Advertisement

Collagen-Based Scaffolds for Bone Tissue Engineering Applications

  • Madhura P. Nijsure
  • Vipuil Kishore
Chapter

Abstract

Over the past three decades, bone tissue engineering (BTE) has garnered significant interest as a potential alternative to autografts and allografts for the repair and regeneration of damaged or diseased bone. BTE entails the use of a viable scaffold, cells and chemical factors to stimulate the formation of functional bone tissue. While a plethora of different materials have been investigated to develop scaffolds for BTE applications, collagen type I is the most extensively studied because it is highly biocompatible, biodegradable, and presents a natural environment to the cells. In this chapter, we present a brief background on BTE and highlight the advantages and limitations of using collagen type I as a biomaterial for BTE applications. Further, we describe the most common scaffold fabrication methodologies that have been employed for the synthesis of collagen-based scaffolds for BTE applications. In vitro and in vivo findings from some of the key studies in the literature that use collagen-based scaffolds for bone repair and regeneration are highlighted. Additionally, advantages and limitations of FDA approved collagen-based scaffolds that are currently used in the clinic for bone applications are also discussed. Finally, some of the current challenges associated with the use of collagen-based scaffolds for BTE applications are identified and areas of future research that have the potential to address these challenges and aid in the development of biomimetic collagen-based scaffolds for the repair and regeneration of functional bone tissue are discussed.

Keywords

Bone Collagen Scaffolds Biomaterial Tissue engineering Hydrogels Freeze drying Electrospinning Electrochemical fabrication Composites Crosslinking Porosity Alignment In vitro In vivo 

References

  1. 1.
    Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3(Suppl 3):S131–9.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Rho J, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20:92–102.PubMedCrossRefGoogle Scholar
  3. 3.
    Downey PA, Siegel MI. Bone biology and the clinical implications for osteoporosis. Phys Ther. 2006;86:77.PubMedCrossRefGoogle Scholar
  4. 4.
    Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77:4–12.PubMedCrossRefGoogle Scholar
  5. 5.
    US Department of Health and Human Services. Bone health and osteoporosis: a report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Office of the Surgeon General; 2004. p. 87.Google Scholar
  6. 6.
    Desai BM. Osteobiologics. Am J Orthop (Belle Mead NJ). 2007;36:8–11.Google Scholar
  7. 7.
    Delgado LM, Bayon Y, Pandit A, Zeugolis DI. To cross-link or not to cross-link? Cross-linking associated foreign body response of collagen-based devices. Tissue Eng B Rev. 2015;21:298–313.CrossRefGoogle Scholar
  8. 8.
    Oryan A, Alidadi S, Moshiri A, Maffulli N. Bone regenerative medicine: classic options, novel strategies, and future directions. J Orthop Surg Res. 2014;9:18.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Burg KJ, Porter S, Kellam JF. Biomaterial developments for bone tissue engineering. Biomaterials. 2000;21:2347–59.PubMedCrossRefGoogle Scholar
  10. 10.
    Amini AR, Laurencin CT, Nukavarapu SP. Bone tissue engineering: recent advances and challenges. Crit Rev Biomed Eng. 2012;40:363–408.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    de Peppo GM, Marolt D. Modulating the biochemical and biophysical culture environment to enhance osteogenic differentiation and maturation of human pluripotent stem cell-derived mesenchymal progenitors. Stem Cell Res Ther. 2013;4:106.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126:677–89.PubMedCrossRefGoogle Scholar
  13. 13.
    Resende RR, Fonseca EA, Tonelli FM, Sousa BR, Santos AK, Gomes KN, Guatimosim S, Kihara AH, Ladeira LO. Scale/topography of substrates surface resembling extracellular matrix for tissue engineering. J Biomed Nanotechnol. 2014;10:1157–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Moore NM, Lin NJ, Gallant ND, Becker ML. Synergistic enhancement of human bone marrow stromal cell proliferation and osteogenic differentiation on BMP-2-derived and RGD peptide concentration gradients. Acta Biomater. 2011;7:2091–100.PubMedCrossRefGoogle Scholar
  15. 15.
