 February 2019Source: Acta BiomaterialiaAuthor(s): Lina Wang, Xiaoyun Liu, Jiqiang Fu, Xinyu Ning, Mengxin Zhang, Ziyun Jiang, Guosheng Cheng, Yimin Zhu, Zhijun Zhang Transplantation of neural progenitor cells (NPCs) can repair the damaged neurons and therefore holds significant promise as a new treatment strategy for Alzheimer’s disease (AD). Development of functional scaffolds for the growth, proliferation, and differentiation of NPCs offers a useful approach for AD therapy. In our study, the functional scaffolds were obtained by fabrication of a poly(lactic-co-glycolic acid) (PLGA) nanofibrous mat by the electrospinning technique, followed by coating of a layer of graphene oxide (GO) and then physisorption of methylene blue (MB) under mild conditions. The precoating of GO on the nanofibrous scaffolds allows efficient loading and release of MB from the substrate for regulating the functions of NPCs. The NPCs cultured on the scaffolds remained in the quiescence phase due to the activation of autophagy signaling pathway by MB. Moreover, the MB-loaded nanofibrous scaffolds diminish tau phosphorylation and protect NPCs from apoptosis. Definitely, more work, especially the in vivo experiment, is highly desired to demonstrate the feasibility of the current strategy for AD treatment.Statement of SignificanceTransplantation of neural progenitor cells (NPCs) can repair the damaged neurons, and holds significant promise as a new treatment strategy for Alzheimer’s disease (AD). Development of functional scaffolds for the growth, proliferation, and differentiation of NPCs offers a novel and useful approach for AD therapy. In this work, we have developed a GO and MB sequentially coated PLGA nanofibrous mat as a new scaffold for NPCs transplantation and tauopathy inhibition. The coating of GO, that we have demonstrated, significantly enhanced the loading and release of MB on the scaffolds. Furthermore, NPCs cultured on the nanofibrous scaffolds entered quiescence phase throughvia the activation of autophagy signaling pathway, leading to improved performance of NPCs to cope with stressors of disease. More importantly, the release of MB from the scaffolds leads to attenuation of tauopathy and protection of NPCs, which may represent a novel, versatile, and effective therapeutic approach for AD and other neurodegenerative diseases.Graphical abstractGraphical abstract for this article
       
  • Role of Polydopamine’s Redox-Activity on its Pro-oxidant,
           Radical-Scavenging, and Antimicrobial Activities
    • Abstract: Publication date: Available online 25 February 2019Source: Acta BiomaterialiaAuthor(s): Huan Liu, Xue Qu, Haoqi Tan, Jialin Song, Miao Lei, Eunkyoung Kim, Gregory F. Payne, Changsheng Liu Polydopamine (PDA) is a bioinspired material and coating that offers diverse functional activities (e.g., photothermal, antioxidant, and antimicrobial) for a broad range of applications. Although PDA is reported to be redox active, the association between PDA’s redox state and its functional performance has been difficult to discern because of PDA’s complex structure and limitations in methods to characterize redox-based functions. Here, we use an electrochemical reverse engineering approach to confirm that PDA is redox-active and can repeatedly accept and donate electrons. We observed that the electron-donating ability of PDA offers the detrimental pro-oxidant effect of donating electrons to O2 to generate reactive oxygen species (ROS) or, alternatively, the beneficial antioxidant effect of quenching oxidative free radicals. Importantly, PDA’s electron-donating ability depends on its redox state and is strongly influenced by external factors including metal ion binding as well as near-infrared (NIR) irradiation. Furthermore, we demonstrated that PDA possesses redox state-dependent antimicrobial properties in vitro and in vivo. We envision that clarification of PDA’s redox activity will enable better understanding of PDA’s context-dependent properties (e.g., antioxidant and pro-oxidant) and provide new insights for further applications of PDA.Statement of significanceWe believe this is the first report to characterize the redox activities of polydopamine (PDA) and to relate these redox activities to functional properties important for various proposed applications of PDA.We observed that polydopamine nanoparticles 1) are redox-active; 2) can repeatedly donate and accept electrons; 3) can accept electrons from reducing agents (e.g., ascorbate), donate electrons to O2 to generate ROS, and donate electrons to free radicals to quench them; 4) have redox state-dependent electron-donating abilities that are strongly influenced by metal ion binding as well as NIR irradiation; and 5) have redox state-dependent antimicrobial activities.Graphical abstractGraphical abstract for this article
       
  • Macroporous Nanofiber Wraps Promote Axonal Regeneration and Functional
           Recovery in Nerve Repair by Limiting Fibrosis
    • Abstract: Publication date: Available online 23 February 2019Source: Acta BiomaterialiaAuthor(s): Karim A. Sarhane, Zuhaib Ibrahim, Russell Martin, Kellin Krick, Christopher R. Cashman, Sami H. Tuffaha, Justin M. Broyles, Nijaguna Prasad, Zhi-Cheng Yao, Damon S. Cooney, Ruifa Mi, WP Andrew Lee, Ahmet Hoke, Hai-Quan Mao, Gerald Brandacher Functional outcomes following nerve repair remain suboptimal. Scarring at the repair site is a major impediment to regeneration. A biomaterial scaffold applied around the coaptation site that decreases inflammation holds great potential in reducing scarring, enhancing axonal growth, and improving functional recovery. In this study, we evaluated the effect of a macroporous nanofiber wrap, comprised of nonwoven electrospun poly-ε-caprolactone (PCL), in improving axonal regeneration in a rat sciatic nerve cut and direct repair model. Controls consisted of conventional epineurial repair. We also evaluated our wrap against the commercially available AxoGuard wrap. At five weeks following repair, the nanofiber wrap group showed a significantly decreased intraneural macrophage invasion and collagen deposition at the repair site. This was associated with increased expression of the anti-inflammatory cytokine (IL-10), decreased expression of the pro-inflammatory cytokine (TNF-α), and a decrease in the M1:M2 macrophage phenotype ratio. These findings suggest that this nanofiber wrap, with its unique macroporosity, is modulating the inflammatory response at the repair site by polarizing macrophages towards a pro-regenerative M2 phenotype. Concomitantly, a higher number of regenerated axons was noted. At sixteen weeks, the nanofiber wrap resulted in enhanced functional recovery as demonstrated by electrophysiology, neuromuscular re-innervation, and muscle histology. When compared to the AxoGuard wrap, the nanofiber wrap showed similar inflammation at the repair site and similar nerve morphometric findings, but there was a trend towards a lower overall number of macrophages invading the wrap wall. These results demonstrate favorable outcomes of the macroporous nanofiber wrap in promoting neuroregeneration and functional recovery following nerve repair.Statement of SignificanceElectrospun nanofiber scaffolds, with specific fiber and pore sizes, were shown to modulate the immune response and create regenerative environment. In this paper, we present a macroporous nanofiber wrap, made of poly-ε-caprolactone, to be applied at the coaptation site in primary nerve repair. We show that it regulates the inflammatory response at the repair site and decreases scarring/fibrosis. This results in enhanced axonal regeneration, allowing a higher number of axons to cross the suture line and reach the target muscle in a timely fashion. Functional outcomes are thus improved.Graphical abstractGraphical abstract for this article
       
  • Human neutrophils degrade methacrylate resin composites and tooth dentin
    • Abstract: Publication date: Available online 23 February 2019Source: Acta BiomaterialiaAuthor(s): Russel Gitalis, Liangyi Zhou, Muna Q. Marashdeh, Chunxiang Sun, Michael Glogauer, Yoav Finer Cholesterol esterase-like (CE) activity from saliva and esterase from cariogenic bacteria hydrolyze ester linkages of dental methacrylate resins. Collagenolytic, matrix metalloproteinase-like (MMP) activities from dentin and bacteria degrade collagen in demineralized tooth dentin. Human neutrophils in the oral cavity contain factors that are hypothesized to have CE and MMP activities that could contribute to the degradation of methacrylate resins and dentinal collagen.ObjectivesTo measure the CE and MMP activities from human neutrophils and their ability to degrade dental methacrylate resin composite and dentinal collagen.Neutrophils’ CE and MMP activities were measured using nitrophenyl-esters or fluorimetric MMP substrates, respectively. Neutrophils’ degradation of resin composite and dentinal collagen was quantified by measuring release of a universal 2,2-Bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane (bisGMA)-derived resin composite degradation byproduct, bishydroxy-propoxy-phenyl-propane (BisHPPP), or a collagen degradation by-product, hydroxyproline, respectively using ultra performance liquid chromatography/mass spectrometry.Neutrophils’ CE activity increased the release of bisHPPP from bisGMA monomer compared to control after 24 and 48 hours (p
       
  • Calcium phosphate scaffolds with defined interconnecting channel structure
           
    • Abstract: Publication date: Available online 20 February 2019Source: Acta BiomaterialiaAuthor(s): Sanja Aveic, Roswitha Davtalab, Michael Vogt, Michael Weber, Patricia Buttler, Gian Paolo Tonini, Horst Fischer Metastasis of tumor cells in the bone marrow (BM) is a multi-step and highly dynamic process during which cells succumb important phenotypic changes. Behavior of disseminated tumor cells in BM is strictly regulated by three-dimensional (3D) cell-cell and cell-matrix interactions. In this study, we explored whether the β-tricalcium-phosphate (β-TCP) scaffolds with a tailored interconnecting channel structure could enable appropriate 3D mimetic BM microenvironment for the growth of metastatic neuroblastoma cells. The scaffolds provided the mechanical support for human mesenchymal stromal cells (hMSC) allowing them to proliferate, differentiate towards osteoblasts, and produce the deposits of extracellular matrix inside the interconnected channels. The in vitro microenvironment shaped by stromal cells was then tailored by neuroblastoma tumor cells. Immunohistological analyses confirmed the organization of tumor cells into the forms of spheres only when co-cultured with hMSC-derived osteoblasts. The growing rate of tumor cells in 3D conditions was less marked comparing to the one of the cells grown as 2D monolayer as confirmed by decreased Ki-67 expression. Instead, the 3D culturing of neuroblastoma cells inside supportive stroma promoted cell quiescence as sustained by increased p27 level. A balance between cell proliferation, survival, and differentiation was more evident for tumor cells grown inside the 3D scaffolds, thus mirroring better the situation that occurs in vivo where the cells do not follow the exponential growth rate. We conclude that the proposed 3D β-TCP scaffold type provides a mimetic 3D in vitro niche suitable for studying behavior of BM metastasized tumor cells.Statement of SignificanceBone marrow (BM) niche is a favorite target of metastatic neuroblastoma cells. To better address the molecular mechanisms that sustain spatiotemporal organization of neuroblastoma cells in the marrow we mimicked the three-dimensional (3D) assembly of stromal and tumor cells inside β-tricalcium-phosphate (β-TCP) scaffolds. β-TCP scaffolds with a tailored interconnecting channel structure provided mechanical support to mesenchymal stromal cells allowing them to differentiate towards osteoblasts and to produce extracellular matrix. A dynamic cell-matrix interplay favored the characteristic rosette-like growth of metastatic neuroblastoma cells and triggered their quiescence. With our study, we confirmed the potential of β-TCP scaffolds with reproduced BM niche as a cost-effective in vitro model for the growth of disseminated tumor cells, and for related biological and pharmacological surveys.Graphical abstractGraphical abstract for this article
       
  • Recent Advancements in Mesoporous Silica Nanoparticles towards Therapeutic
           Applications for Cancer
    • Abstract: Publication date: Available online 20 February 2019Source: Acta BiomaterialiaAuthor(s): Tingting Li, Sixiang Shi, Shreya Goel, Xue Shen, Xiaoxue Xie, Zhongyuan Chen, Hanxi Zhang, Shun Li, Xiang Qin, Hong Yang, Chunhui Wu, Yiyao Liu Recently, drug delivery systems based on nanotechnology have received great attention in cancer therapeutics and diagnostics since they can not only improve the treatment efficacy but also reduce the side effects. Among them, mesoporous silica nanoparticles (MSNs) with large surface area, high pore volume, tunable pore size, abundant surface chemistry, and acceptable biocompatibility exhibit unique advantages and are considered as promising candidates for cancer diagnosis and therapy. In this review, we update the recent progress on MSN-based systems for cancer treatment purposes. We also discuss the drug loading mechanism of MSNs, stimuli-responsive drug release, and surface modification strategies for improving biocompatibility, and targeting functionalities.Statement of SignificanceThe development of MSN-based delivery systems that can be used in both diagnosis and treatment of cancer has attracted tremendous interest in the past decade. MSN-based delivery systems can improve therapeutic efficacy and reduce cytotoxicity to normal tissue. To further improve the in vivo properties of MSNs and potential translation to the clinics, it is critical to design MSNs with appropriate surface engineering and desirable cancer targeting. This review is intended to provide the readers a comprehensive background of the vast literature till date on silica-based drug delivery systems, and to inspire further innovations in silica nanomedicine in the future.Graphical abstractGraphical abstract for this article
       
  • Racioethnic Differences in the Biomechanical Response of the Lamina
           Cribrosa
    • Abstract: Publication date: Available online 20 February 2019Source: Acta BiomaterialiaAuthor(s): Reza Behkam, Hirut G. Kollech, Anirban Jana, Amy Hill, Forest Danford, Stephen Howerton, Sundaresh Ram, Jeffrey J. Rodríguez, Urs Utzinger, Christopher A. Girkin, Jonathan P. Vande Geest Glaucoma is the second leading cause of irreversible blindness in the world with a higher prevalence in those of African Descent (AD) and Hispanic Ethnicity (HE) than in those of European Descent (ED). The objective of this study was to investigate the pressure dependent biomechanical response of the lamina cribrosa (LC) in normal human donor tissues from these racioethnic backgrounds. Pressure inflation tests were performed on 24 human LCs (n=9 AD, n=6 ED, and n=9 HE) capturing the second harmonic generation (SHG) signal of collagen at 5, 15, 30, and 45 mmHg from an anterior view. A non-rigid image registration technique was utilized to determine the 3D displacement field in each LC from which 3D Green strains were calculated. The peak shear strain in the superior quadrant of the LC in those of ED was significantly higher than in those of AD and HE (p-value = 0.005 & 0.034, respectively) where ED = 0.017 [IQR = 0.012 - 0.027], AD = 0.0002 [IQR = -0.001 - 0.007], HE = 0.0016 [IQR = -0.002 - 0.012]). There were also significant differences in the regional strain heterogeneity in those of AD and HE that were absent in those of ED. This work represents, to our knowledge, the first ex-vivo study identifying significant differences in the biomechanical response of the LC in populations at increased risk of glaucoma. Future work will be necessary to assess if and how these differences play a role in predisposing those of Hispanic Ethnicity and African Descent to the onset and/or progression of primary open angle glaucoma.Statement of SignificanceGlaucoma is the second leading cause of irreversible blindness in the world and occurs more frequently in those of African Descent and Hispanic Ethnicity than in those of European Descent. To date, there has been no ex-vivo study quantifying differences in the biomechanical response of the non-glaucomatous lamina cribrosa (LC) across these racioethnic backgrounds. In this work we report, for the first time, differences in the pressure dependent biomechanical response of LC across different racioethnic groups as quantified using nonlinear optical microscopy. This study lays the foundation for future work investigating if and how these differences may play a role in predisposing those at increased risk to the onset and/or progression of primary open angle glaucoma.Graphical abstractGraphical abstract for this article
       
