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  Subjects -> BIOLOGY (Total: 3149 journals)
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BIOLOGY (1495 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 22)
Achievements in the Life Sciences     Open Access   (Followers: 5)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 24)
Acta Biologica Colombiana     Open Access   (Followers: 7)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 27)
Acta Biotheoretica     Hybrid Journal   (Followers: 4)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales : The Journal of Silesian Museum in Opava     Open Access  
Acta Neurobiologiae Experimentalis     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 10)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis     Open Access  
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Journal of Graduate Research     Open Access  
Advanced 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: 8)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 7)
Advances in Cell Biology     Open Access   (Followers: 25)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Ecological Research     Full-text available via subscription   (Followers: 42)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 17)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Genome Biology     Full-text available via subscription   (Followers: 8)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 3)
Advances in Life Science and Technology     Open Access   (Followers: 16)
Advances in Life Sciences     Open Access   (Followers: 6)
Advances in Marine Biology     Full-text available via subscription   (Followers: 14)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 21)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 6)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 1)
Ageing Research Reviews     Hybrid Journal   (Followers: 10)
Aging Cell     Open Access   (Followers: 12)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Full-text available via subscription   (Followers: 14)
AJP Endocrinology and Metabolism     Full-text available via subscription   (Followers: 23)
AJP Lung Cellular and Molecular Physiology     Full-text available via subscription   (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: 10)
American Journal of Human Biology     Hybrid Journal   (Followers: 13)
American Journal of Medical and Biological Research     Open Access   (Followers: 8)
American Journal of Plant Sciences     Open Access   (Followers: 18)
American Journal of Primatology     Hybrid Journal   (Followers: 14)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 70)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anadolu University Journal of Science and Technology : C Life Sciences and Biotechnology     Open Access  
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 10)
Anatomical Science International     Hybrid Journal   (Followers: 2)
Animal Cells and Systems     Hybrid Journal   (Followers: 4)
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)
Annales UMCS, Biologia     Open Access   (Followers: 1)
Annals of Applied Biology     Hybrid Journal   (Followers: 7)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Human Biology     Hybrid Journal   (Followers: 5)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 15)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 23)
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: 13)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 23)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 10)
Anthropological Review     Open Access   (Followers: 23)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antibiotics     Open Access   (Followers: 9)
Antioxidants     Open Access   (Followers: 4)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 8)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 4)
Apmis     Hybrid Journal   (Followers: 1)
APOPTOSIS     Hybrid Journal   (Followers: 8)
Applied Bionics and Biomechanics     Open Access   (Followers: 8)
Applied Vegetation Science     Full-text available via subscription   (Followers: 10)
Aquaculture Environment Interactions     Open Access   (Followers: 2)
Aquaculture International     Hybrid Journal   (Followers: 22)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 6)
Aquatic Biology     Open Access   (Followers: 5)
Aquatic Ecology     Hybrid Journal   (Followers: 33)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 14)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 21)
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: 8)
Archives of Natural History     Hybrid Journal   (Followers: 6)
Archives of Oral Biology     Hybrid Journal   (Followers: 2)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 2)
Arquivos do Instituto Biológico     Open Access   (Followers: 1)
Arquivos do Museu Dinâmico Interdisciplinar     Open Access  
Arthropod Structure & Development     Hybrid Journal   (Followers: 2)
Arthropods     Open Access   (Followers: 1)
Artificial DNA: PNA & XNA     Hybrid Journal   (Followers: 3)
Artificial Photosynthesis     Open Access   (Followers: 1)
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: 3)
Asian Journal of Nematology     Open Access   (Followers: 4)
Asian Journal of Poultry Science     Open Access   (Followers: 3)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 6)
Autophagy     Hybrid Journal   (Followers: 2)
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: 15)
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)
Biodiversitas : Journal of Biological Diversity     Open Access  
Biodiversity : Research and Conservation     Open Access   (Followers: 26)
Biodiversity Data Journal     Open Access   (Followers: 3)
Biodiversity Informatics     Open Access   (Followers: 1)
Biodiversity Information Science and Standards     Open Access  
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: 2)
Bioengineering and Bioscience     Open Access   (Followers: 1)
BioEssays     Hybrid Journal   (Followers: 10)
Bioethics     Hybrid Journal   (Followers: 14)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 5)
Biofilms     Full-text available via subscription   (Followers: 1)
Biogeosciences (BG)     Open Access   (Followers: 10)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 2)
Bioinformatics     Hybrid Journal   (Followers: 293)
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  
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: 19)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 18)
Biological Letters     Open Access   (Followers: 5)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 46)
Biological Psychology     Hybrid Journal   (Followers: 7)
Biological Research     Open Access  
Biological Rhythm Research     Hybrid Journal   (Followers: 2)
Biological Theory     Hybrid Journal   (Followers: 2)
Biological Trace Element Research     Hybrid Journal  

        1 2 3 4 5 6 7 8 | Last

Journal Cover
Acta Biomaterialia
Journal Prestige (SJR): 1.967
Citation Impact (citeScore): 7
Number of Followers: 27  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1742-7061
Published by Elsevier Homepage  [3163 journals]
  • In vitro response of mesenchymal stem cells to biomimetic hydroxyapatite
           substrates: a new strategy to assess the effect of ion exchange
    • Abstract: Publication date: Available online 20 June 2018
      Source:Acta Biomaterialia
      Author(s): Joanna Maria Sadowska, Jordi Guillem-Marti, Montserrat Espanol, Christoph Stähli, Nicola Döbelin, Maria-Pau Ginebra
      Biomaterials can interact with cells directly, that is, by direct contact of the cells with the material surface, or indirectly, through soluble species that can be released to or uptaken from the surrounding fluids. However, it is difficult to characterise the relevance of this fluid-mediated interaction separately from the topography and composition of the substrate, because they are coupled variables. These fluid-mediated interactions are amplified in the case of highly reactive CaPs such as biomimetic calcium deficient hydroxyapatite (CDHA), particularly in static in vitro cultures. The present work proposes a strategy to decouple the effect of ion exchange from topographical features by adjusting the volume ratio between the cell culture medium and biomaterial (VCM/VB). Increasing this ratio allowed mitigating the drastic ionic exchanges associated to the compositional changes experienced by the material exposed to the cell culture medium. This strategy was validated using rat mesenchymal stem cells (rMSCs) cultured on CDHA and beta-tricalcium phosphate (β-TCP) discs using different (VCM/VB) ratios. Whereas in the case of β-TCP the cell response was not affected by this ratio, a significant effect on cell adhesion and proliferation was found for the more reactive CDHA. The ionic exchange, produced by CDHA at low VCM/VB, altered cell adhesion due to the reduced number of focal adhesions, caused cell shrinkage and further rMCSs apoptosis. This was mitigated when using a high VCM/VB, which attenuated the changes of calcium and phosphate concentrations in the cell culture medium, resulting in rMSCs spreading and a viability over time. Moreover, rMSCs showed an earlier expression of osteogenic genes on CDHA compared to sintered β-TCP when extracellular calcium fluctuations were reduced. Statement of significance Fluid mediated interactions play a significant role in the bioactivity of calcium phosphates. Ionic exchange is amplified in the case of biomimetic hydroxyapatite, which makes the in vitro characterisation of cell-material interactions especially challenging. The present work proposes a novel and simple strategy to explore the mechanisms of interaction of biomimetic and sintered calcium phosphates with mesenchymal stem cells. The effects of topography and ion exchange are analysed separately by modifying the volume ratio between cell culture medium and biomaterial. High ionic fluctuations interfered in the maturation of focal adhesions, hampering cell adhesion and leading to increased apoptosis and reduced proliferation rate.
      Graphical abstract image

      PubDate: 2018-06-21T15:13:43Z
       
  • Titania coating of mesoporous silica nanoparticles for improved
           biocompatibility and drug release within blood vessels
    • Abstract: Publication date: Available online 20 June 2018
      Source:Acta Biomaterialia
      Author(s): Asima Farooq, Ali Shukur, Cai Astley, Lubomira Tosheva, Peter Kelly, Debra Whitehead, May Azzawi
      Blood vessel disease is a major contributor to cardiovascular morbidity and mortality and is hallmarked by dysfunction of the lining endothelial cells (ECs). These cells play a significant role in vascular homeostasis, through the release of mediators to control vessel diameter, hence tissue perfusion. Mesoporous silica nanoparticles (MSNs) can be used as potential drug delivery platforms for vasodilator drugs. Here, using an ex vivo model of vascular function, we examine the use of titania coating for improved biocompatibility and release dynamics of MSN loaded sodium nitroprusside (SNP). MSNs (95 ± 23 nm diameter; pore size 2.7 nm) were synthesised and fully characterised. They were loaded with SNP and coated with titania (TiO2), using the magnetron sputtering technique. Pre-constricted aortic vessels were exposed to drug loaded MSNs (at 1.96 x 1012 MSN mL-1) and the time course of vessel dilation observed, in real time. Exposure of viable vessels to MSNs lead to their internalization into the cytoplasm of ECs, while TiMSNs were also observed in the elastic lamina and smooth muscle cell layers. We demonstrate that titania coating of MSNs significantly improves their biocompatibility and alters the dynamics of drug release. A slow and more sustained relaxation was evident after uptake of TiMSN-SNP, in comparison to uncoated MSN-SNP (rate of dilation was 0.08% per min over a 2.5 h period). The use of titania coated MSNs for drug delivery to the vasculature may be an attractive strategy for therapeutic clinical intervention in cardiovascular disease. Statement of significance Cardiovascular disease is a major cause of mortality and morbidity worldwide, with a total global cost of over $918 billion, by 2030. Mesoporous silica nanoparticles (MSNs) have great potential for the delivery of drugs that can treat vessel disease. This paper provides the first description for the use of titania coated MSNs with increased vascular penetration, for the delivery of vasodilator drugs, without compromising overall vessel function. We demonstrate that titania coating of MSNs significantly improves their biocompatibility and uptake within aortic blood vessels and furthermore, enables a slower and more sustained release of the vasodilator drug, sodium nitroprusside within the vessel, thus making them an attractive strategy for the treatment of vascular disease.
      Graphical abstract image

      PubDate: 2018-06-21T15:13:43Z
       
  • Stimulation of calvarial bone healing with human bone marrow stromal cells
           versus inhibition with adipose-tissue stromal cells on nanostructured
           β-TCP-collagen
    • Abstract: Publication date: Available online 20 June 2018
      Source:Acta Biomaterialia
      Author(s): Friederike Bothe, Benedict Lotz, Elisabeth Seebach, Jennifer Fischer, Eliane Hesse, Solvig Diederichs, Wiltrud Richter
      Bioactive functional scaffolds are essential for support of cell-based strategies to improve bone regeneration. Adipose-tissue-derived-stromal cells (ASC) are more accessible multipotent cells with faster proliferation than bone-marrow-derived-stromal-cells (BMSC) having potential to replace BMSC for therapeutic stimulation of bone-defect healing. Their osteogenic potential is, however lower compared to BMSC, a deficit that may be overcome in growth factor-rich orthotopic bone defects with enhanced bone-conductive scaffolds. Objective of this study was to compare the therapeutic potency of human ASC and BMSC for bone regeneration on a novel nanoparticulate β-TCP/collagen-carrier (β-TNC). Cytotoxicity of β-TCP nanoparticles and multilineage differentiation of cells were characterized in vitro. Cell-seeded β-TNC versus cell-free controls were implanted into 4 mm calvarial bone-defects in immunodeficient mice and bone healing was quantified by µCT at 4 and 8 weeks. Tissue-quality and cell-origin were assessed by histology. β-TNC was non-toxic, radiolucent and biocompatible, lent excellent support for human cell persistence and allowed formation of human bone tissue by BMSC but not ASC. Opposite to BMSC, ASC-grafting significantly inhibited calvarial bone healing compared to controls. Bone formation progressed significantly from 4 to 8 weeks only in BMSC and controls yielding 5.6-fold more mineralized tissue in BMSC versus ASC-treated defects. Conclusively, β-TNC was simple to generate, biocompatible, osteoconductive, and stimulated osteogenicity of BMSC to enhance calvarial defect healing while ASC had negative effects. Thus, an orthotopic environment and β-TNC could not compensate for cell-autonomous deficits of ASC which should systematically be considered when choosing the right cell source for tissue engineering-based stimulation of bone regeneration. Statement of Significance Bone-marrow-derived-stromal cells (BMSC) implanted on bone replacement materials can support bone defect healing and adipose-tissue-derived-stromal cells (ASC) being more accessible and better proliferating are considered as alternate source. This first standardized comparison of the bone regeneration potency of human ASC and BMSC was performed on a novel nanoparticular β-TCP-enriched collagen-carrier (β-TNC) designed to overcome the known inferior osteogenicity of ASC. β-TNC was non-toxic, biocompatible and osteoconductive supporting human bone formation and defect-closure by BMSC but not ASC. Long-term cell-persistence and the distinct secretome of ASC appear as main reasons why ASC inhibited bone healing opposite to BMSC. Overall, ASC-grafting is at considerable risk of producing negative effects on bone-healing while no such risks are known for BMSC.
      Graphical abstract image

      PubDate: 2018-06-21T15:13:43Z
       
  • Engineering Folate-Targeting Diselenide-containing Triblock Copolymer as a
           Redox-Responsive Shell-sheddable Micelle for Antitumor Therapy In Vivo
    • Abstract: Publication date: Available online 19 June 2018
      Source:Acta Biomaterialia
      Author(s): Farnaz Behroozi, Mohammad-Jafar Abdkhodaie, Hamid Sadeghi Abandansari, Leila Satarian, Mohammad Molazem, Khuloud T. Al-Jamal, Hossein Baharvand
      The oxidation-reduction (redox)–responsive micelle system is based on a diselenide-containing triblock copolymer, poly(ε-caprolactone)-bis(diselenide-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate) [PCL-(SeSe-mPEG/PEG-FA)2]. This has helped in the development of tumor-targeted delivery for hydrophobic anticancer drugs. The diselenide bond, as a redox-sensitive linkage, was designed in such a manner that it is located at the hydrophilic–hydrophobic hinge to allow complete collapse of the micelle and thus efficient drug release in redox environments. The amphiphilic block copolymers self-assembled into micelles at concentrations higher than the critical micelle concentration (CMC) in an aqueous environment. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses showed that the micelles were spherical with an average diameter of 120 nm. The insoluble anticancer drug paclitaxel (PTX) was loaded into micelles, and its triggered release behavior under different redox conditions was verified. Folate-targeting micelles showed an enhanced uptake in 4T1 breast cancer cells and in vitro cytotoxicity by flow cytometry and (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay, respectively. Delayed tumor growth was confirmed in the subcutaneously implanted 4T1 breast cancer in mice after intraperitoneal injection. The proposed redox-responsive copolymer offers a new type of biomaterial for drug delivery into cancer cells in vivo. Statement of Significance On-demand drug actuation is highly desired. Redox-responsive polymeric DDSs have been shown to be able to respond and release their cargo in a selective manner when encountering a significant change in the potential difference, such as that present between cancerous and healthy tissues. This study offers an added advantage to the field of redox-responsive polymers by reporting a new type of shell-sheddable micelle based on an amphiphilic triblock co-polymer, containing diselenide as a redox-sensitive linkage. The linkage was smartly located at the hydrophilic-hydrophilic bridge in the co-polymer offering complete collapse of the micelle when exposed to the right trigger. The system was able to delay tumor growth and reduce toxicity in a breast cancer tumor model following intraperitoneal injection in mice.
      Graphical abstract image