    Park JS, Yang HN, Jeon SY, Woo DG, Na K, Park K. Osteogenic differentiation of human mesenchymal stem cells using RGD-modified BMP-2 coated microspheres. Biomaterials. 2010;31:6239–48.PubMedCrossRefGoogle Scholar
  16. 16.
    Hakkarainen M, Höglund A, Odelius K, Albertsson A. Tuning the release rate of acidic degradation products through macromolecular design of caprolactone-based copolymers. J Am Chem Soc. 2007;129:6308–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Ferreira AM, Gentile P, Chiono V, Ciardelli G. Collagen for bone tissue regeneration. Acta Biomater. 2012;8:3191–200.PubMedCrossRefGoogle Scholar
  18. 18.
    Cunniffe GM, O'Brien FJ. Collagen scaffolds for orthopedic regenerative medicine. JOM. 2011;63:66.CrossRefGoogle Scholar
  19. 19.
    Davidenko N, Bax DV, Schuster CF, Farndale RW, Hamaia SW, Best SM, Cameron RE. Optimisation of UV irradiation as a binding site conserving method for crosslinking collagen-based scaffolds. J Mater Sci Mater Med. 2016;27:14.PubMedCrossRefGoogle Scholar
  20. 20.
    Ahearne M, Yang Y, Then KY, Liu KK. Non-destructive mechanical characterisation of UVA/riboflavin crosslinked collagen hydrogels. Br J Ophthalmol. 2008;92:268–71.PubMedCrossRefGoogle Scholar
  21. 21.
    Ibusuki S, Halbesma GJ, Randolph MA, Redmond RW, Kochevar IE, Gill TJ. Photochemically cross-linked collagen gels as three-dimensional scaffolds for tissue engineering. Tissue Eng. 2007;13:1995–2001.PubMedCrossRefGoogle Scholar
  22. 22.
    Suri S, Schmidt CE. Photopatterned collagen–hyaluronic acid interpenetrating polymer network hydrogels. Acta Biomater. 2009;5:2385–97.PubMedCrossRefGoogle Scholar
  23. 23.
    Friess W. Collagen–biomaterial for drug delivery. Eur J Pharm Biopharm. 1998;45:113–36.PubMedCrossRefGoogle Scholar
  24. 24.
    Weadock KS, Miller EJ, Bellincampi LD, Zawadsky JP, Dunn MG. Physical crosslinking of collagen fibers: comparison of ultraviolet irradiation and dehydrothermal treatment. J Biomed Mater Res. 1995;29:1373–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Gorham S, Light N, Diamond A, Willins M, Bailey A, Wess T, Leslie N. Effect of chemical modifications on the susceptibility of collagen to proteolysis. II. Dehydrothermal crosslinking. Int J Biol Macromol. 1992;14:129–38.PubMedCrossRefGoogle Scholar
  26. 26.
    Drexler JW, Powell HM. Dehydrothermal crosslinking of electrospun collagen. Tissue Eng C Methods. 2010;17:9–17.CrossRefGoogle Scholar
  27. 27.
    Haugh MG, Jaasma MJ, O'Brien FJ. The effect of dehydrothermal treatment on the mechanical and structural properties of collagen‐GAG scaffolds. J Biomed Mater Res A. 2009;89:363–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Kawahara J, Ishikawa K, Uchimaru T, Takaya H. Chemical cross-linking by glutaraldehyde between amino groups: its mechanism and effects. In: Anonymous polymer modification. New York: Springer; 1997. p. 119–31.Google Scholar
  29. 29.
    Jorge-Herrero E, Fernandez P, Turnay J, Olmo N, Calero P, Garcı́a R, Freile I, Castillo-Olivares J. Influence of different chemical cross-linking treatments on the properties of bovine pericardium and collagen. Biomaterials. 1999;20:539–45.PubMedCrossRefGoogle Scholar
  30. 30.
