for Journals by Title or ISSN
for Articles by Keywords
  Subjects -> BIOLOGY (Total: 3003 journals)
    - BIOCHEMISTRY (237 journals)
    - BIOENGINEERING (108 journals)
    - BIOLOGY (1427 journals)
    - BIOPHYSICS (46 journals)
    - BIOTECHNOLOGY (218 journals)
    - BOTANY (220 journals)
    - CYTOLOGY AND HISTOLOGY (28 journals)
    - ENTOMOLOGY (63 journals)
    - GENETICS (162 journals)
    - MICROBIOLOGY (256 journals)
    - MICROSCOPY (10 journals)
    - ORNITHOLOGY (25 journals)
    - PHYSIOLOGY (70 journals)
    - ZOOLOGY (133 journals)

BIOLOGY (1427 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 20)
Achievements in the Life Sciences     Open Access   (Followers: 4)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
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: 25)
Acta Biotheoretica     Hybrid Journal   (Followers: 5)
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: 9)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Studies in Biology     Open Access  
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Bioinformatics     Open Access   (Followers: 18)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 6)
Advances in Cell Biology     Open Access   (Followers: 24)
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: 41)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 1)
Advances in Life Science and Technology     Open Access   (Followers: 14)
Advances in Life Sciences     Open Access   (Followers: 4)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
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: 8)
Aging Cell     Open Access   (Followers: 10)
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: 13)
AJP Endocrinology and Metabolism     Full-text available via subscription   (Followers: 22)
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)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Biology Teacher     Full-text available via subscription   (Followers: 13)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 10)
American Journal of Bioethics     Hybrid Journal   (Followers: 10)
American Journal of Biostatistics     Open Access   (Followers: 9)
American Journal of Human Biology     Hybrid Journal   (Followers: 12)
American Journal of Medical and Biological Research     Open Access   (Followers: 6)
American Journal of Plant Sciences     Open Access   (Followers: 19)
American Journal of Primatology     Hybrid Journal   (Followers: 15)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 69)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 9)
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: 4)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 17)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 25)
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: 38)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 19)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 10)
Anthropological Review     Open Access   (Followers: 24)
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: 9)
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: 30)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 13)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 19)
Archaea     Open Access   (Followers: 3)
Archiv für Molluskenkunde: International Journal of Malacology     Full-text available via subscription   (Followers: 3)
Archives of Biomedical Sciences     Open Access   (Followers: 7)
Archives of Microbiology     Hybrid Journal   (Followers: 8)
Archives of Natural History     Hybrid Journal   (Followers: 7)
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: 3)
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: 2)
Artificial Photosynthesis     Open Access   (Followers: 1)
Asian Bioethics Review     Full-text available via subscription   (Followers: 1)
Asian Journal of Biodiversity     Open Access   (Followers: 5)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 6)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 2)
Asian Journal of Nematology     Open Access   (Followers: 3)
Asian Journal of Poultry Science     Open Access   (Followers: 4)
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: 12)
Bacteriology Journal     Open Access   (Followers: 2)
Bacteriophage     Full-text available via subscription   (Followers: 4)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Plant Taxonomy     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
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)
Biochemistry and Cell Biology     Hybrid Journal   (Followers: 14)
Biochimie     Hybrid Journal   (Followers: 7)
BioControl     Hybrid Journal   (Followers: 5)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 5)
Biodemography and Social Biology     Hybrid Journal   (Followers: 1)
Biodiversidad Colombia     Open Access  
Biodiversity : Research and Conservation     Open Access   (Followers: 26)
Biodiversity and Natural History     Open Access   (Followers: 5)
Biodiversity Data Journal     Open Access   (Followers: 3)
Biodiversity Informatics     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: 3)
Biogeosciences (BG)     Open Access   (Followers: 10)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 1)
Bioinformatics     Hybrid Journal   (Followers: 313)
Bioinformatics and Biology Insights     Open Access   (Followers: 15)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 6)
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: 5)
Biological Control     Hybrid Journal   (Followers: 4)
Biological Invasions     Hybrid Journal   (Followers: 16)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 16)
Biological Letters     Open Access   (Followers: 4)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 42)
Biological Psychology     Hybrid Journal   (Followers: 6)
Biological Research     Open Access  
Biological Rhythm Research     Hybrid Journal   (Followers: 2)
Biological Theory     Hybrid Journal   (Followers: 1)
Biological Trace Element Research     Hybrid Journal  
Biologicals     Full-text available via subscription   (Followers: 9)
Biologics: Targets & Therapy     Open Access   (Followers: 1)
Biologie Aujourd'hui     Full-text available via subscription  
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42)
Biologija     Open Access  
Biology     Open Access   (Followers: 5)
Biology and Philosophy     Hybrid Journal   (Followers: 17)
Biology Bulletin     Hybrid Journal   (Followers: 1)
Biology Bulletin Reviews     Hybrid Journal  
Biology Direct     Open Access   (Followers: 7)
Biology Letters     Full-text available via subscription   (Followers: 36)

        1 2 3 4 5 6 7 8 | Last

Journal Cover Acta Biomaterialia
  [SJR: 2.02]   [H-I: 104]   [25 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7061
   Published by Elsevier Homepage  [3043 journals]
  • Regenerating bone with bioactive glass scaffolds: A review of in vivo
           studies in bone defect models
    • Authors: Aiah A. El-Rashidy; Judith A. Roether; Leila Harhaus; Ulrich Kneser; Aldo R. Boccaccini
      Pages: 1 - 28
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Aiah A. El-Rashidy, Judith A. Roether, Leila Harhaus, Ulrich Kneser, Aldo R. Boccaccini
      Large bone defects resulting from fractures and disease are a medical concern, being often unable to heal spontaneously by the body’s repair mechanisms. Bone tissue engineering (BTE) is a promising approach for treating bone defects through providing a template to guide osseous regeneration. 3D scaffolds with microstructure mimicking host bone are necessary in common BTE strategies. Bioactive glasses (BGs) attract researchers’ attention as BTE scaffolds as they are osteoconductive and osteoinductive in certain formulations. In vivo animal models allow understanding and evaluation of materials’ performance in the complex physiological environment, being an inevitable step before clinical trials. The aim of this paper is to review for the first time published research investigating the in vivo osseous regenerative capacity of 3D BG scaffolds in bone defect animal models, to better understand and evaluate the progress and future outlook of the use of such scaffolds in BTE. The literature analysis reveals that the regenerative capacity of BG scaffolds depends on several factors; including BG composition, fabrication method, scaffold microstructure and pore characteristics, in addition to scaffold pretreatment and whether or not the scaffolds are loaded with growth factors. In addition, animal species selected, defect size and implantation time affect the scaffold in vivo behavior and outcomes. The review of the literature also makes clear the difficulty encountered to compare different types of bioactive glass scaffolds in their bone forming ability. Even considering such limitations of the current state-of-the-art, results generated from animal bone defect models provide an essential source of information to guide the design of BG scaffolds in future. Statement of Significance Bioactive glasses are at the centre of increasing research efforts in bone tissue engineering as the number of research groups around the world carrying out research on this type of biomaterials continues to increase. However, there are no previous reviews in literature which specifically cover investigations of the performance of bioactive glass scaffolds in bone defect animal models. This is the topic of the present review, in which we have analysed comprehensively all available literature in the field. The review thus fills a gap in the biomaterials literature providing a broad platform of information for researchers interested in bioactive glasses in general and specifically in the outcomes of in vivo models. Bioactive glass scaffolds of different compositions tested in relevant bone defect models are covered.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.030
      Issue No: Vol. 62 (2017)
  • A comprehensive review of cryogels and their roles in tissue engineering
    • Authors: Katherine R. Hixon; Tracy Lu; Scott A. Sell
      Pages: 29 - 41
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Katherine R. Hixon, Tracy Lu, Scott A. Sell
      The extracellular matrix is fundamental in providing an appropriate environment for cell interaction and signaling to occur. Replicating such a matrix is advantageous in the support of tissue ingrowth and regeneration through the field of tissue engineering. While scaffolds can be fabricated in many ways, cryogels have recently become a popular approach due to their macroporous structure and durability. Produced through the crosslinking of gel precursors followed by a subsequent controlled freeze/thaw cycle, the resulting cryogel provides a unique, sponge-like structure. Therefore, cryogels have proven advantageous for many tissue engineering applications including roles in bioreactor systems, cell separation, and scaffolding. Specifically, the matrix has been demonstrated to encourage the production of various molecules, such as antibodies, and has also been used for cryopreservation. Cryogels can pose as a bioreactor for the expansion of cell lines, as well as a vehicle for cell separation. Lastly, this matrix has shown excellent potential as a tissue engineered scaffold, encouraging regrowth at numerous damaged tissue sites in vivo. This review will briefly discuss the fabrication of cryogels, with an emphasis placed on their application in various facets of tissue engineering to provide an overview of this unique scaffold’s past and future roles. Statement of Significance Cryogels are unique scaffolds produced through the controlled freezing and thawing of a polymer solution. There is an ever-growing body of literature that demonstrates their applicability in the realm of tissue engineering as extracellular matrix analogue scaffolds; with extensive information having been provided regarding the fabrication, porosity, and mechanical integrity of the scaffolds. Additionally, cryogels have been reviewed with respect to their role in bioseparation and as cellular incubators. This all-inclusive view of the roles that cryogels can play is critical to advancing the technology and expanding its niche within biomaterials and tissue engineering research. To the best of the authors’ knowledge, this is the first comprehensive review of cryogel applications in tissue engineering that includes specific looks at their growing roles as extracellular matrix analogues, incubators, and in bioseparation processes.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.033
      Issue No: Vol. 62 (2017)
  • Manufacturing of hydrogel biomaterials with controlled mechanical
           properties for tissue engineering applications
    • Authors: Armin Vedadghavami; Farnaz Minooei; Mohammad Hossein Mohammadi; Sultan Khetani; Ahmad Rezaei Kolahchi; Shohreh Mashayekhan; Amir Sanati-Nezhad
      Pages: 42 - 63
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Armin Vedadghavami, Farnaz Minooei, Mohammad Hossein Mohammadi, Sultan Khetani, Ahmad Rezaei Kolahchi, Shohreh Mashayekhan, Amir Sanati-Nezhad
      Hydrogels have been recognized as crucial biomaterials in the field of tissue engineering, regenerative medicine, and drug delivery applications due to their specific characteristics. These biomaterials benefit from retaining a large amount of water, effective mass transfer, similarity to natural tissues and the ability to form different shapes. However, having relatively poor mechanical properties is a limiting factor associated with hydrogel biomaterials. Controlling the biomechanical properties of hydrogels is of paramount importance. In this work, firstly, mechanical characteristics of hydrogels and methods employed for characterizing these properties are explored. Subsequently, the most common approaches used for tuning mechanical properties of hydrogels including but are not limited to, interpenetrating polymer networks, nanocomposites, self-assembly techniques, and co-polymerization are discussed. The performance of different techniques used for tuning biomechanical properties of hydrogels is further compared. Such techniques involve lithography techniques for replication of tissues with complex mechanical profiles; microfluidic techniques applicable for generating gradients of mechanical properties in hydrogel biomaterials for engineering complex human tissues like intervertebral discs, osteochondral tissues, blood vessels and skin layers; and electrospinning techniques for synthesis of hybrid hydrogels and highly ordered fibers with tunable mechanical and biological properties. We finally discuss future perspectives and challenges for controlling biomimetic hydrogel materials possessing proper biomechanical properties. Statement of Significance Hydrogels biomaterials are essential constituting components of engineered tissues with the applications in regenerative medicine and drug delivery. The mechanical properties of hydrogels play crucial roles in regulating the interactions between cells and extracellular matrix and directing the cells phenotype and genotype. Despite significant advances in developing methods and techniques with the ability of tuning the biomechanical properties of hydrogels, there are still challenges regarding the synthesis of hydrogels with complex mechanical profiles as well as limitations in vascularization and patterning of complex structures of natural tissues which barricade the production of sophisticated organs. Therefore, in addition to a review on advanced methods and techniques for measuring a variety of different biomechanical characteristics of hydrogels, the new techniques for enhancing the biomechanics of hydrogels are presented. It is expected that this review will profit future works for regulating the biomechanical properties of hydrogel biomaterials to satisfy the demands of a variety of different human tissues.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.07.028
      Issue No: Vol. 62 (2017)
  • Engineering cell aggregates through incorporated polymeric microparticles
    • Authors: Caroline C. Ahrens; Ziye Dong; Wei Li
      Pages: 64 - 81
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Caroline C. Ahrens, Ziye Dong, Wei Li
      Ex vivo cell aggregates must overcome significant limitations in the transport of nutrients, drugs, and signaling proteins compared to vascularized native tissue. Further, engineered extracellular environments often fail to sufficiently replicate tethered signaling cues and the complex architecture of native tissue. Co-cultures of cells with microparticles (MPs) is a growing field directed towards overcoming many of these challenges by providing local and controlled presentation of both soluble and tethered proteins and small molecules. Further, co-cultured MPs offer a mechanism to better control aggregate architecture and even to report key characteristics of the local microenvironment such as pH or oxygen levels. Herein, we provide a brief introduction to established and developing strategies for MP production including the choice of MP materials, fabrication techniques, and techniques for incorporating additional functionality. In all cases, we emphasize the specific utility of each approach to form MPs useful for applications in cell aggregate co-culture. We review established techniques to integrate cells and MPs. We highlight those strategies that promote targeted heterogeneity or homogeneity, and we describe approaches to engineer cell-particle and particle–particle interactions that enhance aggregate stability and biological response. Finally, we review advances in key application areas of MP aggregates and future areas of development. Statement of Significant Cell-scaled polymer microparticles (MPs) integrated into cellular aggregates have been shown to be a powerful tool to direct cell response. MPs have supported the development of healthy cartilage, islets, nerves, and vasculature by the maintenance of soluble gradients as well as by the local presentation of tethered cues and diffusing proteins and small molecules. MPs integrated with pluripotent stem cells have directed in vivo expansion and differentiation. Looking forward, MPs are expected to support both the characterization and development of in vitro tissue systems for applications such as drug testing platforms. However, useful co-cultures must be designed keeping in mind the limitations and attributes of each material strategy within the context of the overall tissue biology. The present review integrates prospectives from materials development, drug delivery, and tissue engineering to provide a toolbox for the development and application of MPs useful for long-term co-culture within cell aggregates.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.003