      PubDate: 2018-06-21T15:13:43Z
       
  • Bioadhesives for internal medical applications: A review
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Wenzhen Zhu, Yon Jin Chuah, Dong-An Wang
      Bioadhesives such as tissue adhesives, hemostatic agents, and tissue sealants have gained increasing popularity in different areas of clinical operations during the last three decades. Bioadhesives can be categorized into internal and external ones according to their application conditions. External bioadhesives are generally applied in topical medications such as wound closure and epidermal grafting. Internal bioadhesives are mainly used in intracorporal conditions with direct contact to internal environment including tissues, organs and body fluids, such as chronic organ leak repair and bleeding complication reduction. This review focuses on internal bioadhesives that, in contrast with external bioadhesives, emphasize much more on biocompatibility and adhesive ability to wet surfaces rather than on gluing time and intensity. The crosslinking mechanisms of present internal bioadhesives can be generally classified as follows: 1) chemical conjugation between reactive groups; 2) free radical polymerization by light or redox initiation; 3) biological or biochemical coupling with specificity; and 4) biomimetic adhesion inspired from natural phenomena. In this review, bioadhesive products of each class are summarized and discussed by comparing their designs, features, and applications as well as their prospects for future development. Statement of Significance Despite the emergence of numerous novel bioadhesive formulations in recent years, thus far, the classification of internal and external bioadhesives has not been well defined and universally acknowledged. Many of the formulations have been proposed for treatment of several diseases even though they are not applicable for such conditions. This is because of the lack of a systematic standard or evaluation protocol during the development of a new adhesive product. In this review, the definition of internal and external bioadhesives is given for the first time, and with a focus on internal bioadhesives, the criteria of an ideal internal bioadhesive are adequately discussed; this is followed by the review of recently developed internal bioadhesives based on different gluing mechanisms.
      Graphical abstract image

      PubDate: 2018-06-18T15:12:15Z
       
  • Artificial inorganic biohybrids: The functional combination of
           microorganisms and cells with inorganic materials
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Ib Holzmeister, Martha Schamel, Jürgen Groll, Uwe Gbureck, Elke Vorndran
      Biohybrids can be defined as the functional combination of proteins, viable cells or microorganisms with non-biological materials. This article reviews recent findings on the encapsulation of microorganisms and eukaryotic cells in inorganic matrices such as silica gels or cements. The entrapment of biological entities into a support material is of great benefit for processing since the encapsulation matrix protects sensitive cells from shear forces, unfavourable pH changes, or cytotoxic solvents, avoids culture-washout, and simplifies the separation of formed products. After reflecting general aspects of such an immobilization as well as the chemistry of the inorganic matrices, we focused on manufacturing aspects and the application of such biohybrids in biotechnology, medicine as well as in environmental science and for civil engineering purpose. Statement of significance The encapsulation of living cells and microorganisms became an intensively studied and rapidly expanding research field with manifold applications in medicine, bio- and environmental technology, or civil engineering. Here, the use of silica or cements as encapsulation matrices have the advantage of a higher chemical and mechanical resistance towards harsh environmental conditions during processing compared to their polymeric counterparts. In this perspective, the article gives an overview about the inorganic material systems used for cell encapsulation, followed by reviewing the most important applications. The future may lay in a combination of the currently achieved biohybrid systems with additive manufacturing techniques. In a longer perspective, this would enable the direct printing of cell loaded bioreactor components.
      Graphical abstract image

      PubDate: 2018-06-18T15:12:15Z
       
  • Biochemistry and biomedicine of quantum dots: from biodetection to
           bioimaging, drug discovery, diagnostics, and therapy
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Jun Yao, Pingfan Li, Lin Li, Mei Yang
      According to recent research, nanotechnology based on quantum dots (QDs) has been widely applied in the field of bioimaging, drug delivery, and drug analysis. Therefore, it has become one of the major forces driving basic and applied research. The application of nanotechnology in bioimaging has been of concern. Through in vitro labeling, it was found that luminescent QDs possess many properties such as narrow emission, broad UV excitation, bright fluorescence, and high photostability. The QDs also show great potential in whole-body imaging. The QDs can be combined with biomolecules, and hence, they can be used for targeted drug delivery and diagnosis. The characteristics of QDs make them useful for application in pharmacy and pharmacology. This review focuses on various applications of QDs, especially in imaging, drug delivery, pharmaceutical analysis, photothermal therapy, biochips, and targeted surgery. Finally, conclusions are made by providing some critical challenges and a perspective of how this field can be expected to develop in the future. Statement of Significance Quantum dots (QDs) is an emerging field of interdisciplinary subject that involves physics, chemistry, materialogy, biology, medicine, and so on. In addition, nanotechnology based on QDs has been applied in depth in biochemistry and biomedicine. Some forward-looking fields emphatically reflected in some extremely vital areas that possess inspiring potential applicable prospects, such as immunoassay, DNA analysis, biological monitoring, drug discovery, in vitro labelling, in vivo imaging, and tumor target are closely connected to human life and health and has been the top and forefront in science and technology to date. Furthermore, this review has not only involved the traditional biochemical detection but also particularly emphasized its potential applications in life science and biomedicine.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Functionality of decellularized matrix in cartilage regeneration: A
           comparison of tissue versus cell sources
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Yu Sun, Lianqi Yan, Song Chen, Ming Pei
      Increasing evidence indicates that decellularized extracellular matrices (dECMs) derived from cartilage tissues (T-dECMs) or chondrocytes/stem cells (C-dECMs) can support proliferation and chondrogenic differentiation of cartilage-forming cells. However, few review papers compare the differences between these dECMs when they serve as substrates for cartilage regeneration. In this review, after an introduction of cartilage immunogenicity and decellularization methods to prepare T-dECMs and C-dECMs, a comprehensive comparison focuses on the effects of T-dECMs and C-dECMs on proliferation and chondrogenic differentiation of chondrocytes/stem cells in vitro and in vivo. Key factors within dECMs, consisting of microarchitecture characteristics and micromechanical properties as well as retained insoluble and soluble matrix components, are discussed in-depth for potential mechanisms underlying the functionality of these dECMs in regulating chondrogenesis. With this information, we hope to benefit dECM based cartilage engineering and tissue regeneration for future clinical application. Statement of Significance The use of decellularized extracellular matrix (dECM) is becoming a promising approach for tissue engineering and regeneration. Compared to dECM derived from cartilage tissue, recently reported dECM from cell sources exhibits a distinct role in cell based cartilage regeneration. In this review paper, for the first time, tissue and cell based dECMs are comprehensively compared for their functionality in cartilage regeneration. This information is expected to provide an update for dECM based cartilage regeneration.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Decellularized matrices in regenerative medicine
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Doris A. Taylor, Luiz C. Sampaio, Zannatul Ferdous, Andrea S. Gobin, Lakeshia J. Taite
      Of all biologic matrices, decellularized extracellular matrix (dECM) has emerged as a promising tool used either alone or when combined with other biologics in the fields of tissue engineering or regenerative medicine – both preclinically and clinically. dECM provides a native cellular environment that combines its unique composition and architecture. It can be widely obtained from native organs of different species after being decellularized and is entitled to provide necessary cues to cells homing. In this review, the superiority of the macro- and micro-architecture of dECM is described as are methods by which these unique characteristics are being harnessed to aid in the repair and regeneration of organs and tissues. Finally, an overview of the state of research regarding the clinical use of different matrices and the common challenges faced in using dECM are provided, with possible solutions to help translate naturally derived dECM matrices into more robust clinical use. Statement of Significance Ideal scaffolds mimic nature and provide an environment recognized by cells as proper. Biologically derived matrices can provide biological cues, such as sites for cell adhesion, in addition to the mechanical support provided by synthetic matrices. Decellularized extracellular matrix is the closest scaffold to nature, combining unique micro- and macro-architectural characteristics with an equally unique complex composition. The decellularization process preserves structural integrity, ensuring an intact vasculature. As this multifunctional structure can also induce cell differentiation and maturation, it could become the gold standard for scaffolds.
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      PubDate: 2018-06-18T15:12:15Z
       