    Scotchford C, Cascone M, Downes S, Giusti P. Osteoblast responses to collagen-PVA bioartificial polymers in vitro: the effects of cross-linking method and collagen content. Biomaterials. 1998;19:1–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Sung HW, Huang RN, Huang LL, Tsai CC, Chiu CT. Feasibility study of a natural crosslinking reagent for biological tissue fixation. J Biomed Mater Res. 1998;42:560–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Sung H, Huang R, Huang LL, Tsai C. In vitro evaluation of cytotoxicity of a naturally occurring cross-linking reagent for biological tissue fixation. J Biomater Sci Polym Ed. 1999;10:63–78.PubMedCrossRefGoogle Scholar
  33. 33.
    Fessel G, Cadby J, Wunderli S, van Weeren R, Snedeker JG. Dose-and time-dependent effects of genipin crosslinking on cell viability and tissue mechanics—toward clinical application for tendon repair. Acta Biomater. 2014;10:1897–906.PubMedCrossRefGoogle Scholar
  34. 34.
    Kishore V, Bullock W, Sun X, Van Dyke WS, Akkus O. Tenogenic differentiation of human MSCs induced by the topography of electrochemically aligned collagen threads. Biomaterials. 2012;33:2137–44.PubMedCrossRefGoogle Scholar
  35. 35.
    Yan L, Wang Y, Ren L, Wu G, Caridade SG, Fan J, Wang L, Ji P, Oliveira JM, Oliveira JT. Genipin‐cross‐linked collagen/chitosan biomimetic scaffolds for articular cartilage tissue engineering applications. J Biomed Mater Res A. 2010;95:465–75.PubMedCrossRefGoogle Scholar
  36. 36.
    Olde Damink LH, Dijkstra PJ, van Luyn MJ, van Wachem PB, Nieuwenhuis P, Feijen J. Cross-linking of dermal sheep collagen using a water-soluble carbodiimide. Biomaterials. 1996;17:765–73.PubMedCrossRefGoogle Scholar
  37. 37.
    Zeugolis DI, Paul GR, Attenburrow G. Cross‐linking of extruded collagen fibers—a biomimetic three‐dimensional scaffold for tissue engineering applications. J Biomed Mater Res A. 2009;89:895–908.PubMedCrossRefGoogle Scholar
  38. 38.
    Cass CA, Burg KJ. Tannic acid cross-linked collagen scaffolds and their anti-cancer potential in a tissue engineered breast implant. J Biomater Sci Polym Ed. 2012;23:281–98.PubMedCrossRefGoogle Scholar
  39. 39.
    Booth BW, Inskeep BD, Shah H, Park JP, Hay EJ, Burg KJ. Tannic acid preferentially targets estrogen receptor-positive breast cancer. Int J Breast Cancer. 2013;2013:369609.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    You BR, Kim SZ, Kim SH, Park WH. Gallic acid-induced lung cancer cell death is accompanied by ROS increase and glutathione depletion. Mol Cell Biochem. 2011;357:295–303.PubMedCrossRefGoogle Scholar
  41. 41.
    Krishnamoorthy G, Selvakumar R, Sastry TP, Sadulla S, Mandal AB, Doble M. Experimental and theoretical studies on Gallic acid assisted EDC/NHS initiated crosslinked collagen scaffolds. Mater Sci Eng C. 2014;43:164–71.CrossRefGoogle Scholar
  42. 42.
    Grover CN, Gwynne JH, Pugh N, Hamaia S, Farndale RW, Best SM, Cameron RE. Crosslinking and composition influence the surface properties, mechanical stiffness and cell reactivity of collagen-based films. Acta Biomater. 2012;8:3080–90.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Alfredo Uquillas J, Kishore V, Akkus O. Genipin crosslinking elevates the strength of electrochemically aligned collagen to the level of tendons. J Mech Behav Biomed Mater. 2012;15:176–89.PubMedCrossRefGoogle Scholar
  44. 44.
    Badylak SF. The extracellular matrix as a scaffold for tissue reconstruction. Semin Cell Dev Biol. 2002;13:377–83.PubMedCrossRefGoogle Scholar
  45. 45.
    Rezwan K, Chen Q, Blaker J, Boccaccini AR. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials. 2006;27:3413–31.PubMedCrossRefGoogle Scholar
  46. 46.