  • A transferrin receptor-binding mucoadhesive elastin-like recombinamer: in
           vitro and in vivo characterization
    • Abstract: Publication date: Available online 19 February 2019Source: Acta BiomaterialiaAuthor(s): Constancio Gonzalez-Obeso, Alessandra Girotti, J. Carlos Rodriguez-Cabello The development of mucoadhesive materials is of great interest and is also a major challenge. Being adsorption sites, mucosae are suitable targets for drug delivery, but as defensive barriers they are complex biological surfaces to interact with, mainly due to their protective mucus layer. As such, first- and second-generation mucoadhesives focused on material-mucus interactions, whereas the third generation of mucoadhesives introduced structural motifs that are able to interact with the cells beneath the mucus layer. The combination of different prerequisites (water solubility, soft gel formation at body temperature and able to interact with the mucus) in a single molecule is easily achieved using elastin-like recombinamers (ELRs) given their multiple block design. Moreover, we have been able to introduce a short amino-acid sequence known as T7 that is able to bind to transferrin receptors in the epithelial cell layer. The T7 sequence enhances the cell-binding properties of the mucoadhesive ELR (MELR), as demonstrated using a Caco-2 epithelial cell model. In vivo experiments confirmed the mucoadhesive properties found in vitro.Statement of SignificanceThe development of a mucoadhesive material is a major challenge. Mucosae are suitable targets for drug delivery, but as defense barriers, they are complex surfaces to interact with. In this work we report the first ELR that combines different functional blocks, in a single molecule, which provide it with the properties of soft-gel forming at body temperature and being able of efficiently adhering to the mucus layer of mucosas, as well as to the underlying epithelial cell layer, as demonstrated in vitro and in vivo.The rationally designed materials presented in this work sets the basis for developing ELR-based, mucosa-directed drug delivery systems, which could improve patient’s compliance, enhancing drug retention at the mucosal site.Graphical abstractGraphical abstract for this article
       
  • Effect of magnesium-degradation products and hypoxia on the angiogenesis
           of human umbilical vein endothelial cells
    • Abstract: Publication date: Available online 19 February 2019Source: Acta BiomaterialiaAuthor(s): Lei Xu, Regine Willumeit-Römer, Bérengère J.C. Luthringer-Feyerabend Biodegradable magnesium (Mg) metals have been applied in orthopaedic and stent applications due to their biodegradability, bioabsorbability and adaptability to tissue regeneration. However, further investigations are still needed to understand how angiogenesis will respond to high concentrations of Mg2+ and oxygen content differences, which are vital to vascular remodelling and bone fracture regeneration or tissue healing. Human primary endothelial cells were exposed to various concentrations (2 to 8 mM) of extracellular Mg2+ degradation products under either hypoxia or normoxia. Increased proliferation was measured with Mg extracts under hypoxia but not under normoxia. Under normoxia and with Mg extracts, HUVEC migration exhibited a bell-shaped curve. The same pattern was observed with VEGFB expression, while VEGFA was constantly downregulated. Under hypoxia, migration and VEGFA levels remained constant; however, VEGFB was upregulated. Similarly, under normoxia, tube formation as well as VEGFA and VEGFB levels were downregulated. Nevertheless, under hypoxia, tube formation remained constant while VEGFA and VEGFB levels were upregulated. These results suggest that Mg extracts did not interfere with angiogenesis under hypoxia.Statement of significanceNeoangiogenesis, mediated by (e.g.) hypoxia, is a key factor for proper tissue healing Thus, effect of Mg2+ degradation products under either hypoxia or normoxia on angiogenesis were investigated. Under normoxia and increased Mg concentrations, a general negative effect was measured on early (migration) and late (tubulogenesis) angiogenesis. However, under hypoxia, this effect was abolished. As magnesium degradation is an oxygen-dependant process, hypoxia condition may be a relevant factor to test material cytocompatibility in vitro.Graphical abstractGraphical abstract for this article
       
  • Epidermal growth factor-nanoparticle conjugates change the activity from
           anti-apoptotic to pro-apoptotic at membrane rafts
    • Abstract: Publication date: Available online 19 February 2019Source: Acta BiomaterialiaAuthor(s): Shota Yamamoto, Yoshifumi Iwamaru, Yoshihisa Shimizu, Yoshibumi Ueda, Moritoshi Sato, Kazuo Yamaguchi, Jun Nakanishi The proliferation epidermal growth factor (EGF) is known to acquire contradictory apoptotic activities upon conjugation with gold nanoparticles (GNPs) through hitherto unknown mechanisms. Here, we identified an essential role of membrane rafts in the drastic activity switching of EGF-GNPs through the following intracellular signaling. 1) In contrast to the rapid diffusion of activated EGF receptor after the soluble EGF stimulation, the receptor is confined within membrane rafts upon binding to the EGF-GNPs. 2) This initial receptor confinements switch its endocytosis process from normal clathrin-mediated endocytosis to caveolin-mediated one, changing the phosphorylation dynamics of essential downstream kinases, i.e., extracellular signal-regulated kinase and AKT. Importantly, the destruction of membrane rafts by β-cyclodextrin reversed this trafficking and signaling, restoring EGF-GNPs to lost anti-apoptotic property. These results reveal the importance of GNP-mediated signal condensation at membrane rafts in conferring the unique apoptotic activity of EGF-nanoparticle conjugates.Statement of SignificanceEpidermal growth factor (EGF) is a small secretory protein that induces cell proliferation upon binding to its receptor existed on cellular plasma membranes. One interesting feature of the protein in the nanobiology field is, its acquisition of apoptosis-inducing (cellular suicide) activity rather than proliferative one upon conjugation to gold nanoparticles through hitherto unknown mechanisms. Here, we identified the involvement of lipid rafts, plasma membrane nanodomains enriched with cholesterol, in the apoptosis processes by changing the receptor trafficking and downstream signal transduction pathways. Moreover, the destruction of lipid rafts restored the EGF-nanoparticle conjugates with lost anti-apoptotic activity. These finding highlight potential applications of EGF-nanoparticle conjugates to cancer therapy, as the EGF receptor are highly expressed in cancer cells.Graphical abstractGraphical abstract for this article
       
  • Toward Tissue-engineering of Nasal Cartilages
    • Abstract: Publication date: Available online 19 February 2019Source: Acta BiomaterialiaAuthor(s): Laura Lavernia, Wendy E. Brown, Brian J.F. Wong, Jerry C. Hu, Kyriacos A. Athanasiou Nasal cartilage pathologies are common; for example, up to 80% of people are afflicted by deviated nasal septum conditions. Because cartilage provides the supportive framework of the nose, afflicted patients suffer low quality of life. To correct pathologies, graft cartilage is often required. Grafts are currently sourced from the patient’s septum, ear, or rib. However, their use yields donor site morbidity and is limited by tissue quantity and quality. Additionally, rhinoplasty revision rates exceed 15%, exacerbating the shortage of graft cartilage. Alternative grafts, such as irradiated allogeneic rib cartilage, are associated with complications. Tissue-engineered neocartilage holds promise to address the limitations of current grafts. The engineering design process may be used to create suitable graft tissues. This process begins by identifying the surgeon’s needs. Second, nasal cartilages’ properties must be understood to define engineering design criteria. Limited investigations have examined nasal cartilage properties; numerous additional studies need to be performed to examine topographical variations, for example. Third, tissue-engineering processes must be applied to achieve the engineering design criteria. Within the recent past, strategies have frequently utilized human septal chondrocytes. As autologous and allogeneic rib graft cartilage is used, its suitability as a cell source should also be examined. Fourth, quantitative verification of engineered neocartilage is critical to check for successful achievement of the engineering design criteria. Finally, following the FDA paradigm, engineered neocartilage must be orthotopically validated in animals. Together, these steps delineate a path to engineer functional nasal neocartilages that may, ultimately, be used to treat human patients.Statement of significanceNasal cartilage pathologies are common and lead to greatly diminished quality of life. The ability to correct pathologies is limited by cartilage graft quality and quantity, as well as donor site morbidity and surgical complications, such as infection and resorption. Despite the significance of nasal cartilage pathologies and high rhinoplasty revision rates (15%), little characterization and tissue-engineering work has been performed compared to other cartilages, such as articular cartilage. Furthermore, most work is published in clinical journals, with little in biomedical engineering. Therefore, this review discusses what nasal cartilage properties are known, summarizes the current state of nasal cartilage tissue-engineering, and makes recommendations via the engineering design process toward engineering functional nasal neocartilage to address current limitations.Graphical abstractGraphical abstract for this article
       
  • Engineering Human Ventricular Heart Tissue Based on Macroporous Iron Oxide
           Scaffolds
    • Abstract: Publication date: Available online 16 February 2019Source: Acta BiomaterialiaAuthor(s): Hui Yang, Lai Wei, Chen Liu, Weiyi Zhong, Bin Li, Yuncan Chen, Rui Han, Jiexian Zhuang, Jianxun Qu, Hongyue Tao, Haiyan Chen, Chen Xu, Qianqian Liang, Chao Lu, Ruizhe Qian, Sifeng Chen, Wenshuo Wang, Ning Sun Myocardial infarction (MI) is a primary cardiovascular disease threatening human health and quality of life worldwide. The development of engineered heart tissues (EHTs) as a transplantable artificial myocardium provides a promising therapy for MI. Since most MIs occur at the ventricle, engineering ventricular-specific myocardium is therefore more desirable for future applications. Here, by combining a new macroporous 3D iron oxide scaffold (IOS) with a fixed ratio of human pluripotent stem cell (hPSC)-derived ventricular-specific cardiomyocytes and human umbilical cord-derived mesenchymal stem cells, we constructed a new type of engineered human ventricular-specific heart tissue (EhVHT). The EhVHT promoted expression of cardiac-specific genes, ion exchange, and exhibited a better Ca2+ handling behaviors and normal electrophysiological activity in vitro. Furthermore, when patched on the infarcted area, the EhVHT effectively promoted repair of heart tissues in vivo and facilitated the restoration of damaged heart function of rats with acute MI. Our results show that it is feasible to generate functional human ventricular heart tissue based on hPSC-derived ventricular myocytes for the treatment of ventricular-specific myocardium damage.Statement of SignificanceWe successfully generated highly purified homogenous human ventricular myocytes and developed a method to generate human ventricular-specific heart tissue (EhVHT) based on three-dimensional iron oxide scaffolds. The EhVHT promoted expression of cardiac-specific genes, ion exchange, and exhibited a better Ca2+ handling behaviors and normal electrophysiological activity in vitro. Patching the EhVHT on the infarct area significantly improved cardiac function in rat acute MI models. This EhVHT has a great potential to meet the specific requirements for ventricular damages in most MI cases and for screening drugs specifically targeting ventricular myocardium.Graphical abstractGraphical abstract for this article
       
  • Fibronectin fiber creep under constant force loading
    • Abstract: Publication date: Available online 16 February 2019Source: Acta BiomaterialiaAuthor(s): Mark J. Bradshawa, Gwendolyn A. Hoffmann, Joyce Y. Wong, Michael L. Smith Viscoelasticity is a fundamental property of virtually all biological materials, and proteinaceous, fibrous materials that constitute the extracellular matrix (ECM) are no exception. Viscoelasticity may be particularly important in the ECM since cells can apply mechanical stress resulting from cell contractility over very long periods of time. However, measurements of ECM fiber response to long-term constant force loading are scarce, despite the increasing recognition that mechanical strain regulates the biological function of some ECM fibers. We developed a dual micropipette system that applies constant force to single fibers for up to 8 hours. We utilized this system to study the time dependent response of fibronectin (Fn) fibers to constant force, as Fn fibers exhibit tremendous extensibility before mechanical failure as well as strain dependent alterations in biological properties. These data demonstrate the Fn fibers continue to stretch under constant force loading for at least 8 hours and that this long-term creep results in plastic deformation of Fn fibers, in contrast to elastic deformation of Fn fibers under short-term, but fast loading rate extension. These data demonstrate that physiologically-relevant loading may impart mechanical features to Fn fibers by switching them into an extended state that may have altered biological functions.Statement of significanceMeasurements of extracellular matrix (ECM) fiber response to constant force loading are scarce, so we developed a novel technique for applying constant force to single ECM fibers. We used this technique to measure constant force creep of fibronectin fibers since these fibers have been shown to be mechanotransducers whose functions can be altered by mechanical strain. We found that fibronectin fibers creep under constant force loading for the duration of the experiment and that this creep behavior resembles a power law. Furthermore, we found that constant force creep results in plastic deformation of the fibers, which suggests that the mechanobiological switching of fibronectin can only occur once after long-term loading.Graphical abstractGraphical abstract for this article
       
  • Laminin polymer treatment accelerates repair of the crushed peripheral
           nerve in adult rats
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Agnes E. Haggerty, Maria R. Bening, Gordon Pherribo, Edward A. Dauer, Martin Oudega Promoting axon growth after peripheral nerve injury may support recovery. Soluble laminin polymers formed at pH 4 (aLam) accelerate axon growth from adult dorsal root ganglion neurons in vitro. We used an adult rat model of a peripheral (peroneal) nerve crush to investigate whether an injection of aLam enhances axon growth and functional recovery in vivo. Rats that received an injection of aLam into the crush at 2 days post-injury show significant improvements in hind limb motor function at 2 and 5 weeks after injury compared with control rats that received phosphate-buffered saline. Functional improvement was not associated with changes in sensitivity to thermal or mechanical stimuli. Treatment with aLam decreased the occurrence of autophagia and abolished non-compliance with treadmill walking. Rats treated with aLam showed increased axon presence in the crush site at 2 weeks post-injury and larger axon diameter at 10 weeks post-injury compared with controls. Treatment with aLam did not affect Schwann cell presence or axon myelination. Our results demonstrated that aLam accelerates axon growth and maturity in a crushed peroneal nerve associated with expedited hind limb motor function recovery. Our data support the therapeutic potential of injectable aLam polymers for treatment of peripheral nerve crush injuries.Statement of SignificanceIncidence of peripheral nerve injury has been estimated to be as high as 5% of all cases entering a Level 1 trauma center and the majority of cases are young males. Peripheral nerves have some endogenous repair capabilities, but overall recovery of function remains limited, which typically has devastating effects on the individual, family, and society, as wages are lost and rehabilitation is extended until the nerves can repair. We report here that laminin polymers injected into a crush accelerated repair and recovery, had no adverse effects on sensory function, obliterated non-compliance for walking tests, and decreased the occurrence of autophagia. These data support the use of laminin polymers for safe and effective recovery after peripheral nerve injury.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Molecular and macro-scale analysis of enzyme-crosslinked
           silk hydrogels for rational biomaterial design” [Acta Biomater. 63
           (2017) 76–84]
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Meghan McGill, Jeannine M. Coburn, Benjamin P. Partlow, Xuan Mu, David L. Kaplan
       