  • A review on fabricating tissue scaffolds using vat photopolymerization
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Nicholas A. Chartrain, Christopher B. Williams, Abby R. Whittington
      Vat Photopolymerization (stereolithography, SLA), an Additive Manufacturing (AM) or 3D printing technology, holds particular promise for the fabrication of tissue scaffolds for use in regenerative medicine. Unlike traditional tissue scaffold fabrication techniques, SLA is capable of fabricating designed scaffolds through the selective photopolymerization of a photopolymer resin on the micron scale. SLA offers unprecedented control over scaffold porosity and permeability, as well as pore size, shape, and interconnectivity. Perhaps even more significantly, SLA can be used to fabricate vascular networks that may encourage angio and vasculogenesis. Fulfilling this potential requires the development of new photopolymers, the incorporation of biochemical factors into printed scaffolds, and an understanding of the effects scaffold geometry have on cell viability, proliferation, and differentiation. This review compares SLA to other scaffold fabrication techniques, highlights significant advances in the field, and offers a perspective on the field’s challenges and future directions. Statement of Significance Engineering de novo tissues continues to be challenging due, in part, to our inability to fabricate complex tissue scaffolds that can support cell proliferation and encourage the formation of developed tissue. The goal of this review is to first introduce the reader to traditional and Additive Manufacturing scaffold fabrication techniques. The bulk of this review will then focus on apprising the reader of current research and provide a perspective on the promising use of vat photopolymerization (stereolithography, SLA) for the fabrication of complex tissue scaffolds.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Curvature-dependent effects of nanotopography on classical immune
           complement activation
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Emma Westas Janco, Mats Hulander, Martin Andersson
      The aim of this study was to investigate how the size of nanosized surface features affect classical immune complement activation through adsorption of IgG and the following binding of C1q. By using model surfaces with immobilized SiO2 nanoparticles of different sizes (8, 32 and 68 nm in diameter), three different curvatures with the same chemistry was systematically studied and analyzed using the acoustic sensing technique; Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D). Circular Dichroism (CD) was employed to study any changes in the secondary structure of IgG using a methodology with stacked functionalized substrates. Our results show that the amount of IgG adsorption increased slightly with nanoparticle size, but also showed a strong size/curvature-dependent effect on the following C1q binding, with the highest binding to IgG adsorbed on the largest nanoparticles and a smooth control surface, indicating that classical immune complement activation possibly increase with decreasing curvature. We conclude that the difference in C1q binding was not due to changes in the secondary structure of IgG, suggesting that geometrical arrangement of adsorbed IgG is the determining factor. Statement of Significance We have shown that small changes at the topographical nanoscale can give large effects on the initiation of the classical immune complement cascade, an important immunological reaction that take place when a foreign material is inserted in the body. By developing a methodology using silicon dioxide nanoparticles with three different sizes, to systematically study their impact on the secondary structure and binding of human immunoglobulin G (IgG) to the initiator protein C1q of the classical complement cascade, we have shown that the initiation of the classical immune complement is hampered by the sharp curvature of the smaller nanoparticles. We conclude that this is not mediated by changes in the secondary structure of the adsorbed proteins, but rather an effect of curvature-induced spatial mismatch. The results provide a possible mechanistic explanation on how nanotopography may effect protein adsorption and protein cascade events.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Biomimetic soft fibrous hydrogels for contractile and pharmacologically
           responsive smooth muscle
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Yonghui Ding, Xin Xu, Sadhana Sharma, Michael Floren, Kurt Stenmark, Stephanie J. Bryant, Corey P. Neu, Wei Tan
      The ability to assess changes in smooth muscle contractility and pharmacological responsiveness in normal or pathological-relevant vascular tissue environments is critical to enable vascular drug discovery. However, major challenges remain in both capturing the complexity of in vivo vascular remodeling and evaluating cell contractility in complex, tissue-like environments. Herein, we developed a biomimetic fibrous hydrogel with tunable structure, stiffness, and composition to resemble the native vascular tissue environment. This hydrogel platform was further combined with the combinatory protein array technology as well as advanced approaches to measure cell mechanics and contractility, thus permitting evaluation of smooth muscle functions in a variety of tissue-like microenvironments. Our results demonstrated that biomimetic fibrous structure played a dominant role in smooth muscle function, while the presentation of adhesion proteins co-regulated it to various degrees. Specifically, fibre networks enabled cell infiltration and upregulated expression of actomyosin proteins in contrast to flat hydrogels. Remarkably, fibrous structure and physiologically relevant stiffness of hydrogels cooperatively enhanced smooth muscle contractility and pharmacological responses to vasoactive drugs at both the single cell and intact tissue levels. Together, this study is the first to demonstrate alterations of human vascular smooth muscle contractility and pharmacological responsiveness in biomimetic soft, fibrous environments with a cellular array platform. The integrated platform produced here could enable investigations for pathobiology and pharmacological interventions by developing a broad range of patho-physiologically relevant in vitro tissue models. Statement of Significance Engineering functional smooth muscle in vitro holds the great potential for diseased tissue replacement and drug testing. A central challenge is recapitulating the smooth muscle contractility and pharmacological responses given its significant phenotypic plasticity in response to changes in environment. We present a biomimetic fibrous hydrogel with tunable structure, stiffness, and composition that enables the creation of functional smooth muscle tissues in the native-like vascular tissue microenvironment. Such fibrous hydrogel is further combined with the combinatory protein array technology to construct a cellular array for evaluation of smooth muscle phenotype, contraction, and cell mechanics. The integrated platform produced here could be promising for developing a broad range of normal or diseased in vitro tissue models.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Mechanically robust cryogels with injectability and bioprinting
           supportability for adipose tissue engineering
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Dianjun Qi, Shaohua Wu, Mitchell A. Kuss, Wen Shi, Soonkyu Chung, Paul T. Deegan, Alexey Kamenskiy, Yini He, Bin Duan
      Bioengineered adipose tissues have gained increased interest as a promising alternative to autologous tissue flaps and synthetic adipose fillers for soft tissue augmentation and defect reconstruction in clinic. Although many scaffolding materials and biofabrication methods have been investigated for adipose tissue engineering in the last decades, there are still challenges to recapitulate the appropriate adipose tissue microenvironment, maintain volume stability, and induce vascularization to achieve long-term function and integration. In the present research, we fabricated cryogels consisting of methacrylated gelatin, methacrylated hyaluronic acid, and 4arm poly(ethylene glycol) acrylate (PEG-4A) by using cryopolymerization. The cryogels were repeatedly injectable and stretchable, and the addition of PEG-4A improved the robustness and mechanical properties. The cryogels supported human adipose progenitor cell (HWA) and adipose derived mesenchymal stromal cell adhesion, proliferation, and adipogenic differentiation and maturation, regardless of the addition of PEG-4A. The HWA laden cryogels facilitated the co-culture of human umbilical vein endothelial cells (HUVEC) and capillary-like network formation, which in return also promoted adipogenesis. We further combined cryogels with 3D bioprinting to generate handleable adipose constructs with clinically relevant size. 3D bioprinting enabled the deposition of multiple bioinks onto the cryogels. The bioprinted flap-like constructs had an integrated structure without delamination and supported vascularization. Statement of Significance Adipose tissue engineering is promising for reconstruction of soft tissue defects, and also challenging for restoring and maintaining soft tissue volume and shape, and achieving vascularization and integration. In this study, we fabricated cryogels with mechanical robustness, injectability, and stretchability by using cryopolymerization. The cryogels promoted cell adhesion, proliferation, and adipogenic differentiation and maturation of human adipose progenitor cells and adipose derived mesenchymal stromal cells. Moreover, the cryogels also supported 3D bioprinting on top, forming vascularized adipose constructs. This study demonstrates the potential of the implementation of cryogels for generating volume-stable adipose tissue constructs and provides a strategy to fabricate vascularized flap-like constructs for complex soft tissue regeneration.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Micropatterned biodegradable polyesters clicked with CQAASIKVAV promote
           cell alignment, directional migration, and neurite outgrowth
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Deteng Zhang, Sai Wu, Jianyong Feng, Yiyuan Duan, Dongming Xing, Changyou Gao
      The interplay of microstructures and biological cues is critical to regulate the behaviors of Schwann cells (SCs) in terms of cellular spatial arrangement and directional migration as well as neurite orientation for bridging the proximal and distal stumps of the injured peripheral nervous system. In this study, stripe micropatterns having ridges/grooves of width 20/20 and 20/40 μm were fabricated on the surface of maleimide-functionalized biodegradable poly(ester carbonate) (P(LLA-MTMC)) films by the polydimethylsiloxane mold-pressing method, respectively. The laminin-derived CQAASIKVAV peptides end-capped with an SH group were then grafted by the thiol-ene click reaction under mild conditions to obtain micropatterned and peptide-grafted films. SCs cultured on these films, especially on the 20/40-μm film, displayed faster and aligned adhesion as well as a larger number of elongated cells with a higher length-to-width (L/W) ratio along the stripe direction than those on the flat-pep film. The migration rate of SCs was significantly enhanced in parallel to the stripe direction with a large net displacement. The micropatterned and peptide-grafted films, especially the 20/40-μm film, could promote SC proliferation and nerve growth factor (NGF) secretion in a manner similar to that of the peptide-grafted planar film. Moreover, the neurites of rat pheochromocytoma 12 (PC12) cells sprouted along the ridges with a longer average length on the micropatterned and peptide-grafted films. The synergistic effect of physical patterns and biological cues was evaluated by considering the results of cell adhesion force; immunofluorescence staining of vinculin; fluorescence staining of F-actin and the nucleus; as well as gene expression of neural cadherin (NCAD), neurocan (NCAN), and myelin protein zero (P0). Statement of Significance The interplay of microstructures and biological cues is critical to regulate the behaviors of Schwann cells (SCs) and nerve cells, and thereby the regeneration of peripheral nerve system. In this study, the combined micropatterning and CQAASIKVAV grafting endowed the modified P(LLA-MTMC) films with both contact guidance and bioactive chemical cues to enhance cell proliferation, directional alignment and migration, longer net displacement and larger NGF secretion, and stronger neurite outgrowth of SCs and PC12 cells. Hence, the integration of physical micropatterns and bioactive molecules is an effective way to obtain featured biomaterials for the regeneration of nerves and other types of tissues.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Icariin conjugated hyaluronic acid/collagen hydrogel for osteochondral
           interface restoration
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Jirong Yang, Yanbo Liu, Long He, Qiguang Wang, Lan Wang, Tun Yuan, Yumei Xiao, Yujiang Fan, Xingdong Zhang
      Over the past decades, numerous tissue-engineered constructs have been investigated for the osteochondral repair. However, it still remains a challenge to regenerate the functionalized calcified layer. In this study, the potential of icariin (Ica) conjugated hyaluronic acid/collagen (Ica-HA/Col) hydrogel to promote the osteochondral interface restoration was investigated. Compared with HA/Col hydrogel, Ica-HA/Col hydrogel simultaneously facilitated chondrogenesis and osteogenesis in vitro. The cells encapsulated in Ica-HA/Col hydrogel tended to aggregate into bigger clusters. The chondrogenic genes’ expression level was remarkably up-regulated, and the matrix synthesis of sGAG and type II collagen was significantly enhanced. Similarly, the osteogenic genes, including RUNX2, ALP, and OCN were also up-regulated at early stage. Consequently, more calcium deposition was observed in the Ica-HA/Col hydrogel construct. Moreover, the gene expression and matrix synthesis of type X collagen, an important marker for the formation of calcified layer; were significantly higher in the Ica-HA/Col hydrogel. Furthermore, the in vivo study showed that Ica-HA/Col constructs facilitated the reconstruction of osteochondral interface in rabbit subchondral defects. In the Ica-HA/Col group, the neo-cartilage layer contained more type II collagen and the newly formed subchondral bone deposited more abundant type I collagen. Overall, the results indicated that Ica-HA/Col hydrogel might be a promising scaffold to reconstruct an osteochondral interface, therefore promoting restoring of osteochondral defect. Statement of Significance The osteochondral defect restoration not only involves the repair of damaged cartilage and the subchondral bone, but also the reconstruction of osteochondral interface (the functional calcified layer). The calcified layer regeneration is essential for integrative and functional osteochondral repair. Over the past decade, numerous tissue engineered constructs have been investigated for the osteochondral repair. However, it still remains a challenge to regenerate a functionalized calcified layer. The present study demonstrates that Ica-HA/Col hydrogel facilitates deposition of matrix related to calcified layer in mixed chondrogenic/osteogenic inductive media and restoration of osteochondral defect in vivo. Since, Ica-HA/Col hydrogel as is cheaper, easier and more efficient, it might be a desired scaffold for the osteochondral defects restoration.
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      PubDate: 2018-06-18T15:12:15Z
       