      Issue No: Vol. 62 (2017)
  • Hydrogel substrate stress-relaxation regulates the spreading and
           proliferation of mouse myoblasts
    • Authors: Aline Bauer; Luo Gu; Brian Kwee; Weiwei Aileen Li; Maxence Dellacherie; Adam D. Celiz; David J. Mooney
      Pages: 82 - 90
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Aline Bauer, Luo Gu, Brian Kwee, Weiwei Aileen Li, Maxence Dellacherie, Adam D. Celiz, David J. Mooney
      Mechanical properties of the extracellular microenvironment are known to alter cellular behavior, such as spreading, proliferation or differentiation. Previous studies have primarily focused on studying the effect of matrix stiffness on cells using hydrogel substrates that exhibit purely elastic behavior. However, these studies have neglected a key property exhibited by the extracellular matrix (ECM) and various tissues; viscoelasticity and subsequent stress-relaxation. As muscle exhibits viscoelasticity, stress-relaxation could regulate myoblast behavior such as spreading and proliferation, but this has not been previously studied. In order to test the impact of stress relaxation on myoblasts, we created a set of two-dimensional RGD-modified alginate hydrogel substrates with varying initial elastic moduli and rates of relaxation. The spreading of myoblasts cultured on soft stress-relaxing substrates was found to be greater than cells on purely elastic substrates of the same initial elastic modulus. Additionally, the proliferation of myoblasts was greater on hydrogels that exhibited stress-relaxation, as compared to cells on elastic hydrogels of the same modulus. These findings highlight stress-relaxation as an important mechanical property in the design of a biomaterial system for the culture of myoblasts. Statement of Significance This article investigates the effect of matrix stress-relaxation on spreading and proliferation of myoblasts by using tunable elastic and stress-relaxing alginate hydrogels substrates with different initial elastic moduli. Many past studies investigating the effect of mechanical properties on cell fate have neglected the viscoelastic behavior of extracellular matrices and various tissues and used hydrogels exhibiting purely elastic behavior. Muscle tissue is viscoelastic and exhibits stress-relaxation. Therefore, stress-relaxation could regulate myoblast behavior if it were to be incorporated into the design of hydrogel substrates. Altogether, we showed that stress-relaxation impacts myoblasts spreading and proliferation. These findings enable a better understanding of myoblast behavior on viscoelastic substrates and could lead to the design of more suitable substrates for myoblast expansion in vitro.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.041
      Issue No: Vol. 62 (2017)
  • Highly porous scaffolds of PEDOT:PSS for bone tissue engineering
    • Authors: Anne Géraldine Guex; Jennifer L. Puetzer; Astrid Armgarth; Elena Littmann; Eleni Stavrinidou; Emmanuel P. Giannelis; George G. Malliaras; Molly M. Stevens
      Pages: 91 - 101
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Anne Géraldine Guex, Jennifer L. Puetzer, Astrid Armgarth, Elena Littmann, Eleni Stavrinidou, Emmanuel P. Giannelis, George G. Malliaras, Molly M. Stevens
      Conjugated polymers have been increasingly considered for the design of conductive materials in the field of regenerative medicine. However, optimal scaffold properties addressing the complexity of the desired tissue still need to be developed. The focus of this study lies in the development and evaluation of a conductive scaffold for bone tissue engineering. In this study PEDOT:PSS scaffolds were designed and evaluated in vitro using MC3T3-E1 osteogenic precursor cells, and the cells were assessed for distinct differentiation stages and the expression of an osteogenic phenotype. Ice-templated PEDOT:PSS scaffolds presented high pore interconnectivity with a median pore diameter of 53.6±5.9µm and a total pore surface area of 7.72±1.7m2·g−1. The electrical conductivity, based on I-V curves, was measured to be 140µS·cm−1 with a reduced, but stable conductivity of 6.1µS·cm−1 after 28days in cell culture media. MC3T3-E1 gene expression levels of ALPL, COL1A1 and RUNX2 were significantly enhanced after 4weeks, in line with increased extracellular matrix mineralisation, and osteocalcin deposition. These results demonstrate that a porous material, based purely on PEDOT:PSS, is suitable as a scaffold for bone tissue engineering and thus represents a promising candidate for regenerative medicine. Statement of Significance Tissue engineering approaches have been increasingly considered for the repair of non-union fractions, craniofacial reconstruction or large bone defect replacements. The design of complex biomaterials and successful engineering of 3-dimensional tissue constructs is of paramount importance to meet this clinical need. Conductive scaffolds, based on conjugated polymers, present interesting candidates to address the piezoelectric properties of bone tissue and to induce enhanced osteogenesis upon implantation. However, conductive scaffolds have not been investigated in vitro in great measure. To this end, we have developed a highly porous, electrically conductive scaffold based on PEDOT:PSS, and provide evidence that this purely synthetic material is a promising candidate for bone tissue engineering.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.045
      Issue No: Vol. 62 (2017)
  • Living nanofiber yarn-based woven biotextiles for tendon tissue
           engineering using cell tri-culture and mechanical stimulation
    • Authors: Shaohua Wu; Ying Wang; Philipp N. Streubel; Bin Duan
      Pages: 102 - 115
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Shaohua Wu, Ying Wang, Philipp N. Streubel, Bin Duan
      Non-woven nanofibrous scaffolds have been developed for tendon graft application by using electrospinning strategies. However, electrospun nanofibrous scaffolds face some obstacles and limitations, including suboptimal scaffold structure, weak tensile and suture-retention strengths, and compact structure for cell infiltration. In this work, a novel nanofibrous, woven biotextile, fabricated based on electrospun nanofiber yarns, was implemented as a tissue engineered tendon scaffold. Based on our modified electrospinning setup, polycaprolactone (PCL) nanofiber yarns were fabricated with reproducible quality, and were further processed into plain-weaving fabrics interlaced with polylactic acid (PLA) multifilaments. Nonwoven nanofibrous PCL meshes with random or aligned fiber structures were generated using typical electrospinning as comparative counterparts. The woven fabrics contained 3D aligned microstructures with significantly larger pore size and obviously enhanced tensile mechanical properties than their nonwoven counterparts. The biological results revealed that cell proliferation and infiltration, along with the expression of tendon-specific genes by human adipose derived mesenchymal stem cells (HADMSC) and human tenocytes (HT), were significantly enhanced on the woven fabrics compared with those on randomly-oriented or aligned nanofiber meshes. Co-cultures of HADMSC with HT or human umbilical vein endothelial cells (HUVEC) on woven fabrics significantly upregulated the functional expression of most tenogenic markers. HADMSC/HT/HUVEC tri-culture on woven fabrics showed the highest upregulation of most tendon-associated markers than all the other mono- and co-culture groups. Furthermore, we conditioned the tri-cultured constructs with dynamic conditioning and demonstrated that dynamic stretch promoted total collagen secretion and tenogenic differentiation. Our nanofiber yarn-based biotextiles have significant potential to be used as engineered scaffolds to synergize the multiple cell interaction and mechanical stimulation for promoting tendon regeneration. Statement of Significance Tendon grafts are essential for the treatment of various tendon-related conditions due to the inherently poor healing capacity of native tendon tissues. In this study, we combined electrospun nanofiber yarns with textile manufacturing strategies to fabricate nanofibrous woven biotextiles with hierarchical features, aligned fibrous topography, and sufficient mechanical properties as tendon tissue engineered scaffolds. Comparing to traditional electrospun random or aligned meshes, our novel nanofibrous woven fabrics possess strong tensile and suture-retention strengths and larger pore size. We also demonstrated that the incorporation of tendon cells and vascular cells promoted the tenogenic differentiation of the engineered tendon constructs, especially under dynamic stretch. This study not only presents a novel tissue engineered tendon scaffold fabrication technique but also provides a useful strategy to promote tendon differentiation and regeneration.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.043
      Issue No: Vol. 62 (2017)
  • Elastin-PLGA hybrid electrospun nanofiber scaffolds for salivary
           epithelial cell self-organization and polarization
    • Authors: Zahraa I. Foraida; Tim Kamaldinov; Deirdre A. Nelson; Melinda Larsen; James Castracane
      Pages: 116 - 127
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Zahraa I. Foraida, Tim Kamaldinov, Deirdre A. Nelson, Melinda Larsen, James Castracane
      Development of electrospun nanofibers that mimic the structural, mechanical and biochemical properties of natural extracellular matrices (ECMs) is a promising approach for tissue regeneration. Electrospun fibers of synthetic polymers partially mimic the topography of the ECM, however, their high stiffness, poor hydrophilicity and lack of in vivo-like biochemical cues is not optimal for epithelial cell self-organization and function. In search of a biomimetic scaffold for salivary gland tissue regeneration, we investigated the potential of elastin, an ECM protein, to generate elastin hybrid nanofibers that have favorable physical and biochemical properties for regeneration of the salivary glands. Elastin was introduced to our previously developed poly-lactic-co-glycolic acid (PLGA) nanofiber scaffolds by two methods, blend electrospinning (EP-blend) and covalent conjugation (EP-covalent). Both methods for elastin incorporation into the nanofibers improved the wettability of the scaffolds while only blend electrospinning of elastin-PLGA nanofibers and not surface conjugation of elastin to PLGA fibers, conferred increased elasticity to the nanofibers measured by Young’s modulus. After two days, only the blend electrospun nanofiber scaffolds facilitated epithelial cell self-organization into cell clusters, assessed with nuclear area and nearest neighbor distance measurements, leading to the apicobasal polarization of salivary gland epithelial cells after six days, which is vital for cell function. This study suggests that elastin electrospun nanofiber scaffolds have potential application in regenerative therapies for salivary glands and other epithelial organs. Statement of Significance Regenerating the salivary glands by mimicking the extracellular matrix (ECM) is a promising approach for long term treatment of salivary gland damage. Despite their topographic similarity to the ECM, electrospun fibers of synthetic polymers lack the biochemical complexity, elasticity and hydrophilicity of the ECM. Elastin is an ECM protein abundant in the salivary glands and responsible for tissue elasticity. Although it’s widely used for tissue regeneration of other organs, little is known about its utility in regenerating the salivary tissue. This study describes the use of elastin to improve the elasticity, hydrophilicity and biochemical complexity of synthetic nanofibers and its potential in directing in vivo-like organization of epithelial salivary cells which helps the design of efficient salivary gland regeneration scaffolds.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.009
      Issue No: Vol. 62 (2017)
  • Use of hydrogel scaffolds to develop an in vitro 3D culture model of human
           intestinal epithelium
    • Authors: R.H. Dosh; A. Essa; N. Jordan-Mahy; C. Sammon; C.L. Le Maitre
      Pages: 128 - 143
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): R.H. Dosh, A. Essa, N. Jordan-Mahy, C. Sammon, C.L. Le Maitre
      The human intestinal cell lines: Caco-2 and HT29-MTX cells have been used extensively in 2D and 3D cell cultures as simple models of the small intestinal epithelium in vitro. This study aimed to investigate the potential of three hydrogel scaffolds to support the 3D culture of Caco-2 and HT29-MTX cells and critically assess their use as scaffolds to stimulate villi formation to model a small intestinal epithelium in vitro. Here, alginate, l-pNIPAM, and l-pNIPAM-co-DMAc hydrogels were investigated. The cells were suspended within or layered on these hydrogels and maintained under static or dynamic culture conditions for up to 21days. Caco-2 cell viability was increased when layered on the synthetic hydrogel scaffolds, but reduced when suspended within the synthetic hydrogels. In contrast, HT29-MTX cells remained viable when suspended within or layered on all 3D cultures. Interestingly, cells cultured in and on the alginate hydrogel scaffolds formed multilayer spheroid structures, whilst the cells layered on synthetic hydrogels formed villus-like structures. Immunohistochemistry staining demonstrated positive expression of enterocyte differentiation markers and goblet cell marker. In conclusion, l-pNIPAM hydrogel scaffolds supported both cell lines and induced formation of villus-like structures when cells were layered on and cultured under dynamic conditions. The ability of the l-pNIPAM to recapitulate the 3D structure and differentiate main cell types of human intestinal villi may deliver a potential alternative in vitro model for studying intestinal disease and for drug testing. Statement of Significance Forty percent of hospital referrals are linked to disorders of the digestive tract. Current studies have utilised animal models or simple cultures of isolated cells which do not behave in the same manner as human intestine. Thus new models are required which more closely mimic the behaviour of intestinal cells. Here, we tested a number of scaffolds and conditions to develop a cell culture model which closely represents the 3D environment seen within the human small intestine. We successfully created structures seen within the intestine which have not previously been possible with other culture models. These models could be used to investigate tissue engineering, drug discovery, and used asan alternative to in vivo animal models in drug toxicity studies.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.035
      Issue No: Vol. 62 (2017)
  • Concurrently suppressing multidrug resistance and metastasis of breast
           cancer by co-delivery of paclitaxel and honokiol with pH-sensitive
           polymeric micelles
    • Authors: Ziqi Wang; Xinru Li; Dishi Wang; Yang Zou; Xiaoyou Qu; Chuyu He; Yunqiang Deng; Yao Jin; Yuanhang Zhou; Yanxia Zhou; Yan Liu
      Pages: 144 - 156
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Ziqi Wang, Xinru Li, Dishi Wang, Yang Zou, Xiaoyou Qu, Chuyu He, Yunqiang Deng, Yao Jin, Yuanhang Zhou, Yanxia Zhou, Yan Liu
      To concurrently suppress multidrug resistance (MDR) and metastasis of breast cancer cells, paclitaxel (PTX) and honokiol (HNK) were coencapsulated into pH-sensitive polymeric micelles based on poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA). The physicochemical properties of dual drug-loaded PEOz-PLA micelles were characterized in size, drug loading and in vitro release. The efficiency of MDR reversal for the micelles was testified by synergetic enhancement of cytotoxicity and uptake by MCF-7/ADR cells. The flow cytometry and fluorescence polarization measurement results reinforced the conclusion that down-regulation of P-gp expression and increase of plasma membrane fluidity appeared to be possible mechanisms of MDR reversal by dual drug-loaded PEOz-PLA micelles. Further, the efficient inhibition of tumor metastasis by dual drug-loaded PEOz-PLA micelles was demonstrated by in vitro anti-invasion and anti-migration assessment in MDA-MB-231 cells and in vivo bioluminescence imaging in nude mice. The suppression of MDR and metastasis by the micelles was assigned to synergistic effects of pH-triggered drug release and HNK/PEOz-PLA-aroused P-gp inhibition, and pH-triggered drug release and PTX/HNK-aroused MMPs inhibition, respectively. In conclusion, our findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis. Statement of Significance Multidrug resistance (MDR) and metastasis are considered to be two of the major barriers for successful chemotherapy. The combination of a chemotherapeutic drug with a modulator has emerged as a promising strategy for efficiently treating MDR cancer and preventing tumor metastasis. Herein, a dual drug (paclitaxel and honokiol)-loaded pH-sensitive polymeric micelle system based on PEOz-PLA was successfully fabricated to ensure that tumor MDR and metastasis could be concurrently suppressed, therefore achieving distinguishing endo/lysosomal pH from physiological pH by accelerating drug release and then enhancing the cytotoxicity of paclitaxel to drug-resistant tumor cells MCF-7/ADR by increasing cellular uptake of paclitaxel, preventing in vitro invasion and migration for MDA-MB-231 cells and in vivo metastasis in nude mice. Further, the mechanism of MDR reversal by dual drug-loaded PEOz-PLA micelles was elucidated to be down-regulation of P-gp expression and increase of plasma membrane fluidity of MCF-7/ADR cells. The present findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.027