  • Cobalt-mediated multi-functional dressings promote bacteria-infected wound
           healing
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Qingying Shi, Xin Luo, Ziqi Huang, Adam C. Midgley, Bo Wang, Ruihua Liu, Dengke Zhi, Tingting Wei, Xin Zhou, Mingqiang Qiao, Jun Zhang, Deling Kong, Kai Wang Wound dressings with multiple functions are required to meet the complexity of the wound healing process. The multifunctionality often leads to an increase in the complexity and difficulty in dressing preparation. To surmount this problem, we used a facile preparation and fabrication process to fabricate a multi-functional dressing by integrating four widely accessible materials: plain gauze, sodium alginate (SA), Ca2+ and Co2+. Firstly, mixed Ca2+/Co2+ ion solutions with different concentration were applied to gauzes. After drying, SA solution was added to ionized gauze and Co2+-Ca2+/Gauze/SA (Ion-GSA) composite dressings were formed easily. In vitro results showed that all Ion-GSA dressings exhibited strong mechanical properties, uniform dispersion and sustained release of Ca2+ and Co2+, and the ability to retain moisture and absorb wound exudate. Besides the above advantages, dressings prepared with 0.25 g/L Co2+ and 4 g/L Ca2+ (Co2+0.25-Ca2+4 GSA composite dressings) exhibited the best overall effect for inducing a hypoxia-like response, and favorable cytocompatibility, hemostatic property and antibacterial activity. In vivo wound healing assays revealed that Co2+0.25-Ca2+4 GSA composite dressings inhibited bacterial growth, increased local Hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1) protein expression, and accelerated full-thickness skin wound healing in mouse bacterial-infected wound model. The quick healing wounds had improved angiogenesis, macrophages regulation, re-epithelialization and dense collagen deposition. Collectively, our results indicated that Co2+0.25-Ca2+4 GSA composite dressings promote wound healing.Statement of SignificanceWound dressings with integrated functionalities are required to meet complex clinical requirements. However, there is often a trade-off between reducing preparation complexity and increasing the multifunctionality of the dressing’s properties. In this study, we prepared multifunctional composite dressings by a facile preparation process using widely accessible materials. The composite dressings possessed the mechanical strength of gauze, had the effective wound exudate absorption, moisture maintenance and hemostatic property capacity of calcium alginate hydrogels, and had the hypoxia-like induction and the antimicrobial effects of Co2+. These functions all together promote bacteria-infected wound healing. Thus, we believed that the composite dressings can be widely applied in skin wound repair duo to their facile preparation method and good therapeutic effect.Graphical abstractGraphical abstract for this article
       
  • A standardized rat burr hole defect model to study maxillofacial bone
           regeneration
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Guanqi Liu, Yuanlong Guo, Linjun Zhang, Xiaoshuang Wang, Runheng Liu, Peina Huang, Yin Xiao, Zhuofan Chen, Zetao Chen With high incidence rate and unique regeneration features, maxillofacial burr hole bone defects require a specially designed bone defect animal model for the evaluation of related bone regenerative approaches. Although some burr hole defect models have been developed in long bones or calvarial bones, the mandible has unique tissue development origins and regenerative environments. This suggests that the defect model should be prepared in the maxillofacial bone area. After dissecting the anatomic structures of rat mandibles, we found that creating defects in the anterior tooth area avoided damaging important organs and improved animal welfare. Furthermore, the available bone volume at the anterior tooth area was superior to that of the posterior tooth and ascending ramus areas. We then managed to standardize the model by controlling the age, weight and gender of the animal, creating standardized measurement instruments and reducing the variations derived from various operators. We also succeeded in deterring the self-rehabilitation of the proposed model by increasing the defect size. The 6 × 2 mm and 8 × 2 mm defects were found to meet the requirements of bone regenerative studies. This study provided a step-by-step standardized burr hole bone defect model with minimal tissue damage in small animals. The evaluations resulting from this model testify to the in vitro outcomes of the proposed regenerative approaches and provide preliminary screening data for further large animal and clinical trials. Therefore, the inclusion of this model may optimize the evaluation systems for maxillofacial burr hole bone defect regenerative approaches.Statement of SignificanceUnremitting effort has been devoted to the development of bone regenerative materials to restore maxillofacial burr hole bone defects because of their high clinical incidence rate. In the development of these biomaterials, in vivo testing in small animals is necessary to evaluate the effects of candidate biomaterials. However, little has been done to develop such defect models in small animals. In this study, we developed a standardized rat mandible burr hole bone defect model with minimal injury to the animals. A detailed description and supplementary video were provided to guide the preparation. The development of this model optimizes the maxillofacial bone regenerative approach evaluation system.Graphical abstractGraphical abstract for this article
       
  • Fabrication of a nanoparticle-containing 3D porous bone scaffold with
           proangiogenic and antibacterial properties
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Juan L. Paris, Nuria Lafuente-Gómez, M. Victoria Cabañas, Jesús Román, Juan Peña, María Vallet-Regí 3D porous scaffolds based on agarose and nanocrystalline apatite, two structural components that act as a temporary mineralized extracellular matrix, were prepared by the GELPOR3D method. This shaping technology allows the introduction of thermally-labile molecules within the scaffolds during the fabrication procedure. An angiogenic protein, Vascular Endothelial Growth Factor, and an antibiotic, cephalexin, loaded in mesoporous silica nanoparticles, were included to design multifunctional scaffolds for bone reconstruction. The dual release of both molecules showed a marked increase in the number of blood vessels on embryonic day 14 in chicken embryos grown ex ovo, while, at the same time providing an antibiotic local concentration capable of inhibiting Staphylococcus aureus bacterial growth. In this sense, different release patterns, monitored by UV-spectroscopy, could be tailored as a function of the cephalexin loading strategy, either releasing all the loaded cephalexin in the first 4 h or less than 50% after 24 h. The scaffold surface was characterized by a high hydrophilicity, with contact angles between 50° and 63°, which enabled the adhesion and proliferation of preosteoblastic cells.Statement of SignificanceThe localized delivery of bioactive molecules has attracted significant attention due to the potential for dose reduction as well as reduced side effects compared to systemic delivery. In this article multifunctional 3D porous scaffolds with a designed porosity have been fabricated. The method also enables the controlled loading of an antibiotic drug and an angiogenic protein into the scaffold. These scaffolds, whose composition resembles the extracellular matrix are suitable for the adhesion of preosteoblast cells, exhibit a sustained cephalexin delivery adequate for inhibiting bacterial growth as well as release the proangiogenic molecule which induces blood vessel formation in chicken embryos grown ex ovo.Graphical abstractGraphical abstract for this article
       
  • Normal trabecular vertebral bone is formed via rapid transformation of
           mineralized spicules: A high-resolution 3D ex-vivo murine study
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Michael Zenzes, Emely L. Bortel, Peter Fratzl, Stefan Mundlos, Michael Schuetz, Hendrik Schmidt, Georg N. Duda, Frank Witte, Paul Zaslansky At birth, mouse vertebrae have a reticular fine spongy morphology, yet in the adult animal they exhibit elaborate trabecular architectures. Here, we characterize the physiological microstructural transformations in growing young female mice of the widely used C57BL/6 strain. Extensive architectural changes lead to the establishment of mature cancellous bone in the spine. Vertebrae were mapped in 3D by high resolution microcomputed tomography (µCT), backed by conventional histology. Three different phases are observed in the natural bony biomaterial: In a prenatal templating phase, early vertebrae are composed of foamy, loosely-packed mineralized spicules. During a consolidation phase in the first 7 days after birth, bone material condenses into struts and forms primitive trabeculae accompanied by a significant (>50%) reduction in bone volume/tissue volume ratio (BV/TV). After day 7, the trabeculae expand, reorient and increase in mineral density. Swift growth ensues such that by day 14 the young lumbar spine exhibits all morphological features observed in the mature animal. The greatly varied micro-morphologies of normal trabecular bone observed in 3D within a short timespan are typical for rodent and presumably for other mammalian forming spines. This suggests that fully structured cancellous bone emerges through rapid post-natal restructuring of a foamy mineralized scaffold.Statement of SignificanceCancellous bone develops in stages that are not well documented. Using a mouse model, we provide an observer-independent quantification of normal bone formation in the spine. We find that within 14 days, the cancellous bone transforms in 3 phases from a scaffold of spicules into well organized, fully mineralized trabeculae in a functional spine. Detailed knowledge of the physiological restructuring of mineralized material may help to better understand bone formation and may serve as a blueprint for studies of pharmaceuticals effects, tissue healing and regeneration.Graphical abstractGraphical abstract for this article
       
  • CaP coated mesoporous polydopamine nanoparticles with responsive membrane
           permeation ability for combined photothermal and siRNA therapy
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Zhenqiang Wang, Liucan Wang, Neeraj Prabhakar, Yuxin Xing, Jessica M. Rosenholm, Jixi Zhang, Kaiyong Cai Combined photothermal and gene therapy provides a promising modality toward cancer treatment, yet facile integration and controlled codelivery of gene payloads and photothermal conversion agents (PTCAs) remains a great challenge. Inspired by the robust wet adhesion of marine mussels, we present a rationally designed nanosystem constructed by using hybrid mesoporous polydopamine nanoparticles (MPDA) with sub-100 nm sizes and a high photothermal conversion efficiency of 37%. The surface of the particles were modified with tertiary amines by the facile Michael addition/Schiff base reactions of PDA to realize high siRNA loading capacity (10 wt%). Moreover, a successful calcium phosphate (CaP) coating via biomineralization was constructed on the cationic nanoparticle to prohibit premature release of siRNA. The CaP coating underwent biodegradation in weakly-acidic subcellular conditions (lysosomes). The synergistic integration of tertiary amines and catechol moieties on the subsequently exposed surfaces was demonstrated to feature the destabilization/disruption ability toward model cellular membranes via the greatly enhanced interfacial adhesion and interactions. Consequently, sufficient permeability of lysosomal membranes, and in turn, a high lysosomal escape efficiency, was realized, which then resulted in high gene silencing efficiencies via sufficient cytosolic delivery of siRNA. When an efficient knocking down (65%) of survivin (an inhibitor of apoptosis proteins) was combined with a subsequent photothermal ablation, remarkably higher therapeutic efficiencies were observed both in vitro and in vivo, as compared with monotherapy. The system may help to pave a new avenue on the utilization of bio-adhesive surfaces for handling the obstacles of combined photothermal and gene therapy.Statement of SignificancePolydopamine (PDA) based porous photothermal-conversion agent (PTCA) with sufficiently high conversion efficiency was employed to deliver photothermal/gene therapy modalities towards cancer treatment.CaP coating via PDA-induced biomineralization was constructed to prohibit premature release of siRNA loaded in the pore space of the nanocarriers.Responsive degradation of CaP also led to the exposure of membrane-lytic surfaces built through the synergistic integration of tertiary amines and catechol moieties, and in turn the significantly enhanced lysosomal escape and cytosol siRNA delivery.Therapeutic targeting of survivin was successfully applied for activation of apoptosis and programmed cell death. Combined photothermal and gene therapy improved therapeutic effectiveness.Graphical abstractGraphical abstract for this article
       
  • Merging metal organic framework with hollow organosilica nanoparticles as
           a versatile nanoplatform for cancer theranostics
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Liang Chen, Jiulong Zhang, Xiaojun Zhou, Shuguang Yang, Qianqian Zhang, Weizhong Wang, Zhengwei You, Chen Peng, Chuanglong He With great potential in nanomedicine, the integration of a metal organic framework (MOF) with a nanocarrier for smart and versatile cancer theranostics still seeks to expand. In this study, MOF was successfully merged with hollow mesoporous organosilica nanoparticles (HMONs) with a polydopamine (PDA) interlayer to form molecularly organic/inorganic hybridized nanocomposites (HMONs-PMOF). The well-defined nanostructure and favorable biocompatibility of HMONs-PMOF were demonstrated first. Doxorubicin hydrochloride (DOX) and indocyanine green (ICG) were separately loaded into the interior cavity of HMONs and the outer porous shell of MOF with high loading efficacy, respectively. The obtained dual drug-loaded nanocomposites (DI@HMONs-PMOF) displayed favorable photothermal properties and pH/NIR-triggered DOX release manner. Furthermore, in vitro cell experiments validated that HMONs-PMOF can efficiently deliver DOX into cancer cells. Upon entry into cancer cells, the photothermal effect of DI@HMONs-PMOF can induce the lysosome rupture, thereby facilitating the “lysosome escape” process and accelerating the DOX diffusion in the cytoplasm. Benefiting from the iron ion coordinated on PDA and ICG confined in MOF, magnetic resonance (MR) and photoacoustic (PA) dual-modality imaging were performed to verify the effective accumulation of DI@HMONs-PMOF at the tumor site. Interestingly, the results also suggested that the existence of ICG can cooperatively enhance the MR imaging capability of prepared nanocomposites. In addition, the significantly improved synergistic therapeutic efficacy was confirmed both in vitro and in vivo. Thus, our results indicated that the merged nanostructure of HMONs and MOF is promising for versatile cancer theranostics.Statement of SignificanceMetal organic framework (MOF) has recently emerged as a class of fascinating nanocarriers. The integration of MOF with other nanostructures can endow the new nanoformulation with collective functionality and synergistic performance that are not accessed from single-component nanostructure. Herein, we reported the successful merging of MOF and hollow mesoporous organosilica nanoparticles (HMONs) to form a hollow nanocontainer with a well-defined nanostructure. The large cavity of HMONs and highly porous network of MOF enable high drug loading efficacy. Moreover, the dual-modality magnetic resonance and photoacoustic imaging can be realized, which is also benefited from the merged nanostructure. Overall, we expected this paradigm could pave way for integrating MOF with other nanocarriers to achieve more diverse applications.Graphical abstractGraphical abstract for this article
       
  • Targeting EGFR of triple-negative breast cancer enhances the therapeutic
           efficacy of paclitaxel- and cetuximab-conjugated nanodiamond nanocomposite
           