  • An integrated biomanufacturing platform for the large-scale expansion and
           neuronal differentiation of human pluripotent stem cell-derived neural
           progenitor cells
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Gayathri Srinivasan, Daylin Morgan, Divya Varun, Nicholas Brookhouser, David A. Brafman
      Human pluripotent stem cell derived neural progenitor cells (hNPCs) have the unique properties of long-term in vitro expansion as well as differentiation into the various neurons and supporting cell types of the central nervous system (CNS). Because of these characteristics, hNPCs have tremendous potential in the modeling and treatment of various CNS diseases and disorders. However, expansion and neuronal differentiation of hNPCs in quantities necessary for these applications is not possible with current two dimensional (2-D) approaches. Here, we used a fully defined peptide substrate as the basis for a microcarrier (MC)-based suspension culture system. Several independently derived hNPC lines were cultured on MCs for multiple passages as well as efficiently differentiated to neurons. Finally, this MC-based system was used in conjunction with a low shear rotating wall vessel (RWV) bioreactor for the integrated, large-scale expansion and neuronal differentiation of hNPCs. Overall, this fully defined and scalable biomanufacturing system will facilitate the generation of hNPCs and their neuronal derivatives in quantities necessary for basic and translational applications. Statement of Significance In this work, we developed a microcarrier (MC)-based culture system that allows for the expansion and neuronal differentiation of human pluripotent stem cell-derived neural progenitor cells (hNPCs) under defined conditions. In turn, this MC approach was implemented in a rotating wall vessel (RWV) bioreactor for the large-scale expansion and neuronal differentiation of hNPCs. This work is of significance as it overcomes current limitations of conventional two dimensional (2-D) culture systems to enable the generation of hNPCs and their neuronal derivatives in quantities required for downstream applications in disease modeling, drug screening, and regenerative medicine.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Arginine-based poly(ester amide) nanoparticle platform: From
           structure–property relationship to nucleic acid delivery
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Xinru You, Zhipeng Gu, Jun Huang, Yang Kang, Chih-Chang Chu, Jun Wu
      Many different types of polycations have been vigorously studied for nucleic acid delivery, but a systematical investigation of the structure–property relationships of polycations for nucleic acid delivery is still lacking. In this study, a new library of biodegradable and biocompatible arginine-based poly(ester amide) (Arg-PEA) biomaterials was designed and synthesized with a tunable structure for such a comprehensive structure–property research. Nanoparticle (NP) complexes were formed through the electrostatic interactions between the polycationic Arg-PEAs and anionic nucleic acids. The following structure effects of the Arg-PEAs on the transfection efficiency of nucleic acids were investigated: 1) the linker/spacer length (length effect and odd–even effect); 2) salt type of arginine; 3) the side chain; 4) chain stiffness; 5) molecular weight (MW). The data obtained revealed that a slight change in the Arg-PEA structure could finely tune its physicochemical property such as hydrophobicity, and this could subsequently affect the nanoparticle size and zeta potential, which, in turn, regulate the transfection efficiency and silencing outcomes. A further study of the Arg-PEA/CpG oligodeoxynucleotide NP complexes indicated that the polymer structure could precisily regulate the immune response of CpG, thus providing a new potential nano-immunotherapy strategy. The in vitro data have further confirmed that the Arg-PEA NPs showed a satisfactory delivery performance for a variety of nucleic acids. Therefore, the data from the current study provide comprehensive information about the Arg-PEA structure–transfection property relationship; the tunable property of the library of Arg-PEA biomaterials can be one of the promising candidates for nucleic acid delivery and other biomedical applications. Statement of Significance Polycations have being intensive utilized for nucleic acid delivery. However, there has not been elucidated about the relationship between polycation’s structure and the physicochemical properties/biological function. In this timely report, an arginine based poly(ester amide) (Arg-PEA) library was prepared with finely tunable structure to systematically investigate the structure–property relationships of polycations for nucleic acid delivery. The results revealed that slight change of Arg-PEA structure could finely tune the physicochemical property (such as hydrophobicity), which subsequently affect the size and zeta potential of Arg-PEA/nucleic acid nanoparticles(NPs), and finally regulate the resulting transfection or silencing outcomes. Further study of Arg-PEA/CpG NPs indicated that the polymer structure could precisely regulate immuno response of CpG, providing new potential nano-immunotherapy strategy. In vitro evaluations confirmed that the NPs showed satisfied delivery performance for a variety types of nucleic acids. Therefore, these studies provide comprehensive information of Arg-PEA structure–property relationship, and the tunable properties of Arg-PEAs make them promising candidates for nucleic acid delivery and other biomedical applications. Overall, we have shown enough significance and novelty in terms of nucleic acid delivery, biomaterials, pharmaceutical science and nanomedicine.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Cross-linked electrospun cartilage acellular
           matrix/poly(caprolactone-co-lactide-co-glycolide) nanofiber as an
           antiadhesive barrier
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Jin Woo Lee, Joon Yeong Park, Seung Hun Park, Min Ju Kim, Bo Ram Song, Hee-Woong Yun, Tae Woong Kang, Hak Soo Choi, Young Jick Kim, Byoung Hyun Min, Moon Suk Kim
      In this work, we chose cartilage acellular matrix (CAM) as a promising antiadhesive material because CAM effectively inhibits the formation of blood vessels, and we used electrospinning to prepare antiadhesive barriers. Additionally, we synthesized N-hydroxysuccinimide (NHS)-poly(caprolactone-co-lactide-co-glycolide)-NHS (MP) copolymers (to tune degradation) as a cross-linking agent for CAM. This is the first report on the development of electrospun cross-linked (Cx) CAM/MP (CA/P) nanofiber (NF) (Cx-CA/P-NF) with a tunable degradation period as an antiadhesive barrier. Compared with the CA/P-NF before cross-linking, the electrospun Cx-CA/P-NF after cross-linking showed different biodegradation. Cx-CA/P-NF significantly inhibited the in vitro attachment and proliferation of human umbilical vein endothelial cells (HUVECs), as confirmed by an MTT assay and scanning electron microscopy images. Cx-CA/P-NFs implanted between a surgically damaged peritoneal wall and cecum gradually degraded in 7 days; this process was monitored by NIR imaging. The in vivo evaluation of the anti–tissue adhesive effect of Cx-CA/P-NFs revealed little adhesion, few blood vessels, and negligible inflammation at 7 days determined by hematoxylin and eosin staining. ED1 staining of Cx-CA/P-NFs showed infiltration of few macrophages because of the inflammatory response to the Cx-CA/P-NF as compared with an untreated injury model. Additionally, Cx-CA/P-NFs significantly suppressed the formation of blood vessels between the peritoneal wall and cecum, according to CD31 staining. Overall, Cx-CA/P-NFs yielded little adhesion, infiltration by macrophages, or formation of blood vessels in a postoperative antiadhesion assay. Thus, it is reasonable to conclude that the Cx-CA/P-NF designed herein successfully works as an antiadhesive barrier with a tunable degradation period. Statement of Significance The cartilage acellular matrix (CAM) can inhibit the formation of fibrous tissue bridges and blood vessels between the tissue at an injured site and the surrounding healthy tissues. However, CAM has not been rigorously investigated as an antiadhesive barrier. In this manuscript, the cross-linked CAM nanofiber (Cx-CA/P-NF) designed herein successfully works as an antiadhesive barrier. Cx-CA/P-NFs yielded little adhesion, infiltration by macrophages, or formation of blood vessels in a postoperative antiadhesion assay. Moreover, we demonstrated the suitable properties of Cx-CA/P-NF such as easy cross-linking by maintaining the antiadhesive properties, controllable biodegradation, and in vivo antiadhesive effect of Cx-CA/P-NF.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Extracellular matrix component expression in human pluripotent stem
           cell-derived retinal organoids recapitulates retinogenesis in vivo and
           reveals an important role for IMPG1 and CD44 in the development of
           photoreceptors and interphotoreceptor matrix
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Majed Felemban, Birthe Dorgau, Nicola Claire Hunt, Dean Hallam, Darin Zerti, Roman Bauer, Yuchun Ding, Joseph Collin, David Steel, Natalio Krasnogor, Jumana Al-Aama, Susan Lindsay, Carla Mellough, Majlinda Lako
      The extracellular matrix (ECM) plays an important role in numerous processes including cellular proliferation, differentiation, migration, maturation, adhesion guidance and axonal growth. To date, there has been no detailed analysis of the ECM distribution during retinal ontogenesis in humans and the functional importance of many ECM components is poorly understood. In this study, the expression of key ECM components in adult mouse and monkey retina, developing and adult human retina and retinal organoids derived from human pluripotent stem cells was studied. Our data indicate that basement membrane ECMs (Fibronectin and Collagen IV) were expressed in Bruch’s membrane and the inner limiting membrane of the developing human retina, whilst the hyalectins (Versican and Brevican), cluster of differentiation 44 (CD44), photoreceptor-specific ECMs Interphotoreceptor Matrix Proteoglycan 1 (IMPG1) and Interphotoreceptor Matrix Proteoglycan 2 (IMPG2) were detected in the developing interphotoreceptor matrix (IPM). The expression of IMPG1, Versican and Brevican in the developing IPM was conserved between human developing retina and human pluripotent stem cell-derived retinal organoids. Blocking the action of CD44 and IMPG1 in pluripotent stem cell derived retinal organoids affected the development of photoreceptors, their inner/outer segments and connecting cilia and disrupted IPM formation, with IMPG1 having an earlier and more significant impact. Together, our data suggest an important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation during human retinogenesis. Statement of Significance The expression and the role of many extracellular matrix (ECM) components during human retinal development is not fully understood. In this study, expression of key ECM components (Collagen IV, Fibronectin, Brevican, Versican, IMPG1 and IMPG2) was investigated during human retinal ontogenesis. Collagen IV and Fibronectin were expressed in Bruch’s membrane; whereas Brevican, Versican, IMPG1 & IMPG2 in the developing interphotoreceptor matrix (IPM). Retinal organoids were successfully generated from pluripotent stem cells. The expression of ECM components was examined in the retinal organoids and found to recapitulate human retinal development in vivo. Using functional blocking experiments, we were able to highlight an important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Therapeutic antibody directed osteogenic differentiation of induced
           pluripotent stem cell derived MSCs
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Qingqing Wu, Bo Yang, Cong Cao, Kevin Hu, Ping Wang, Yi Man
      Induced pluripotent stem cells (iPSCs) are regarded as a new cell source for regenerative medicine. Recent advances in tissue engineering have brought to light the therapeutic application of induced pluripotent stem cells (iPSCs) in bone defect repair. However, a safe and efficient way to differentiate iPSCs into osteogenic lineage remains to be a major challenge. Here we describe an approach using anti-BMP2 antibodies (Abs) to mediate osteogenic differentiation of iPSC-derived mesenchymal stromal cells (iMSCs). We first proved that 3G7 (an anti-BMP2 Ab) not only bound to BMP2, but also allowed the bound BMP2 to engage the BMP2 receptors on iMSCs. Subcutaneous implantation sites loaded with iMSCs + 3G7 group showed significant bone formation and vascularization in mice while those sites with exogenous BMP2 exhibited dystrophic calcification and significantly lower vascularization. Our in vitro study demonstrated that the anti-BMP2 Ab/BMP2 immune complex were capable of dictating the acquisition of osteogenic phenotype of iMSCs and subsequent mineralization. The study provided the first evidence of antibody-mediated differentiation of iMSCs and osseous regeneration in vivo. This novel strategy takes full advantage of the endogenous bioactive molecules for osseous regeneration and its potential therapeutic application is promising. Statement of Significance Induced pluripotent stem cells (iPSCs) and its derived cells hold significant promise for the treatment of bone defects. In present study, we carried out the concept of antibody-mediated bone regeneration into the iPSC research for the first time. We demonstrated that anti-BMP2 Ab/BMP2 immune complex was capable of promoting osteogenic differentiation of iPSC-derived MSCs (iMSCs), likely through the classical BMP2/Smad1/Runx2 pathway. Subcutaneous co-delivery of iMSCs and anti-BMP2 Abs resulted in significant bone formation and vascularization. These findings suggested antibody mediated osteogenic differentiation may be a favorable approach for iPSC-based bone tissue engineering.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Evaluation of genotoxicity and mutagenic effects of vector/DNA
           nanocomplexes in transfected mesenchymal stem cells by flow cytometry
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Alireza Nomani, Xuguang Chen, Arash Hatefi
      In recent years, there has been a great deal of interest in ex-vivo genetic modification of mesenchymal stem cells (MSCs) to meet various biomedical needs. Considering the self-renewal potential of MSCs, it is critically important to ensure that transfection vectors (gene carriers) do not induce genotoxicity because they could theoretically turn a single stem cell into a cancer-initiating cell. Unfortunately, there is currently no reliable, unbiased, and quantitative method to measure genotoxicity (micronuclei formation) of gene carriers directly in transfected MSCs. Consequently, it has not been possible to study the correlation of vectors’ physicochemical characteristics with their impact on stem cell genome stability. To address this deficiency, a flow cytometry-based method with a specialized gating protocol was developed that not only measures micronuclei formation, but also determines the mechanism of mutagenesis (i.e., clastogenic vs. aneugenic) of each vector in transfected MSCs. This gating protocol effectively eliminates all interfering signals associated with aggregated nanoparticles (viral and non-viral), exogenous DNA, and apoptotic/necrotic bodies from the micronuclei measurement process. The presented gating protocol for flow cytometry, which is provided as a template, enables investigators in academia, industry and regulatory bodies to rapidly and reliably evaluate the genosafety profiles of gene carriers. The findings of this study also indicate that highly positively charged lipid- and polymeric-based vectors can induce genotoxicity even without manifesting substantial somatic toxicity. Thus, extreme care must be taken before implanting ex-vivo-modified MSCs back into a patient’s body. Statement of Significance There is a great interest in genetic modification of stem cells (SCs) by using vectors for various biomedical needs. Considering the self-renewal potential of SCs, it is essential to ensure that such vectors do not induce genetic aberrations (genotoxicity) because they could theoretically turn a single stem cell into a cancer-initiating cell. Unfortunately, there is currently no reliable method to measure genotoxicity of vectors directly in transfected SCs. To address this deficiency, a specialized flow cytometry-based method was developed that quantitatively analyzed genotoxicity and determined the mechanism of mutagenesis that occurred in transfected SCs during the transfection process. The developed technique will enable scientists to design safer vectors for genetic modification of stem cells.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Construction of tendon replacement tissue based on collagen sponge and
           mesenchymal stem cells by coupled mechano-chemical induction and
           evaluation of its tendon repair abilities
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Bingyu Zhang, Qing Luo, Bin Deng, Yasuyuki Morita, Yang Ju, Guanbin Song
      Tissue engineering is an ideal therapeutic strategy for the development of functional tendon replacement tissue for tendon repair in the clinic. Currently, the synergistic roles of mechano-chemical factors and the mechanisms involved in tendon repair and regeneration are not fully understood. In this study, we developed a three-dimensional (3D) culture system based on a silicone chamber and collagen sponge scaffold that can deliver cyclic mechanical stretch and biochemical stimulation to bone marrow-derived mesenchymal stem cells (BMSCs) seeded on the scaffold. We found that the combined stimulation of cyclic stretch and transforming growth factor beta 1 (TGF-β1) treatment not only increased cell viability but also synergistically promoted the differentiation of BMSCs into tenocytes in a 3D culture environment. Meanwhile, the combined stimulation increased the Young’s modulus of the BMSC-collagen sponge constructs by reducing the porosity of the scaffold compared to the non-treated constructs. Furthermore, a rat Achilles tendon in situ repair experiment showed that enhanced tendon regeneration was achieved using the BMSC-collagen sponge construct combined with cyclic stretch and TGF-β1, as confirmed by Achilles functional index (AFI) measurement, morphological observation, histological analysis, and mechanical testing. These results suggest that this approach could offer a practical benefit in tendon healing and future tendon tissue engineering. Statement of Significance This study aims to disclose the crucial roles of the coupled induction by mechano-chemical stimulation in tendon tissue engineering and clarifies their collaborative control mechanisms. We developed a three-dimensional (3D) culture system based on a silicone chamber and collagen sponge scaffold that could deliver cyclic mechanical stretch and biochemical stimulation to bone marrow-derived mesenchymal stem cells (BMSCs). We found that the combined stimulation of cyclic stretch and transforming growth factor beta 1 (TGF-β1) could result in an improvement of tissue-engineered construct for enhancing tendon healing. These results suggest that this approach could offer a practical benefit in tendon healing and future tendon tissue engineering.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Compressive mechanical characterization of non-human primate spinal cord
           white matter
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Shervin Jannesar, Mark Allen, Sarah Mills, Anne Gibbons, Jacqueline C. Bresnahan, Ernesto A. Salegio, Carolyn J. Sparrey
      The goal of developing computational models of spinal cord injury (SCI) is to better understand the human injury condition. However, finite element models of human SCI have used rodent spinal cord tissue properties due to a lack of experimental data. Central nervous system tissues in non human primates (NHP) closely resemble that of humans and therefore, it is expected that material constitutive models obtained from NHPs will increase the fidelity and the accuracy of human SCI models. Human SCI most often results from compressive loading and spinal cord white matter properties affect FE predicted patterns of injury; therefore, the objectives of this study were to characterize the unconfined compressive response of NHP spinal cord white matter and present an experimentally derived, finite element tractable constitutive model for the tissue. Cervical spinal cords were harvested from nine male adult NHPs (Macaca mulatta). White matter biopsy samples (3 mm in diameter) were taken from both lateral columns of the spinal cord and were divided into four strain rate groups for unconfined dynamic compression and stress relaxation (post-mortem <1-hour). The NHP spinal cord white matter compressive response was sensitive to strain rate and showed substantial stress relaxation confirming the viscoelastic behavior of the material. An Ogden 1st order model best captured the non-linear behavior of NHP white matter in a quasi-linear viscoelastic material model with 4-term Prony series. This study is the first to characterize NHP spinal cord white matter at high (>10/sec) strain rates typical of traumatic injury. The finite element derived material constitutive model of this study will increase the fidelity of SCI computational models and provide important insights for transferring pre-clinical findings to clinical treatments. Statement of Significance Spinal cord injury (SCI) finite element (FE) models provide an important tool to bridge the gap between animal studies and human injury, assess injury prevention technologies (e.g. helmets, seatbelts), and provide insight into the mechanisms of injury. Although, FE model outcomes depend on the assumed material constitutive model, there is limited experimental data for fresh spinal cords and all was obtained from rodent, porcine or bovine tissues. Central nervous system tissues in non human primates (NHP) more closely resemble humans. This study characterizes fresh NHP spinal cord material properties at high strains rates and large deformations typical of SCI for the first time. A constitutive model was defined that can be readily implemented in finite strain FE analysis of SCI.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Dynamic shear-lag model for understanding the role of matrix in energy
           dissipation in fiber-reinforced composites
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Junjie Liu, Wenqing Zhu, Zhongliang Yu, Xiaoding Wei
      Lightweight and high impact performance composite design is a big challenge for scientists and engineers. Inspired from well-known biological materials, e.g., the bones, spider silk, and claws of mantis shrimp, artificial composites have been synthesized for engineering applications. Presently, the design of ballistic resistant composites mainly emphasizes the utilization of light and high-strength fibers, whereas the contribution from matrix materials receives less attention. However, recent ballistic experiments on fiber-reinforced composites challenge our common sense. The use of matrix with “low-grade” properties enhances effectively the impact performance. In this study, we establish a dynamic shear-lag model to explore the energy dissipation through viscous matrix materials in fiber-reinforced composites and the associations of energy dissipation characteristics with the properties and geometries of constituents. The model suggests that an enhancement in energy dissipation before the material integrity is lost can be achieved by tuning the shear modulus and viscosity of a matrix. Furthermore, our model implies that an appropriately designed staggered microstructure, adopted by many natural composites, can repeatedly activate the energy dissipation process and thus improve dramatically the impact performance. This model demonstrates the role of matrix in energy dissipation, and stimulates new advanced material design concepts for ballistic applications. Statement of Significance Biological composites found in nature often possess exceptional mechanical properties that man-made materials haven’t be able to achieve. For example, it is predicted that a pencil thick spider silk thread can stop a flying Boeing airplane. Here, by proposing a dynamic shear-lag model, we investigate the relationships between the impact performance of a composite with the dimensions and properties of its constituents. Our analysis suggests that the impact performance of fiber-reinforced composites could improve surprisingly with “low-grade” matrix materials, and discontinuities (often regarded as “defects”) may play an important role in energy dissipation. Counter-intuitive as it may seem, our work helps understanding the secrets of the outstanding dynamic properties of some biological materials, and inspire novel ideas for man-made composites.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Injectable nanocomposite analgesic delivery system for musculoskeletal
           pain management
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Manakamana Khanal, Shalini V. Gohil, Emmanuel Kuyinu, Ho-Man Kan, Brittany E. Knight, Kyle M. Baumbauer, Kevin W.-H. Lo, Joseph Walker, Cato T. Laurencin, Lakshmi S. Nair
      Musculoskeletal pain is a major health issue which results from surgical procedures (i.e. total knee and/or hip replacements and rotator cuff repairs), as well as from non-surgical conditions (i.e. sympathetically-mediated pain syndrome and occipital neuralgia). Local anesthetics, opioids or corticosteroids are currently used for the pain management of musculoskeletal conditions. Even though local anesthetics are highly preferred, the need for multiple administration presents significant disadvantages. Development of unique delivery systems that can deliver local anesthetics at the injection site for prolonged time could significantly enhance the therapeutic efficacy and patient comfort. The goal of the present study is to evaluate the efficacy of an injectable local anesthetic nanocomposite carrier to provide sustained analgesic effect. The nanocomposite carrier was developed by encapsulating ropivacaine, a local anesthetic, in lipid nanocapsules (LNC-Rop), and incorporating the nanocapsules in enzymatically crosslinked glycol chitosan (0.3GC) hydrogels. Cryo Scanning Electron Microscopic (Cryo SEM) images showed the ability to distribute the LNCs within the hydrogel without adversely affecting their morphology. The study demonstrated the feasibility to achieve sustained release of lipophilic molecules from the nanocomposite carrier in vitro and in vivo. A rat chronic constriction injury (CCI) pain model was used to evaluate the efficacy of the nanocomposite carrier using thermal paw withdrawal latency (TWL). The nanocomposite carriers loaded with ropivacaine and dexamethasone showed significant improvement in pain response compared to the control groups for at least 7 days. The study demonstrated the clinical potential of these nanocomposite carriers for post-operative and neuropathic pain. Statement of Significance Acute or chronic pain associated with musculoskeletal conditions is considered a major health issue, with healthcare costs totaling several billion dollars. The opioid crisis presents a pressing clinical need to develop alternative and effective approaches to treat musculoskeletal pain. The goal of this study was to develop a long-acting injectable anesthetic formulation which can sustain a local anesthetic effect for a prolonged time. This in turn could increase the quality of life and rehabilitation outcome of patients, and decrease opioid consumption. The developed injectable nanocomposite demonstrated the feasibility to achieve prolonged pain relief in a rat chronic constriction injury (CCI) model.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Surface potential-governed cellular osteogenic differentiation on
           ferroelectric polyvinylidene fluoride trifluoroethylene films
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Bolin Tang, Bo Zhang, Junjun Zhuang, Qi Wang, Lingqing Dong, Kui Cheng, Wenjian Weng
      Surface potential of biomaterials can dramatically influence cellular osteogenic differentiation. In this work, a wide range of surface potential on ferroelectric polyvinylidene fluoride trifluoroethylene (P(VDF-TrFE)) films was designed to get insight into the interfacial interaction of cell-charged surface. The P(VDF-TrFE) films poled by contact electric poling at various electric fields obtained well stabilized surface potential, with wide range from −3 to 915 mV. The osteogenic differentiation level of cells cultured on the films was strongly dependent on surface potential and reached the optimum at 391 mV in this system. Binding specificity assay indicated that surface potential could effectively govern the binding state of the adsorbed fibronectin (FN) with integrin. Molecular dynamic (MD) simulation further revealed that surface potential brought a significant difference in the relative distance between RGD and synergy PHSRN sites of adsorbed FN, resulting in a distinct integrin-FN binding state. These results suggest that the full binding of integrin α5β1 with both RGD and PHSRN sites of FN possesses a strong ability to activate osteogenic signaling pathway. This work sheds light on the underlying mechanism of osteogenic differentiation behavior on charged material surfaces, and also provides a guidance for designing a reasonable charged surface to enhance osteogenic differentiation. Statement of Significance The ferroelectric P(VDF-TrFE) films with steady and a wide range of surface potential were designed to understand underlying mechanism of cell-charged surface interaction. The results showed that the charged surface well favored upregulation of osteogenic differentiation of MC3T3-E1 cells, and more importantly, a highest level occurred on the film with a moderate surface potential. Experiments and molecular dynamics simulation demonstrated that the surface potential could govern fibronectin conformation and then the integrin-fibronectin binding. We propose that a full binding state of integrin α5β1 with fibronectin induces effective activation of integrin-mediated FAK/ERK signaling pathway to upregulate cellular osteogenic differentiation. This work provides a guidance for designing a reasonable charged surface to enhance osteogenic differentiation.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Injectable magnetic supramolecular hydrogel with magnetocaloric
           liquid-conformal property prevents post-operative recurrence in a breast
           cancer model
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Haoan Wu, Lina Song, Ling Chen, Wei Zhang, Yi Chen, Fengchao Zang, Hong Chen, Ming Ma, Ning Gu, Yu Zhang
      Locoregional recurrence of breast cancer after tumor resection represents several clinical challenges. Here, we demonstrate that co-delivery of chemotherapy and thermotherapeutic agents by a magnetic supramolecular hydrogel (MSH) following tumor resection prevents tumor recurrence in a breast cancer mouse model. The self-assembled MSH was designed through the partial inclusion complexation associated with the threading of α-CD on the copolymer moieties on the surface of the PEGylated iron oxide (Fe3O4) nanoparticles, which enables shear-thinning injection and controllable thermoreversible gel-sol transition. MSH was injected to the postoperative wound uniformly, which became mobile and perfect match with irregular cavity without blind angle due to the magnetocaloric gel-sol transition when exposed to alternating current magnetic field (ACMF). The magnetic nanoparticle-mediated induction heat during the gel-sol transition process caused the triggered release of dual-encapsulated chemotherapeutic drugs and provided an effect of thermally induced cell damage. The hierarchical structure of the MSH ensured that both hydrophobic and hydrophilic drugs can be loaded and consecutively delivered with different release curves. The hydrogel nanocomposite might provide a potential locally therapeutic approach for the precise treatment of locoregional recurrence of cancer. Statement of Significance Tumor recurrence after resection represents several clinical challenges. In this study, we prepared shear-thinning injectable magnetic supramolecular hydrogel (MSH) and demonstrated their therapeutic applications in preventing the post-operative recurrence of breast cancer with facile synthesis and minimally invasive implantation in vivo. MSH was injected to the postoperative wound uniformly, which become mobile and perfect match with irregular cavity without blind angle through magnetocaloric gel-sol transition when exposed to ACMF. The magnetic nanoparticles mediated induction heat during the gel-sol transition process caused the triggered release of dual-encapsulated chemotherapeutic drugs as well as thermally induced cell damage. This study demonstrates that MSH with the controlled administration of combined thermo-chemotherapy exhibit great superiority in terms of preventing post-operation cancer relapse.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Supramolecular poly(acrylic acid)/F127 hydrogel with hydration-controlled
           nitric oxide release for enhancing wound healing
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Mathilde Champeau, Valéria Póvoa, Lucas Militão, Flávia M. Cabrini, Guilherme F. Picheth, Florian Meneau, Carlos P. Jara, Eliana P. de Araujo, Marcelo G. de Oliveira
      Topical nitric oxide (NO) delivery has been shown to accelerate wound healing. However, delivering NO to wounds at appropriate rates and doses requires new biomaterial-based strategies. Here, we describe the development of supramolecular interpolymer complex hydrogels comprising PEO-PPO-PEO (F127) micelles embedded in a poly(acrylic acid) (PAA) matrix, with S-nitrosoglutathione (GSNO) molecules dissolved in the hydrophilic domain. We show that PAA:F127/GSNO hydrogels start releasing NO upon hydration at rates controlled by their rates of water absorption. SAXS measurements indicate that the supramolecular structure of the hydrogels retains long-range order domains of F127 micelles. The PAA/F1227 hydrogels displayed dense morphologies and reduced rates of hydration. The NO release rates remain constant over the first 200 min, are directly correlated with the hydration rates of the PAA:F127/GSNO hydrogels, and can be modulated in the range of 40 nmol/g h to 1.5 μmol/g h by changing the PAA:F127 mass ratio. Long-term NO-release profiles over 5 days are governed by the first-order exponential decay of GSNO, with half-lives in the range of 0.5–3.4 days. A preliminary in vivo study on full-thickness excisional wounds in mice showed that topical NO release from the PAA:F127/GSNO hydrogels is triggered by exudate absorption and leads to increased angiogenesis and collagen fiber organization, as well as TGF-β, IGF-1, SDF-1, and IL-10 gene expressions in the cicatricial tissue. In summary, these results suggest that hydration-controlled NO release from topical PAA:F127/GSNO hydrogels is a potential strategy for enhancing wound healing. Statement of Significance The topical delivery of nitric oxide (NO) to wounds may provide significant beneficial results and represent a promising strategy to treat chronic wounds. However, wound dressings capable of releasing NO after application and allowing the modulation of NO release rates, demand new platforms. Here, we describe a novel strategy to overcome these challenges, based on the use of supramolecular poly(acrylic acid) (PAA):F127 hydrogels charged with the NO donor S-nitrosoglutathione (GSNO) from whereby the NO release can be triggered by exudate absorption and delivered to the wound at rates controlled by the PAA:F127 mass ratio. Preliminary in vivo results offer a proof of concept for this strategy by demonstrating increased angiogenesis; collagen fibers organization; and TGF-β, IGF-1, SDF-1, and IL-10 gene expressions in the cicatricial tissue after topical treatment with a PAA:F127/GSNO hydrogel.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Short-time dental resin biostability and kinetics of enzymatic degradation
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Xiaohong Wang, Sheng Song, Lei Chen, Christopher M. Stafford, Jirun Sun
      Resin biostability is of critical importance to the durability of methacrylate-based dental resin restorations. Current methods for evaluating biostability take considerable time, from weeks to months, and provide no short-time kinetics of resin degradation. The objective of this study is to develop a more sensitive method to assess resin biostability over short-time spans (hours to days) that will enhance our understanding of biostability and its resin chemistry. Ultra-flat resin films of equimolar urethane dimethacrylate (UDMA) and triethylene glycol dimethacrylate (TEGDMA) are produced through photo-curing between two flat surfaces. Next, metal-covered enclaves and bare-resin channels are generated using stencil lithography to create both degradable and protected (internal reference) regions simultaneously in a single specimen. Resins having three different degrees of vinyl conversion (DC) are compared, and changes of surface roughness and step height in the two regions are monitored by atomic force microscopy (AFM) before and after incubated in enzyme solutions and saline controls. Specimen biostability is ranked based on the topological profile changes when viewed in cross-section before and after enzymatic challenges. In addition, a model is proposed to quantify specimen enzymatic degradation. Based on this model, enzymatic degradation is detected as early as 4 h, and a surge of enzymatic degradation is detected between 4 h and 8 h. The correlation between the DC of resin network and the surge in degradation is discussed. In summary, this new method is effective in ranking biostability and quantifying enzymatic degradation while also reducing labor, time and cost, which lends itself well to materials development and evaluation of dental resins. Statement of Significance We report, for the first time, the short-time kinetics of enzymatic degradation of methacrylate dental resins. A nanotechnology based method is developed to accelerate the evaluation of resin biostability. This new method reduces experimental time from weeks to one or two days, which will significantly reduce the costs of labor and enzymes. It also introduces a corresponding parameter (ΔH) and a three-cause model for ranking biostability, which confirms the correlation of chemical structure (DC) and material performance and opens new opportunities for studying the resin biostability and its impact on dental applications. Overall, this is a new tool for evaluating resin biostability and developing new materials.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Multifunctional NIR-responsive poly(vinylpyrrolidone)-Cu-Sb-S
           nanotheranostic agent for photoacoustic imaging and
           photothermal/photodynamic therapy
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Meirong Hou, Chenggong Yan, Zelong Chen, Qingliang Zhao, Miaomiao Yuan, Yikai Xu, Bingxia Zhao
      Ternary copper-based chalcogenide nanomaterials have become rather attractive due to the near-infrared (NIR) response in cancer theranostic fields. However, it is still challenging to further improve the theranostic efficiency of these nanomaterials. Herein, Cu-Sb-S nanoparticles (NPs) around 24 nm are synthesized facilely and functionalized with poly(vinylpyrrolidone) (PVP). Under the NIR irradiation, the resultant PVP-Cu-Sb-S NPs exhibit a relatively high photothermal conversion efficiency of 53.16% and a simultaneous reactive oxygen species (ROS) generation effect. Due to these outstanding photothermal/photodynamic effects, excellent tumor ablation results can be achieved by the combination of PVP-Cu-Sb-S NPs and 808 nm NIR laser treatments without obvious side effect. In addition, they show remarkable contrast enhancement according to in vitro and in vivo photoacoustic (PA) imaging. These PVP-Cu-Sb-S NPs could be served as a multifunctional nanotheranostic agent for PA imaging, photothermal/photodynamic cancer therapy. Statement of Significance Highly theranostic efficiency ternary copper-based chalcogenide nanomaterials has not been fully developed yet. Herein we report the PVP-Cu-Sb-S nanoparticles (NPs) with relatively high photothermal efficiency, simultaneous reactive oxygen species generation effect and photoacoustic imaging capability. The photothermal conversion efficiency of PVP-Cu-Sb-S NPs is higher than most of copper-based chalcogenide nanomaterials reported before. These findings provide a new kind of ternary copper-based chalcogenide with an enhanced theranostic effect, which could be served as a promising multifunctional nanotheranostic agent in the field of biomedical application.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Nanoparticle-in-microparticle oral drug delivery system of a clinically
           relevant darunavir/ritonavir antiretroviral combination
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Robin Augustine, Dana Levin Ashkenazi, Roni Sverdlov Arzi, Vita Zlobin, Rona Shofti, Alejandro Sosnik
      Nanonizationhas been extensively investigated to increase theoral bioavailability of hydrophobicdrugsin general andantiretrovirals(ARVs)used inthe therapy of the human immunodeficiency virus (HIV) infection in particular. Weanticipatedthatin the caseofprotease inhibitors, a family of pH-dependent ARVsthatdisplay high aqueous solubility undertheacidconditionsof thestomach andextremely low solubilityunder the neutral ones ofthe small intestine, this strategy might failowing to an uncontrolled dissolution-re-precipitation process that will take place along the gastrointestinal tract.To tackle thisbiopharmaceutical challenge, in this work, wedesigned, produced and fully characterized a novelNanoparticle-in-MicroparticleDelivery System(NiMDS)comprised of pure nanoparticlesofthefirst-line protease inhibitor darunavir(DRV) and itsboosting agentritonavir (RIT) encapsulated within film-coated microparticles.For this, a clinically relevant combination of pure DRV and RIT nanoparticles wassynthesized by a sequential nanoprecipitation/solvent diffusion and evaporation method employing sodium alginateas viscosity stabilizer. Then, pure nanoparticles were encapsulated within calcium alginate/chitosanmicroparticlesthat were film-coated with a series ofpoly(methacrylate) copolymers with differential solubility in the gastrointestinal tract. This coating ensured full stability under gastric-like pH and sustained drug release under intestinal one. PharmacokineticstudiesconductedinalbinoSpragueDawleyratsshowed that DRV/RIT-loadedNiMDSs containing 17% w/w drug loading based on dry weight significantlyincreasedthe oral bioavailabilityof DRVby 2.3-foldwith respect to both theunprocessedandthenanonized DRV/RIT combinations that showed statistically similar performance. Moreover, they highlighted the limited advantage of only drugnanonizationto improve the oral pharmacokinetics of protease inhibitors and the potential of our novel delivery approach to improve the oral pharmacokinetics of nanonized poorly water-soluble drugs displaying pH-dependent solubility. Statement of significance Protease inhibitors (PIs) are gold-standard drugs in many ARV cocktails. Darunavir (DRV) is the latest approved PI and it is included in the 20th WHO Model List of Essential Medicines. PIs poorly-water soluble at intestinal pH and more soluble under gastric conditions. Drug nanonization represents one of the most common nanotechnology strategies to increase dissolution rate of hydrophobic drugs and thus, their oral bioavailability. For instance, pure drug nanosuspensions became the most clinically relevant nanoformulation. However, according to the physicochemical properties of PIs, nanonization does not appear as a very beneficial strategy due to the fast dissolution rate anticipated under the acid conditions of the stomach and their uncontrolled recrystallization and precipitation in the small intestine that might result in the formation of particles of unpredictable size and structure (e.g., crystallinity and polymorphism) and consequently, unknown dissolution rate and bioavailability. In this work, we developed a sequential nanoprecipitation method for the production of pure nanoparticles of DRV and its boosting agent ritonavir in a clinically relevant 8:1 wt ratio using alginate as viscosity stabilizer and used this nanosuspension to produce a novel kind of nanoparticle-in-microparticle delivery system that was fully characterized and the pharmacokinetics assessed in rats. The most significant points of the current manuscript are: 1) Development of a sequential nanoprecipitation method to produce a fixed-dose combination of two antiretrovirals 2) Design and characterization of a novel kind of nanoparticle-in-microparticle drug delivery system with high stability and low drug release in the stomach 3) Demonstration for the...
      PubDate: 2018-06-18T15:12:15Z
       