      Issue No: Vol. 62 (2017)
  • Improved tumor tissue penetration and tumor cell uptake achieved by
           delayed charge reversal nanoparticles
    • Authors: Jingxin Gou; Yuheng Liang; Linlin Miao; Wei Guo; Yanhui Chao; Haibing He; Yu Zhang; Jingyu Yang; Chunfu Wu; Tian Yin; Yanjiao Wang; Xing Tang
      Pages: 157 - 166
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Jingxin Gou, Yuheng Liang, Linlin Miao, Wei Guo, Yanhui Chao, Haibing He, Yu Zhang, Jingyu Yang, Chunfu Wu, Tian Yin, Yanjiao Wang, Xing Tang
      The high affinity of positively charged nanoparticles to biological interfaces makes them easily taken up by tumor cells but limits their tumor permeation due to non-specific electrostatic interactions. In this study, polyion complex coated nanoparticles with different charge reversal profiles were developed to study the influence of charge reversal profile on tumor penetration. The system was constructed by polyion complex coating using micelles composed of poly (lysine)-b-polycaprolactone (PLys-b-PCL) as the cationic core and poly (glutamic acid)-g- methoxyl poly (ethylene glycol) (PGlu-g-mPEG) as the anionic coating material. Manipulation of charge reversal profile was achieved by controlling the polymer chain entanglement and electrostatic interaction in the polyion complex layer through glutaraldehyde-induced shell-crosslinking. The delayed charge reversal nanoparticles (CTCL30) could maintain negatively charged in pH 6.5 PBS for at least 2h and exhibit pH-responsive cytotoxicity and cellular uptake in an extended time scale. Compared with a faster charge reversal counterpart (CTCL70) with similar pharmacokinetic profile, CTCL30 showed deeper penetration, higher in vivo tumor cell uptake and stronger antitumor activity in vivo (tumor inhibition rate: 72.3% vs 60.2%, compared with CTCL70). These results indicate that the delayed charge reversal strategy could improve therapeutic effect via facilitating tumor penetration. Statement of Significance Here, the high tumor penetration capability of PEG-coated nanoparticles and the high cellular uptake of cationic nanoparticles were combined by a delayed charge reversal drug delivery system. This drug delivery system was composed of a drug-loading cationic inner core and a polyion complex coating. Manipulation of charge reversal profile was realized by varying the crosslinking degree of the shell of the cationic inner core, through which changed the strength of the polyion complex layer. Nanoparticles with delayed charge reversal profile exhibited improved tumor penetration, in vivo tumor cell uptake and in vivo tumor growth inhibition effect although they have similar pharmacokinetic and biodistribution behaviors with their instant charge reversal counterpart.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.025
      Issue No: Vol. 62 (2017)
  • ECM turnover-stimulated gene delivery through collagen-mimetic
           peptide-plasmid integration in collagen
    • Authors: Morgan A. Urello; Kristi L. Kiick; Millicent O. Sullivan
      Pages: 167 - 178
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Morgan A. Urello, Kristi L. Kiick, Millicent O. Sullivan
      Gene therapies have great potential in regenerative medicine; however, clinical translation has been inhibited by low stability and limited transfection efficiencies. Herein, we incorporate collagen-mimetic peptide (CMP)-linked polyplexes in collagen scaffolds to increase DNA stability by up to 400% and enable tailorable in vivo transgene expression at 100-fold higher levels and 10-fold longer time periods. These improvements were directly linked to a sustained interaction between collagen and polyplexes that persisted during cellular remodeling, polyplex uptake, and intracellular trafficking. Specifically, incorporation of CMPs into polyethylenimine (PEI) polyplexes preserved serum-exposed polyplex-collagen activity over a period of 14days, with 4 orders-of-magnitude more intact DNA present in CMP-modified polyplex-collagen relative to unmodified polyplex-collagen after a 10day incubation under cell culture conditions. CMP-modification also altered endocytic uptake, as indicated by gene silencing studies showing a nearly 50% decrease in transgene expression in response to caveolin-1 silencing in modified samples versus only 30% in unmodified samples. Furthermore, cellular internalization studies demonstrated that polyplex-collagen association persisted within cells in CMP polyplexes, but not in unmodified polyplexes, suggesting that CMP linkage to collagen regulates intracellular transport. Moreover, experiments in an in vivo repair model showed that CMP modification enabled tailoring of transgene expression from 4 to 25days over a range of concentrations. Overall, these findings demonstrate that CMP decoration provides substantial improvements in gene retention, altered release kinetics, improved serum-stability, and improved gene activity in vivo. This versatile technique has great potential for multiple applications in regenerative medicine. Statement of Significance In this work, we demonstrate a novel approach for stably integrating DNA into collagen scaffolds to exploit the natural process of collagen remodelling for high efficiency non-viral gene delivery. The incorporation of CMPs into DNA polyplexes, coupled with the innate affinity between CMPs and collagen, not only permitted improved control over polyplex retention and release, but also provided a series of substantial and highly unique benefits via the stable and persistent linkage between CMP-polyplexes and collagen fragments. Specifically, CMP-modification of polyplexes was demonstrated to (i) control release for nearly a month, (ii) improve vector stability under physiological-like conditions, and (iii) provide ligands able to efficiently transfer genes via endocytic collagen pathways. These unique properties overcome key barriers inhibiting non-viral gene therapy.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.08.038
      Issue No: Vol. 62 (2017)
  • An in situ photocrosslinkable platelet rich plasma – Complexed hydrogel
           glue with growth factor controlled release ability to promote cartilage
           defect repair
    • Authors: Xiaolin Liu; Yunlong Yang; Xin Niu; Qiuning Lin; Bizeng Zhao; Yang Wang; Linyong Zhu
      Pages: 179 - 187
      Abstract: Publication date: 15 October 2017
      Source:Acta Biomaterialia, Volume 62
      Author(s): Xiaolin Liu, Yunlong Yang, Xin Niu, Qiuning Lin, Bizeng Zhao, Yang Wang, Linyong Zhu
      The repair of articular cartilage injury is a great clinical challenge. Platelet-rich plasma (PRP) has attracted much attention for the repair of articular cartilage injury, because it contains various growth factors that are beneficial for wound repair. However, current administration methods of PRP have many shortcomings, such as unstable biological fixation and burst release of growth factors, all of which complicate its application in the repair of articular cartilage and compromise its therapeutic efficacy. In this study, based on our previously reported photoinduced imine crosslinking (PIC) reaction, we developed an in situ photocrosslinkable PRP hydrogel glue (HNPRP) through adding a photoresponsive hyaluronic acid (HA-NB) which could generate aldehyde groups upon light irradiation and subsequently react with amino groups, into autologous PRP. Our study showed that HNPRP hydrogel glue was cytocompatible and could be conveniently and rapidly prepared in situ, forming a robust hydrogel scaffold. In addition, our results demonstrated that HNPRP hydrogel not only achieved controlled release of growth factors, but also showed strong tissue adhesive ability. Therefore, HNPRP hydrogel was quite suitable for cartilage defect regeneration. Our further in vitro experiment showed that HNPRP hydrogel could promote the proliferation and migration of chondrocytes and bone marrow stem cells (BMSCs). In vivo testing using a rabbit full-thickness cartilage defect model demonstrated that HNPRP hydrogel could achieve integrative hyaline cartilage regeneration and its therapeutic efficacy was better than thrombin activated PRP gel. Statement of Significance In this study, we have developed a photocrosslinkable platelet rich plasma (PRP) – complexed hydrogel glue (HNPRP) for cartilage regeneration. The in situ formed HNPRP hydrogel glue showed not only the controlled release ability of growth factors, but also strong tissue adhesiveness, which could resolve the current problems in clinical application of PRP. Furthermore, HNPRP hydrogel glue could promote integrative hyaline cartilage regeneration, and its reparative efficacy for cartilage defect was better than thrombin activated PRP gel. This study provided not only an effective repair material for cartilage regeneration, but also developed an advanced method for PRP application.
      Graphical abstract image

      PubDate: 2017-09-30T14:39:54Z
      DOI: 10.1016/j.actbio.2017.05.023
      Issue No: Vol. 62 (2017)
  • Silk scaffolds in bone tissue engineering: An overview
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Promita Bhattacharjee, Banani Kundu, Deboki Naskar, Hae-Won Kim, Tapas K. Maiti, Debasis Bhattacharya, Subhas C. Kundu
      Bone tissue plays multiple roles in our day-to-day functionality. The frequency of accidental bone damage and disorder is increasing worldwide. Moreover, as the world population continues to grow, the percentage of the elderly population continues to grow, which results in an increased number of bone degenerative diseases. This increased elderly population pushes the need for artificial bone implants that specifically employ biocompatible materials. A vast body of literature is available on the use of silk in bone tissue engineering. The current work presents an overview of this literature from materials and fabrication perspective. As silk is an easy-to-process biopolymer; this allows silk-based biomaterials to be molded into diverse forms and architectures, which further affects the degradability. This makes silk-based scaffolds suitable for treating a variety of bone reconstruction and regeneration objectives. Silk surfaces offer active sites that aid the mineralization and/or bonding of bioactive molecules that facilitate bone regeneration. Silk has also been blended with a variety of polymers and minerals to enhance its advantageous properties or introduce new ones. Several successful works, both in vitro and in vivo, have been reported using silk-based scaffolds to regenerate bone tissues or other parts of the skeletal system such as cartilage and ligament. A growing trend is observed toward the use of mineralized and nanofibrous scaffolds along with the development of technology that allows to control scaffold architecture, its biodegradability and the sustained releasing property of scaffolds. Further development of silk-based scaffolds for bone tissue engineering, taking them up to and beyond the stage of human trials, is hoped to be achieved in the near future through a cross-disciplinary coalition of tissue engineers, material scientists and manufacturing engineers. Statement of Significance The state-of-art of silk biomaterials in bone tissue engineering, covering their wide applications as cell scaffolding matrices to micro-nano carriers for delivering bone growth factors and therapeutic molecules to diseased or damaged sites to facilitate bone regeneration, is emphasized here. The review rationalizes that the choice of silk protein as a biomaterial is not only because of its natural polymeric nature, mechanical robustness, flexibility and wide range of cell compatibility but also because of its ability to template the growth of hydroxyapatite, the chief inorganic component of bone mineral matrix, resulting in improved osteointegration. The discussion extends to the role of inorganic ions such as Si and Ca as matrix components in combination with silk to influence bone regrowth. The effect of ions or growth factor-loaded vehicle incorporation into regenerative matrix, nanotopography is also considered.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Tendon injury and repair – A perspective on the basic mechanisms of
           tendon disease and future clinical therapy
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Jess G. Snedeker, Jasper Foolen
      Tendon is an intricately organized connective tissue that efficiently transfers muscle force to the bony skeleton. Its structure, function, and physiology reflect the extreme, repetitive mechanical stresses that tendon tissues bear. These mechanical demands also lie beneath high clinical rates of tendon disorders, and present daunting challenges for clinical treatment of these ailments. This article aims to provide perspective on the most urgent frontiers of tendon research and therapeutic development. We start by broadly introducing essential elements of current understanding about tendon structure, function, physiology, damage, and repair. We then introduce and describe a novel paradigm explaining tendon disease progression from initial accumulation of damage in the tendon core to eventual vascular recruitment from the surrounding synovial tissues. We conclude with a perspective on the important role that biomaterials will play in translating research discoveries to the patient. Statement of Significance Tendon and ligament problems represent the most frequent musculoskeletal complaints for which patients seek medical attention. Current therapeutic options for addressing tendon disorders are often ineffective, and the need for improved understanding of tendon physiology is urgent. This perspective article summarizes essential elements of our current knowledge on tendon structure, function, physiology, damage, and repair. It also describes a novel framework to understand tendon physiology and pathophysiology that may be useful in pushing the field forward.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Soft tissue fillers for adipose tissue regeneration: From hydrogel
           development toward clinical applications
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): I. Van Nieuwenhove, L. Tytgat, M. Ryx, P. Blondeel, F. Stillaert, H. Thienpont, H. Ottevaere, P. Dubruel, S. Van Vlierberghe
      There is a clear and urgent clinical need to develop soft tissue fillers that outperform the materials currently used for adipose tissue reconstruction. Recently, extensive research has been performed within this field of adipose tissue engineering as the commercially available products and the currently existing techniques are concomitant with several disadvantages. Commercial products are highly expensive and associated with an imposing need for repeated injections. Lipofilling or free fat transfer has an unpredictable outcome with respect to cell survival and potential resorption of the fat grafts. Therefore, researchers are predominantly investigating two challenging adipose tissue engineering strategies: in situ injectable materials and porous 3D printed scaffolds. The present work provides an overview of current research encompassing synthetic, biopolymer-based and extracellular matrix-derived materials with a clear focus on emerging fabrication technologies and developments realized throughout the last decade. Moreover, clinical relevance of the most promising materials will be discussed, together with potential concerns associated with their application in the clinic.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Long-term retention of ECM hydrogel after implantation into a sub-acute
           stroke cavity reduces lesion volume
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Harmanvir Ghuman, Madeline Gerwig, Francesca J. Nicholls, Jessie R. Liu, Julia Donnelly, Stephen F. Badylak, Michel Modo