    Gleeson JP, Plunkett NA, O'Brien FJ. Addition of hydroxyapatite improves stiffness, interconnectivity and osteogenic potential of a highly porous collagen-based scaffold for bone tissue regeneration. Eur Cell Mater. 2010;20:218–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Roeder RK, Converse GL, Kane RJ, Yue W. Hydroxyapatite-reinforced polymer biocomposites for synthetic bone substitutes. JOM J Miner Met Mater Soc. 2008;60:38–45.CrossRefGoogle Scholar
  48. 48.
    Hench LL. The story of Bioglass®. J Mater Sci Mater Med. 2006;17:967–78.PubMedCrossRefGoogle Scholar
  49. 49.
    Xynos ID, Edgar AJ, Buttery LD, Hench LL, Polak JM. Ionic products of bioactive glass dissolution increase proliferation of human osteoblasts and induce insulin-like growth factor II mRNA expression and protein synthesis. Biochem Biophys Res Commun. 2000;276:461–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Carlisle EM. Silicon: a requirement in bone formation independent of vitamin D 1. Calcif Tissue Int. 1981;33:27–34.PubMedCrossRefGoogle Scholar
  51. 51.
    Xynos I, Hukkanen M, Batten J, Buttery L, Hench L, Polak J. Bioglass® 45S5 stimulates osteoblast turnover and enhances bone formation in vitro: implications and applications for bone tissue engineering. Calcif Tissue Int. 2000;67:321–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Oonishi H, Kushitani S, Yasukawa E, Iwaki H, Hench LL, Wilson J, Tsuji E, Sugihara T. Particulate bioglass compared with hydroxyapatite as a bone graft substitute. Clin Orthop Relat Res. 1997;334:316–25.CrossRefGoogle Scholar
  53. 53.
    Sarker B, Hum J, Nazhat SN, Boccaccini AR. Combining collagen and bioactive glasses for bone tissue engineering: a review. Adv Healthc Mater. 2015;4:176–94.PubMedCrossRefGoogle Scholar
  54. 54.
    Bruno E, Luikart SD, Long MW, Hoffman R. Marrow-derived heparan sulfate proteoglycan mediates the adhesion of hematopoietic progenitor cells to cytokines. Exp Hematol. 1995;23:1212–7.PubMedGoogle Scholar
  55. 55.
    Gupta P, McCarthy JB, Verfaillie CM. Stromal fibroblast heparan sulfate is required for cytokine-mediated ex vivo maintenance of human long-term culture-initiating cells. Blood. 1996;87:3229–36.PubMedGoogle Scholar
  56. 56.
    Netelenbos T, van den Born J, Kessler FL, Zweegman S, Huijgens PC, Drager AM. In vitro model for hematopoietic progenitor cell homing reveals endothelial heparan sulfate proteoglycans as direct adhesive ligands. J Leukoc Biol. 2003;74:1035–44.PubMedCrossRefGoogle Scholar
  57. 57.
    Mathews S, Mathew SA, Gupta PK, Bhonde R, Totey S. Glycosaminoglycans enhance osteoblast differentiation of bone marrow derived human mesenchymal stem cells. J Tissue Eng Regen Med. 2014;8:143–52.PubMedCrossRefGoogle Scholar
  58. 58.
    Tierney CM, Haugh MG, Liedl J, Mulcahy F, Hayes B, O’Brien FJ. The effects of collagen concentration and crosslink density on the biological, structural and mechanical properties of collagen-GAG scaffolds for bone tissue engineering. J Mech Behav Biomed Mater. 2009;2:202–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Tierney CM, Jaasma MJ, O'Brien FJ. Osteoblast activity on collagen‐GAG scaffolds is affected by collagen and GAG concentrations. J Biomed Mater Res A. 2009;91:92–101.PubMedCrossRefGoogle Scholar
  60. 60.
    Pieper J, Hafmans T, Veerkamp J, Van Kuppevelt T. Development of tailor-made collagen–glycosaminoglycan matrices: EDC/NHS crosslinking, and ultrastructural aspects. Biomaterials. 2000;21:581–93.PubMedCrossRefGoogle Scholar
  61. 61.