  • Near-infrared light-activated red-emitting upconverting nanoplatform for
           T1-weighted magnetic resonance imaging and photodynamic therapy
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Xiang-long Tang, Jun Wu, Ben-lan Lin, Sheng Cui, Hong-mei Liu, Ru-tong Yu, Xiao-dong Shen, Ting-wei Wang, Wei Xia
      Photodynamic therapy (PDT) has increasingly become an efficient and attractive cancer treatment modality based on reactive oxygen species (ROS) that can induce tumor death after irradiation with ultraviolet or visible light. Herein, to overcome the limited tissue penetration in traditional PDT, a novel near-infrared (NIR) light-activated NaScF4: 40% Yb, 2% Er@CaF2 upconversion nanoparticle (rUCNP) is successfully designed and synthesized. Chlorin e6, a photosensitizer and a chelating agent for Mn2+, is loaded into human serum albumin (HSA) that further conjugates onto rUCNPs. To increase the ability to target glioma tumor, an acyclic Arg–Gly–Asp peptide (cRGDyK) is linked to rUCNPs@HSA(Ce6-Mn). This nanoplatform enables efficient adsorption and conversion of NIR light (980 nm) into bright red emission (660 nm), which can trigger the photosensitizer Ce6-Mn complex for PDT and T1-weighted magnetic resonance imaging (T1-weighted MRI) for glioma diagnosis. Our in vitro and in vivo experiments demonstrate that NIR light-activated and glioma tumor-targeted PDT can generate large amounts of intracellular ROS that induce U87 cell apoptosis and suppress glioma tumor growth owing to the deep tissue penetration of irradiated light and excellent tumor-targeting ability. Thus, this nanoplatform holds potential for applications in T1-weighted MRI diagnosis and PDT of glioma for antitumor therapy. Statement of Significance A near-infrared (NIR) light-activated nanoplatform for photodynamic therapy (PDT) was designed and synthesized. The Red-to-Green (R/G) ratio of NaScF4: 40% Yb, 2% Er almost reached 9, a value that was much higher than that of a traditional Yb/Er-codoped upconversion nanoparticle (rUCNP). By depositing a CaF2 shell, the red-emission intensities of the rUCNPs were seven times strong as that of NaScF4: 40% Yb, 2% Er. The enhanced red-emitting rUCNPs could be applied in many fields such as bioimaging, controlled release, and real-time diagnosis. The nanoplatform had a strong active glioma-targeting ability, and all results achieved on subcutaneous glioma demonstrated that our NIR light-activated red-emitting upconverting nanoplatform was efficient for PDT. By loading Ce6-Mn complex into rUCNPs@HSA-RGD, the nanoplatform could be used as a T1-weighted magnetic resonance imaging agent for tumor diagnosis.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Folic acid modified cell membrane capsules encapsulating doxorubicin and
           indocyanine green for highly effective combinational therapy in vivo
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Xiao Li, Xinlian Zhao, Dinesh Pardhi, Qianqian Wu, Yong Zheng, Huihui Zhu, Zhengwei Mao
      A combination of chemotherapy and phototherapy has emerged as a promising strategy for cancer treatment. To achieve effective combinational therapy of cancer with reduced toxicity, it is highly desirable to improve the targeting of chemotherapeutic and near-infrared photosensitizers to enhance their accumulation in tumor. Here we report a novel tumor targeting cell membrane capsule (CMC), originate from living cells, to load doxorubicin hydrochloride (DOX) and indocyanine green (ICG), for combinational photo-chemotherapy against cancer. As a result, folic acid modified CMC (CMC-FA, with a diameter about 200 nm and a FA density of 0.4 molecule/nm2) showed 3–4 fold higher cell uptake by cancer cells in vitro and 2.3 times higher accumulation in mouse cancer xenografts in vivo than pristine CMC. DOX and ICG with therapeutically significant concentrations can be sequentially encapsulated into CMC-FA by temporary permeating the plasma membranes with high efficiency. The systematic administration of cancer targeting CMC-FA loaded with DOX and ICG could significantly inhibit tumor growth in mouse xenografts in the presence of a near-infrared light at 808 nm, without noticeable toxicity. These findings suggest that cancer targeting CMC may have considerable benefits in drug delivery and combinational cancer therapy. Statement of Significance A combination of chemotherapy and photothermal/photodynamic therapy has emerged as a promising strategy for cancer therapy. In current study, a novel cancer targeting cell membrane capsule (CMC-FA), originate from living cells and surface modified with folic acid, was developed to load doxorubicin hydrochloride (DOX) and indocyanine green (ICG), for combinational photo-chemotherapy against cancer. The systematic administration of drug loaded CMC-FA can significantly inhibit tumor growth in mouse xenografts in the presence of a near-infrared light at 808 nm, without noticeable toxicity. This study provides a simple and robust strategy to develop biocompatible therapeutic cell membrane capsules, holds strong translational potential in precise cancer treatment.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Self-stabilized silk sericin-based nanoparticles: In vivo biocompatibility
           and reduced doxorubicin-induced toxicity
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Doudou Hu, Ting Li, Zongpu Xu, Di Liu, Mingying Yang, Liangjun Zhu
      A variety of colloid stabilizers and cryoprotectants confer improved nanoparticle (NP) colloidal stability and redisperability. However, discounted tumor targetability, delivery efficacy and possible side effects limit the application in vascular delivery of NPs. Here we present water-soluble silk sericin (SS) not only as a material for the preparation of NPs, but also both a dispersion stabilizer and a cryoprotectant. In the absence of any stabilizers, SS-based NPs (SSC@NPs) can resist the adsorption of serum proteins, preventing the formation of particle agglomerates. Following freeze-drying without addition of cryoprotectants, SSC@NPs powder can be easily resuspended into NP dispersion with a nearly monodispersed distribution. Additionally, SSC@NPs do not result in acute toxicity in mice at a dose of 400 mg/kg with a slow injection. Moreover, doxorubicin (DOX)-loaded SSC@NPs (DOX-SSC@NPs) diminish the biodistribution of DOX in the heart, mitigating DOX-induced cardiotoxicity of mice without compromising therapeutic efficacy. Our results suggest that the self-stabilized SSC@NPs could be a secure and effective drug carrier for intravenous administration when deprived of protective agents. Statement of Significance During manufacturing process such as freeze-drying, or interaction with complex fluids like blood, NPs for systemic drug delivery need to be highly dispersible and structurally intact. In this work, we have demonstrated the self-stability of SSC@NPs subjected to biological media and freeze-drying. This study represents the first work showing water-soluble SS could both act as a dispersion stabilizer and a cryoprotectant due to its hydrophilicity. Plus, good in vivo biocompatibility of SSC@NPs has been confirmed. Therefore, it may be promising that water-soluble SS can be generally used as a safe biomaterial against serum adsorption.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Targeted and controlled drug delivery by multifunctional mesoporous silica
           nanoparticles with internal fluorescent conjugates and external
           polydopamine and graphene oxide layers
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Anh-Vy Tran, KyuHwan Shim, Thu-Thao Vo Thi, Jeong-Keun Kook, Seong Soo A. An, Sang-Wha Lee
      This study demonstrated the targeted delivery and controlled release of cisplatin drug molecules from doubly decorated mesoporous silica nanoparticles (MSNs), which were internally grafted with fluorescent conjugates and externally coated with polydopamine (PDA) and graphene oxide (GO) layers. The brush-like internal conjugates conferred fluorescent functionality and high capacity of cisplatin loading into MSNs, as well as contributing to a sustained release of the cisplatin through a porous channel with the assistance of external PDA layer. A consolidated double-layer formed by electrostatic interactions between the GO nanosheet and the PDA layer induced more controlled release kinetics which was well predicted by Higuchi model. In addition, Our MSNs exhibited stimuli (pH, NIR irradiation)-responsive controlled release as a potential chemo-photothermal agent against cancer cells. In a cell test, multifunctional MSNs showed a low toxicity itself, but gave a high cytotoxicity against human epithelial neuroblastoma cells (SH-SY5Y) after loading cisplatin. Notably, GO-wrapped MSNs exhibited very effective drug delivery because GO wrapping enhanced their dispensability in aqueous solution, photothermal heating effect, and efficient endocytosis into cells. Furthermore, monoclonal antibody (anti-human epidermal growth factor receptor)-conjugated MSNs showed a higher specificity, which resulted in more enhanced anticancer effects in vitro. The current study demonstrated a reliable synthesis of multifunctional MSNs, endowed with fluorescent imaging, stimuli-responsive controlled release, higher specificity, and efficient cytotoxicity toward cancer cells. Statement of Significance The current study demonstrated the reliable synthesis of multifunctional mesoporous silica nanoparticles (MSNs) with internal fluorescent conjugates and external polydopamine and graphene oxide (GO) layers. The combination of internal conjugates and external coating layers produced an effective pore closure effect, leading to controlled and sustained release of small drug molecules. Notably, GO wrapping improved the dispensability and cellular uptake of the MSNs, as well as enhanced drug-controlled release. Our multifunctional MSNs revealed very efficient drug delivery effects against human epithelial neuroblastoma cells by demonstrating several strengths: i) fluorescent imaging, ii) sustained and controlled release of small drug molecules, iii) efficient cellular uptake, cytotoxicity and specificity, and v) stimuli (pH, NIR irradiation)-responsive controlled release as a potential chemo-photothermal agent.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Lipid-modified cell-penetrating peptide-based self-assembly micelles for
           co-delivery of narciclasine and siULK1 in hepatocellular carcinoma therapy
           