      Salvaging or functional replacement of damaged tissue caused by stroke in the brain remains a major therapeutic challenge. In situ gelation and retention of a hydrogel bioscaffold composed of 8mg/mL extracellular matrix (ECM) can induce a robust invasion of cells within 24h and potentially promote a structural remodeling to replace lost tissue. Herein, we demonstrate a long-term retention of ECM hydrogel within the lesion cavity. A decrease of approximately 32% of ECM volume is observed over 12weeks. Lesion volume, as measured by magnetic resonance imaging and histology, was reduced by 28%, but a battery of behavioral tests (bilateral asymmetry test; footfault; rotameter) did not reveal a therapeutic or detrimental effect of the hydrogel. Glial scarring and peri-infarct astrocytosis were equivalent between untreated and treated animals, potentially indicating that permeation into host tissue is required to exert therapeutic effects. These results reveal a marked difference of biodegradation of ECM hydrogel in the stroke-damaged brain compared to peripheral soft tissue repair. Further exploration of these structure-function relationships is required to achieve a structural remodeling of the implanted hydrogel, as seen in peripheral tissues, to replace lost tissue and promote behavioral recovery. Statement of Significance In situ gelation of ECM is essential for its retention within a tissue cavity. The brain is a unique environment with restricted access that necessitates image-guided delivery through a thin needle to access tissue cavities caused by stroke, as well as other conditions, such as traumatic brain injury or glioma resection. Knowledge about a brain tissue response to implanted hydrogels remains limited, especially in terms of long-term effects and potential impact on behavioral function. We here address the long-term retention of hydrogel within the brain environment, its impact on behavioral function, as well as its ability to reduce further tissue deformation caused by stroke. This study highlights considerable differences in the brain’s long-term response to an ECM hydrogel compared to peripheral soft tissue. It underlines the importance of understanding the effect of the structural presence of a hydrogel within a cavity upon host brain tissue and behavioral function. As demonstrated herein, ECM hydrogel can fill a cavity long-term to reduce further progression of the cavity, while potentially serving as a reservoir for local drug or cell delivery.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Silk fibroin-chondroitin sulfate scaffold with immuno-inhibition property
           for articular cartilage repair
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Feifei Zhou, Xianzhu Zhang, Dandan Cai, Jun Li, Qin Mu, Wei Zhang, Shouan Zhu, Yangzi Jiang, Weiliang Shen, Shufang Zhang, Hong Wei Ouyang
      The demand of favorable scaffolds has increased for the emerging cartilage tissue engineering. Chondroitin sulfate (CS) and silk fibroin have been investigated and reported with safety and excellent biocompatibility as tissue engineering scaffolds. However, the rapid degradation rate of pure CS scaffolds presents a challenge to effectively recreate neo-tissue similar to natural articular cartilage. Meanwhile the silk fibroin is well used as a structural constituent material because its remarkable mechanical properties, long-lasting in vivo stability and hypoimmunity. The application of composite silk fibroin and CS scaffolds for joint cartilage repair has not been well studied. Here we report that the combination of silk fibroin and CS could synergistically promote articular cartilage defect repair. The silk fibroin (silk) and silk fibroin/CS (silk-CS) scaffolds were fabricated with salt-leaching, freeze-drying and crosslinking methodologies. The biocompatibility of the scaffolds was investigated in vitro by cell adhesion, proliferation and migration with human articular chondrocytes. We found that silk-CS scaffold maintained better chondrocyte phenotype than silk scaffold; moreover, the silk-CS scaffolds reduced chondrocyte inflammatory response that was induced by interleukin (IL)-1β, which is in consistent with the well-documented anti-inflammatory activities of CS. The in vivo cartilage repair was evaluated with a rabbit osteochondral defect model. Silk-CS scaffold induced more neo-tissue formation and better structural restoration than silk scaffold after 6 and 12weeks of implantation in ICRS histological evaluations. In conclusion, we have developed a silk fibroin/ chondroitin sulfate scaffold for cartilage tissue engineering that exhibits immuno-inhibition property and can improve the self-repair capacity of cartilage. Statement of Significance Severe cartilage defect such as osteoarthritis (OA) is difficult to self-repair because of its avascular, aneural and alymphatic nature. Current scaffolds often focus on providing sufficient mechanical support or bio-mimetic structure to promote cartilage repair. Thus, silk has been adopted and investigated broadly. However, inflammation is one of the most important factors in OA. But few scaffolds for cartilage repair reported anti-inflammation property. Meanwhile, chondroitin sulfate (CS) is a glycosaminoglycan present in the natural cartilage ECM, and has exhibited a number of useful biological properties including anti-inflammatory activity. Thus, we designed this silk-CS scaffold and proved that this scaffold exhibited good anti-inflammatory effects both in vitro and in vivo, promoted the repair of articular cartilage defect in animal model.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Molecular and macro-scale analysis of enzyme-crosslinked silk hydrogels
           for rational biomaterial design
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Meghan McGill, Jeannine M. Coburn, Benjamin P. Partlow, Xuan Mu, David L. Kaplan
      Silk fibroin-based hydrogels have exciting applications in tissue engineering and therapeutic molecule delivery; however, their utility is dependent on their diffusive properties. The present study describes a molecular and macro-scale investigation of enzymatically-crosslinked silk fibroin hydrogels, and demonstrates that these systems have tunable crosslink density and diffusivity. We developed a liquid chromatography tandem mass spectroscopy (LC-MS/MS) method to assess the quantity and order of covalent tyrosine crosslinks in the hydrogels. This analysis revealed between 28 and 56% conversion of tyrosine to dityrosine, which was dependent on the silk concentration and reactant concentration. The crosslink density was then correlated with storage modulus, revealing that both crosslinking and protein concentration influenced the mechanical properties of the hydrogels. The diffusive properties of the bulk material were studied by fluorescence recovery after photobleaching (FRAP), which revealed a non-linear relationship between silk concentration and diffusivity. As a result of this work, a model for synthesizing hydrogels with known crosslink densities and diffusive properties has been established, enabling the rational design of silk hydrogels for biomedical applications. Statement of Significance Hydrogels from naturally-derived silk polymers offer versitile opportunities in the biomedical field, however, their design has largely been an empirical process. We present a fundamental study of the crosslink density, storage modulus, and diffusion behavior of enzymatically-crosslinked silk hydrogels to better inform scaffold design. These studies revealed unexpected non-linear trends in the crosslink density and diffusivity of silk hydrogels with respect to protein concentration and crosslink reagent concentration. This work demonstrates the tunable diffusivity and crosslinking in silk fibroin hydrogels, and enables the rational design of biomaterials. Further, the characterization methods presented have applications for other materials with dityrosine crosslinks, which are found in nature as post-translational modificaitons, as well as in engineered matrices such as tyramine-substituted hyaluronic acid and recombinant resilin.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Thermo-responsive in-situ forming hydrogels as barriers to prevent
           post-operative peritendinous adhesion
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Pang-Yun Chou, Shih-Heng Chen, Chih-Hao Chen, Shih-Hsien Chen, Yi Teng Fong, Jyh-Ping Chen
      In this study, we aimed to assess whether thermo-responsive in-situ forming hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) could prevent post-operative peritendinous adhesion. The clinical advantages of the thermo-responsive hydrogels are acting as barrier material to block penetration of fibroblasts, providing mobility and flexibility during application and enabling injection through a small opening to fill spaces of any shape after surgery. The thermo-responsiveness of hydrogels was determined to ensure their clinic uses. By grafting hydrophilic biopolymers chitosan (CS) and hyaluronic acid (HA) to PNIPAM, the copolymer hydrogels show enhanced water retention and lubrication, while reduced volume shrinkage during phase transition. In cell culture experiments, the thermo-responsive hydrogel has good biocompatibility and reduces fibroblast penetration. In animal experiments, the effectiveness of preventing post-operative peritendinous adhesion was studied in a rabbit deep flexor tendon model. From gross examination, histology, bending angles of joints, tendon gliding excursion and pull-out force, HA-CS-PNIPAM (HACPN) was confirmed to be the best barrier material to prevent post-operative peritendinous adhesion compared to PNIPAM and CS-PNIPAM (CPN) hydrogels and a commercial barrier film Seprafilm®. There was no significant difference in the breaking strength of HACPN-treated tendons and spontaneously healed ones, indicating HACPN hydrogel application did not interfere with normal tendon healing. We conclude that HACPN hydrogel can provide the best functional outcomes to significantly prevent post-operative tendon adhesion in vivo. Statement of Significance We prepared thermo-responsive in-situ forming hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) to prevent post-operative peritendinous adhesion. The injectable barrier hydrogel could have better anti-adhesive properties than current commercial products by acting as barrier material to block penetration of fibroblasts, providing mobility and flexibility during application and enabling injection through a small opening to fill spaces of any shape after surgery. The effectiveness of preventing post-operative peritendinous adhesion was studied in a rabbit deep flexor tendon model. From gross examination, histology, bending angles of joints, tendon gliding excursion and pull-out force, HA-CS-PNIPAM (HACPN) was confirmed to be the best barrier material to prevent post-operative peritendinous adhesion compared to PNIPAM and CS-PNIPAM (CPN) hydrogels and a commercial barrier film Seprafilm®.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Pro-inflammatory chitosan/poly(γ-glutamic acid) nanoparticles modulate
           human antigen-presenting cells phenotype and revert their pro-invasive
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Flávia Castro, Marta L. Pinto, Andreia M. Silva, Catarina L. Pereira, Graciosa Q. Teixeira, Maria Gomez-Lazaro, Susana G. Santos, Mário A. Barbosa, Raquel M. Gonçalves, Maria J. Oliveira
      Anticancer immune responses depend on efficient presentation of tumor antigens and co-stimulatory signals provided by antigen-presenting cells (APCs). However, it is described that immature dendritic cells (DCs) and macrophages at the tumor site may have an immunosuppressive profile, which limits the activity of effector T cells and supports tumor progression. Therapeutic targeting of these innate immune cells, either aiming at their elimination or re-polarization towards an immunostimulatory profile, has been pointed as an attractive approach to control tumor progression. In the present work, we assessed the potential of Chitosan (Ch)/Poly(γ-glutamic acid) (γ-PGA) nanoparticles (NPs) to modulate macrophages and DCs inflammatory profile and to impair their ability to promote cancer cell invasion. Interestingly, Ch/γ-PGA NPs, prepared by co-acervation method, induced an immunostimulatory DCs phenotype, enhancing the expression of the co-stimulatory molecules CD86, CD40 and HLA-DR, and the secretion of the pro-inflammatory cytokines TNF-α, IL-12p40 and IL-6. Furthermore, Ch/γ-PGA NPs re-educated IL-10-stimulated macrophages towards a pro-inflammatory profile, decreasing the expression of CD163 and promoting the secretion of IL-12p40 and TNF-α. These alterations in the immune cells phenotype promoted CD4+ and CD8+ T cell activation/proliferation and partially inhibited APCs’ ability to induce colorectal cancer cell invasion. Overall, our findings open new perspectives on the use of Ch/γ-PGA NPs as an immunomodulatory therapy for antigen-presenting cells reprogramming, providing a new tool for anticancer therapies. Statement of Significance The immune system is responsible to detect and destroy abnormal cells preventing the development of cancer. However, the immunosuppressive tumor microenvironment can compromise the immune response favoring tumor progression. Thus, immune system modulation towards an immunostimulatory profile can improve anticancer therapies. This research focus on the development of chitosan/poly(γ-glutamic acid) nanoparticles (NPs) to modulate human antigen-presenting cells (APCs) phenotype and to counteract their pro-invasive capacity. Interestingly, Ch/γ-PGA NPs had a prominent effect in inducing macrophages and dendritic cells immunostimulatory phenotype, thus favoring T cell proliferation and inhibiting colorectal cancer cell invasion. We propose that their combination with other immunomodulatory drugs or conventional anticancer therapies can improve patients’ outcome.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Tissue-engineered magnetic cell sheet patches for advanced strategies in
           tendon regeneration
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Ana I. Gonçalves, Márcia T. Rodrigues, Manuela E. Gomes
      Tendons are powerful 3D biomechanically structures combining a few cells in an intrincated and highly hierarchical niche environment. When tendon homeostasis is compromised, restoration of functionality upon injury is limited and requires alternatives to current augmentation or replacement strategies. Cell sheet technologies are a powerful tool for the fabrication of living extracellular-rich patches towards regeneration of tenotopic defects. Thus, we originally propose the development of magnetically responsive tenogenic patches through magnetic cell sheet (magCSs) technology that enable the remote control upon implantation of the tendon-mimicking constructs. A Tenomodulin positive (TNMD+) subpopulation of cells sorted from a crude population of human adipose stem cells (hASCs) previously identified as being prone to tenogenesis was selected for the magCSs patch construction. We investigated the stability, the cellular co-location of the iron oxide nanoparticles (MNPs), as well as the morphology and mechanical properties of the developed magCSs. Moreover, the expression of tendon markers and collagenous tendon-like matrix were further assessed under the actuation of an external magnetic field. Overall, this study confirms the potential to bioengineer tendon patches using a magnetic cell sheet construction with magnetic responsiveness, good mechanoelastic properties and a tenogenic prone stem cell population envisioning cell-based functional therapies towards tendon regeneration. Statement of Significance The concept of magnetic force-based tissue engineering may assist the development of innovative solutions to treat tendon (or other tissues) disorders upon remote control of biological processes as cell migration or differentiation. Herein, we originally fabricated magnetic responsive cell sheets (magCSs) with a Tenomodulin positive subpopulation of adipose tissue derived stem cells identified to commit to the tenogenic lineage. To the best of authors knowledge, this is the first time a tendon oriented strategy resorting on magCSsis reported. Moreover, the promising role of tenogenic living constructs fabricated as magnetically responsive ECM-rich patches is highlighted, envisioning the stimulation of endogenous regenerative mechanisms. Altogether, these findings contribute to future stem cell studies and their translation toward tendon therapies.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Discerning the composition of penetratin for safe penetration from cornea
           to retina
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Kuan Jiang, Xin Gao, Qing Shen, Changyou Zhan, Yanyu Zhang, Cao Xie, Gang Wei, Weiyue Lu
      Delivery of biomacromolecules into the eye is greatly hindered by several protective barriers. The cell-penetrating peptide, penetratin, has been found to be an effective absorption enhancer for noninvasive intraocular gene delivery. To discern the composition of penetratin for safe penetration from cornea to retina, we designed a series of penetratin derivatives by varying the hydrophobicity and evaluated their potency for retina-targeted delivery. The hydrophilic amino acids of penetratin, excluding the conserved basic amino acid residues, were respectively replaced with tryptophan. Secondary structure of the resultant derivatives was analyzed by computer simulation and circular dichroism, exhibiting that the hydrophobic derivatives had a propensity to form high content of helix and entered corneal and conjunctival cells more easily than did penetratin. As expected, the hydrophobic derivatives showed improved permeability in excised rabbit cornea and sclera, and kept intact after penetration. When instilled topically in the conjunctival sac of mice eyes, the hydrophobic derivatives distributed safely and rapidly into both cornea and retina, with increased amount and prolonged retention time in comparison to penetratin. In conclusion, we demonstrated that the ocular permeability of penetratin derivatives closely correlated with their hydrophobicity, and introducing hydrophobic amino acids in penetratin was a feasible approach to develop more powerful ocular absorption enhancers. Statement of Significance Due to the defensive barriers of the eye, efficient and safe absorption enhancers are indispensable for noninvasive delivery of exogenous biomacromolecules to the posterior segment. In this manuscript, we designed a series of penetratin derivatives and validated they had significantly improved penetration ability from cornea to retina than wild-type penetratin, without increasing toxicity. More importantly, we provided a sequence of solid evidences that the ocular permeability of penetratin derivatives closely correlated with their hydrophobicity, and introducing hydrophobic amino acids in penetratin was a feasible approach to develop more powerful ocular absorption enhancers. We also demonstrated that the penetratin derivatives permeated through cornea and sclera with intact structure, and might enter the eye by non-corneal pathway.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Facile construction of bioreducible crosslinked polypeptide micelles for