    Mathews S, Bhonde R, Gupta PK, Totey S. Novel biomimetic tripolymer scaffolds consisting of chitosan, collagen type 1, and hyaluronic acid for bone marrow‐derived human mesenchymal stem cells‐based bone tissue engineering. J Biomed Mater Res B Appl Biomater. 2014;102:1825–34.PubMedCrossRefGoogle Scholar
  62. 62.
    Di Martino A, Sittinger M, Risbud MV. Chitosan: a versatile biopolymer for orthopaedic tissue-engineering. Biomaterials. 2005;26:5983–90.PubMedCrossRefGoogle Scholar
  63. 63.
    Wang L, Stegemann JP. Thermogelling chitosan and collagen composite hydrogels initiated with β-glycerophosphate for bone tissue engineering. Biomaterials. 2010;31:3976–85.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Huang Z, Tian J, Yu B, Xu Y, Feng Q. A bone-like nano-hydroxyapatite/collagen loaded injectable scaffold. Biomed Mater. 2009;4:055005.PubMedCrossRefGoogle Scholar
  65. 65.
    Chicatun F, Pedraza CE, Ghezzi CE, Marelli B, Kaartinen MT, McKee MD, Nazhat SN. Osteoid-mimicking dense collagen/chitosan hybrid gels. Biomacromolecules. 2011;12:2946–56.PubMedCrossRefGoogle Scholar
  66. 66.
    Melke J, Midha S, Ghosh S, Ito K, Hofmann S. Silk fibroin as biomaterial for bone tissue engineering. Acta Biomater. 2016;31:1–16.PubMedCrossRefGoogle Scholar
  67. 67.
    Meinel L, Fajardo R, Hofmann S, Langer R, Chen J, Snyder B, Vunjak-Novakovic G, Kaplan D. Silk implants for the healing of critical size bone defects. Bone. 2005;37:688–98.PubMedCrossRefGoogle Scholar
  68. 68.
    Chen L, Hu J, Ran J, Shen X, Tong H. Preparation and evaluation of collagen-silk fibroin/hydroxyapatite nanocomposites for bone tissue engineering. Int J Biol Macromol. 2014;65:1–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Vozzi G, Corallo C, Carta S, Fortina M, Gattazzo F, Galletti M, Giordano N. Collagen‐gelatin‐genipin‐hydroxyapatite composite scaffolds colonized by human primary osteoblasts are suitable for bone tissue engineering applications: In vitro evidences. J Biomed Mater Res A. 2014;102:1415–21.PubMedCrossRefGoogle Scholar
  70. 70.
    Perez RA, Kim M, Kim T, Kim J, Lee JH, Park J, Knowles JC, Kim H. Utilizing core–shell fibrous collagen-alginate hydrogel cell delivery system for bone tissue engineering. Tissue Eng A. 2013;20:103–14.CrossRefGoogle Scholar
  71. 71.
    Liao S, Wang W, Uo M, Ohkawa S, Akasaka T, Tamura K, Cui F, Watari F. A three-layered nano-carbonated hydroxyapatite/collagen/PLGA composite membrane for guided tissue regeneration. Biomaterials. 2005;26:7564–71.PubMedCrossRefGoogle Scholar
  72. 72.
    Hesse E, Hefferan TE, Tarara JE, Haasper C, Meller R, Krettek C, Lu L, Yaszemski MJ. Collagen type I hydrogel allows migration, proliferation, and osteogenic differentiation of rat bone marrow stromal cells. J Biomed Mater Res A. 2010;94:442–9.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Hayrapetyan A, Bongio M, Leeuwenburgh SC, Jansen JA, Beucken JJ. Effect of nano-HA/collagen composite hydrogels on osteogenic behavior of mesenchymal stromal cells. Stem Cell Rev Rep. 2016;12:352–64.CrossRefGoogle Scholar
  74. 74.
    Wang L, Stegemann JP. Glyoxal crosslinking of cell-seeded chitosan/collagen hydrogels for bone regeneration. Acta Biomater. 2011;7:2410–7.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Brown RA, Wiseman M, Chuo CB, Cheema U, Nazhat SN. Ultrarapid engineering of biomimetic materials and tissues: Fabrication of nano- and microstructures by plastic compression. Adv Funct Mater. 2005;15:1762–70.CrossRefGoogle Scholar
  76. 76.