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Xiaoyun Wang, Fengbo Wu, Guoyou Li, Nan Zhang, Xiangrong Song, Yu Zheng, Changyang Gong, Bo Han, Gu He
      Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and one therapeutic approach is to target both the AMPK and autophagy pathways in order to synergistically promote programmed cell death. Here, a series of amphiphilic, lipid-modified cell-penetrating peptides were synthesized and allowed to self-assemble into micelles loaded with the AMPK activator narciclasine (Narc) and short interfering RNA targeting the unc-51-like kinase 1 (siULK1). The size of these micelles, their efficiency of transfection into cells, and their ability to release drug or siRNA cargo in vitro were pH-sensitive, such that drug release was facilitated in the acidic microenvironment of the tumor. Transfecting the micelles into HCC cells significantly inhibited protective autophagy within tumor cells, and delivering the micelles into mice carrying HCC xenografts induced apoptosis, slowed tumor growth, and inhibited autophagy. Our results indicate that co-delivering Narc and siULK1 in biocompatible micelles can safely inhibit tumor growth and protective autophagy, justifying further studies into this promising therapeutic approach against HCC. Statement of Significance We have focused on the targeted therapy of HCC via synergistically inhibiting the autophagy and inducing apoptosis. The lipid-modified cell-penetrating peptide can not only aggregate into micelles to load natural product narciclasine and ULK1 siRNA simultaneously, but also facilitate uptake and endosome escape with a pH-sensitive manner in HepG2 cells. HepG2 cell treated with siULK1-M-Narc has increased apoptotic levels and declined autophagy via the targeted regulation of AMPK-ULK1 signaling axis. The in vivo studies have confirmed that siULK1-M-Narc efficiently reduce the growth of tumor on HCC xenograft models with good safety. Thus, we suppose the lipid-modified cell-penetrating peptide has good application prospects in the targeted combinational therapy of HCC.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Collagenase nanocapsules: An approach to fibrosis treatment
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): M. Rocío Villegas, Alejandro Baeza, Alicia Usategui, Pablo L Ortiz-Romero, José L. Pablos, María Vallet-Regí
      Fibrosis is a common lesion in different pathologic diseases and defined by the excessive accumulation of collagen. Different approaches have been used to treat different conditions characterized by fibrosis. The FDA and EMA approved the use of collagenase to treat palmar fibromatosis (Dupuytren’s contracture). The EMA approved additionally its use in severe Peyronie’s disease, but it has been used off label in other conditions [1,2]. The approved treatment includes up to three (in palmar fibromatosis) or up to eight (in penile fibromatosis) injections followed by finger extension or penile modeling procedures, typically causing severe pain. Frequent single injections are adequate to treat palmar fibromatosis [3]. The need to repeatedly inject doses of this enzyme can be due to the labile nature of collagenase, which exhibits a complete activity loss after a short period of time. This study presents a novel strategy to manage this enzyme based on the synthesis of polymeric nanocapsules that contain collagenase encapsulated within their matrix. These nanocapsules have been engineered for achieving a gradual release of the encapsulated enzyme for a longer time, which can be up to ten days. The efficacy of these nanocapsules has been tested in a murine model of local dermal fibrosis, and the results demonstrate a reduction in fibrosis greater than that with the injection of free enzyme; this type of treatment showed a significant improvement compared to conventional therapy of free collagenase. Statement of Significance The use of proteins as therapeutic molecules has recently attracted great interest. Collagenase injection is the current treatment for fibrotic diseases. Unfortunately, proteins have a low stability and presume several repetition cycles to obtain an effective treatment. This article describes a novel treatment for these types of diseases using collagenase nanocapsules designed to exhibit a sustainable release of the encapsulated enzyme, which maintains the enzymatic activity for a long period of time. The therapeutic effect of nanocapsules was tested in a murine mouse model of local dermal fibrosis, and the results showed an important improved effect compared to the effect of the administration of free enzyme. These results indicate a high potential for this novel system to improve the current treatment for fibrotic diseases.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Thermoresponsive polysaccharide-based composite hydrogel with
           antibacterial and healing-promoting activities for preventing recurrent
           adhesion after adhesiolysis
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Ershuai Zhang, Qi Guo, Feng Ji, Xinlu Tian, Jing Cui, Yihang Song, Hong Sun, Junjie Li, Fanglian Yao
      Postoperative adhesions are very common complications after general abdominal surgery. Although adhesiolysis has been proven effective in eliminating the preexisting adhesions, the new trauma caused by surgical lysis can induce recurrent adhesion. The prevention of recurrent adhesion after adhesiolysis is more difficult because the injury is more severe and adhesion mechanism is more complicated compared with the primary adhesion. In this study, a thermoresponsive hydrogel contained galactose modified xyloglucan (mXG) and hydroxybutyl chitosan (HBC) was developed as a barrier device for recurrent adhesion prevention after adhesiolysis due to its injectability and spontaneous gelling behaviors at the body temperature without any chemical reactions or extra driving factors. First, mXG and HBC were synthesized via enzymatic modification and etherification reaction, respectively. Rheological measurements indicated that the mXG/HBC composite system showed excellent thermosensitivity properties, and their gelation temperature and time can be modulated via adjusting the mXG/HBC ratio. Moreover, the mXG/HBC hydrogel exhibited excellent cytocompatibility and hemocompatibility in vitro. Furthermore, the mXG/HBC hydrogel could promote wound healing in the rat skin wound model. Finally, the efficacy of the mXG/HBC composite hydrogel in the prevention of recurrent adhesion was evaluated in a more rigorous rat repeated-injury adhesion model. The results demonstrated that the composite hydrogel could not only effectively prevent recurrent adhesion after adhesiolysis, but also promote wound healing and reduce scare formation. These results suggested that the mXG/HBC composite hydrogel may be a promising candidate as an injectable anti-adhesion system for clinical applications. Statement of Significance Although adhesiolysis has been proven effective in eliminating the preexisting adhesions, the new trauma caused by surgical lysis can induce recurrent adhesion. So far, most of the existing barrier systems and pharmacological approaches were developed for primary adhesion prevention while few attention has paid on prevention of recurrent adhesion after adhesiolysis. In the present study, we developed a thermoresponsive polysaccharide-based composite hydrogel by simple mixing galactose modified xyloglucan (mXG) and hydroxybutyl chitosan (HBC). The resulting mXG/HBC composite hydrogel not only was easy to handle and highly effective in preventing the recurrent adhesion after adhesiolysis, but also could promote wound healing and reduce scare formation. Our study provide an effective anti-adhesion system for preventing recurrent adhesion after adhesiolysis.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Fabrication of in vitro 3D mineralized tissue by fusion of composite
           spheroids incorporating biomineral-coated nanofibers and human
           adipose-derived stem cells
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Taufiq Ahmad, Hyeok Jun Shin, Jinkyu Lee, Young Min Shin, Sajeesh Kumar Madhurakat Perikamana, So Yeon Park, Hyun Suk Jung, Heungsoo Shin
      Development of a bone-like 3D microenvironment with stem cells has always been intriguing in bone tissue engineering. In this study, we fabricated composite spheroids by combining functionalized fibers and human adipose-derived stem cells (hADSCs), which were fused to form a 3D mineralized tissue construct. We prepared fragmented poly (ι-lactic acid) (PLLA) fibers approximately 100 μm long by partial aminolysis of electrospun fibrous mesh. PLLA fibers were then biomineralized with various concentrations of NaHCO3 (0.005, 0.01, and 0.04 M) to form mineralized fragmented fibers (mFF1, mFF2, and mFF3, respectively). SEM analysis showed that the minerals in mFF2 and mFF3 completely covered the fiber surface, and surface chemistry analysis confirmed the presence of hydroxyapatite peaks. Additionally, mFFs formed composite spheroids with hADSCs, demonstrating that the cells were strongly attached to mFFs and homogeneously distributed throughout the spheroid. In vitro culture of spheroids in the media without osteogenic supplements showed significantly enhanced expression of osteogenic genes including Runx2 (20.83 ± 2.83 and 22.36 ± 2.18 fold increase), OPN (14.24 ± 1.71 and 15.076 ± 1.38 fold increase), and OCN (4.36 ± 0.41 and 5.63 ± 0.51 fold increase) in mFF2 and mFF3, respectively, compared to the no mineral fiber group. In addition, mineral contents were significantly increased at day 7. Blocking the biomineral-mediated signaling by PSB 603 significantly down regulated the expression of these genes in mFF3 at day 7. Finally, we fused composite spheroids to form a mineralized 3D tissue construct, which maintained the viability of cells and showed pervasively distributed minerals within the structure. Our composite spheroids could be used as an alternative platform for the development of in vitro bone models, in vivo cell carriers, and as building blocks for bioprinting 3D bone tissue. Statement of Significance This manuscript described our recent work for the preparation of biomimeral-coated fibers that can be assembled with mesenchymal stem cells and provide bone-like environment for directed control over osteogenic differentiation. Biomineral coating onto synthetic, biodegradable single fibers was successfully carried out using multiple steps, combination of template protein coating inspired from mussel adhesion and charge-charge interactions between template proteins and mineral ions. The biomineral-coated single micro-scale fibers (1–2.5 μm in diameter) were then assembled with human adipose tissue derived stem cells (hADSCs). The assembled structure exhibited spheroidal architecture with few hundred micrometers. hADSCs within the spheroids were differentiated into osteogenic lineage in vitro and mineralized in the growth media. These spheroids were fused to form in vitro 3D mineralized tissue with larger size.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Formation and transformation of calcium phosphate phases under
           biologically relevant conditions: Experiments and modelling
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Agnese Carino, Christian Ludwig, Antonio Cervellino, Elisabeth Müller, Andrea Testino
      The experimental data on calcium phosphates formation were collected in dilute solution at constant pH (7.40) and temperature (37.0 °C) at different levels of ionic strength (IS). The evolution of the solid phase formation is described in detail using a thermodynamic-kinetic model. The thermodynamic model takes into account all relevant chemical species as well as Posner’s clusters; the kinetic model, based on the discretized population balance approach, accounts for the solid formation from solution. The experimental data are consistent with an initial formation of dicalcium phosphate dihydrate (DCPD, brushite), which dominates the nucleation rate, and its rapid transformation into octacalcium phosphate (OCP) or hydroxyapatite (HA), which dominates the growth rate. Depending on the experimental conditions and, including the influence of the IS level, OCP may be further transformed into apatite. The classical nucleation theory is able to describe the experimental results very well and the solid phase growth is limited by the diffusion of Ca2+ ions. The precipitation pathway described by a complete thermodynamic-kinetic model is expected to contribute to the understating of the in vivo osteogenesis. Statement of Significance The formation mechanism of calcium phosphates under biomimetic conditions is unraveled. The formation pathway is mathematically described based on a thermodynamic-kinetic model in which (i) the nucleation stages (primary and secondary) are dominated by the formation of dicalcium phosphate dihydrate (DCPD) and (ii) the fast growth stage is limited by the diffusion of Ca2+ ions under the driving force of octacalcium phosphate (OCP), or hydroxyapatite (HA), solubility. The obtained solid phase seems correlated to the activity coefficient of phosphate ions, thus to the ionic strength and local phosphate speciation. The model, being able to highlight the details of the precipitation pathway, is expected to contribute to the understanding of the apatitic phase formation in the biomineralization-biodemineralization processes under in-vivo conditions.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Multilayered coating of titanium implants promotes coupled osteogenesis
           and angiogenesis in vitro and in vivo
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Weizhen Chen, Kui Xu, Bailong Tao, Liangliang Dai, Yonglin Yu, Caiyun Mu, Xinkun Shen, Yan Hu, Ye He, Kaiyong Cai
      We used surface-modified titanium (Ti) substrates with a multilayered structure composed of chitosan-catechol (Chi-C), gelatin (Gel) and hydroxyapatite (HA) nanofibers, which were previously shown to improve osteogenesis, as a platform to investigate the interaction of osteogenesis and angiogenesis during bone healing. Combined techniques of Transwell co-culture, wound healing assay, enzyme linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical staining were used to evaluate adhesion, morphology and migration of adipose-derived mesenchymal stem cells (Ad-MSCs) and human umbilical vein endothelial cells (HUVECs) grown on different Ti substrates. We investigated the effect of substrates on the osteogenic differentiation of Ad-MSCs and reciprocal paracrine effects of Ad-MSCs on HUVECs or vice versa. The multilayered Ti substrates directly regulated the cellular functions of Ad-MSCs and angiogenic HUVECs and mediated communication between them by enhancing paracrine effects via cell–matrix interactions in vitro. The in vivo results showed that the change of microenvironment induced by surface-modified Ti implants promoted the adhesion, recruitment and proliferation of MSCs and facilitated coupled osteogenesis and angiogenesis in bone healing. The study proved that multilayer-film-coated Ti substrates positively mediated cellular biological function in vitro and improved bone healing in vivo. Statement of Significance Recent studies have revealed that osteogenesis and angiogenesis are coupled, and that communication between osteoblasts and endothelial cells is essential for bone healing and remodeling processes; however, these conclusions only result from in vitro studies or in vivo studies using transgenic murine models. Relatively little is known about the communication between osteoblasts and endothelial cells in peri-implants during bone healing processes. Our results revealed the cellular/molecular mechanism of how multilayered Ti substrates mediate reciprocal paracrine effects between adipose-derived mesenchymal stem cells and human umbilical vein endothelial cells; moreover, the interactions between the cell-matrix and peri-implant was proven in vivo with enhanced bone healing. This study contributes to our understanding of the fundamental mechanisms of angiogenesis and osteogenesis that affect peri-implantation, and thus, provides new insights into the design of future high-quality orthopedic implants.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Biosafety, stability, and osteogenic activity of novel implants made of
           Zr70Ni16Cu6Al8 bulk metallic glass for biomedical application
    • Abstract: Publication date: 1 July 2018
      Source:Acta Biomaterialia, Volume 74
      Author(s): Hiroto Ida, Masahiro Seiryu, Nobuo Takeshita, Masanari Iwasaki, Yoshihiko Yokoyama, Yusuke Tsutsumi, Etsuko Ikeda, Satoshi Sasaki, Shunro Miyashita, Shutaro Sasaki, Tomohiro Fukunaga, Toru Deguchi, Teruko Takano-Yamamoto
      Superior mechanical and chemical properties of Zr70Ni16Cu6Al8 bulk metallic glass (BMG) demonstrate its promise as a novel biomaterial for fabrication of implants. The aim of the present study was to validate mechanical, chemical, and biological properties of Zr70Ni16Cu6Al8 BMG through comparison with titanium (Ti). Our data indicated higher tensile strength, lower Young’s modulus, and reduced metal ion release of Zr70Ni16Cu6Al8 BMG compared with Ti. Biosafety of bone marrow mesenchymal cells on Zr70Ni16Cu6Al8 BMG was comparable to that of Ti. Next, screw-type implant prototypes made of Zr70Ni16Cu6Al8 BMG were fabricated and inserted into rat long bones. Zr70Ni16Cu6Al8 BMG implants indicated a higher removal-torque value and lower Periotest value compared with Ti implants. In addition, higher amounts of new bone formation and osseointegration were observed around Zr70Ni16Cu6Al8 BMG implants compared with Ti implants. Moreover, gene expression analysis displayed higher expression of osteoblast- and osteoclast-associated genes in the Zr70Ni16Cu6Al8 BMG group compared with the Ti group. Importantly, loading to implants upregulated bone formation, as well as osteoblast- and osteoclast-associated gene expression in the peri-implant area. No significant difference in concentrations of Ni, Al, Cu, and Zr in various organs was shown between in the Zr70Ni16Cu6Al8 BMG and Ti groups. Collectively, these findings suggest that Zr70Ni16Cu6Al8 BMG is suitable for fabricating novel implants with superior mechanical properties, biocompatibility, stability, and biosafety compared with Ti. Statement of Significance Titanium is widely used to fabricate orthopedic and dental implants. However, Titanium has disadvantages for biomedical applications in regard to strength, elasticity, and biosafety. Recently, we developed a novel hypoeutectic Zr70Ni16Cu6Al8 BMG, which has superior mechanical and chemical properties. However, the validity of Zr70Ni16Cu6Al8 BMG for biomedical application has not been cleared. The aim of the present study was to validate the mechanical, chemical, and biological properties of Zr70Ni16Cu6Al8 BMG for biomedical applications through comparison with Titanium. The present study clarifies that Zr70Ni16Cu6Al8 BMG has good mechanical properties, corrosion resistance, and osteogenic activity, which are necessary features for biomedical applications. The present study provides for the first time the superiority of Zr70Ni16Cu6Al8 BMG implants to Titanium implants for biomedical applications.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Bone matrix development in steroid-induced osteoporosis is associated with
           a consistently reduced fibrillar stiffness linked to altered bone mineral
           quality
    • Abstract: Publication date: Available online 15 June 2018
      Source:Acta Biomaterialia
      Author(s): L. Xi, P. De Falco, E. Barbieri, A. Karunaratne, L. Bentley, C.T. Esapa, N.J. Terrill, S.D.M. Brown, R.D. Cox, G.R. Davis, N.M. Pugno, R.V. Thakker, H.S. Gupta
      Glucocorticoid-induced osteoporosis (GIOP) is a major secondary form of osteoporosis, with the fracture risk significantly elevated – at similar levels of bone mineral density – in patients taking glucocorticoids compared with non-users. The adverse bone structural changes at multiple hierarchical levels in GIOP, and their mechanistic consequences leading to reduced load-bearing capacity, are not clearly understood. Here we combine experimental X-ray nanoscale mechanical imaging with analytical modelling of the bone matrix mechanics to determine mechanisms causing bone material quality deterioration during development of GIOP. In situ synchrotron small-angle X-ray diffraction combined with tensile testing was used to measure nanoscale deformation mechanisms in a murine model of GIOP, due to a corticotrophin-releasing hormone promoter mutation, at multiple ages (8-, 12-, 24- and 36 weeks), complemented by quantitative micro-computed tomography and backscattered electron imaging to determine mineral concentrations. We develop a two-level hierarchical model of the bone matrix (mineralized fibril and lamella) to predict fibrillar mechanical response as a function of architectural parameters of the mineralized matrix. The fibrillar elastic modulus of GIOP-bone is lower than healthy bone throughout development, and nearly constant in time, in contrast to the progressively increasing stiffness in healthy bone. The lower mineral platelet aspect ratio value for GIOP compared to healthy bone in the multiscale model can explain the fibrillar deformation. Consistent with this result, independent measurement of mineral platelet lengths from wide-angle X-ray diffraction finds a shorter mineral platelet length in GIOP. Our results show how lowered mineralization combined with altered mineral nanostructure in GIOP leads to lowered mechanical competence. Significance Statement Increased fragility in musculoskeletal disorders like osteoporosis are believed to arise due to alterations in bone structure at multiple length-scales from the organ down to the supramolecular-level, where collagen molecules and elongated mineral nanoparticles form stiff fibrils. However, the nature of these molecular-level alterations are not known. Here we used X-ray scattering to determine both how bone fibrils deform in secondary osteoporosis, as well as how the fibril orientation and mineral nanoparticle structure changes. We found that osteoporotic fibrils become less stiff both because the mineral nanoparticles became shorter and less efficient at transferring load from collagen, and because the fibrils are more randomly oriented. These results will help in the design of new composite musculoskeletal implants for bone repair.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Sustained delivery of siRNA/mesoporous silica nanoparticle (siRNA/MSN)
           complexes from nanofiber scaffolds for long-term gene silencing
    • Abstract: Publication date: Available online 15 June 2018
      Source:Acta Biomaterialia
      Author(s): Coline Pinese, Junquan Lin, Ulla Milbreta, Mingqiang Li, Yucai Wang, Kam W. Leong, Sing Yian Chew
      A low toxicity and efficient delivery system is needed to deliver small interfering RNAs (siRNA) in vitro and in vivo. The use of mesoporous silica nanoparticles (MSN) is becoming increasingly common due to its biocompatibility, tunable pore size and customizable properties. However, bolus delivery of siRNA/MSN complexes remains suboptimal, especially when a sustained and long-term administration is required. Here, we utilized electrospun scaffolds for sustained delivery of siRNA/MSN-PEI through surface adsorption and nanofiber encapsulation. As a proof-of-concept, we targeted collagen type I expression to modulate fibrous capsule formation. Surface adsorption of siRNA/MSN-PEI provided sustained availability of siRNA for at least 30 days in vitro. As compared to conventional bolus delivery, such scaffold-mediated transfection provided more effective gene silencing (p < 0.05). On the contrary, a longer sustained release was attained (at least 5 months) when siRNA/MSN-PEI complexes were encapsulated within the electrospun fibers. In vivo subcutaneous implantation and biodistribution analysis of these scaffolds revealed that siRNA remained localized up to ∼290 μm from the implants. Finally, a fibrous capsule reduction of ∼45.8 % was observed after 4 weeks in vivo as compared to negative scrambled siRNA treatment. Taken together, these results demonstrate the efficacy of scaffold-mediated sustained delivery of siRNA/MSN-PEI for long-term non-viral gene silencing applications. Statement of Significance The bolus delivery of siRNA/ Mesoporous Silica Nanoparticles (MSN) complexes shows high efficiency to silence protein agonists of tumoral processes as cancer treatments. However, in tissue engineering area, scaffold mediated delivery is desired to achieve a local and sustained release of therapeutics. We showed the feasibility and the efficacy of siRNA/MSN delivered from electrospun scaffolds through surface adsorption and nanofiber encapsulation. We showed that this method enhances siRNA transfection efficiency and sustained targeted proteins silencing in vitro and in vivo. As a proof of concept, in this study, we targeted collagen type I expression to modulate fibrous capsule formation. However this platform can be applied to the release and transfection of siRNA or miRNA in cancer and tissue engineering applications.
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      PubDate: 2018-06-18T15:12:15Z
       