           enhanced cancer combination therapy
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Hima Bindu Ruttala, Natarajan Chitrapriya, Kaliappan Kaliraj, Thiruganesh Ramasamy, Woo Hyun Shin, Jee-Heon Jeong, Jae Ryong Kim, Sae Kwang Ku, Han-Gon Choi, Chul Soon Yong, Jong Oh Kim
      In this study, we developed pH and redox-responsive crosslinked polypeptide-based combination micelles for enhanced chemotherapeutic efficacy and minimized side effects. The stability and drug release properties of the polypeptide micelles were efficiency balanced by the corona-crosslinking of the triblock copolymer, poly(ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr) with coordinated redox and pH dual-sensitivity by introducing disulfide crosslinkages. Because of the crosslinking of the middle shell of the triblock polypeptide micelles, their robust structure was maintained in strong destabilization conditions and exhibited excellent stability. GSH concentrations were significantly higher in tumor tissue than in normal tissue, which formed the basis for our design. Drug release was elevated under redox and low acidic conditions. Furthermore, crosslinked micelles showed a superior anticancer effect compared to that of non-crosslinked micelles. Incorporation of docetaxel (DTX) and lonidamine (LND) in crosslinked polypeptide micelles increased the intracellular reactive oxygen species (ROS) level and oxidative stress and caused damage to intracellular components that resulted in greater apoptosis of cancer cells than when DTX or LND was used alone. The combination of DTX and LND in crosslinked micelles exhibited efficacious inhibition of tumor growth with an excellent safety profile compared to that reported for drug cocktail combinations and non-crosslinked micelles. Overall, redox/pH-responsive polypeptide micelles could be an interesting platform for efficient chemotherapy. Statement of Significance We have synthesized a biodegradable polypeptide block copolymer to construct a facile pH and redox-responsive polymeric micelle asan advanced therapeutic system for cancer therapy. We have designed a corona-crosslinked triblock copolymer (poly (ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr)) micelles co-loaded with docetaxel and lonidamine (cl-M/DL). The corona of triblock polymer was crosslinked to maintain its structural integrity in the physiological environment. The mitochondrial targeting LND is expected to generate ROS, oxidative stress and thereby synergize the chemotherapeutic efficacy of DTX in killing cancer cells. Consistently, cl-M/DL exhibited excellent antitumor efficacy in xenograft tumor model with remarkable tumor regression. Overall, we demonstrated the construction of bioreducible nanosystem for the effective synergistic delivery of DTX/LND in tumor tissues towards cancer treatment.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Unsaturated nitrogen-rich polymer poly(l-histidine) gated reversibly
           switchable mesoporous silica nanoparticles using “graft to” strategy
           for drug controlled release
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Shengjun Mu, Yongjun Liu, Tianqi Wang, Jing Zhang, Dandan Jiang, Xiaoyue Yu, Na Zhang
      A novel and intelligent pH-controlled system having an “on-off” switch based on poly(l-histidine) (PLH) and poly(ethylene glycol) (PEG) coated mesoporous silica nanoparticles (MSNs) (MSNs-PLH-PEG) was designed and evaluated for tumor specific drug release. The unsaturated nitrogen-rich polymer, PLH, which can change its solubility at different pH values, was employed for establishing the reversible “on-off” switch. In vitro drug release results demonstrated that MSNs-PLH-PEG has a pH-controlled “on-off” profile with the change of pH value between pH 7.4 and 5.0. Furthermore, in vitro cellular uptake study results showed that the entrapped drug could be efficiently released from MSNs-PLH-PEG under acidic endosome/lysosome. In vitro cell cytotoxicity and in vivo antitumor studies results indicated that sorafenib loaded MSNs-PLH-PEG exhibited good anti-proliferation and tumor growth inhibition effects. Haemolysis assay and histological analysis of MSNs-PLH-PEG showed negligible haemolysis activity and no visible tissue toxicity at the test dose. This study represents a promising and intelligent pH-controlled intelligent system for drug delivery and controlled release. Statement of Significance A novel pH-controlled intelligent and reversible “on-off” switch system based on poly(l-histidine) and poly(ethylene glycol) coated mesoporous silica nanoparticles (MSNs-PLH-PEG) by “graft to” synthesis method was constructed for tumor specific drug release. The unsaturated nitrogen-rich pH-sensitive polymer, PLH, which can change its solubility in different pH values, was employed as the reversible “on-off” switch in MSNs for the first time. The pH-controlled “on-off” switch manner was observed in the drug release results in vitro. In the in vivo antitumor studies, sorafenib loaded MSNs-PLH-PEG could effectively suppressed tumor growth in H22 tumor bearing mice. It is expected that the pH-controlled intelligent “on-off” switch system we designed holds remarkable promise and provides valuable strategy for possible applications in cancer therapy.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Efficient VEGF targeting delivery of DOX using Bevacizumab conjugated
           SiO2@LDH for anti-neuroblastoma therapy
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Rongrong Zhu, Zhaoqi Wang, Peng Liang, Xiaolie He, Xizhen Zhuang, Ruiqi Huang, Mei Wang, Qigang Wang, Yechang Qian, Shilong Wang
      Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and is highly expressed in carcinoma, which make it an important target for tumor targeting therapy. Neuroblastoma is the main cause for cancer-related death in children. Like most solid tumors, it is also accompanied with the overexpression of VEGF. Doxorubicin Hydrochloride (DOX), a typical chemotherapeutic agent, exhibits efficient anticancer activities for various cancers. However, DOX, without targeting ability, usually causes severe damage to normal tissues. To overcome the shortages, we designed a novel nano-composite, which is Bevacizumab (Bev) modified SiO2@LDH nanoparticles (SiO2@LDH-Bev), loading with DOX to achieve targeting ability and curative efficiency. SiO2@LDH-DOX and SiO2@LDH-Bev-DOX nanoparticles were synthesized and the physicochemical properties were characterized by TEM detection, Zeta potential analysis, FTIR, Raman and XPS analysis. Then in vitro and in vivo anti-neuroblastoma efficiency, targeting ability and mechanisms of anti-carcinoma and anti-angiogenesis of SiO2@LDH-Bev-DOX were explored. Our results indicated that we obtained the core-shell structure SiO2@LDH-Bev with an average diameter of 253±10nm and the amount of conjugated Bev was 4.59±0.38μg/mg SiO2@LDH-Bev. SiO2@LDH-Bev-DOX could improve the cellular uptake and the targeting effect of DOX to brain and tumor, enhance the anti-neuroblastoma and anti-angiogenesis efficiency both in vitro and in vivo, and alleviate side effects of DOX sharply, especially hepatic injury. In addition, we also demonstrated that angiogenesis inhibitory effect was mediated by DOX and VEGF triggered signal pathways, including PI3K/Akt, Raf/MEK/ERK, and adhesion related pathways. In summary, SiO2@LDH-Bev could be a potential VEGF targeting nanocarrier applied in VEGF positive cancer therapy. Statement of Significance This paper explored that a novel core-shell structure nanomaterial SiO2@LDH and modified SiO2@LDH with Bevacizumab (Bev) to form a new tumor vasculature targeting nanocarrier SiO2@LDH-Bev as vector of DOX, which was not reported before. The results indicated that SiO2@LDH-Bev could improve the VEGF targeting ability, anti-neuroblastoma and anti-angiogenesis efficiency of DOX. At the same time, SiO2@LDH-Bev-DOX could erase the cardiac toxicity and hepatic injury coming from DOX. Tube formation showed SiO2@LDH-Bev-DOX had the strongest effect on inhibiting angiogenesis among all the four formulations. SiO2@LDH-Bev-DOX could downregulate expression of p-VEGFR and inhibit activation of the Raf/MEK/ERK, p38MAPK, PI3K/Akt and FAK signaling pathways to achieve the goal of anti-angiogenesis. This work provides a novel system for the safe and efficient use of Bev and DOX on Neuroblastoma and explores the mechanism of the function of nano carrier in cancer therapy both in vitro and in vivo.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Multivalent interactions between streptavidin-based pretargeting fusion
           proteins and cell receptors impede efficient internalization of
           biotinylated nanoparticles
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Christina L. Parker, Qi Yang, Bing Yang, Justin D. McCallen, Steven I. Park, Samuel K. Lai
      Pretargeting represents a promising strategy to enhance delivery of nanoparticles. The strategy involves first introducing bispecific antibodies or fusion proteins (BFP) that can bind specific epitopes on target cells with one arm, and use the other arm to capture subsequently administered effector molecules, such as radionuclides or drug-loaded nanoparticles. Nevertheless, it remains unclear whether BFP that bind slowly- or non-internalizing epitopes on target cells can facilitate efficient intracellular delivery. Here, we investigated the cellular uptake of biotin-functionalized nanoparticles with streptavidin-scFv against TAG-72, a membrane protein on Jurkat T-cell leukemia cells. Unlike conventional active-targeted nanoparticles, we found that pretargeting resulted in preferential retention of ∼100nm nanoparticles at the plasma membrane rather than internalization into cells. We found no improvement in nanoparticle internalization by simply reducing nanoparticle concentration or surface biotin density. Interestingly, by adding both the BFP and a monoclonal antibody against TAG-72, we observed a twofold improvement in internalization of pretargeted nanoparticles. Our work illustrates that the cellular fate of pretargeted nanoparticles can be controlled by carefully tuning the interactions between pretargeting molecules and nanoparticles on the cell surface. Statement of Significance Pretargeting is a multi-step strategy that utilizes bispecific proteins that recognize both cellular epitopes and subsequently administered therapeutic molecules. This approach has been extensively studied for radiotherapy of blood cancers; however, pretargeting remains largely underexplored for nanoparticle targeting, including whether pretargeting can facilitate efficient intracellular delivery. Here, we found that high density of targeting proteins on the cell surface can effectively limit internalization of pretargeted nanoparticles. Our work underscores the need to carefully assess specific cell-pretargeting molecule pairs for applications requiring intracellular delivery, and the key design requirements for such bispecific pretargeting molecules.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Nitric oxide releasing hydrogel promotes endothelial differentiation of
           mouse embryonic stem cells
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Yan Nie, Kaiyue Zhang, Shuaiqiang Zhang, Dan Wang, Zhibo Han, Yongzhe Che, Deling Kong, Qiang Zhao, Zhongchao Han, Zuo-Xiang He, Na Liu, Fengxia Ma, Zongjin Li
      Transplantation of endothelial cells (ECs) holds great promise for treating various kinds of ischemic diseases. However, the major challenge in ECs-based therapy in clinical applications is to provide high quality and enough amounts of cells. In this study, we developed a simple and efficient system to direct endothelial differentiation of mouse embryonic stem cells (ESCs) using a controllable chitosan nitric oxide (NO)-releasing hydrogel (CS-NO). ESCs were plated onto the hydrogel culture system, and the expressions of differentiation markers were measured. We found that the expression of Flk-1 (early ECs marker) and VE-cadherin (mature ECs marker) increased obviously under the controlled NO releasing environment. Moreover, the Flk-1 upregulation was accompanied by the activation of the phospho-inositide-3 kinase (PI3K)/Akt signaling. We also found that in the presence of the PI3K inhibitor (LY294002), the endothelial commitment of ESCs was abolished, indicating the importance of Akt phosphorylation in the endothelial differentiation of ESCs. Interestingly, in the absence of NO, the activation of Akt phosphorylation alone by using AKT activator (SC-79) did not profoundly promote the endothelial differentiation of ESCs, suggesting an interdependent relationship between NO and the Akt phosphorylation in driving endothelial fate specification of ESCs. Taken together, we demonstrated that NO releasing in a continuous and controlled manner is a simple and efficient method for directing the endothelial differentiation of ESCs without adding growth factors. Statement of Significance Fascinating data continues to show that artificial stem cell niche not only serve as a physical supporting scaffold for stem cells proliferation, but also as a novel platform for directing stem cell differentiation. Because of the lack of proper microenvironment for generating therapeutic endothelial cells (ECs) in vitro, the source of ECs for transplantation is the major limitation in ECs-based therapy to clinical applications. The current study established a feeder cell-free, 2-dimensional culture system for promoting the differentiation processes of embryonic stem cells (ESCs) committed to the endothelial lineage via using a nitric oxide (NO) controlled releasing hydrogel (CS-NO). Notably, the NO releasing from the hydrogel could selectively up-regulate Flk-1 (early ECs marker) and VE-cadherin (mature ECs marker) in the absence of growth factors, which was of crucial importance in the endothelial differentiation of ESCs. In summary, the current study proposes a simple and efficient method for directing the endothelial differentiation of ESCs without extra growth factors.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Effects of PDGF-BB delivery from heparinized collagen sutures on the
           healing of lacerated chicken flexor tendon in vivo
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Mousa Younesi, Derrick M. Knapik, Jameson Cumsky, Baris Ozgur Donmez, Ping He, Anowarul Islam, Greg Learn, Philip McClellan, Michael Bohl, Robert J. Gillespie, Ozan Akkus
      Flexor tendon lacerations are traditionally repaired by using non-absorbable monofilament sutures. Recent investigations have explored to improve the healing process by growth factor delivery from the sutures. However, it is difficult to conjugate growth factors to nylon or other synthetic sutures. This study explores the performance of a novel electrochemically aligned collagen suture in a flexor tendon repair model with and without platelet derived growth factor following complete tendon laceration in vivo. Collagen suture was fabricated via electrochemical alignment process. Heparin was covalently bound to electrochemically aligned collagen sutures (ELAS) to facilitate affinity bound delivery of platelet-derived growth factor-BB (PDGF-BB). Complete laceration of the flexor digitorum profundus in the third digit of the foot was performed in 36 skeletally mature White Leghorn chickens. The left foot was used as the positive control. Animals were randomly divided into three groups: control specimens treated with standard nylon suture (n=12), specimens repaired with heparinated ELAS suture without PDGF-BB (n=12) and specimens repaired with heparinated ELAS suture with affinity bound PDGF-BB (n=12). Specimens were harvested at either 4weeks or 12weeks following tendon repair. Differences between groups were evaluated by the degree of gross tendon excursion, failure load/stress, stiffness/modulus, absorbed energy at failure, elongation/strain at failure. Quantitative histological scoring was performed to assess cellularity and vascularity. Closed flexion angle measurements demonstrated no significant differences in tendon excursion between the study groups at 4 or 12weeks. Biomechanical testing showed that the group treated with PDGF-BB bound heparinated ELAS suture had significantly higher stiffness and failure load (p<0.05) at 12-weeks relative to both heparinated ELAS suture and nylon suture. Similarly, the group treated with PDGF-BB bound suture had significantly higher ultimate tensile strength and Young’s modulus (p<0.05) at 12-weeks relative to both ELAS suture and nylon suture. Compared to nylon controls, heparinized ELAS with PDGF-BB improved biomechanics and vascularity during tendon healing by 12-weeks following primary repair. The ability of ELAS to deliver PDGF-BB to the lacerated area of tendon presents investigators with a functional bioinductive platform to improve repair outcomes following flexor tendon repair. Statement of significance A high strength aligned collagen suture was fabricated via linear electrocompaction and heparinized for prolonged delivery of PDFG-BB. When it was used to suture a complete lacerated flexor tendon in a chicken model controlled release of the PDGF-BB improved the strength of treated tendon after 12 weeks compared to tendon sutured with commercial nylon suture. Furthermore, Collagen suture with affinity bound PDGF-BB enhanced the vascularization and remodeling of lacerated tendon when it compare to synthetic nylon suture. Overall, electrocompacted collagen sutures holds potential to improve repair outcome in flexor tendon surgeries by improving repair strength and stiffness, vascularity, and remodeling via sustained delivery of the PDGF-BB. The bioinductive collagen suture introduces a platform for sustained delivery of other growth factors for a wide-array of applications.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Enzyme-crosslinked gene-activated matrix for the induction of mesenchymal