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Wei-Siang Liao, Yu Ho, Yu-Wei Lin, Emmanuel Naveen Raj, Kuang-Kai Liu, Chinpiao Chen, Xiao-Zhen Zhou, Kun-Ping Lu, Jui-I Chao Breast cancer is the most common malignancy and a leading cause of cancer-related mortality among women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). However, epidermal growth factor receptor (EGFR) is highly expressed in most of the TNBCs, which may provide a potential target for EGFR targeting therapy. Nanodiamond (ND) is a carbon-based nanomaterial with several advantages, including fluorescence emission, biocompatibility, and drug delivery applications. In this study, we designed a nanocomposite by using ND conjugated with paclitaxel (PTX) and cetuximab (Cet) for targeting therapy on the EGFR-positive TNBC cells. ND-PTX inhibited cell viability and induced mitotic catastrophe in various human breast cancer cell lines (MDA-MB-231, MCF-7, and BT474); in contrast, ND alone did not induce cell death. ND-PTX inhibited the xenografted human breast tumors in nude mice. We further investigated ND-PTX-Cet drug efficacy on the TNBC of MDA-MB-231 breast cancer cells. ND-PTX-Cet could specifically bind to EGFR and enhanced the anticancer effects including drug uptake levels, mitotic catastrophe, and apoptosis in the EGFR-expressed MDA-MB-231 cells but not in the EGFR-negative MCF-7 cells. In addition, ND-PTX-Cet increased the protein levels of active caspase-3 and phospho-histone H3 (Ser10). Furthermore, ND-PTX-Cet showed more effective on the reduction of TNBC tumor volume by comparison with ND-PTX. Taken together, these results demonstrated that ND-PTX-Cet nanocomposite enhanced mitotic catastrophe and apoptosis by targeting EGFR of TNBC cells, which can provide a feasible strategy for TNBC therapy.Statement of significanceCurrent TNBC treatment is ineffective against the survival rate of TNBC patients. Therefore, the development of new treatment strategies for TNBC patients is urgently needed. Here, we have designed a nanocomposite by targeting on the EGFR of TNBC to enhance therapeutic efficacy by ND-conjugated PTX and Cet (ND-PTX-Cet). Interestingly, we found that the co-delivery of Cet and PTX by ND enhanced the apoptosis, mitotic catastrophe and tumor inhibition in the EGFR-expressed TNBC in vitro and in vivo. Consequently, this nanocomposite ND-PTX-Cet can be applied for targeting EGFR of human TNBC therapy.Graphical abstractGraphical abstract for this article
       
  • Doxorubicin-polyglycerol-nanodiamond composites stimulate glioblastoma
           cell immunogenicity through activation of autophagy
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Tong-Fei Li, Yong-Hong Xu, Ke Li, Chao Wang, Xin Liu, Yuan Yue, Zhuo Chen, Shen-Jun Yuan, Yu Wen, Quan Zhang, Min Han, Naoki Komatsu, Li Zhao, Xiao Chen Immunosuppression is a salient feature of GBM associated with the disease’s grim prognosis and the limited success of anti-GBM immunotherapy. Stimulating immunogenicity of the GBM cells (GC) is a promising approach to subverting the GBM-associated immunosuppression. We had previously devised a drug composite based on polyglycerol-functionalized nanodiamonds bearing doxorubicin (Nano-DOX) and demonstrated that Nano-DOX effectively modulated GBM’s immunosuppressive microenvironment through stimulating the immunogenicity of GC and initiated anti-GBM immune responses. The present study now explored the mechanism of Nano-DOX’s immunostimulatory action. Nano-DOX was found to induce autophagy rather than apoptosis in GC and stimulated GC to emit antigens and damage-associated molecular patterns (DAMPs) that are potent adjuvants, which resulted in enhanced activation of dendritic cells (DC). Heightened autophagosome release was observed in Nano-DOX-treated GC but was shown not to be a major channel of antigen donation. Blocking autophagy in GC not only reduced Nano-DOX-stimulated GC antigen donation and DAMPs emission, but also efficiently attenuated DC activation stimulated by Nano-DOX-treated GC. Taken together, these findings suggest that activation of autophagy is a central mechanism whereby Nano-DOX stimulates GC’s immunogenicity. Our work provides new insight on how nanotechnology can be applied to therapeutically modulate the GBM immune microenvironment by harnessing autophagy in the cancer cells.Statement of SignificanceImmunosuppression is a salient feature of GBM associated with the grim prognosis of the disease and the limited success of anti-GBM immunotherapy. We demonstrated that Doxorubicin-polyglycerol-nanodiamond composites could activate autophagy in GBM cells and thereby stimulate the immunogenecity of GBM cells. This discovery 1, sheds new light on how nanotechnology could be applied to therapeutically modulate the tumor immune microenvironment, and 2, provides a powerful tool for subverting the GBM's immunosuppressive microenvironment, which has great therapeutic potential for the treatment of GBM.Graphical abstractGraphical abstract for this article
       
  • Oriented immobilization to nanoparticles enhanced the therapeutic efficacy
           of antibody drugs
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Masumi Iijima, Kyoko Araki, Quishi Liu, Masaharu Somiya, Shun'ichi Kuroda Antibody drugs have been important therapeutic agents for treating various diseases, such as cancer, rheumatism, and hypercholesterolemia, for the last three decades. Despite showing excellent therapeutic efficacy with good safety in vivo, they require high doses. We have developed a ∼30-nm bio-nanocapsule (ZZ-BNC) consisting of hepatitis B virus envelope L protein fused with the tandem form of protein A-derived IgG Fc-binding Z domain (ZZ-L protein), for tethering antibodies in an oriented immobilization manner. In this study, antibody drugs were spontaneously conjugated to ZZ-BNC, which displayed the IgG Fv regions outwardly. The anti-human epidermal growth factor receptor IgG conjugated to ZZ-BNC (α-hEGFR-ZZ-BNC) was endocytosed by the human epidermoid carcinoma A431 cells, with increases in cellular uptake by ∼1.5 fold, compared that of α-hEGFR IgG alone. The amount of α-hEGFR IgG in the late endosomes and lysosomes was increased from 4% to 33% by the conjugation to ZZ-BNC. The in vitro cytotoxicity of α-hEGFR-ZZ-BNC was higher by ∼10-fold than that of α-hEGFR IgG alone. Furthermore, in vivo tumor growth was significantly reduced by α-hEGFR-ZZ-BNC than by α-hEGFR IgG alone. Taken together, since endosomal EGFR, not cell surface EGFR, played a pivotal role in the EGFR-mediated signaling cascade, ZZ-BNC increased α-hEGFR IgG avidity by efficiently repressing the activation of hEGFR not only on the cell surface, but presumably also in the endosomes. These results strongly suggested that ZZ-BNC is a promising nano-scaffold for enhancing the therapeutic efficacy and reducing the dose of antibody drugs.Statement of SignificanceAntibody drugs are widely used for treating severe diseases, such as cancer, rheumatism, and hypercholesterolemia. These drugs are composed of naturally occurring biomaterials with low immunogenicity and toxicity, as well as long in vivo serum half-life. To achieve sufficient therapeutic efficacy, the dose of antibody drugs are unavoidably higher than those of conventional drugs. The present study shows an innovative way to reduce the dose of antibody drugs by using a nanocarrier-conjugated antibody. Oriented immobilization of the antibody enhanced its avidity, endocytosis efficiency, and therapeutic efficacy.Graphical abstractGraphical abstract for this article
       
  • Enzyme-responsive multifunctional peptide coating of gold nanorods
           improves tumor targeting and photothermal therapy efficacy
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Liming Wu, Bingyi Lin, Huang Yang, Jing Chen, Zhengwei Mao, Weilin Wang, Changyou Gao It is well known that stealth coating effectively extends the circulation lifetime of nanomaterials in blood, which favors systemic delivery but also limits their cellular internalization and in turn prevents efficient tumor-targeting and accumulation. In this study, we address this dilemma by developing an enzyme-responsive zwitterionic stealth peptide coating capable of responding to matrix metalloproteinase-9 (MMP-9) which is overexpressed in tumor microenvironment. The peptide consists of a cell-penetrating Tat sequence, an MMP-9 cleavable sequence, and a zwitterionic antifouling sequence. Using this coating to protect photothermal gold nanorods (AuNRs), we found that responsive AuNRs showed both satisfactory systemic circulation lifetime and significantly enhanced cellular uptake in tumors, resulting in clearly improved photothermal therapeutic efficacy in mouse models. These results suggest that multifunctional peptide coated AuNRs sensitive to MMP-9 are promising nanomaterials, conferring both extended systemic circulation and enhanced tumor tissue accumulation, for more specific and efficient tumor therapy.Statement of significanceIt is well known that stealth coating effectively extends the circulation lifetime of nanomaterials in blood, which favors systemic delivery but also limits their cellular internalization and in turn prevents efficient tumor-targeting and accumulation. In this study, we address this dilemma by developing an enzyme-responsive zwitterionic stealth peptide coating capable of responding to matrix metalloproteinase-9 (MMP-9) which is overexpressed in tumor microenvironment. The peptide consists of a cell-penetrating Tat sequence, an MMP-9 cleavable sequence, and a zwitterionic antifouling sequence. Using this coating to protect photothermal gold nanorods (AuNRs), we found that responsive AuNRs showed both satisfactory systemic circulation lifetime and significantly enhanced cellular uptake in tumors, resulting in clearly improved photothermal therapeutic efficacy in mouse models.Graphical abstractGraphical abstract for this article
       
  • Effect of gold nanoparticles on timolol uptake and its release kinetics
           from contact lenses: In vitro and in vivo evaluation
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Furqan A. Maulvi, Rahul J. Patil, Ankita R. Desai, Manish R. Shukla, Rutvi J. Vaidya, Ketan M. Ranch, Bhavin A. Vyas, Shailesh A. Shah, Dinesh O. Shah Contact lenses are ideally suited for extended drug delivery to the ocular tissues, but incorporation of any particulate system affects the critical properties of the contact lens. Timolol loading by the conventional soaking method does not significantly alter the critical properties of the contact lens. However, there are challenges of low drug loading and high burst release. This research work aimed to investigate the effect of gold nanoparticles (GNPs) on loading and its release kinetics from the contact lens using the soaking method. In one approach, GNPs were loaded into the timolol soaking solution (GNPs-SS), and in another approach, GNPs were incorporated into the contact lenses (GNPs-CL) during fabrication. The contact lenses were soaked at two different concentrations of timolol (i.e., 2 mg/ml and 4 mg/ml). Swelling and optical transmittance were not significantly affected by the presence of GNPs in the contact lenses. A significant uptake/loading of timolol using the GNPs in both the approaches was observed. The in vitro flux data showed no significant improvement in the release rate profiles of timolol when using both approaches. However, the in vivo study in the rabbit tear fluid showed high timolol concentration with the GNPs-laden contact lens at all timepoints in comparison to the soaked contact lenses without GNPs. The in vivo pharmacodynamic study in rabbits showed a 2 mmHg average fall in intraocular pressure (72 h) using the GNPs-laden contact lenses, while the soaked contact lenses without GNPs and eye drops solution (0.5 %w/v) showed 2 mmHg. The drug distribution study in the ocular tissue showed a significant improvement in the drug deposition with the GNPs-laden contact lenses in the ciliary muscle and conjunctiva. This study successfully demonstrated the potential of GNPs to enhance the uptake of drug from the drug soaking solution to treat glaucoma without compromising the critical properties of contact lens.Statement of SignificanceIn this study, we have overcome the limitation of the conventional soaking method of low drug loading and high burst release from the contact lenses. We have investigated the effect of gold nanoparticles (GNPs) on the timolol loading and its release kinetics from the contact lenses. The study revealed the potential of GNPs to enhance the uptake of timolol from the timolol soaking solution to treat glaucoma without compromising the critical lens properties.Graphical abstractGraphical abstract for this article
       
  • Effects of a roughened femoral head and the locus of grafting on the wear
           resistance of the phospholipid polymer-grafted acetabular liner
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Toru Moro, Kazuhiko Ishihara, Yoshio Takatori, Sakae Tanaka, Masayuki Kyomoto, Masami Hashimoto, Hisatoshi Ishikura, Ryo Hidaka, Takeyuki Tanaka, Hiroshi Kawaguchi, Kozo Nakamura Although laboratory tests and mid-term clinical outcomes show the clinical safety and remarkable wear resistance of the highly cross-linked polyethylene (HXLPE) acetabular liner with a nanometer-scaled graft layer of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), the wear resistance of the layer under severe abrasive conditions is concerning. We evaluated the effects of a roughened femoral head and the grafting locus on the wear resistance of the PMPC-grafted HXLPE liner and the effect of PMPC grafting on wear resistance of the HXLPE substrate by removing the PMPC-grafted layer using a severely roughened femoral head. Against a moderately roughened femoral head, the PMPC-grafted HXLPE liner showed negative wear, although an untreated HXLPE liner increased the wear by 154.1% compared with wear against a polished femoral head, confirming that PMPC grafts were unaffected. Against a severely roughened femoral head, the PMPC-grafted layer of the head contact area might be removed under severe conditions. However, the wear rate was reduced by 52.5% compared to that of untreated HXLPE liners. Moreover, the head non-contact area-modified PMPC-grafted HXLPE liner against a polished femoral head reduced the wear by 76.8% compared with untreated HXLPE liner; thus, this area may be also important in the development of fluid-film lubrication.Statement of significanceHere we describe effects of a roughened femoral head and the locus of grafting on the wear-resistance of the phospholipid polymer grafted highly cross-linked polyethylene (PMPC-HXLPE) liner. Against a moderately roughened femoral head, the PMPC-HXLPE liner showed negative wear, confirming that PMPC grafts were unaffected. After removing the PMPC layer of the head contact area using a severely roughened femoral head, the wear rate not only exceeded that of untreated HXLPE liners, but was reduced by 52.5%, confirming that PMPC grafting does not affect the wear-resistance of the HXLPE substrate. In addition, the head non-contact area-modified PMPC-HXLPE liner reduced the wear by 76.8%. Thus, this area may also may be important in the development of fluid-film lubrication.Graphical abstractGraphical abstract for this article
       