    Cheema U, Brown RA. Rapid fabrication of living tissue models by collagen plastic compression: understanding three-dimensional cell matrix repair in vitro. Adv Wound Care. 2013;2:176–84.CrossRefGoogle Scholar
  77. 77.
    Bitar M, Salih V, Brown RA, Nazhat SN. Effect of multiple unconfined compression on cellular dense collagen scaffolds for bone tissue engineering. J Mater Sci Mater Med. 2007;18:237–44.PubMedCrossRefGoogle Scholar
  78. 78.
    Bitar M, Brown RA, Salih V, Kidane AG, Knowles JC, Nazhat SN. Effect of cell density on osteoblastic differentiation and matrix degradation of biomimetic dense collagen scaffolds. Biomacromolecules. 2008;9:129–35.PubMedCrossRefGoogle Scholar
  79. 79.
    Buxton PG, Bitar M, Gellynck K, Parkar M, Brown RA, Young AM, Knowles JC, Nazhat SN. Dense collagen matrix accelerates osteogenic differentiation and rescues the apoptotic response to MMP inhibition. Bone. 2008;43:377–85.PubMedCrossRefGoogle Scholar
  80. 80.
    Pedraza CE, Marelli B, Chicatun F, McKee MD, Nazhat SN. An in vitro assessment of a cell-containing collagenous extracellular matrix–like scaffold for bone tissue engineering. Tissue Eng A. 2009;16:781–93.CrossRefGoogle Scholar
  81. 81.
    Marelli B, Ghezzi CE, Barralet JE, Boccaccini AR, Nazhat SN. Three-dimensional mineralization of dense nanofibrillar collagen-bioglass hybrid scaffolds. Biomacromolecules. 2010;11:1470–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Marelli B, Ghezzi CE, Mohn D, Stark WJ, Barralet JE, Boccaccini AR, Nazhat SN. Accelerated mineralization of dense collagen-nano bioactive glass hybrid gels increases scaffold stiffness and regulates osteoblastic function. Biomaterials. 2011;32:8915–26.PubMedCrossRefGoogle Scholar
  83. 83.
    Liu G, Pastakia M, Fenn MB, Kishore V. Saos‐2 cell‐mediated mineralization on collagen gels: Effect of densification and bioglass incorporation. J Biomed Mater Res A. 2016;104(5):1121–34.PubMedCrossRefGoogle Scholar
  84. 84.
    Ghezzi CE, Marelli B, Donelli I, Alessandrino A, Freddi G, Nazhat SN. The role of physiological mechanical cues on mesenchymal stem cell differentiation in an airway tract-like dense collagen–silk fibroin construct. Biomaterials. 2014;35:6236–47.PubMedCrossRefGoogle Scholar
  85. 85.
    Ghezzi CE, Marelli B, Muja N, Hirota N, Martin JG, Barralet JE, Alessandrino A, Freddi G, Nazhat SN. Mesenchymal stem cell‐seeded multilayered dense collagen‐silk fibroin hybrid for tissue engineering applications. Biotechnol J. 2011;6:1198–207.PubMedCrossRefGoogle Scholar
  86. 86.
    Stoppato M, Carletti E, Sidarovich V, Quattrone A, Unger RE, Kirkpatrick CJ, Migliaresi C, Motta A. Influence of scaffold pore size on collagen I development: a new in vitro evaluation perspective. J Bioact Compat Polym. 2013;28:16–32.CrossRefGoogle Scholar
  87. 87.
    Cao H, Kuboyama N. A biodegradable porous composite scaffold of PGA/β-TCP for bone tissue engineering. Bone. 2010;46:386–95.PubMedCrossRefGoogle Scholar
  88. 88.
    Hsu F, Lu M, Weng R, Lin H. Hierarchically biomimetic scaffold of a collagen–mesoporous bioactive glass nanofiber composite for bone tissue engineering. Biomed Mater. 2015;10:025007.PubMedCrossRefGoogle Scholar
  89. 89.
    Doillon C, Whyne C, Brandwein S, Silver F. Collagen‐based wound dressings: control of the pore structure and morphology. J Biomed Mater Res A. 1986;20:1219–28.CrossRefGoogle Scholar
  90. 90.