           stem cells in osteochondral tissue regeneration
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Yi-Hsuan Lee, Hsi-Chin Wu, Chia-Wei Yeh, Chen-Hsiang Kuan, Han-Tsung Liao, Horng-Chaung Hsu, Jui-Che Tsai, Jui-Sheng Sun, Tzu-Wei Wang
      The development of osteochondral tissue engineering is an important issue for the treatment of traumatic injury or aging associated joint disease. However, the different compositions and mechanical properties of cartilage and subchondral bone show the complexity of this tissue interface, making it challenging for the design and fabrication of osteochondral graft substitute. In this study, a bilayer scaffold is developed to promote the regeneration of osteochondral tissue within a single integrated construct. It has the capacity to serve as a gene delivery platform to promote transfection of human mesenchymal stem cells (hMSCs) and the functional osteochondral tissues formation. For the subchondral bone layer, the bone matrix with organic (type I collagen, Col) and inorganic (hydroxyapatite, Hap) composite scaffold has been developed through mineralization of hydroxyapatite nanocrystals oriented growth on collagen fibrils. We also prepare multi-shell nanoparticles in different layers with a calcium phosphate core and DNA/calcium phosphate shells conjugated with polyethyleneimine to act as non-viral vectors for delivery of plasmid DNA encoding BMP2 and TGF-β3, respectively. Microbial transglutaminase is used as a cross-linking agent to crosslink the bilayer scaffold. The ability of this scaffold to act as a gene-activated matrix is demonstrated with successful transfection efficiency. The results show that the sustained release of plasmids from gene-activated matrix can promote prolonged transgene expression and stimulate hMSCs differentiation into osteogenic and chondrogenic lineages by spatial and temporal control within the bilayer composite scaffold. This improved delivery method may enhance the functionalized composite graft to accelerate healing process for osteochondral tissue regeneration. Statement of Significance In this study, a gene-activated matrix (GAM) to promote the growth of both cartilage and subchondral bone within a single integrated construct is developed. It has the capacity to promote transfection of human mesenchymal stem cells (hMSCs) and the functional osteochondral tissues formation. The results show that the sustained release of plasmids including TGF-beta and BMP-2 from GAM could promote prolonged transgene expression and stimulate hMSCs differentiation into the osteogenic and chondrogenic lineages by spatial control manner. This improved delivery method should enhance the functionalized composite graft to accelerate healing process in vitro and in vivo for osteochondral tissue regeneration.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • A deep learning approach to estimate chemically-treated collagenous tissue
           nonlinear anisotropic stress-strain responses from microscopy images
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Liang Liang, Minliang Liu, Wei Sun
      Biological collagenous tissues comprised of networks of collagen fibers are suitable for a broad spectrum of medical applications owing to their attractive mechanical properties. In this study, we developed a noninvasive approach to estimate collagenous tissue elastic properties directly from microscopy images using Machine Learning (ML) techniques. Glutaraldehyde-treated bovine pericardium (GLBP) tissue, widely used in the fabrication of bioprosthetic heart valves and vascular patches, was chosen to develop a representative application. A Deep Learning model was designed and trained to process second harmonic generation (SHG) images of collagen networks in GLBP tissue samples, and directly predict the tissue elastic mechanical properties. The trained model is capable of identifying the overall tissue stiffness with a classification accuracy of 84%, and predicting the nonlinear anisotropic stress-strain curves with average regression errors of 0.021 and 0.031. Thus, this study demonstrates the feasibility and great potential of using the Deep Learning approach for fast and noninvasive assessment of collagenous tissue elastic properties from microstructural images. Statement of Significance In this study, we developed, to our best knowledge, the first Deep Learning-based approach to estimate the elastic properties of collagenous tissues directly from noninvasive second harmonic generation images. The success of this study holds promise for the use of Machine Learning techniques to noninvasively and efficiently estimate the mechanical properties of many structure-based biological materials, and it also enables many potential applications such as serving as a quality control tool to select tissue for the manufacturing of medical devices (e.g. bioprosthetic heart valves).
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Engineered, axially-vascularized osteogenic grafts from human
           adipose-derived cells to treat avascular necrosis of bone in a rat model
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Tarek Ismail, Rik Osinga, Atanas Todorov, Alexander Haumer, Laurent A. Tchang, Christian Epple, Nima Allafi, Nadia Menzi, René D. Largo, Alexandre Kaempfen, Ivan Martin, Dirk J. Schaefer, Arnaud Scherberich
      Background Avascular necrosis of bone (AVN) leads to sclerosis and collapse of bone and joints. The standard of care, vascularized bone grafts, is limited by donor site morbidity and restricted availability. The aim of this study was to generate and test engineered, axially vascularized SVF cells-based bone substitutes in a rat model of AVN. Methods SVF cells were isolated from lipoaspirates and cultured onto porous hydroxyapatite scaffolds within a perfusion-based bioreactor system for 5days. The resulting constructs were inserted into devitalized bone cylinders mimicking AVN-affected bone. A ligated vascular bundle was inserted upon subcutaneous implantation of constructs in nude rats. After 1 and 8weeks in vivo, bone formation and vascularization were analyzed. Results Newly-formed bone was found in 80% of SVF-seeded scaffolds after 8weeks but not in unseeded controls. Human ALU+cells in the bone structures evidenced a direct contribution of SVF cells to bone formation. A higher density of regenerative, M2 macrophages was observed in SVF-seeded constructs. In both experimental groups, devitalized bone was revitalized by vascularized tissue after 8 weeks. Conclusion SVF cells-based osteogenic constructs revitalized fully necrotic bone in a challenging AVN rat model of clinically-relevant size. SVF cells contributed to accelerated initial vascularization, to bone formation and to recruitment of pro-regenerative endogenous cells. Statement of significance Avascular necrosis (AVN) of bone often requires surgical treatment with autologous bone grafts, which is surgically demanding and restricted by significant donor site morbidity and limited availability. This paper describes a de novo engineered axially-vascularized bone graft substitute and tests the potential to revitalize dead bone and provide efficient new bone formation in a rat model. The engineering of an osteogenic/vasculogenic construct of clinically-relevant size with stromal vascular fraction of human adipose, combined to an arteriovenous bundle is described. This construct revitalized and generated new bone tissue. This successful approach proposes a novel paradigm in the treatment of AVN, in which an engineered, vascularized osteogenic graft would be used as a germ to revitalize large volumes of necrotic bone.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Fish scale-derived collagen patch promotes growth of blood and lymphatic
           vessels in vivo
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Jun Kit Wang, Kim Pin Yeo, Yong Yao Chun, Timothy Thatt Yang Tan, Nguan Soon Tan, Véronique Angeli, Cleo Choong
      In this study, Type I collagen was extracted from fish scales asa potential alternative source of collagen for tissue engineering applications. Since unmodified collagen typically has poor mechanical and degradation stability both in vitro and in vivo, additional methylation modification and 1,4-butanediol diglycidyl ether (BDE) crosslinking steps were used to improve the physicochemical properties of fish scale-derived collagen. Subsequently, in vivo studies using a murine model demonstrated the biocompatibility of the different fish scale-derived collagen patches. In general, favorable integration of the collagen patches to the surrounding tissues, with good infiltration of cells, blood vessels (BVs) and lymphatic vessels (LVs) were observed under growth factor-free conditions. Interestingly, significantly higher (p <0.05) number of LVs was found to be more abundant around collagen patches with methylation modification and BDE crosslinking. Overall, we have demonstrated the potential application of fish scale-derived collagen as a promising scaffolding material for various biomedical applications. Statement of Significance Currently the most common sources of collagen are of bovine and porcine origins, although the industrial use of collagen obtained from non-mammalian species is growing in importance, particularly since they have a lower risk of disease transmission and are not subjected to any cultural or religious constraints. However, unmodified collagen typically has poor mechanical and degradation stability both in vitro and in vivo. Hence, in this study, Type I collagen was successfully extracted from fish scales and chemically modified and crosslinked. In vitro studies showed overall improvement in the physicochemical properties of the material, whilst in vivo implantation studies showed improvements in the growth of blood and lymphatic host vessels in the vicinity of the implants.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • In vitro and in vivo study of the application of volvox spheres to
           co-culture vehicles in liver tissue engineering
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Siou Han Chang, Han Hsiang Huang, Pei Leun Kang, Yu Chian Wu, Ming-Huang Chang, Shyh Ming Kuo
      Volvox sphere is a biomimetic concept of a natural Volvox, wherein a large outer sphere contains smaller inner spheres, which can encapsulate cells and provide a double-layer three-dimensional environment for culturing cells. This study simultaneously encapsulated rat mesenchymal stem cells (MSCs) and AML12 hepatocytes in volvox spheres and extensively evaluated the effects of various culturing modes on cell functions and fates. The results showed that compared with a static flask culture, MSCs encapsulated in volvox spheres differentiated into hepatocyte-like cells with a 2-fold increase in albumin (ALB) expression and a 2.5-fold increase in cytokeratin 18 expression in a dynamic bioreactor. Moreover, the restorative effects of volvox spheres encapsulating cells on retrorsine-exposed CCl4-induced liver injuries in rats were evaluated. The data presented significant reductions in AST and ALT levels after the implantation of volvox spheres encapsulating both MSCs and AML12 hepatocytes in vivo. In contrast to the negative control group, histopathological analysis demonstrated liver repair and formation of the new liver tissue in groups implanted with volvox spheres containing cells. These results demonstrate that liver cells implanted with volvox spheres encapsulating both MSCs and AML12 hepatocytes promote liver repair and liver tissue regeneration in liver failure caused by necrotizing agents such as retrorsine and CCl4. Hence, volvox spheres encapsulating MSCs and liver cells can be a promising and clinically effective therapy for liver injury. Statement of Significance In this study, we used a volvox sphere, which is a unique design that mimics the natural Volvox, that consists of a large outer sphere that contains smaller inner spheres, which provide a three-dimensional environment to culture cells. The purpose of this study is to co-culture mesenchymal stem cells (MSCs) and AML12 liver cells in volvox spheres and evaluate two different culture methods, dynamic bioreactor and static culture flask,on the cultured cells. In addition, we aimed to evaluate the restorative effects of volvox spheres encapsulating MSCs and/or AML12 liver cells on rats with retrorsine-exposed CCl4-induced liver injuries. The results showed that MSCs encapsulated in volvox spheres differentiated into hepatocyte-like cells with a 2-fold increase in albumin expression and a 2.5-fold increase in cytokeratin 18 expression ina dynamic bioreactor. Moreover, the data presented significant reductions in AST and ALT levels after the implantation of volvox spheres encapsulating both MSCs and AML12 hepatocytes in vivo. In contrast to the negative control group, histopathological analysis demonstrated liver repair and formation of new liver tissue in groups implanted with volvox spheres containing cells. These results demonstrate that liver cells implanted with volvox spheres encapsulating both MSCs and AML12 hepatocytes promote liver repair and liver tissue regeneration in liver failure caused by necrotizing agents such as retrorsine and CCl4. Hence, volvox spheres encapsulating MSCs and liver cells can be a promising and clinically effective therapy for liver injury.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • The effects of needle damage on annulus fibrosus micromechanics
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Claudio Vergari, Jessica C. Mansfield, Daniel Chan, Andrew Clarke, Judith R. Meakin, Peter C. Winlove
      Needle puncture of the intervertebral disc can initiate a mechanical and biochemical cascade leading to disc degeneration. Puncture’s mechanical effects have been shown near the puncture site, mechanical effects should be observed far, relative to needle size, from the puncture site, given the disc-wide damage induced by the stab. The aim of this work was to quantify these far-field effects, and to observe the local structural damage provoked by the needle. Strips of cow tail annulus fibrosus underwent two consecutive mechanical loadings to 5% tensile strain; fifteen samples were punctured in a radial direction with a randomly assigned needle between the two loadings (needle gauges between 19 and 23). Ten samples (control group) were not punctured. During loading, the tissue strains were imaged using second harmonic generation microscopy in a <600×800µm region about 4.4mm from the puncture site. After mechanical testing, the puncture site was imaged in 3D. Puncture had no significant effect on annulus elastic modulus. Imaging showed a modest change in the shearing between fibre bundles however, the linear strain between bundles, intra-bundle shear and linear strain were not significantly affected. At the puncture site, detached lumps of tissue were present. These results suggest that the mechanical effects observed in intact discs are due to the depressurization of the disc, rather than the local damage to the annulus. Needle profiles could be designed, aiming at separating fibre bundles rather than cutting through them, to avoid leaving dying tissue behind. Statement of Significance Needle puncture of the intervertebral disc can initiate a mechanical and biochemical cascade leading to disc degeneration, but the link between the local damage of the puncture and the disc-wide effects is not well understood. This work aimed at determining the micro-mechanical effects of the puncture far from its site, and to observe the damage induced by the puncture with high resolution imaging. Results show that the puncture had modest effect far from the puncture, but lumps of tissue were left by the needle, detached from the disc; these could cause further damage through friction and inflammation of the surrounding tissues. This suggests that the cascade leading to degeneration is probably driven by a biochemical response rather than disc-wide mechanical effects.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Design of protein delivery systems by mimicking extracellular mechanisms
           for protection of growth factors
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Carla Silva, Agatha Carretero, Diana Soares da Costa, Rui L. Reis, Ramon Novoa-Carballal, Iva Pashkuleva