  • NiTi-Nb Micro-trusses Fabricated via Extrusion-based 3D-printing of
           Powders and Transient-liquid-phase Sintering
    • Abstract: Publication date: Available online 15 June 2018
      Source:Acta Biomaterialia
      Author(s): Shannon L. Taylor, Amaka J. Ibeh, Adam E. Jakus, Ramille N. Shah, David C. Dunand
      We present a novel additive manufacturing method for NiTi-Nb micro-trusses combining (i) extrusion-based 3D-printing of liquid inks containing NiTi and Nb powders, solvents, and a polymer binder into micro-trusses with 0/90° ABAB layers of parallel, ∼600 µm struts spaced 1 mm apart and (ii) subsequent heat-treatment to remove the binder and solvents, and then bond the NiTi powders using liquid phase sintering via the formation of a transient NiTi-Nb eutectic phase. We investigate the effects of Nb concentration (0, 1.5, 3.1, 6.7 at.% Nb) on the porosity, microstructure, and phase transformations of the printed NiTi-Nb micro-trusses. Micro-trusses with the highest Nb content exhibit long channels (from 3D-printing) and struts with smaller interconnected porosity (from partial sintering), resulting in overall porosity of ∼75% and low compressive stiffnesses of 1-1.6 GPa, similar to those of trabecular bone and in agreement with analytical and finite element modeling predictions. Diffusion of Nb into the NiTi particles from the bond regions results in a Ni-rich composition as the Nb replaces Ti atoms, leading to decreased martensite/austenite transformation temperatures. Adult human mesenchymal stem cells seeded on these micro-trusses showed excellent viability, proliferation, and extracellular matrix deposition over 14 days in culture. Statement of Significance Near-equiatomic NiTi micro-trusses are attractive for biomedical applications such as stents, actuators and bone implants because of their combination of biocompatibility, low compressive stiffness, high surface area, and shape-memory or superelasticity. Extrusion-based 3D-printing of NiTi powder-based inks into micro-trusses is feasible, but the subsequent sintering of the powders into dense struts is unachievable due to low diffusivity, large particle size, and low packing density of the NiTi powders. We present a solution, whereby Nb powders are added to the NiTi inks, thus forming during sintering a eutectic NiTi-Nb liquid phase which bonds the solid NiTi powders and improves densification of the struts. This study investigates the microstructure, porosity, phase transformation behavior, compressive stiffness, and cytocompatibility of these printed NiTi-Nb micro-trusses.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Differential effect of hydroxyapatite nano-particle versus nano-rod
           decorated titanium micro-surface on osseointegration
    • Abstract: Publication date: Available online 15 June 2018
      Source:Acta Biomaterialia
      Author(s): Long Bai, Yanlian Liu, Zhibin Du, Zeming Weng, Wei Yao, Xiangyu Zhang, Xiaobo Huang, Xiaohong Yao, Ross Crawford, Ruiqiang Hang, Di Huang, Bin Tang, Yin Xiao
      Coating materials applied for intraosseous implants must be optimized to stimulate osseointegration. Osseointegration is a temporal and spatial physiological process that not only requires interactions between osteogenesis and angiogenesis but also necessitates a favorable immune microenvironment. It is now well-documented that hierarchical nano-micro surface structures promote the long-term stability of implants, the interactions between nano-micro structure and the immune response are largely unknown. Here, we report the effects of microporous titanium (Ti) surfaces coated with nano-hydroxyapatite (HA) produced by micro-arc oxidation and steam-hydrothermal treatment (SHT) on multiple cell behavior and osseointegration. By altering the processing time of SHT it was possible to shift HA structures from nano-particles to nano-rods on the microporous Ti surfaces. Ti surfaces coated with HA nano-particles were found to modulate the inflammatory response resulting in an osteoimmune microenvironment more favorable for osteo-/angio-genesis, most likely via the activation of certain key signaling pathways (TGF-β, OPG/RANKL, and VEGF). By contrast, Ti surfaces coated with nano-rod shaped HA particles had a negative impact on osteo-/angio-genesis and osteoimmunomodulation. In vivo results further demonstrated that Ti implant surfaces decorated with HA nano-particles can stimulate new bone formation and osseointegration with enhanced interaction between osteocytes and implant surfaces.This study demonstrated that Ti implants with micro-surfaces coated with nano-particle shaped HA have a positive impact on osseointegration. Statement of Significance Osteo-/angio-genesis are of importance during osteointegration of the implants. Recent advances unravel that immune response of macrophages and its manipulated osteoimmunomodulation also exerts a pivotal role to determine the fate of the implant. Surface nano-micro modification has evidenced to be efficient to influence osteogenesis, however, little is known links nano-microstructured surface to immune response, as well the osteoimmunomodulation. This study demonstrates that the nano-particles decorated micro-surface, compared with the nano-rods decorated micro-surface enables osteogenesis and angiogenesis concurrently that has not been investigated previously. This study also unravels that the immune response of macrophages can be manipulated by the nano-micro surface, especially the nano-dimension matters, leading to a differential effect on osteointegration. The additional knowledge obtained from this study may provide foundation and reference for future design of the coating materials for implantable materials.
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      PubDate: 2018-06-18T15:12:15Z
       