  • Multifunctional sulfonated polyetheretherketone coating with
           beta-defensin-14 for yielding durable and broad-spectrum antibacterial
           activity and osseointegration
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Xiangwei Yuan, Liping Ouyang, Yao Luo, Zhenjie Sun, Chao Yang, Jiaxing Wang, Xuanyong Liu, Xianlong Zhang To address periprosthetic joint infection (PJI), a formidable complication after joint arthroplasty, an implant with excellent osseointegration and effective antibacterial activity has being extensively pursued and developed. In this work, the mouse beta-defensin-14 (MBD-14) was immobilized on the polyetheretherketone (PEEK) surface with three-dimensional (3D) porous structure to improve its antibacterial activity and osseointegration. An in vitro antibacterial evaluation showed that the porous PEEK loaded with MBD-14 wages a durable and effective fight against both Staphylococcus aureus (gram-positive) and Pseudomonas aeruginosa (gram-negative). In addition to the superior antibacterial activity, we found that the enhanced proliferation and osteogenic differentiation of bone mesenchymal stem cells were verified through various in vitro analyses. To evaluate the in vivo bactericidal effect and osseointegration of the samples, the rat femoral models with infection and non-infection were established. The enhanced osseointegration of the MBD-14-loaded samples was found in both two in vivo models. And no bacteria survived on the surfaces of samples with a relatively high MBD-14 concentration. Above results indicate that the 3D porous PEEK coating loaded with MBD-14 simultaneously yields excellent osseointegration while exerting durable and broad-spectrum antibacterial activity. And it paves the way for PEEK to be applied clinically to address PJI.Statement of significance(1). By using the physio-chemical technique including sulfonation and lyophilization etc., a three-dimensional porous network is developed on polyetheretherketone (PEEK) surface, in which mouse beta-defensin-14 (MBD-14, a broad-spectrum antimicrobial peptide) is then loaded. It endows PEEK with antibacterial activity and osseointegration. (2). Two in vivo animal models with infection and non-infection are used to prove the new bone formation around the samples. (3). Supplementary material also proves that MBD-14 promotes the osteogenic differentiation of BMSCs. However, its potential mechanism needs to be further studied in future. (4). The modified PEEK, including excellent osseointegration and a durable and broad-spectrum antibacterial activity, could be applied clinically to address PJI which is a hot potato for surgeons and patients undergoing total joint arthroplasty.Graphical abstractGraphical abstract for this article
       
  • Aligned hydrogel tubes guide regeneration following spinal cord injury
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Courtney M. Dumont, Mitchell A. Carlson, Mary K. Munsell, Andrew J. Ciciriello, Katerina Strnadova, Jonghyuck Park, Brian J. Cummings, Aileen J. Anderson, Lonnie D. Shea Directing the organization of cells into a tissue with defined architectures is one use of biomaterials for regenerative medicine. To this end, hydrogels are widely investigated as they have mechanical properties similar to native soft tissues and can be formed in situ to conform to a defect. Herein, we describe the development of porous hydrogel tubes fabricated through a two-step polymerization process with an intermediate microsphere phase that provides macroscale porosity (66.5%) for cell infiltration. These tubes were investigated in a spinal cord injury model, with the tubes assembled to conform to the injury and to provide an orientation that guides axons through the injury. Implanted tubes had good apposition and were integrated with the host tissue due to cell infiltration, with a transient increase in immune cell infiltration at 1 week that resolved by 2 weeks post injury compared to a gelfoam control. The glial scar was significantly reduced relative to control, which enabled robust axon growth along the inner and outer surface of the tubes. Axon density within the hydrogel tubes (1744 axons/mm2) was significantly increased more than 3-fold compared to the control (456 axons/mm2), with approximately 30% of axons within the tube myelinated. Furthermore, implantation of hydrogel tubes enhanced functional recovery relative to control. This modular assembly of porous tubes to fill a defect and directionally orient tissue growth could be extended beyond spinal cord injury to other tissues, such as vascular or musculoskeletal tissue.Statement of SignificanceTissue engineering approaches that mimic the native architecture of healthy tissue are needed following injury. Traditionally, pre-molded scaffolds have been implemented but require a priori knowledge of wound geometries. Conversely, hydrogels can conform to any injury, but do not guide bi-directional regeneration. In this work, we investigate the feasibility of a system of modular hydrogel tubes to promote bi-directional regeneration after spinal cord injury. This system allows for tubes to be cut to size during surgery and implanted one-by-one to fill any injury, while providing bi-directional guidance. Moreover, this system of tubes can be broadly applied to tissue engineering approaches that require a modular guidance system, such as repair to vascular or musculoskeletal tissues.Graphical abstractGraphical abstract for this article
       
  • Sustained release of GDF5 from a designed coacervate attenuates disc
           degeneration in a rat model
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Jian Zhu, Kaishun Xia, Wei Yu, Yitian Wang, Jianming Hua, Bing Liu, Zhe Gong, Junjie Wang, Ankai Xu, Zhengwei You, Qixin Chen, Fangcai Li, Huimin Tao, Chengzhen Liang Low back pain is often caused by intervertebral disc degeneration, which is characterized by nucleus pulposus (NP) and extracellular matrix (ECM) degeneration. Human adipose-derived stem cells (hADSCs) induced by growth and differentiation factor-5 (GDF5) can differentiate into an NP-like phenotype. Although stem cell-based therapy with prolonged exposure to growth factors is regarded as a promising treatment, the efficacy of this approach in attenuating the disc degeneration process is limited by the short lifespan of growth factors. In our study, a unique growth factor delivery vehicle composed of heparin and the synthetic polycation poly(ethylene argininylaspartate diglyceride) (PEAD) was used to sustain GDF5 release. The results showed that sustained release of GDF5 by the PEAD:heparin delivery system promoted hADSC differentiation to an NP-like phenotype in vitro. After injection of the PEAD:heparin:GDF5 delivery platform and hADSCs into intervertebral spaces of coccygeal (Co) vertebrae Co7/Co8 and Co8/Co9 of the rat, the disc height, water content, and structure of the NPs decreased more slowly than other treatment groups. This new strategy may be used as an alternative treatment for attenuating intervertebral disc degeneration with hADSCs without the need for gene therapy.Statement of significanceLow back pain is often caused by intervertebral disc degeneration, which is characterized by nucleus pulposus (NP) and extracellular matrix (ECM) degeneration. Human adipose-derived stem cells (hADSCs) induced by growth and differentiation factor-5 (GDF-5) can differentiate into an NP-like phenotype. Although stem cell-based therapy with prolonged exposure to growth factor is regarded as a promising treatment, the efficacy of this approach in the disc regeneration process is limited by the short life of growth factors. In our study, a unique growth factor delivery vehicle comprised of heparin and the synthetic polycation poly(ethylene argininylaspartate diglyceride) (PEAD) was used to sustain the release of GDF-5. Numerous groups have explored IDD regeneration methods in vitro and in vivo. Our study differs in that GDF5 was incorporated into a vehicle through charge attraction and exhibited a sustained release profile. Moreover, GDF-5 seeded coacervate combined with hADSC injection could be a minimally invasive approach for tissue engineering that is suitable for clinical application. We investigated the stimulatory effects of our GDF-5 seeded coacervate on the differentiation of ADSCs in vitro and the reparative effect of the delivery system on degenerated NP in vivo.Graphical abstractGraphical abstract for this article
       
  • Biomimetic modification of poly(vinyl alcohol): Encouraging
           endothelialization and preventing thrombosis with antiplatelet monotherapy
           
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Deirdre E.J. Anderson, Katie P. Truong, Matthew W. Hagen, Evelyn K.F. Yim, Monica T. Hinds Poly(vinyl alcohol) (PVA) has shown promise as a biomaterial for cardiovascular application. However, its antifouling properties prevent in vivo endothelialization. This work examined the endothelialization and thrombogenicity of modified PVA with different concentrations of proteins and adhesion peptides: collagen, laminin, fibronectin, GFPGER, YIGSR, and cRGD. Material surface properties were quantified, and the endothelialization potential was determined with human endothelial colony forming cells. Additionally, platelet attachment was assessed in vitro with human platelet rich plasma, and promising samples were tested in an ex vivo shunt model. This well-established arteriovenous shunt model was used with and without clinically-relevant antiplatelet therapies, specifically acetylsalicylic acid (ASA) with and without clopidogrel to examine the minimum necessary treatment to prevent thrombosis. Collagen, laminin, and GFPGER biomolecules increased endothelialization, with GFPGER showing the greatest effect at the lowest concentrations. GFPGER-PVA tubes tested under whole blood did exhibit an increase in platelet (but not fibrin) attachment compared to plain PVA and clinical controls. However, application of ASA monotherapy reduced the thrombogenicity of GFPGER-PVA below the clinical control with the ASA. This work is significant in developing cardiovascular biomaterials—increasing endothelialization potential while reducing bleeding side effects by using an antiplatelet monotherapy, typical of clinical patients.Statement of significanceWe modified the endothelialization potential of synthetic, hydrogel vascular grafts with proteins and peptides of the vascular tissue matrix. Cell attachment was dramatically increased with the GFPGER peptide, and while some additional platelet attachment was seen under flow with whole blood, this was completely knocked down using clinical antiplatelet monotherapy. This indicates that long-term patency of this biomaterial could be improved without the associated bleeding risk of multiple platelet therapies.Graphical abstractGraphical abstract for this article
       
  • In situ chemically crosslinked injectable hydrogels for the subcutaneous
           delivery of trastuzumab to treat breast cancer
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Yu-Wen Lo, Ming-Thau Sheu, Wen-Hsuan Chiang, Ya-Ling Chiu, Chia-Mu Tu, Wen-Yu Wang, Ming-Hsi Wu, Yu-Cheng Wang, Maggie Lu, Hsiu-O Ho Recently, novel approaches for the delivery of therapeutic antibodies have attracted much attention, especially sustained release formulations. However, sustained release formulations capable of carrying a high antibody load remain a challenge for practical use. In this study, a novel injectable hydrogel composed of maleimide-modified γ-polyglutamic acid (γ-PGA-MA) and thiol end-functionalized 4-arm poly(ethylene glycol) (4-arm PEG-SH) was developed for the subcutaneous delivery of trastuzumab. γ-PGA-MA and 4-arm PEG-SH formed a hydrogel through thiol-maleimide reactions, which had shear-thinning properties and reversible rheological behaviors. Moreover, a high content of trastuzumab (>100 mg/mL) could be loaded into this hydrogel, and trastuzumab demonstrated a sustained release over several weeks through electrostatic attraction. In addition, trastuzumab released from the hydrogel had adequate stability in terms of its structural integrity, binding bioactivity, and antiproliferative effect on BT-474 cells. Pharmacokinetic studies demonstrated that trastuzumab-loaded hydrogel (Her-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, and 10 mg/mL trastuzumab) and trastuzumab/Zn-loaded hydrogel (Her/Zn-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, 5 mM ZnCl2, and 10 mg/mL trastuzumab) could lower the maximum plasma concentration (Cmax) than the trastuzumab solution. Furthermore, Her/Zn-hydrogel-10 was better able to release trastuzumab in a controlled manner, which was ascribed to electrostatic attraction and formation of trastuzumab/Zn nanocomplexes. In a BT-474 xenograft tumor model, Her-hydrogel-10 had a similar tumor growth-inhibitory effect as that of the trastuzumab solution. By contrast, Her/Zn-hydrogel-10 exhibited a superior tumor growth-inhibitory capability due to the functionality of Zn. This study demonstrated that this hydrogel has potential as a carrier for the local and systemic delivery of proteins and antibodies.Statement of SignificanceRecently, novel sustained-release formulations of therapeutic antibodies have attracted much attention. However, these formulations should be able to carry a high antibody load owing to the required high dose, and these formulations remain a challenge for practical use. In this study, a novel injectable chemically cross-linked hydrogel was developed for the subcutaneous delivery of trastuzumab. This novel hydrogel possessed ideal characteristics of loading high content of trastuzumab (>100 mg/mL), sustained release of trastuzumab over several weeks, and maintaining adequate stability of trastuzumab. In vivo studies demonstrated that a trastuzumab-loaded hydrogel possessed the ability of controlled release of trastuzumab and maintained antitumor efficacy same as that of trastuzumab. These results implied that a γ-PGA-MA and 4-arm PEG-SH-based hydrogel has great potential in serving as a carrier for the local or systemic delivery of therapeutic proteins or antibodies.Graphical abstractGraphical abstract for this article
       
  • Dual growth factor-immobilized bioactive injection material for enhanced
           treatment of glottal insufficiency
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Young Hwan Choi, Hee-Jin Ahn, Mi Ri Park, Mi-Jung Han, Jin Ho Lee, Seong Keun Kwon With increasing demand for treatment of glottal insufficiency, several injection materials have been examined. However, biological resorption, degradation of injected materials, and the subsequent need to perform multiple injections still remain major clinical problems. In this study, we fabricated two different growth factor (GF) [single basic fibroblast growth factor (bFGF), single hepatocyte growth factor (HGF), or dual bFGF/HGF]-immobilized polycaprolactone (PCL)/Pluronic F127 microspheres. These materials were investigated for their potential use as bioactive injection laryngoplasty agents. HGF was found to be continuously released over 20 days and the bFGF was found to be continuously released over 25 days, as demonstrated by ELISA assay. Human vocal fold fibroblasts (hVFFs) showed significantly higher proliferative ability on dual GF-immobilized microspheres. GF-immobilized microspheres (bFGF, HGF, and dual GF) were injected into paralyzed vocal folds of New Zealand white rabbits. Through endoscopic observation and H&E staining, we identified that the microspheres remained localized at the injection site, resulting in constant volume augmentation of the paralyzed vocal fold without significant loss of the initial volume after 4 weeks. The expression of genes related to the extracellular matrix (ECM) in the vocal fold was upregulated by dual GF-immobilized microspheres. Furthermore, dual GF-immobilized microspheres inhibited muscle degeneration and upregulation of myogenic-related genes. In conclusion, dual GF-immobilized microspheres passively augmented the volume of the paralyzed vocal fold while actively inducing ECM synthesis at the injected vocal fold and preserving muscle tissue. Dual GF-immobilized microspheres could be a new and promising injection material for paralyzed vocal folds.Statement of SignificanceLimitation of prolonged augmentation of vocal fold and degeneration of vocal fold tissue still remain as major clinical problems in the treatment of vocal fold paralysis. Herein, we fabricated the polycaprolactone (PCL)/Pluronic F127 microspheres to augment volume of paralyzed vocal folds. On top of that, we additionally immobilized the growth factors (bFGF, HGF, or dual bFGF/HGF) on the surface of these microspheres. We highlight the efficacy of the dual GF-immobilized microspheres which augmented the volume of the paralyzed vocal fold passively, induced ECM synthesis actively at the injected vocal fold and preserved laryngeal muscle tissue. Our results suggest that the dual GF-immobilized microsphere could be a new promising injection material for injection laryngoplasty to treat paralyzed vocal fold.Graphical abstractGraphical abstract for this article
       