    Schoof H, Apel J, Heschel I, Rau G. Control of pore structure and size in freeze‐dried collagen sponges. J Biomed Mater Res. 2001;58:352–7.PubMedCrossRefGoogle Scholar
  91. 91.
    O’Brien FJ, Harley BA, Yannas IV, Gibson L. Influence of freezing rate on pore structure in freeze-dried collagen-GAG scaffolds. Biomaterials. 2004;25:1077–86.PubMedCrossRefGoogle Scholar
  92. 92.
    O’Brien FJ, Harley B, Yannas IV, Gibson LJ. The effect of pore size on cell adhesion in collagen-GAG scaffolds. Biomaterials. 2005;26:433–41.PubMedCrossRefGoogle Scholar
  93. 93.
    Haugh MG, Murphy CM, O'Brien FJ. Novel freeze-drying methods to produce a range of collagen–glycosaminoglycan scaffolds with tailored mean pore sizes. Tissue Eng Part C Methods. 2009;16:887–94.CrossRefGoogle Scholar
  94. 94.
    Murphy CM, Haugh MG, O'Brien FJ. The effect of mean pore size on cell attachment, proliferation and migration in collagen–glycosaminoglycan scaffolds for bone tissue engineering. Biomaterials. 2010;31:461–6.PubMedCrossRefGoogle Scholar
  95. 95.
    Karageorgiou V, Kaplan D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials. 2005;26:5474–91.PubMedCrossRefGoogle Scholar
  96. 96.
    Tomihata K, Burczak K, Shiraki K, Ikada Y. Cross-linking and biodegradation of native and denatured collagen. Washington, DC: ACS Publications; 1994.Google Scholar
  97. 97.
    Kane RJ, Roeder RK. Effects of hydroxyapatite reinforcement on the architecture and mechanical properties of freeze-dried collagen scaffolds. J Mech Behav Biomed Mater. 2012;7:41–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Cunniffe GM, Dickson GR, Partap S, Stanton KT, O’Brien FJ. Development and characterisation of a collagen nano-hydroxyapatite composite scaffold for bone tissue engineering. J Mater Sci Mater Med. 2010;21:2293–8.PubMedCrossRefGoogle Scholar
  99. 99.
    Ryan AJ, Gleeson JP, Matsiko A, Thompson EM, O’brien FJ. Effect of different hydroxyapatite incorporation methods on the structural and biological properties of porous collagen scaffolds for bone repair. J Anat. 2015;227:732–45.PubMedCrossRefGoogle Scholar
  100. 100.
    Al‐Munajjed AA, Plunkett NA, Gleeson JP, Weber T, Jungreuthmayer C, Levingstone T, Hammer J, O'Brien FJ. Development of a biomimetic collagen‐hydroxyapatite scaffold for bone tissue engineering using a SBF immersion technique. J Biomed Mater Res B Appl Biomater. 2009;90:584–91.PubMedCrossRefGoogle Scholar
  101. 101.
    Akkouch A, Zhang Z, Rouabhia M. A novel collagen/hydroxyapatite/poly (lactide‐co‐ε‐caprolactone) biodegradable and bioactive 3D porous scaffold for bone regeneration. J Biomed Mater Res A. 2011;96:693–704.PubMedCrossRefGoogle Scholar
  102. 102.
    Cholas R, Padmanabhan SK, Gervaso F, Udayan G, Monaco G, Sannino A, Licciulli A. Scaffolds for bone regeneration made of hydroxyapatite microspheres in a collagen matrix. Mater Sci Eng C. 2016;63:499–505.CrossRefGoogle Scholar
  103. 103.
    Al-Munajjed AA, O’Brien FJ. Influence of a novel calcium-phosphate coating on the mechanical properties of highly porous collagen scaffolds for bone repair. J Mech Behav Biomed Mater. 2009;2:138–46.PubMedCrossRefGoogle Scholar
  104. 104.