      Heparin sulfate proteoglycans (HSPGs) are responsible for the storage and stabilization of numerous growth factors in the extracellular matrix. In this complex native environment, the efficient binding of the growth factors is determined by multivalent, specific and reversible electrostatic interactions between the sulfate groups of HSPGs and the positively charged amino acids of the growth factor. Inspired by this naturally occurring stabilization process, we propose the use of diblock copolymers of heparin and polyethylene glycol (Hep-b-PEG) for protection and delivery of FGF-2. We describe the encapsulation of FGF-2 into spontaneously assembling polyelectrolyte complexes (PECs) with Hep-b-PEG in which the Hep block ensures the formation of the PECs, while the PEG moiety confers stability of the generated complex by a stealth corona. Our results demonstrate that by this method we can generate homogeneous complexes (ca. 400nm diameter, PDI 0.29±0.07) with a very high encapsulation efficiency (about 99% encapsulated FGF-2). The release of the growth factor in response to different stimuli such as pH, ionic strength or presence of heparinase was also studied. We report a sustained release of up to 80% during 28days which is not influenced by the presence of heparinase – a result that clearly demonstrates the protective effect of the stealth corona. We also show that FGF-2 remains bioactive as it influences the morphology of bone marrow mesenchymal stem cells. Statement of Significance We describe a biopolymer that uses the way the cells shield a type of proteins (growth factors) to simultaneously assemble, slowly deliver and shield the protein in a “nanocarrier”. Growth factors are essential for the regeneration of cartilage, bones by stem cell therapies but have a short life time as when added directly to tissues. Our design makes use of the heparin bioactivity towards such proteins in combination with a polyethylene glycol moiety (PEG) that makes a protecting shell. PEG, is biocompatible and used in approved medicines and countless cosmetic products. The highest novelty is the reaction (oxime click) used to bound these molecules that does not require modification of heparin and allows preservation of its bioactivity.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Three-dimensional nano-architected scaffolds with tunable stiffness for
           efficient bone tissue growth
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Alessandro Maggi, Hanqing Li, Julia R. Greer
      The precise mechanisms that lead to orthopedic implant failure are not well understood; it is believed that the micromechanical environment at the bone-implant interface regulates structural stability of an implant. In this work, we seek to understand how the 3D mechanical environment of an implant affects bone formation during early osteointegration. We employed two-photon lithography (TPL) direct laser writing to fabricate 3-dimensional rigid polymer scaffolds with tetrakaidecahedral periodic geometry, herewith referred to as nanolattices, whose strut dimensions were on the same order as osteoblasts’ focal adhesions (∼2μm) and pore sizes on the order of cell size, ∼10μm. Some of these nanolattices were subsequently coated with thin conformal layers of Ti or W, and a final outer layer of 18nm-thick TiO2 was deposited on all samples to ensure biocompatibility. Nanomechanical experiments on each type of nanolattice revealed the range of stiffnesses of 0.7–100MPa. Osteoblast-like cells (SAOS-2) were seeded on each nanolattice, and their mechanosensitve response was explored by tracking mineral secretions and intracellular f-actin and vinculin concentrations after 2, 8 and 12days of cell culture in mineralization media. Experiments revealed that the most compliant nanolattices had ∼20% more intracellular f-actin and ∼40% more Ca and P secreted onto them than the stiffer nanolattices, where such cellular response was virtually indistinguishable. We constructed a simple phenomenological model that appears to capture the observed relation between scaffold stiffness and f-actin concentration. This model predicts a range of optimal scaffold stiffnesses for maximum f-actin concentration, which appears to be directly correlated with osteoblast-driven mineral deposition. This work suggests that three-dimensional scaffolds with titania-coated surfaces may provide an optimal microenvironment for cell growth when their stiffness is similar to that of cartilage (∼0.5–3MPa). These findings help provide a greater understanding of osteoblast mechanosensitivity and may have profound implications in developing more effective and safer bone prostheses. Statement of Significance Creating prostheses that lead to optimal bone remodeling has been a challenge for more than two decades because of a lack of thorough knowledge of cell behavior in three-dimensional (3D) environments. Literature has shown that 2D substrate stiffness plays a significant role in determining cell behavior, however, limitations in fabrication techniques and difficulties in characterizing cell-scaffold interactions have limited our understanding of how 3D scaffolds’ stiffness affects cell response. The present study shows that scaffold structural stiffness affects osteoblasts cellular response. Specifically this work shows that the cells grown on the most compliant nanolattices with a stiffness of 0.7MPa expressed ∼20% higher concentration of intracellular f-actin and secreted ∼40% more Ca and P compared with all other nanolattices. This suggests that bone scaffolds with a stiffness close to that of cartilage may serve as optimal 3D scaffolds for new synthetic bone graft materials.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Polyurethane foam scaffold as in vitro model for breast cancer bone
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Valentina Angeloni, Nicola Contessi, Cinzia De Marco, Serena Bertoldi, Maria Cristina Tanzi, Maria Grazia Daidone, Silvia Farè
      Breast cancer (BC) represents the most incident cancer case in women (29%), with high mortality rate. Bone metastasis occurs in 20–50% cases and, despite advances in BC research, the interactions between tumor cells and the metastatic microenvironment are still poorly understood. In vitro 3D models gained great interest in cancer research, thanks to the reproducibility, the 3D spatial cues and associated low costs, compared to in vivo and 2D in vitro models. In this study, we investigated the suitability of a poly-ether-urethane (PU) foam as 3D in vitro model to study the interactions between BC tumor-initiating cells and the bone microenvironment. PU foam open porosity (>70%) appeared suitable to mimic trabecular bone structure. The PU foam showed good mechanical properties under cyclic compression (E=69–109kPa), even if lower than human trabecular bone. The scaffold supported osteoblast SAOS-2 cell line proliferation, with no cytotoxic effects. Human adipose derived stem cells (ADSC) were cultured and differentiated into osteoblast lineage on the PU foam, as shown by alizarin red staining and RT-PCR, thus offering a bone biomimetic microenvironment to the further co-culture with BC derived tumor-initiating cells (MCFS). Tumor aggregates were observed after three weeks of co-culture by e-cadherin staining and SEM; modification in CaP distribution was identified by SEM-EDX and associated to the presence of tumor cells. In conclusion, we demonstrated the suitability of the PU foam to reproduce a bone biomimetic microenvironment, useful for the co-culture of human osteoblasts/BC tumor-initiating cells and to investigate their interaction. Statement of significance 3D in vitro models represent an outstanding alternative in the study of tumor metastases development, compared to traditional 2D in vitro cultures, which oversimplify the 3D tissue microenvironment, and in vivo studies, affected by low reproducibility and ethical issues. Several scaffold-based 3D in vitro models have been proposed to recapitulate the development of metastases in different body sites but, still, the crucial challenge is to correctly mimic the tissue to be modelled in terms of physical, mechanical and biological properties. Here, we prove the suitability of a porous polyurethane foam, synthesized using an appropriate formulaton, in mimicking the bone tissue microenvironment and in reproducing the metastatic colonization derived from human breast cancer, particularly evidencing the devastating effects on the bone extracellular matrix caused by metastatic spreading.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Azopolymer photopatterning for directional control of angiogenesis
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Chiara Fedele, Maria De Gregorio, Paolo A. Netti, Silvia Cavalli, Chiara Attanasio
      Understanding cellular behavior in response to microenvironmental stimuli is central to tissue engineering. An increasing number of reports emphasize the high sensitivity of cells to the physical characteristics of the surrounding milieu and in particular, topographical cues. In this work, we investigated the influence of dynamic topographic signal presentation on sprout formation and the possibility to obtain a space–time control over sprouting directionality without growth factors, in order to investigate the contribution of just topography in the angiogenic process. To test our hypothesis, we employed a 3D angiogenesis assay based on the use of spheroids derived from human umbilical vein endothelial cells (HUVECs). We then modulated the in situ presentation of topographical cues during early-stage angiogenesis through real-time photopatterning of an azobenzene-containing polymer, poly (Disperse Red 1 methacrylate) (pDR1m). Pattern inscription on the polymer surface was made using the focused laser of a confocal microscope. We demonstrate that during early-stage angiogenesis, sprouts followed the pattern direction, while spheroid cores acquired a polarized shape. These findings confirmed that sprout directionality was influenced by the photo-inscribed pattern, probably through contact guidance of leader cells, thus validating the proposed platform as a valuable tool for understanding complex processes involved in cell-topography interactions in multicellular systems. Statement of Significance The complex relationship between endothelial cells and the surrounding environment that leads to formation of a newly formed vascular network during tissue repair is currently unknown. We have developed an innovative in vitro platform to study these mechanisms in a space and time controlled fashion simulating what happens during regeneration. In particular, we combine a “smart” surface, namely a polymer film, with a three-dimensional living cell aggregate. The polymer is activated by light through which we can design a path to guide cells toward the formation of a new vessel. Our work lies at the intersection of stimuli-responsive biointerfaces and cell biology and may be particularly inspiring for those interested in designing biomaterial surface related to angiogenesis.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Tunable denture adhesives using biomimetic principles for enhanced tissue
           adhesion in moist environments
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Simrone K. Gill, Nima Roohpour, Paul D. Topham, Brian J. Tighe
      Nature provides many interesting examples of adhesive strategies. Of particular note, the protein glue secreted by marine mussels delivers high adhesion in wet and dynamic environments owing to existence of catechol moieties. As such, this study focuses on denture fixatives, where a non-zinc-containing commercial-based formulation has been judiciously modified by a biomimetic catechol-inspired polymer, poly(3,4-dihydroxystyrene/styrene-alt-maleic acid) in a quest to modulate adhesive performance. In vitro studies, in a lap-shear configuration, revealed that the catechol-modified components were able to enhance adhesion to both the denture base and hydrated, functional oral tissue mimic, with the resulting mode of failure prominently being adhesive rather than cohesive. These characteristics are desirable in prosthodontic fixative applications, for which temporary adhesion must be maintained, with ultimately an adhesive failure from the mucosal tissue surface preferred. These insights provide an experimental platform in the design of future biomimetic adhesive systems. Statement of Significance Mussel adhesive proteins have proven to be promising biomimetic adhesive candidates for soft tissues and here for the first time we have adapted marine adhesive technology into a denture fixative application. Importantly, we have incorporated a soft tissue mimic in our in vitro adhesion technique that more closely resembles the oral mucosa than previously studied substrates. The novel biomimetic-modified adhesives showed the ability to score the highest adhesive bonding out of all the formulations included in this study, across all moisture levels. This paper will be of major interest to the Acta Biomaterialia readership since the study has illustrated the potential of biomimetic principles in the design of effective prosthodontic tissue adhesives in a series of purpose-designed in vitro experiments in the context of the challenging features of the oral environment.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Biodegradable and adjustable sol-gel glass based hybrid scaffolds from
           multi-armed oligomeric building blocks
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Christian Kascholke, Stephan Hendrikx, Tobias Flath, Dzmitry Kuzmenka, Hans-Martin Dörfler, Dirk Schumann, Mathias Gressenbuch, F. Peter Schulze, Michaela Schulz-Siegmund, Michael C. Hacker
      Biodegradability is a crucial characteristic to improve the clinical potential of sol-gel-derived glass materials. To this end, a set of degradable organic/inorganic class II hybrids from a tetraethoxysilane(TEOS)-derived silica sol and oligovalent cross-linker oligomers containing oligo(d,l-lactide) domains was developed and characterized. A series of 18 oligomers (Mn: 1100–3200Da) with different degrees of ethoxylation and varying length of oligoester units was established and chemical composition was determined. Applicability of an established indirect rapid prototyping method enabled fabrication of a total of 85 different hybrid scaffold formulations from 3-isocyanatopropyltriethoxysilane-functionalized macromers. In vitro degradation was analyzed over 12months and a continuous linear weight loss (0.2–0.5wt%/d) combined with only moderate material swelling was detected which was controlled by oligo(lactide) content and matrix hydrophilicity. Compressive strength (2–30MPa) and compressive modulus (44–716MPa) were determined and total content, oligo(ethylene oxide) content, oligo(lactide) content and molecular weight of the oligomeric cross-linkers as well as material porosity were identified as the main factors determining hybrid mechanics. Cytocompatibility was assessed by cell culture experiments with human adipose tissue-derived stem cells (hASC). Cell migration into the entire scaffold pore network was indicated and continuous proliferation over 14days was found. ALP activity linearly increased over 2weeks indicating osteogenic differentiation. The presented glass-based hybrid concept with precisely adjustable material properties holds promise for regenerative purposes. Statement of Significance Adaption of degradation kinetics toward physiological relevance is still an unmet challenge of (bio-)glass engineering. We therefore present a glass-derived hybrid material with adjustable degradation. A flexible design concept based on degradable multi-armed oligomers was combined with an established indirect rapid prototyping method to produce a systematic set of porous sol-gel-derived class II hybrid scaffolds. Mechanical properties in the range of cancellous bone were narrowly controlled by hybrid composition. The oligoester introduction resulted in significantly increased compressive moduli. Cytocompatible hybrids degraded in physiologically relevant time frames and a promising linear and controllable weight loss profile was found. To our knowledge, our degradation study represents the most extensive long-term investigation of sol-gel-derived class II hybrids. Due to the broad adjustability of material properties, our concept offers potential for engineering of biodegradable hybrid materials for versatile applications.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Mechanical characterization of structurally porous biomaterials built via
           additive manufacturing: experiments, predictive models, and design maps
           for load-bearing bone replacement implants
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): D. Melancon, Z.S. Bagheri, R.B. Johnston, L. Liu, M. Tanzer, D. Pasini