  • Prolonged cell persistence with enhanced multipotency and rapid
           angiogenesis of hypoxia pre-conditioned stem cells encapsulated in
           marine-inspired adhesive and immiscible liquid micro-droplets
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Tae Yoon Park, Eun Young Jeon, Hyo Jeong Kim, Bong-Hyuk Choi, Hyung Joon Cha Stem cell therapies are emerging regenerative treatments for ischemic and chronic diseases. Although high cell retention and prompt angiogenesis are prerequisites to improving efficacy, advancements have not yet been developed. Here, we proposed long-term surviving and angiogenesis-inducing stem cell with high cell retention thanks to fluid immiscible liquid micro-droplets bio-inspired by a glue modality ‘complex coacervate’ found in the sandcastle worm. Formed by the Coulombic force between polycationic MAP and polyanionic hyaluronic acid, the exploited coacervate micro-droplets enabled the encapsulation of stem cells. The underwater adhesiveness facilitated integrating the encapsulated stem cells onto various surfaces with impressive cell retention after facile injection. Stem cells encapsulated in the coacervate platform formed cell clusters capable of pre-adjusting to hypoxia by expressing hypoxia-inducible factor 1α (HIF-1α), increasing viability and reducing apoptosis under hypoxia and ischemia as well as normoxia. Interestingly, multipotent and angiogenic factors were significantly enhanced by HIF-1α expression. In the in vivo evaluation, the coacervate platform showed impressive angiogenesis with biocompatibility and long-term cell retention capacity with sustainable release as protein factories. Therefore, the proposed MAP-based water-immiscible, injectable, sticky, and bioactive 3D coacervate micro-droplets offers a promising tool for chronic diseases in body fluid-rich environments.Statement of SignificanceHigh cell retention, long-term survival, and rapid angiogenesis are prerequisites of successful stem cell therapy. However, no previous advancements have simultaneously satisfied all of these requirements. In this work, we clearly developed a novel, revolutionary stem cell carrier platform with underwater adhesiveness from a mussel-derived glue protein and water immiscibility from a sandcastle-worm-inspired glue modality via ‘complex coacervation’. To the best of our knowledge, no report has emerged employing coacervate as a stem cell therapeutic platform. This fluid-immiscible, injectable, sticky, and bioactive 3-dimensional stem cell micro-droplets demonstrated the excellent stem cell retention and viability under hypoxia environments and enhanced multipotent and angiogenic effects with minimal immune response.Graphical abstractGraphical abstract for this article
       
  • Artificial cellular nano-environment composed of collagen-based nanofilm
           promotes osteogenic differentiation of mesenchymal stem cells
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Jun-Ha Hwang, Uiyoung Han, Miso Yang, Yonghyun Choi, Jonghoon Choi, Jong-Min Lee, Han-Sung Jung, Jinkee Hong, Jeong-Ho Hong In regenerative medicine, the generation of therapeutic stem cells and tissue engineering are important for replacing damaged tissues. Numerous studies have attempted to produce cellular components that mimic the native tissue for gaining optimal function. Particularly, the extracellular matrix (ECM) composition plays an important role in cellular functions including determining the fates of mesenchymal stem cells (MSCs). Here, we evaluated the osteogenic effects of a nanofilm in which oppositely charged polyelectrolytes were alternately adsorbed onto the cell surface to create an artificial ECM environment for single MSCs. Interestingly, nanofilm composed of collagen (Col) and alginate (AA) showed relatively high stiffness and MSCs coated with the Col/AA nanofilm showed increased osteogenic differentiation efficiency compared to other nanofilm-coated MSCs. Further analysis revealed that the Col/AA nanofilm coating stimulated osteogenesis by activating transcriptional coactivators with the PDZ binding motif through extracellular signal-related kinase and p38 MAPK signaling. This nano-sized cellular coating will facilitate the development of nanotechnology for controlling cellular functions and advance stem cell-based clinical applications for regenerative medicine.State of SignificanceIn this study, we developed an artificial cellular nano-environment formed by multilayer nanofilms. We demonstrated that the nanofilms introduced to mesenchymal stem cells (MSCs) stimulate osteogenic differentiation by regulating intracellular signaling. Among the various nanofilm combinations, the induction of osteogenic gene transcription in collagen (Col) and alginate (AA) film-coated MSCs was the most pronounced compared to that on other nanofilms. A minimum number of Col/AA nanofilm bilayers (n = 2) was required for effective induction of MSC osteogenic differentiation. In addition, we observed the correlation between the promoting effect of osteogenic differentiation and stiffness of the nanofilm. Our results may be useful for developing a cell coating model system widely applicable in bioengineering and regenerative medicine.Graphical abstractGraphical abstract for this article
       
  • An injectable and thermosensitive hydrogel: Promoting periodontal
           regeneration by controlled-release of aspirin and erythropoietin
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Xiaowei Xu, Zhongyi Gu, Xi Chen, Ce Shi, Cangwei Liu, Min Liu, Lei Wang, Maolei Sun, Kai Zhang, Qilin Liu, Yuqin Shen, Chongtao Lin, Bai Yang, Hongchen Sun Periodontitis is an inflammatory disease induced by complex interactions between host immune system and plaque microorganism. Alveolar bone resorption caused by periodontitis is considered to be one of the main reasons for tooth loss in adults. To terminate the alveolar bone resorption, simultaneous anti-inflammation and periodontium regeneration is required, which has not appeared in the existing methods. In this study, chitosan (CS), β-sodium glycerophosphate (β-GP), and gelatin were used to prepare an injectable and thermosensitive hydrogel, which could continuously release aspirin and erythropoietin (EPO) to exert pharmacological effects of anti-inflammation and tissue regeneration, respectively. The releasing profile showed that aspirin and EPO could be continuously released from the hydrogels, which exhibited no toxicity both in vitro and in vivo, for at least 21 days. Immunohistochemistry staining and micro-CT analyses indicated that administration of CS/β-GP/gelatin hydrogels loaded with aspirin/EPO could terminate the inflammation and recover the height of the alveolar bone, which is further confirmed by histological observations. Our results suggested that CS/β-GP/gelatin hydrogels are easily prepared as drug-loading vectors with excellent biocompatibility, and the CS/β-GP/gelatin hydrogels loaded with aspirin/EPO are quite effective in anti-inflammation and periodontium regeneration, which provides a great potential candidate for periodontitis treatment in the dental clinic.Statement of SignificanceTo terminate the alveolar bone resorption caused by periodontitis, simultaneous anti-inflammation and periodontium regeneration is required, which has not appeared in the existing methods. Here, (1) the chitosan (CS)/β-sodium glycerophosphate/gelatin hydrogels loaded with aspirin/erythropoietin (EPO) can form at body temperature in 5 min with excellent biocompatibility in vitro and in vivo; (2) The faster release of aspirin than EPO in the early stage is beneficial for anti-inflammation and provides a microenvironment for ensuring the regeneration function of EPO in the following step. In vivo experiments revealed that the hydrogels are effective in the control of inflammation and regeneration of the periodontium. These results indicate that our synthesized hydrogels have a great potential in the future clinical application.Graphical abstractGraphical abstract for this article
       
  • A collagen hydrogel loaded with HDAC7-derived peptide promotes the
           regeneration of infarcted myocardium with functional improvement in a
           rodent model
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Yue Zhang, Dashuai Zhu, Yongzhen Wei, Yifan Wu, Weilong Cui, Lingfei Liuqin, Guanwei Fan, Qiang Yang, Zhexiang Wang, Zhelong Xu, Deling Kong, Lingfang Zeng, Qiang Zhao Myocardial infarction (MI) leads to the loss of cardiomyocytes, left ventricle (LV) dilation, and cardiac dysfunction, eventually developing into heart failure. Most of the strategies for MI therapy require biomaterials that can support tissue regeneration. In this study, we hypothesized that the extracellular matrix (ECM)-derived collagen I hydrogel loaded with histone deacetylase 7 (HDAC7)-derived-phosphorylated 7-amino-acid peptide (7Ap) could restrain LV remodeling and improve cardiac function after MI. An MI model was established by ligation of the left anterior descending coronary artery (LAD) of C57/B6 mice. The 7Ap-loaded collagen I hydrogel was intramyocardially injected to the infarcted region of the LV wall of the heart. After local delivery, the 7Ap-collagen increased neo-microvessel formation, enhanced stem cell antigen-1 positive (Sca-1+) stem cell recruitment and differentiation, decreased cellular apoptosis, and promoted cardiomyocyte cycle progression. Furthermore, the 7Ap-collagen restricted the fibrosis of the LV wall, reduced the infarct wall thinning, and improved cardiac performance significantly at 2 weeks post-MI. These results highlight the promising implication of 7Ap-collagen as a novel candidate for MI therapy.Statement of SignificanceThe mammalian myocardium has a limited regenerative capability following myocardial infarction (MI). MI leads to extensive loss of cardiomyocytes, thus culminating in adverse cardiac remodeling and congestive heart failure. In situ tissue regeneration through endogenous cell mobilization has great potential for tissue regeneration. A 7-amino-acid-peptide (7A) domain encoded by a short open-reading frame (sORF) of the HDAC7 gene. The phosphorylated from of 7A (7Ap) has been reported to promote in situ tissue repair via the mobilization and recruitment of endogenous stem cell antigen-1 positive (Sca-l+) stem cells. In this study, 7Ap was shown to improve H9C2 cell survival, in vitro. In vivo investigations in a mouse MI model demonstrated that intra-myocardial delivery of 7Ap-loaded collagen hydrogel promoted neovascularization, stimulated Sca-l+ stem cell recruitment and differentiation, reduced cardiomyocyte apoptosis and promoted cell cycle progression. As a result, treated infarcted hearts had increased wall thickness, had improved heart function and exhibited attenuation of adverse cardiac remodeling, observed for up to 2 weeks. Overall, these results highlighted the positive impact of implanting 7Ap-collagen as a novel constituent for MI repair.Graphical abstractGraphical abstract for this article
       
  • Repopulation of an auricular cartilage scaffold, AuriScaff, perforated
           with an enzyme combination
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): S. Nürnberger, C. Schneider, G.V.M. van Osch, C. Keibl, B. Rieder, X. Monforte, A.H. Teuschl, S. Mühleder, W. Holnthoner, B. Schädl, C. Gahleitner, H. Redl, S. Wolbank Biomaterials currently in use for articular cartilage regeneration do not mimic the composition or architecture of hyaline cartilage, leading to the formation of repair tissue with inferior characteristics. In this study we demonstrate the use of “AuriScaff”, an enzymatically perforated bovine auricular cartilage scaffold, as a novel biomaterial for repopulation with regenerative cells and for the formation of high-quality hyaline cartilage. AuriScaff features a traversing channel network, generated by selective depletion of elastic fibers, enabling uniform repopulation with therapeutic cells. The complex collagen type II matrix is left intact, as observed by immunohistochemistry, SEM and TEM. The compressive modulus is diminished, but three times higher than in the clinically used collagen type I/III scaffold that served as control.Seeding tests with human articular chondrocytes (hAC) alone and in co-culture with human adipose-derived stromal/stem cells (ASC) confirmed that the network enabled cell migration throughout the scaffold. It also guides collagen alignment along the channels and, due to the generally traverse channel alignment, newly deposited cartilage matrix corresponds with the orientation of collagen within articular cartilage. In an osteochondral plug model, AuriScaff filled the complete defect with compact collagen type II matrix and enabled chondrogenic differentiation inside the channels. Using adult articular chondrocytes from bovine origin (bAC), filling of even deep defects with high-quality hyaline-like cartilage was achieved after 6 weeks in vivo.With its composition and spatial organization, AuriScaff provides an optimal chondrogenic environment for therapeutic cells to treat cartilage defects and is expected to improve long-term outcome by channel-guided repopulation followed by matrix deposition and alignment.Statement of SignificanceAfter two decades of tissue engineering for cartilage regeneration, there is still no optimal strategy available to overcome problems such as inconsistent clinical outcome, early and late graft failures. Especially large defects are dependent on biomaterials and their scaffolding, guiding and protective function. Considering the currently used biomaterials, structure and mechanical properties appear to be insufficient to fulfill this task. The novel scaffold developed within this study is the first approach enabling the use of dense cartilage matrix, repopulate it via channels and provide the cells with a compact collagen type II environment. Due to its density, it also provides better mechanical properties than materials currently used in clinics. We therefore think, that the auricular cartilage scaffold (AuriScaff) has a high potential to improve future cartilage regeneration approaches.Graphical abstractGraphical abstract for this article
       
  • Devising micro/nano-architectures in multi-channel nerve conduits towards
           a pro-regenerative matrix for the repair of spinal cord injury
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Xiumin Sun, Ying Bai, Hong Zhai, Sheng Liu, Chi Zhang, Yiwei Xu, Jianlong Zou, Tao Wang, Shihao Chen, Qingtang Zhu, Xiaolin Liu, Haiquan Mao, Daping Quan Multi-channel nerve conduits have shown significant advantages in guidance of axonal growth and functional restoration after spinal cord injury (SCI). It was realized that the micro/nano-architectures of these implanted conduits can effectively tune the lesion-induced biological responses, including inflammation and scar formation. In this work, two PLLA multi-channel conduits were fabricated with ladder-like porous channel wall (labelled as LNCs) and nano-fibrous channel wall (labelled as NNCs), respectively, and transferred into complete spinal cord transected injury model in rats. The implantation of such two scaffolds significantly alleviated the infiltration of macrophages/microglia and accumulation of astrocyte and collagen scar, especially in the NNCs group. Meanwhile, recruitment of endogenous stem cells and axonal growth was observed in both of the multi-channel conduits. Compared to the LNCs, the extracellular matrix (ECM) – mimicry nanostructures in the NNCs promoted directional nerve fiber growth within the channels. Moreover, a relatively denser nano-architecture in the channel wall confined the nerve fiber extension within the channels. These results from in vivo evaluations suggested that the NNCs implants possess a great potential in future application for SCI treatment and nerve regeneration.Statements of SignificanceThe implantation of biocompatible and degradable polymeric scaffolds holds great potential in clinical treatment and tissue regeneration after spinal cord injury (SCI). In this work, the ladder-like nerve conduits (LNCs) and nano-fibrous nerve conduits (NNCs) were fabricated and implanted into completely spinal cord transected rats, respectively. In vivo characteristics showed significant reduction in post-injury inflammation and scar formation, with elevated nerve stem cells (NSCs) recruitment and nerve fiber growth, hence both conduits resulted in significant functional restoration after implantation. Remarkably, we noticed that not only the multi-channels in the conduits can guide nerve fiber regeneration, their micro-/nano-structured walls also played a critical role in modulating the post-implantation biological responses.Graphical abstractGraphical abstract for this article
       