  • Dual surface modification of PDMS-based silicone implants to suppress
           capsular contracture
    • Abstract: Publication date: Available online 14 June 2018
      Source:Acta Biomaterialia
      Author(s): Byoung Yong Yoo, Byung Hwi Kim, Jae Sang Lee, Byung Ho Shin, Heeyeon Kwon, Won-Gun Koh, Chan Yeong Heo
      In this study, we report a new physicochemical surface on poly(dimethylsiloxane) (PDMS)-based silicone implants in an effort to minimize capsular contracture. Two different surface modification strategies, namely, microtexturing as a physical cue and multilayer coating as a chemical cue, were combined to achieve synergistic effects. The deposition of uniformly sized microparticles onto uncured PDMS surfaces and the subsequent removal after curing generated microtextured surfaces with concave hemisphere micropatterns. The size of the individual micropattern was controlled by the microparticle size. Micropatterns of three different sizes (37.16, 70.22, and 97.64 μm) smaller than 100 μm were produced for potential application to smooth and round-shaped breast implants. The PDMS surface was further chemically modified by layer-by-layer (LbL) deposition of poly-L-lysine and hyaluronic acid. Short-term in vitro experiments demonstrated that all the PDMS samples were cytocompatible. However, lower expression of TGF-β and α-SMA, the major profibrotic cytokine and myofibroblast marker, respectively, was observed in only multilayer-coated PDMS samples with larger size micropatterns (70.22 and 97.64 μm), thereby confirming the synergistic effects of physical and chemical cues. An in vivo study conducted for 8 weeks after implantation in rats also indicated that PDMS samples with larger size micropatterns and multilayer coating most effectively inhibited capsular contracture based on analyses of tissue inflammation, number of macrophage, fibroblast and myofibroblast, TGF-β expression, collagen density, and capsule thickness. Statement of Significance Although PDMS-based silicone implants have been widely used for various applications including breast implants, they usually cause typical side effect called as capsular contracture. Prior studies have shown that microtexturing and surface coating could reduce capsular contracture. However, previous methods are limited in application scope and difficult to obtain FDA approval because of large and non-uniform size of microtexture as well as the use of toxic chemical components. Here, those issues could be addressed by creating microtexture less than 100 μm with narrow size distribution and using layer-by-layer deposition of biocompatible polymer without using any toxic compounds. Furthermore, this is first attempt to combine microtexture with multilayer coating to obtain synergetic effects in minimizing the capsular contracture.
      Graphical abstract image

      PubDate: 2018-06-18T15:12:15Z
       
  • Platelet-derived growth factor-coated decellularized meniscus scaffold for
           integrative healing of meniscus tears
    • Abstract: Publication date: Available online 14 June 2018
      Source:Acta Biomaterialia
      Author(s): Kwang Il Lee, Merissa Olmer, Jihye Baek, Darryl D. D'Lima, Martin K. Lotz
      The aim of this study was to examine the potential of platelet-derived growth factor (PDGF)-coated decellularized meniscus scaffold in mediating integrative healing of meniscus tears by inducing endogenous cell migration. Fresh bovine meniscus was chemically decellularized and covalently conjugated with heparin and PDGF-BB. In vitro PDGF release kinetics was measured. The scaffold was transplanted into experimental tears in avascular bovine meniscus explants and cultured for 2 and 4 weeks. The number migrating and proliferating cells at the borderline between the scaffold and injured explant and PDGF receptor-β (PDGFR β) expressing cells were counted. The alignment of the newly produced ECM and collagen was analyzed by Safranin-O, picrosirius red staining, and differential interference contrast (DIC). Tensile testing of the explants was performed after culture for 2 and 4 weeks. Heparin conjugated scaffold showed immobilization of high levels of PDGF-BB, with sustained release over 2 weeks. Insertion of the PDGF-BB treated scaffold in defects in avascular meniscus led to increased PDGFR β expression, cell migration and proliferation into the defect zone. Safranin-O, picrosirius red staining and DIC showed tissue integration between the scaffold and injured explants. Tensile properties of injured explants treated with PDGF-BB coated scaffold were significantly higher than in the scaffold without PDGF. In conclusion, PDGF-BB-coated scaffold increased PDGFR β expression and promoted migration of endogenous meniscus cells to the defect area. New matrix was formed that bridged the space between the native meniscus and the scaffold and this was associated with improved biomechanical properties. The PDGF-BB-coated scaffold will be promising for clinical translation to healing of meniscus tears. Statement of Significance Meniscus tears are the most common injury of the knee joint. The most prevalent forms that occur in the inner third typically do not spontaneously heal and represent a major risk factor for the development of knee osteoarthritis. The goal of this project was to develop an approach that is readily applicable for clinical use. We selected a natural and readily available decellularized meniscus scaffold and conjugated it with PDGF, which we had previously found to have strong chemotactic activity for chondrocytes and progenitor cells. The present results show that insertion of the PDGF-conjugated scaffold in defects in avascular meniscus led to endogenous cell migration and proliferation into the defect zone with tissue integration between the scaffold and injured explants and improved tensile properties. This PDGF-conjugated scaffold will be promising for a translational approach to healing of meniscus tears.
      Graphical abstract image

      PubDate: 2018-06-18T15:12:15Z
       
 
 
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