      Porous biomaterials can be additively manufactured with micro-architecture tailored to satisfy the stringent mechano-biological requirements imposed by bone replacement implants. In a previous investigation, we introduced structurally porous biomaterials, featuring strength five times stronger than commercially available porous materials, and confirmed their bone ingrowth capability in an in vivo canine model. While encouraging, the manufactured biomaterials showed geometric mismatches between their internal porous architecture and that of its as-designed counterpart, as well as discrepancies between predicted and tested mechanical properties, issues not fully elucidated. In this work, we propose a systematic approach integrating computed tomography, mechanical testing, and statistical analysis of geometric imperfections to generate statistical based numerical models of high-strength additively manufactured porous biomaterials. The method is used to develop morphology and mechanical maps that illustrate the role played by pore size, porosity, strut thickness, and topology on the relations governing their elastic modulus and compressive yield strength. Overall, there are mismatches between the mechanical properties of ideal-geometry models and as-manufactured porous biomaterials with average errors of 49% and 41% respectively for compressive elastic modulus and yield strength. The proposed methodology gives more accurate predictions for the compressive stiffness and the compressive strength properties with a reduction of the average error to 11% and 7.6%. The implications of the results and the methodology here introduced are discussed in the relevant biomechanical and clinical context, with insight that highlights promises and limitations of additively manufactured porous biomaterials for load-bearing bone replacement implants. Statement of Significance In this work, we perform mechanical characterization of load-bearing porous biomaterials for bone replacement over their entire design space. Results capture the shift in geometry and mechanical properties between as-designed and as-manufactured biomaterials induced by additive manufacturing. Characterization of this shift is crucial to ensure appropriate manufacturing of bone replacement implants that enable biological fixation through bone ingrowth as well as mechanical property harmonization with the native bone tissue. In addition, we propose a method to include manufacturing imperfections in the numerical models that can reduce the discrepancy between predicted and tested properties. The results give insight into the use of structurally porous biomaterials for the design and additive fabrication of load-bearing implants for bone replacement.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Ion channel functional protein kinase TRPM7 regulates Mg ions to promote
           the osteoinduction of human osteoblast via PI3K pathway: In vitro
           simulation of the bone-repairing effect of Mg-based alloy implant
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Xiuzhi Zhang, Haiyue Zu, Dewei Zhao, Ke Yang, Simiao Tian, Xiaoming Yu, Faqiang Lu, Baoyi Liu, Xiaobing Yu, Benjie Wang, Wei Wang, Shibo Huang, Yongxuan Wang, Zihua Wang, Zhaodong Zhang
      Mg-based alloys, as the potential orthopaedic implant, can self-degrade to avoid second operation for its remove, and enable to promote bone repair; however, the underlying molecular mechanisms remain unclear. In the present study, we examined the effect of Mg ions on osteogenesis, chemotaxis and anti-alkaline stress in hFOB1.19 human osteoblast cells to simulate bone-repairing effect of a biodegradable Mg-based alloy implant in vitro, and explored the regulatory role of the transient receptor potential melastatin 7 (TRPM7)/phosphoinositide 3-kinase (PI3K) signalling pathway in the process of Mg ion-induced bone repair by knockdown of TRPM7 and antagonizing PI3K activity. Results indicate that Mg ions up-regulated the expression of Runx2 and alkaline phosphatase (ALP) through TRPM7/PI3K signalling pathway, which could significantly enhance the osteogenic activity of human osteoblasts. Furthermore, the expression levels of MMP2, MMP9 and vascular endothelial growth factor (VEGF) were increased by TRPM7/PI3K signalling pathway, which recruits osteoblasts from low- to high-Mg ion environments by inducing cell migration. Although an alkaline environment has antibacterial effects, alkaline stress can cause cytotoxicity and induce cell death. Finally, we found that Mg ions could activate PI3K phosphorylation to promote cell growth and survival, protecting cells against the alkaline-stress-induced cytotoxicity caused by the degradation of Mg-based alloy implants. Our study not only revealed the molecular mechanism of Mg in promoting bone repair but also explained the protective effects of Mg ions on osteoblasts in an alkaline environment, which provides a theoretical basis and new directions for the application of Mg-based alloy implant material in orthopaedics fixations and osteosarcoma treatment. Statements of Significance As a potential biomaterial for orthopaedic implant, biodegradable magnesium has several advantages including self-degradation and bone repair promotion; however, the underlying mechanisms and effective concentration by which molecular regulates the bone repair remain unclear. The present study revealed that Mg ion and its effective concentration for activating PI3K phosphorylation via TRPM7, which causes three processes affecting bone repair, namely, osteoblast recruitment, osteogenesis and resistance to alkaline stress in human osteoblast. Therefore, our results have provided insight into the underlying molecular biological basis, and guidance for manipulating degradation rate, such as surface modification, of orthopaedic Mg-based implants.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Strontium and magnesium ions released from bioactive titanium metal
           promote early bone bonding in a rabbit implant model
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Yaichiro Okuzu, Shunsuke Fujibayashi, Seiji Yamaguchi, Koji Yamamoto, Takayoshi Shimizu, Takashi Sono, Koji Goto, Bungo Otsuki, Tomiharu Matsushita, Tadashi Kokubo, Shuichi Matsuda
      We have previously developed the “alkali and heat treatment” method to confer bioactivity (bone-bonding ability) to titanium metal (Ti). As strontium (Sr) and magnesium (Mg) ions reportedly promote osteoblastic cell proliferation and differentiation and accelerate bone formation, we improved this method to induce the release of Sr (Sr-Ti) or Mg (Mg-Ti) ions from Ti in a previous study. Here, we evaluated the bioactivity of these novel surface treatments, Sr-Ti and Mg-Ti. In vitro evaluation of cell viability, expression of integrin β1, β catenin, and cyclin D1, osteogenic gene expression, alkaline phosphatase activity, and extracellular mineralization using MC3T3-E1 cells revealed that Sr-Ti and Mg-Ti enhanced proliferation and osteogenic differentiation. In rabbit in vivo studies, Sr-Ti and Mg-Ti also provided greater biomechanical strength and bone-implant contact than the positive control Ti (Ca-Ti), especially at the early stage (4–8weeks), and maintained these properties for a longer period (16–24weeks). Advantages of the improved method include process simplicity, applicability for any implant shape, and lack of adverse effects on implant composition and structure. Therefore, our treatment is promising for clinical applications to achieve early bone bonding. Statement of Significance Implantation into osteoporotic bone constitutes a challenging problem because of early migration or loosening of the implant, which is primarily due to insufficient initial fixation in porotic bone. Therefore, it is desirable to provide implants with a capacity for early bone bonding. We have achieved conferring early bone bonding ability to titanium metal by releasing strontium ions or magnesium ions. Our treatment is promising for clinical applications to achieve early bone bonding of orthopedic or dental Ti-based implants.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Magnesium (Mg) based interference screws developed for promoting tendon
           graft incorporation in bone tunnel in rabbits
    • Abstract: Publication date: November 2017
      Source:Acta Biomaterialia, Volume 63
      Author(s): Jiali Wang, Jiankun Xu, Bin Song, Dick Hokiu Chow, Patrick Shu-hang Yung, Ling Qin
      How to enhance tendon graft incorporation into bone tunnels for achieving satisfactory healing outcomes in patients with anterior cruciate ligament reconstruction (ACLR) is one of the most challenging clinical problems in orthopaedic sports medicine. Several studies have recently reported the beneficial effects of Mg implants in bone fracture healing, indicating the use potential of Mg devices in promoting the tendon graft osteointegration. Here, we developed an innovative Mg-based interference screws for fixation of the tendon graft in rabbits underwent ACLR and investigated the biological role of Mg-based implants in the graft healing. The titanium (Ti) interference screw was used as the control. We demonstrated that Mg interference screw significantly accelerated the incorporation of the tendon graft into bone tunnels via multiscale analytical methods including scanning electronic microscopy/energy dispersive spectrometer (SEM/EDS), micro-hardness, micro-Fourier transform infrared spectroscopy (μFTIR), and histology. Our in vivo study showed that Mg implants enhanced the recruitment of bone marrow stromal stem cells (BMSCs) towards peri-implant bone tissue, which may be ascribed to the upregulation of local TGF-β1 and PDGF-BB. Besides, the in vitro study revealed that higher Mg ions was beneficial to the improvement of capability in cell adhesion and osteogenic differentiation of BMSCs. Thus, the enhancement in cell migration, cell adhesion and osteogenic differentiation of BMSCs may contribute to an improved tendon graft osteointegration in the Mg group. Our findings in this work may further facilitate clinical applications of Mg-based interference screws for enhancing tendon graft-bone junction healing in patients indicated for ACLR. Statement of Significance How to promote tendon-bone junction healing is one of the major challenging issues for satisfactory clinical outcomes in patients after ACL reconstruction. The improvement of bony ingrowth into the tendon graft-bone interface can enhance the tendon graft osteointegration. In this study, we applied Mg based interference screws to fix the tendon graft in rabbits and found the use of Mg screws could accelerate and significantly increase mineralized matrix formation at the tendon-bone interface in animals when compared to those with Ti screws. We elucidated the mechanism behind the favorable effects of Mg screws on the graft healing in both in vitro and in vivo studies from multiscale technologies. The optimized interface structure and function in Mg group may be ascribed to the improved cell migration capability, enhanced cell adhesion strength and promoted osteogenic differentiation ability of BMSCs under the stimuli of Mg ions degraded from implanted Mg screws. Our findings may help us broaden our thinking in the application potential of Mg interference screws in future clinical trials.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • A Cyclo-trimer of Acetonitrile Combining Fluorescent Property with Ability
           to Induce Osteogenesis and Its Potential as Multifunctional Biomaterial
    • Abstract: Publication date: Available online 20 October 2017
      Source:Acta Biomaterialia
      Author(s): Xujie Liu, Yong Xie, Rui Liu, Ranran Zhang, Hao Yan, Xing Yang, Qianli Huang, Wei He, Bo Yu, Qingling Feng, Shengli Mi, Qiang Cai
      A biomaterial combining fluorescent property with ability to induce osteogenesis can serve as an ideal multifunctional scaffold in bone tissue engineering. However, the frequently used fluorescent agents can only serve as imaging probes. The polymer or oligomer with a conjugated system containing nitrogen atoms will fulfill these criteria. In this study, a cyclo-trimer of acetonitrile is synthesized using a facile method, which is proved to be 4-amino-2,6-dimethylpyrimidine. The cyclo-trimer of acetonitrile demonstrates strong intrinsic photoluminescence and has the potential for in vivo imaging. The cyclo-trimer of acetonitrile shows no toxicity both in vitro and in vivo. Moreover, the cyclo-trimer of acetonitrile significantly promotes the osteogenesis of SaOS-2 cells by improving alkaline phosphatase activity, collagen type I and osteocalcin expression, as well as expressions of osteoblastic genes, and enhances the matrix mineralization of rBMSCs. Thus, the cyclo-trimer of acetonitrile synthesized in present study illustrates the employment of this kind multifunctional biomaterial in bone tissue engineering and may offer great potential in biomedical applications where bioimaging and osteogenesis are both required. Statement of significance A conjugated cyclo-trimer of acetonitrile combining intrinsic fluorescent property with ability to induce osteogenesis was reported. Different from the traditional fluorescent dye or quantum dots, which are just “imaging agents”, the cyclo-trimer of acetonitrile can serve as a multifuctional biomaterial and offer great potential in biomedical applications where bioimaging and osteogenesis are both required. To our best knowledge, the fluorescent property, especially fluorescent property in vivo and the ability of this molecule to induce osteogenesis have not been reported before. Our work illustrates the employment of this kind multifunctional biomaterial in bone tissue engineering and will highlight the importance of multifunctional biomaterial in biomedical applications.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Injectable iodine-125 labeled tissue marker for radioactive localization
           of non-palpable breast lesions
    • Abstract: Publication date: Available online 19 October 2017
      Source:Acta Biomaterialia
      Author(s): Henrik Schaarup-Jensen, Andreas Ingemann Jensen, Anders Elias Hansen, Henrik H. El Ali, Peter Hammershøj, Rasmus Irming Jølck, Andreas Kjær, Thomas L. Andresen, Mads H. Clausen
      We have developed a 125I-radiolabeled injectable fiducial tissue marker with the potential to replace current methods used for surgical guidance of non-palpable breast tumors. Methods in routine clinical use today such as radioactive seed localization, radio-guided occult lesion localization and wire-guided localization suffers from limitations that this injectable fiducial tissue marker offers solutions to. The developed 125I-radiolabeled injectable fiducial tissue marker is based on highly viscous sucrose acetate isobutyrate. The marker was readily inserted in NMRI mice and proved to be spatially well-defined and stable over a seven day period with excellent CT contrast (>1500 HU), enabling fluoroscopic visualization of markers during placement. The radioactivity remains strongly associated with the marker during the implantation period, which limits exposure to healthy tissue. Biodistribution studies show that there is negligible radioactivity in all non-tumor tissues sampled, with the exception of the thyroid gland, where limited accumulation was observed (0.06% of injected dose after 7 days). Based on the excellent performance of the marker and the fact that it can be delivered through thin hypodermic needles (≥27G), the marker holds great promise for clinical application, since patient discomfort is reduced significantly compared to current methods. Statement of Significance A new type of tissue marker for local administration to non-palpable breast tumors has been developed. The surgical guidance marker is based on derivatives of the biomaterial sucrose acetate isobutyrate and unlike currently used markers it is injectable in the tissue using thin needles, reducing the discomfort to the patients significantly. The marker confers CT contrast and has radioactive properties, meaning it also could find use in brachytherapy. The design of the iodine-125 labeled fiducial tissue marker enables control of dosimetry as well as a choice of iodine isotope used. The marker is anticipated to be clinical applicable due to its contrast performance in mice and its potential for enhanced flexibility in surgical procedures, compared to current methods.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
  • Determining the Effects of PEI Adsorption on the Permeability of DPPC/BMP
           Membranes under Osmotic Stress
    • Abstract: Publication date: Available online 17 October 2017
      Source:Acta Biomaterialia
      Author(s): Scott R. Clark, Keel Yong Lee, Hoyoung Lee, Jawahar Khetan, Hyun Chang Kim, Yun Hwa Choi, Kwanwoo Shin, You-Yeon Won
      Polycations are used for a number of biological applications, including antibiotics and gene therapy. One aspect of the use of polycation gene carriers such as polyethylenemine (PEI) in gene therapy that is not well understood is their ability to escape from the vesicles they are internalized in. Here, in an attempt to gain a better understanding of PEI interaction with endosomal lipids under osmotic stress, we performed investigations using monolayers and vesicles derived from a mixture of neutral and negative lipids (1,2-dipalmitoylphosphatidylcholine (DPPC) and bis(monoacylglycero)phosphate (BMP), respectively). X-ray reflectivity (XR) and Langmuir trough measurements confirmed PEI adsorption to the negatively charged membrane. Confocal microscopy imaging indicated that PEI adsorption actually increases the overall integrity of the DPPC/BMP vesicle against osmotic stresses while also causing overall deformation and permeabilization of the lipid membrane, thus leading to leakage of contents from the interior of the vesicle. These confocal microscopy observations were also supported by data gathered by dynamic light scattering (DLS). Significance In recent decades, researchers have investigated polyamine-based gene delivery systems as useful alternatives to viral gene carriers. One step that is crucial to the performance of polyamine gene carriers such as polyethylenemine (PEI) is escape from late endosomal vesicles during intracellular delivery. However, the ability of polyamine/DNA polyplexes to effectively escape from endosomes is a little-understood part of the gene therapy techniques that use these polyplexes. Here, we performed investigations using monolayers and vesicles derived from a mixture of neutral and negative lipids (1,2-dipalmitoylphosphatidylcholine (DPPC) and bis(monoacylglycero)phosphate (BMP), respectively) as model systems for late endosomes in order to examine the interactions of PEI with the DPPC/BMP membranes and study the subsequent effects on the stability and permeability of these membranes.
      Graphical abstract image

      PubDate: 2017-10-21T15:02:15Z
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
Home (Search)
Subjects A-Z
Publishers A-Z
Your IP address:
About JournalTOCs
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016