  • Exosome-integrated titanium oxide nanotubes for targeted bone regeneration
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Fei Wei, Mengting Li, Ross Crawford, Yinghong Zhou, Yin Xiao Exosomes are extracellular nanovesicles that play an important role in cellular communication. The modulatory effects of bone morphogenetic protein 2 (BMP2) on macrophages have encouraged the functionalization of scaffolds through the integration of the exosomes from the BMP2-stimulated macrophages to avoid ectopic bone formation and reduce adverse effects. To determine the functionality of exosomal nanocarriers from macrophages after BMP2 stimulation, we isolated the exosomes from Dulbecco’s modified Eagle’s medium (DMEM)- or BMP2-stimulated macrophages and evaluated their effects on osteogenesis. Morphological characterization of the exosomes derived from DMEM- or BMP2-treated macrophages revealed no significant differences, and the bone marrow-derived mesenchymal stromal cells showed similar cellular uptake patterns for both exosomes. In vitro study using BMP2/macrophage-derived exosomes indicated their beneficial effects on osteogenic differentiation. To improve the bio-functionality for titanium implants, BMP2/macrophage-derived exosomes were used to modify titanium nanotube implants to favor osteogenesis. The incorporation of BMP2/macrophage-derived exosomes dramatically increased the expression of early osteoblastic differentiation markers, alkaline phosphatase (ALP) and BMP2, indicative of the pro-osteogenic role of the titanium nanotubes incorporated with BMP2/macrophage-derived exosomes. The titanium nanotubes functionalized with BMP2/macrophage-derived exosomes activated autophagy during osteogenic differentiation. In conclusion, the exosome-integrated titanium nanotube may serve as an emerging functional material for bone regeneration.Statement of SignificanceThe clinical application of bone morphogenetic protein 2 (BMP2) is often limited by its side effects. Exosomes are naturally secreted nanosized vesicles derived from cells and play an important role in intercellular communication.The contributions of this study include (1) the demonstration of the potential regulatory role of BMP2/macrophage-derived exosomes on the osteogenic differentiation of mesenchymal stromal cells (MSCs); (2) fabrication of titanium nanotubes incorporated with exosomes; (3) new insights into the application of titanium nanotube-based materials for the safe use of BMP2.Graphical abstractGraphical abstract for this article
       
  • Collagen I-based scaffolds negatively impact fracture healing in a
           mouse-osteotomy-model although used routinely in research and clinical
           application
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Annemarie Lang, Marieluise Kirchner, Jonathan Stefanowski, Mattea Durst, Marie-Christin Weber, Moritz Pfeiffenberger, Alexandra Damerau, Anja E. Hauser, Paula Hoff, Georg N. Duda, Frank Buttgereit, Katharina Schmidt-Bleek, Timo Gaber Although several biomaterials for bone regeneration have been developed in the last decades, clinical application of bone morphogenetic protein 2 is clinically only approved when applied on an absorbable bovine collagen I scaffold (ACS) (Helistat; ACS-H). In research, another ACS, namely Lyostypt (ACS-L) is frequently used as a scaffold in bone-linked studies. Nevertheless, until today, the influence of ACS alone on bone healing remains unknown. Unexpectedly, in vitro studies using ASC-H revealed a suppression of osteogenic differentiation and a significant reduction of cell vitality when compared to ASC-L. In mice, we observed a significant delay in bone healing when applying ACS-L in the fracture gap during femoral osteotomy. The results of our study show for the first time a negative influence of both ACS-H and ACS-L on bone formation demonstrating a substantial need for more sophisticated delivery systems for local stimulation of bone healing in both clinical application and research.Statement of SignificanceOur study provides evidence-based justification to promote the development and approval of more suitable and sophisticated delivery systems in bone healing research. Additionally, we stimulate researchers of the field to consider that the application of those scaffolds as a delivery system for new substances represents a delayed healing approach rather than a normal bone healing which could greatly impact the outcome of those studies and play a pivotal role in the translation to the clinics. Moreover, we provide impulses on underlying mechanism involving the roles of small-leucine rich proteoglycans (SLRP) for further detailed investigations.Graphical abstractGraphical abstract for this article
       
  • Cellular response to collagen-elastin composite materials
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Daniel V. Bax, Helen E. Smalley, Richard W. Farndale, Serena M. Best, Ruth E. Cameron Collagen is used extensively in tissue engineering due to its biocompatibility, near-universal tissue distribution, low cost and purity. However, native tissues are composites that include diverse extracellular matrix components, which influence strongly their mechanical and biological properties. Here, we provide important new findings on the differential regulation, by collagen and elastin, of the bio-response to the composite material. Soluble and insoluble elastin had differing effects on the stiffness and failure strength of the composite films. We established that Rugli cells bind elastin via EDTA-sensitive receptors, whilst HT1080 cells do not. These cells allowed us to probe the contribution of collagen alone (HT1080) and collagen plus elastin (Rugli) to the cellular response. In the presence of elastin, Rugli cell attachment, spreading and proliferation increased, presumably through elastin-binding receptors. By comparison, the attachment and spreading of HT1080 cells was modified by elastin inclusion, but without affecting their proliferation, indicating indirect modulation by elastin of the response of cells to collagen. These new insights highlight that access to elastin dominates the cellular response when elastin-binding receptors are present. In the absence of these receptors, modification of the collagen component and/or physical properties dictate the cellular response. Therefore, we can attribute the contribution of each constituent on the ultimate bioactivity of heterogeneous collagen-composite materials, permitting informed, systematic biomaterials design.Statement of SignificanceIn recent years there has been a desire to replicate the complex extracellular matrix composition of tissues more closely, necessitating the need for composite protein-based materials. In this case both the physical and biochemical properties are altered with the addition of each component, with potential consequences on the cell. To date, the different contributions of each component have not been deconvolved, and instead the cell response to the scaffold as a whole has been observed. Instead, here, we have used specific cell lines, that are sensitive to specific components of an elastin-collagen composite, to resolve the bio-activity of each protein. This has shown that elastin-induced alteration of the collagen component can modulate early stage cell behaviour. By comparison the elastin component directly alters the cell response over the short and long term, but only where appropriate receptors are present on the cell. Due to the widespread use of collagen and elastin, we feel that this data permits, for the first time, the ability to systematically design collagen-composite materials to promote desired cell behaviour with associated advantages for biomaterials fabrication.Graphical abstractGraphical abstract for this article
       
  • Genetically engineered bi-functional silk material with improved cell
           proliferation and anti-inflammatory activity for medical application
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Yuancheng Wang, Feng Wang, Sheng Xu, Riyuan Wang, Wenjing Chen, Kai Hou, Chi Tian, Fan Wang, Ling Yu, Zhisong Lu, Ping Zhao, Qingyou Xia Functional silk is a promising material for future medical applications. These include fabrication of diverse silk fiber and silk protein-regenerated biomaterials such as silk sutures, hydrogel, films, and 3D scaffolds for wound healing and tissue regeneration and reconstruction. Here, a novel bi-functional silk with improved cell proliferation and anti-inflammatory activities was created by co-expressing the human basic fibroblast growth factor (FGF2) and transforming growth factor-β1 (TGF_β1) genes in silkworm. First, both FGF2 and TGF_β1 genes were confirmed to be successfully expressed in silk thread. The characterization of silk properties by SEM, FTIR, and mechanical tests showed that this new silk (FT silk) had a similar diameter, inner molecular composition, and mechanical properties as those of normal silk. Additionally, expressed FGF2 and TGF_β1 proteins were continuously and slowly released from FT silk for one week. Most importantly, the FGF2 and TGF_β1 contained in FT silk not only promoted cell proliferation by activating the ERK pathway but also significantly reduced LPS-induced inflammation responses in macrophages by mediating the Smad pathway. Moreover, this FT silk had no apparent toxicity for cell growth and caused no cell inflammation. These properties suggest that it has a potential for medical applications.Statement of SignificanceSilk spun by domestic silkworm is a promising material for fabricating various silk protein regenerated biomaterials in medical area, since it owes good biocompatibility, biodegradability and low immunogenicity. Recently, fabricating various functional silk fibers and regenerated silk protein biomaterials which has ability of releasing functional protein factor is the hot point field. This study is a first time to create a novel bi-functional silk material with the improved cell proliferation and anti-inflammatory activity by genetic engineered technology. This novel silk has a great application potential as new and novel medical material, and this study also provides a new strategy to create various functional or multifunctional silk fiber materials in future.Graphical abstractGraphical abstract for this article
       
  • Hyaluronan/collagen hydrogels containing sulfated hyaluronan improve wound
           healing by sustained release of heparin-binding EGF-like growth factor
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Stephan Thönes, Sandra Rother, Tom Wippold, Joanna Blaszkiewicz, Kanagasabai Balamurugan, Stephanie Moeller, Gloria Ruiz-Gómez, Matthias Schnabelrauch, Dieter Scharnweber, Anja Saalbach, Joerg Rademann, M. Teresa Pisabarro, Vera Hintze, Ulf Anderegg Functional biomaterials that are able to bind, stabilize and release bioactive proteins in a defined manner are required for the controlled delivery of such to the desired place of action, stimulating wound healing in health-compromised patients. Glycosaminoglycans (GAG) represent a very promising group of components since they may be functionally engineered and are well tolerated by the recipient tissues due to their relative immunological inertness.Ligands of the Epidermal Growth Factor (EGF) receptor (EGFR) activate keratinocytes and dermal fibroblasts and, thus, contribute to skin wound healing. Heparin-binding EGF-like growth factor (HB-EGF) bound to GAG in biomaterials (e.g. hydrogels) might serve as a reservoir that induces prolonged activation of the EGF receptor and to recover disturbed wound healing.Based on previous findings, the capacity of hyaluronan (HA) and its sulfated derivatives (sHA) to bind and release HB-EGF from HA/collagen-based hydrogels was investigated. Docking and molecular dynamics analysis of a molecular model of HB-EGF led to the identification of residues in the heparin-binding domain of the protein being essential for the recognition of GAG derivatives. Furthermore, molecular modeling and surface plasmon resonance (SPR) analyses demonstrated that sulfation of HA increases binding strength to HB-EGF thus providing a rationale for the development of sHA-containing hydrogels. In line with computational observations and in agreement with SPR results, gels containing sHA displayed a retarded HB-EGF release in vitro compared to pure HA/collagen gels. Hydrogels containing HA and collagen or a mixture with sHA were shown to bind and release bioactive HB-EGF over at least 72 h, which induced keratinocyte migration, EGFR-signaling and HGF expression in dermal fibroblasts. Importantly, hydrogels containing sHA strongly increased the effectivity of HB-EGF in inducing epithelial tip growth in epithelial wounds shown in a porcine skin organ culture model. These findings suggest that hydrogels containing HA and sHA can be engineered for smart and effective wound dressings.Statement of SignificanceImmobilization and sustained release of recombinant proteins from functional biomaterials might overcome the limited success of direct application of non-protected solute growth factors during the treatment of impaired wound healing.We developed HA/collagen-based hydrogels supplemented with acrylated sulfated HA for binding and release of HB-EGF. We analyzed the molecular basis of HB-EGF interaction with HA and its chemical derivatives by in silico modeling and surface plasmon resonance. These hydrogels bind HB-EGF reversibly. Using different in vitro assays and organ culture we demonstrate that the introduction of sulfated HA into the hydrogels significantly increases the effectivity of HB-EGF action on target cells. Therefore, sulfated HA-containing hydrogels are promising functional biomaterials for the development of mediator releasing wound dressings.Graphical abstractGraphical abstract for this article
       
  • Biophysical phenotypes and determinants of anterior vs. posterior
           primitive streak cells derived from human pluripotent stem cells
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Feng Lin, Yue Shao, Xufeng Xue, Yi Zheng, Zida Li, Chunyang Xiong, Jianping Fu Formation of the primitive streak (PS) marks one of the most important developmental milestones in embryonic development. However, our understanding of cellular mechanism(s) underlying cell fate diversification along the anterior-posterior axis of the PS remains incomplete. Furthermore, differences in biophysical phenotypes between anterior and posterior PS cells, which could affect their functions and regulate their fate decisions, remain uncharacterized. Herein, anterior and posterior PS cells were derived using human pluripotent stem cell (hPSC)-based in vitro culture systems. We observed that anterior and posterior PS cells displayed significantly different biophysical phenotypes, including cell morphology, migration, and traction force generation, which was further regulated by different levels of Activin A- and BMP4-mediated developmental signaling. Our data further suggested that intracellular cytoskeletal contraction could mediate anterior and posterior PS differentiation and phenotypic bifurcation through its effect on Activin A- and BMP4-mediated intracellular signaling events. Together, our data provide new information about biophysical phenotypes of anterior and posterior PS cells and reveal an important role of intracellular cytoskeletal contractility in regulating anterior and posterior PS differentiation of hPSCs.Statement of SignificanceFormation of the primitive streak (PS) marks one of the most important developmental milestones in embryonic development. However, molecular and cellular mechanism(s) underlying functional diversification of embryonic cells along the anterior-posterior axis of the PS remains incompletely understood. This work describes the first study to characterize the biophysical properties of anterior and posterior PS cells derived from human pluripotent stem cells (hPSCs). Importantly, our data showing the important role of cytoskeleton contraction in controlling anterior vs. posterior PS cell phenotypic switch (through its effect on intracellular Smad signaling activities downstream of Activin A and BMP4) should shed new light on biomechanical regulations of the development and anterior-posterior patterning of the PS. Our work will contribute significantly to uncovering new biophysical principles and cellular mechanisms driving cell lineage diversification and patterning during the PS formation.Graphical abstractGraphical abstract for this article
       
  • Biomechanical properties of female dolphin reproductive tissue
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): D.N. Orbach, S. Rattan, M. Hogan, A.J. Crosby, P.L.R. Brennan Whales, dolphins, and porpoises have unusual vaginal folds of unknown function(s) that are hypothesized to play an important role in sexual selection. The potential function of vaginal folds was assessed by testing the mechanical properties of common bottlenose dolphin (Tursiops truncatus) reproductive tract tissues in 6 different regions and across age classes in post-mortem specimens. We assessed the regional (local) and overall effective elastic modulus of tissues using indentation and tensile tests, respectively. We explore the non-linear mechanical response of biological tissues, which are not often quantified. Indentation tests demonstrated that sexual maturity state, tissue region, force history, and force magnitude values significantly affected the measured effective elastic modulus. Tissue was stiffest in the vaginal fold region and overall stiffer in sexually immature compared to mature animals, likely reflecting biomechanical adaptations associated with copulation and parturition. Tensile tests showed that only tissue region significantly affected the effective modulus. Our data support the hypothesis that vaginal folds function as mechanical barriers to the penis and may provide females with mechanisms to reduce copulatory forces on other reproductive tissue.Statement of SignificanceCetaceans have unusual folds of vaginal wall tissue that appear to evolve under sexual selection mechanisms and present physical barriers to the penis during copulation. We explore the biomaterial properties of vaginal fold tissue, how it varies from other reproductive tract tissues, and ontogenetic patterns. We demonstrate that vaginal folds can withstand higher mechanical forces and respond in a manner conducive to dissipating copulatory forces to other reproductive tissues. This study yields exciting insights on how female genital tissue may function during copulation, and is the first to do so in any vertebrate species. Additionally, we provide an example for testing biological tissues, non-linear properties, and materials with uneven surface structure and uneven thickness.Graphical abstractGraphical abstract for this article
       
  • Time-lapse three-dimensional imaging of crack propagation in beetle
           cuticle
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Dan Sykes, Rebecca Hartwell, Rob S. Bradley, Timothy L. Burnett, Benjamin Hornberger, Russell J. Garwood, Philip J. Withers Arthropod cuticle has extraordinary properties. It is very stiff and tough whilst being lightweight, yet it is made of rather ordinary constituents. This desirable combination of properties results from a hierarchical structure, but we currently have a poor understanding of how this impedes damage propagation. Here we use non-destructive, time-lapse in situ tensile testing within an X-ray nanotomography (nCT) system to visualise crack progression through dry beetle elytron (wing case) cuticle in 3D. We find that its hierarchical pseudo-orthogonal laminated microstructure exploits many extrinsic toughening mechanisms, including crack deflection, fibre and laminate pull-out and crack bridging. We highlight lessons to be learned in the design of engineering structures from the toughening methods employed.Statement of SignificanceWe present the first comprehensive study of the damage and toughening mechanisms within arthropod cuticle in a 3D time-lapse manner, using X-ray nanotomography during crack growth. This technique allows lamina to be isolated despite being convex, which limits 2D analysis of microstructure. We report toughening mechanisms previously unobserved in unmineralised cuticle such as crack deflection, fibre and laminate pull-out and crack bridging; and provide insights into the effects of hierarchical microstructure on crack propagation. Ultimately the benefits of the hierarchical microstructure found here can not only be used to improve biomimetic design, but also helps us to understand the remarkable success of arthropods on Earth.Graphical abstractGraphical abstract for this article
       
  • Adaptive structural reorientation: Developing extraordinary mechanical
           properties by constrained flexibility in natural materials
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Zengqian Liu, Yanyan Zhang, Mingyang Zhang, Guoqi Tan, Yankun Zhu, Zhefeng Zhang, Robert O. Ritchie Seeking strategies to enhance the overall combinations of mechanical properties is of great significance for engineering materials, but still remains a key challenge because many of these properties are often mutually exclusive. Here we reveal from the perspective of materials science and mechanics that adaptive structural reorientation during deformation, which is an operating mechanism in a wide variety of composite biological materials, functions more than being a form of passive response to allow for flexibility, but offers an effective means to simultaneously enhance rigidity, robustness, mechanical stability and damage tolerance. As such, the conflicts between different mechanical properties can be “defeated” in these composites merely by adjusting their structural orientation. The constitutive relationships are established based on the theoretical analysis to clarify the effects of structural orientation and reorientation on mechanical properties, with some of the findings validated and visualized by computational simulations. Our study is intended to give insight into the ingenious designs in natural materials that underlie their exceptional mechanical efficiency, which may provide inspiration for the development of new man-made materials with enhanced mechanical performance.Statement of SignificanceIt is challenging to attain certain combinations of mechanical properties in man-made materials because many of these properties – for example, strength with toughness and stability with flexibility – are often mutually exclusive. Here we describe an effective solution utilized by natural materials, including wood, bone, fish scales and insect cuticle, to “defeat” such conflicts and elucidate the underlying mechanisms from the perspective of materials science and mechanics. We show that, by adaptation of their structural orientation on loading, composite biological materials are capable of developing enhanced rigidity, strength, mechanical stability and damage tolerance from constrained flexibility during deformation – combinations of attributes that are generally unobtainable in man-made systems. The design principles extracted from these biological materials present an unusual yet potent new approach to guide the development of new synthetic composites with enhanced combinations of mechanical properties.Graphical abstractGraphical abstract for this article
       
  • Tensile behavior and structural characterization of pig dermis
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Andrei Pissarenko, Wen Yang, Haocheng Quan, Katherine A. Brown, Alun Williams, William G. Proud, Marc A. Meyers Skin, the outermost layer of the body, fulfills a broad range of functions, protecting internal organs from damage and infection, while regulating the body’s temperature and water content via the exchange of heat and fluids. It must be able to withstand and recover from extensive deformation and damage that can occur during growth, movement, and potential injuries. A detailed investigation of the evolution of the collagen architecture of the dermis as a function of deformation is conducted, which reveals new aspects that help us to understand the mechanical response of skin. Juvenile pig is used as a model material because of its similarity to human skin. The dermis is found to have a tridimensional woven structure of collagen fibers, which evolves with deformation. After failure, we observe that the fibers have straightened and aligned in the direction of tension. The effects of strain-rate change, cyclic loading, stress relaxation, and orientation are quantitatively established. Digital image correlation techniques are implemented to quantify skin’s anisotropy; measurements of the Poisson ratio are reported. This is coupled with transmission electron microscopy which enables obtaining quantitative strain parameters evaluated through the orientation and curvature of the collagen fibers and their changes, for the first time in all three dimensions of the tissue. A model experiment using braided human hair in tension exhibits a similar J-curve response to skin, and we propose that this fiber configuration is at least partially responsible for the monotonic increase of the tangent modulus of skin with strain. The obtained results are intended to serve as a basis for structurally-based models of skin.Statement of SignificanceOur study reveals a new aspect of the dermis: it is comprised of a tridimensional woven structure of collagen fibers, which evolves with deformation. This is enabled by primarily two techniques, transmission electron microscopy on three perpendicular planes and confocal images with second harmonic generation fluorescence of collagen, captured at different intervals of depth. After failure, the fibers have straightened and aligned in the direction of tension. Digital image correlation techniques are implemented to quantify skin’s anisotropy; measurements of the Poisson ratio are reported. A model experiment using braided human hair in tension exhibits a similar J-curve response to skin, and we propose that this fiber configuration is at least partially responsible for the monotonic increase of the tangent modulus of skin with strain.Graphical abstractGraphical abstract for this article
       
  • Multiscale characterization of heart failure
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): F. Sahli Costabal, J.S. Choy, K.L. Sack, J.M. Guccione, G.S. Kassab, E. Kuhl Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic wall strains trigger mechanotransduction pathways that initiate the addition of sarcomeres in series and an overall increase in myocyte length. At the whole organ level, this results in a chronic dilation of the ventricles, an increase in end diastolic and end systolic volumes, and a decrease in ejection fraction. However, how exactly changes in sarcomere number translate into changes in myocyte morphology, and how these cellular changes translate into ventricular dilation remains incompletely understood. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. In an eight-week long volume overload study of six pigs, we found that the average sarcomere number increased by +3.8%/week, from 47 to 62, resulting in a myocyte lengthening of +3.3%/week, from 85 to 108 μm, while the sarcomere length and myocyte width remained unchanged. At the same time, the average end diastolic volume increased by +6.0%/week. Using continuum growth modeling and Bayesian inference, we correlated alterations on the subcellular, cellular, and organ scales and found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results demonstrate that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. We anticipate our study to be a starting point for more sophisticated multiscale models of heart failure. Our study suggests that altering sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse the progression of heart failure.Statement of SignificanceHeart failure is a significant global health problem that affects more than 25 million people worldwide and increases in prevalence as the population ages. Heart failure has been studied excessively at various scales; yet, there is no compelling concept to connect knowledge from the subcellular, cellular, and organ level across the scales. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. We found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results show that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. This suggests that altering the sarcomere turnover—and with it myocyte morphology and ventricular dimensions–could be a potential therapeutic target to attenuate or reverse heart failure.Graphical abstractGraphical abstract for this article
       
  • Cosmetic reconstruction in breast cancer patients: Opportunities for
           nanocomposite materials
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Karthika Prasad, Renwu Zhou, Rusen Zhou, David Schuessler, Kostya Ken Ostrikov, Kateryna Bazaka The most common malignancy in women, breast cancer remains a major medical challenge that affects the life of thousands of patients every year. With recognized benefits to body image and self-esteem, the use of synthetic mammary implants for elective cosmetic augmentation and post-mastectomy reconstruction continues to increase. Higher breast implant use leads to an increased occurrence of implant-related complications associated with implant leakage and rupture, capsular contracture, necrosis and infections, which include delayed healing, pain, poor aesthetic outcomes and the need for revision surgeries. Along with the health status of the implant recipient and the skill of the surgeon, the properties of the implant determine the likelihood of implant-related complications and, in doing so, specific patient outcomes. This paper will review the challenges associated with the use of silicone, saline and “gummy bear” implants in view of their application in patients recovering from breast cancer-related mastectomy, and investigate the opportunities presented by advanced functional nanomaterials in meeting these challenges and potentially opening new dimensions for breast reconstruction.Statement of SignificanceBreast cancer is a significant cause of morbidity and mortality in women worldwide, which is difficult to prevent or predict, and its treatment carries long-term physiological and psychological consequences. Post-mastectomy breast reconstruction addresses the cosmetic aspect of cancer treatment. Yet, drawbacks of current implants contribute to the development of implant-associated complications, which may lead to prolonged patient care, pain and loss of function.Nanomaterials can help resolve the intrinsic biomechanical mismatch between implant and tissues, enhance mechanical properties of soft implantable materials, and provide an alternative avenue for controlled drug delivery. Here, we explore advances in the use of functionalized nanomaterials to enhance the properties of breast implants, with representative examples that highlight the utility of nanomaterials in addressing key challenges associated with breast reconstruction.Graphical abstractGraphical abstract for this article
       
  • Structure-function relationships of nonviral gene vectors: Lessons from
           antimicrobial polymers
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Haonan Xing, Mei Lu, Tianzhi Yang, Hui Liu, Yanping Sun, Xiaoyun Zhao, Hui Xu, Li Yang, Pingtian Ding In recent years, substantial advances have been achieved in the design and synthesis of nonviral gene vectors. However, lack of effective and biocompatible vectors still remains a major challenge that hinders their application in clinical settings. In the past decade, there has been a rapid expansion of cationic antimicrobial polymers, due to their potent, rapid, and broad-spectrum biocidal activity against resistant microbes, and biocompatible features. Given that antimicrobial polymers share common features with nonviral gene vectors in various aspects, such as membrane affinity, functional groups, physicochemical characteristics, and unique macromolecular architectures, these polymers may provide us with inspirations to overcome challenges in the design of novel vectors toward more safe and efficient gene delivery in clinic. Building off these observations, we provide here an overview of the structure-function relationships of polymers for both antimicrobial applications and gene delivery by elaborating some key structural parameters, including functional groups, charge density, hydrophobic/hydrophilic balance, MW, and macromolecular architectures. By borrowing a leaf from antimicrobial agents, great advancement in the development of newer nonviral gene vectors with high transfection efficiency and biocompatibility will be more promising.Statement of SignificanceThe development of gene delivery is still in the preclinical stage for the lack of effective and biocompatible vectors. Given that antimicrobial polymers share common features with gene vectors in various aspects, such as membrane affinity, functional groups, physicochemical characteristics, and unique macromolecular architectures, these polymers may provide us with inspirations to overcome challenges in the design of novel vectors toward more safe and efficient gene delivery in clinic. In this review, we systematically summarized the structure-function relationships of antimicrobial polymers and gene vectors, with which the design of more advanced nonviral gene vectors is anticipated to be further boosted in the future.Graphical abstractGraphical abstract for this article
       
  • Exosomes: The next generation of endogenous nanomaterials for advanced
           drug delivery and therapy
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Wen Liao, Yu Du, Chenghao Zhang, Fangwei Pan, Yang Yao, Ting Zhang, Qiang Peng Development of functional nanomaterials is of great importance and significance for advanced drug delivery and therapy. Nevertheless, exogenous nanomaterials have a great ability to induce undesired immune responses and nano-protein interactions, which may result in toxicity and failure of therapy. Exosomes, a kind of endogenous extracellular vesicle (40–100 nm in diameter), are considered as a new generation of a natural nanoscale delivery system. Exosomes secreted by different types of cells carry different signal molecules (such as RNAs and proteins) and thus have a great potential for targeted drug delivery and therapy. Herein, we provide comprehensive understanding of the properties and applications of exosomes, including their biogenesis, biofunctions, isolation, purification, and drug loading, and typical examples in drug delivery and therapy. Furthermore, their advantages compared to other nanoparticles and potential in tumor immunotherapy are also discussed.Statement of SignificanceExosomes, a kind of endogenous extracellular vesicle, have emerged as a novel and attractive endogenous nanomaterial for advanced drug delivery and targeted therapy. Exosomes are secreted by many types of cells and carry some unique signals obtained from their parental cells. Furthermore, the liposome-like structure allows exosomes to load various drugs. Hence, the potential of exosomes in drug delivery, tumor targeted therapy, and immunotherapy has been investigated in recent years. On the basis of their endogenous features and multifunctional properties, exosomes are of great significance and interest for the development of future medicine and pharmaceuticals.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Metallic microneedles with interconnected porosity: A
           scalable platform for biosensing and drug delivery” [Acta Biomater. 80
           (2018) 401–411]
    • Abstract: Publication date: 1 March 2019Source: Acta Biomaterialia, Volume 86Author(s): Ellen M. Cahill, Shane Keaveney, Vivien Stuettgen, Paulina Eberts, Pamela Ramos-Luna, Nan Zhang, Manita Dangol, Eoin D. O'Cearbhaill
       
  • Engineering of gradient osteochondral tissue: from nature to lab
    • Abstract: Publication date: Available online 2 February 2019Source: Acta BiomaterialiaAuthor(s): Sana Ansari, Sajedeh Khorshidi, Akbar Karkhaneh The osteochondral tissue is an interface between two distinct tissues: articular cartilage and bone. These two tissues are significantly diverse with regard to their chemical compositions, mechanical properties, structure, electrical properties, and the amount of nutrient and oxygen consumption. Thus, transition from the surface of the articular cartilage to the subchondral bone needs to face several smooth gradients. These gradients are imperative to study to generate a scaffold suitable for the reconstruction of the cartilaginous and osseous layers of a defected osteochondral tissue, simultaneously. The aim of this review is to peruse the alternation of biochemical, biomechanical, structural, electrical, and metabolic properties of the osteochondral tissue moving from the surface of the articular cartilage to the subchondral bone. Moreover, this review also discusses currently developed approaches and ideal techniques with a focus on gradients present in the interface of the cartilage and bone.Statement of significanceThe submitted review paper entitled as “Engineering of the gradient osteochondral tissue: from nature to lab” is a complete review in regards to osteochondral tissue and transition of different properties between the cartilage and bone tissues. Moreover, the previous researches on the osteochondral tissue engineering are reviewed. This complete information can be a valuable and useful source for current and future researchers and scientists. Considering the scope of the submitted paper, the Acta biomaterialia would be a suitable journal for publishing this article.
       
 
 
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