    Sarikaya B, Aydin HM. Collagen/beta-tricalcium phosphate based synthetic bone grafts via dehydrothermal processing. Biomed Res Int. 2015;2015:576532.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Arahira T, Todo M. Effects of proliferation and differentiation of mesenchymal stem cells on compressive mechanical behavior of collagen/β-TCP composite scaffold. J Mech Behav Biomed Mater. 2014;39:218–30.PubMedCrossRefGoogle Scholar
  106. 106.
    Arahira T, Todo M. Variation of mechanical behavior of β-TCP/collagen two phase composite scaffold with mesenchymal stem cell in vitro. J Mech Behav Biomed Mater. 2016;61:464–74.PubMedCrossRefGoogle Scholar
  107. 107.
    Kim H, Song J, Kim H. Bioactive glass nanofiber–collagen nanocomposite as a novel bone regeneration matrix. J Biomed Mater Res A. 2006;79:698–705.PubMedCrossRefGoogle Scholar
  108. 108.
    Xu C, Su P, Chen X, Meng Y, Yu W, Xiang AP, Wang Y. Biocompatibility and osteogenesis of biomimetic bioglass-collagen-phosphatidylserine composite scaffolds for bone tissue engineering. Biomaterials. 2011;32:1051–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Mooyen S, Charoenphandhu N, Teerapornpuntakit J, Thongbunchoo J, Suntornsaratoon P, Krishnamra N, Tang I, Pon‐On W. Physico‐chemical and in vitro cellular properties of different calcium phosphate‐bioactive glass composite chitosan‐collagen (CaP@ ChiCol) for bone scaffolds. J Biomed Mater Res B Appl Biomater. 2016;105(7):1758–66.PubMedCrossRefGoogle Scholar
  110. 110.
    Kane RJ, Weiss-Bilka HE, Meagher MJ, Liu Y, Gargac JA, Niebur GL, Wagner DR, Roeder RK. Hydroxyapatite reinforced collagen scaffolds with improved architecture and mechanical properties. Acta Biomater. 2015;17:16–25.PubMedCrossRefGoogle Scholar
  111. 111.
    Meagher MJ, Weiss‐Bilka HE, Best ME, Boerckel JD, Wagner DR, Roeder RK. Acellular hydroxyapatite‐collagen scaffolds support angiogenesis and osteogenic gene expression in an ectopic murine model: effects of hydroxyapatite volume fraction. J Biomed Mater Res A. 2016;104:2178–88.PubMedCrossRefGoogle Scholar
  112. 112.
    Li W, Laurencin CT, Caterson EJ, Tuan RS, Ko FK. Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J Biomed Mater Res. 2002;60:613–21.PubMedCrossRefGoogle Scholar
  113. 113.
    Taylor G. Electrically driven jets. Proc R Soc Lond A. 1969;313:453–75.CrossRefGoogle Scholar
  114. 114.
    Bhardwaj N, Kundu SC. Electrospinning: a fascinating fiber fabrication technique. Biotechnol Adv. 2010;28:325–47.PubMedCrossRefGoogle Scholar
  115. 115.
    Zhong S, Teo WE, Zhu X, Beuerman RW, Ramakrishna S, Yung LYL. An aligned nanofibrous collagen scaffold by electrospinning and its effects on in vitro fibroblast culture. J Biomed Mater Res A. 2006;79:456–63.PubMedCrossRefGoogle Scholar
  116. 116.
    Subramanian A, Krishnan UM, Sethuraman S. Fabrication of uniaxially aligned 3D electrospun scaffolds for neural regeneration. Biomed Mater. 2011;6:025004.PubMedCrossRefGoogle Scholar
  117. 117.
    Matthews JA, Wnek GE, Simpson DG, Bowlin GL. Electrospinning of collagen nanofibers. Biomacromolecules. 2002;3:232–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Shih YV, Chen C, Tsai S, Wang YJ, Lee OK. Growth of mesenchymal stem cells on electrospun type I collagen nanofibers. Stem Cells. 2006;24:2391–7.PubMedCrossRefGoogle Scholar
  119. 119.
    Zeugolis DI, Khew ST, Yew ES, Ekaputra AK, Tong YW, Yung LL, Hutmacher DW, Sheppard C, Raghunath M. Electro-spinning of pure collagen nano-fibres–just an expensive way to make gelatin? Biomaterials. 2008;29:2293–305.PubMedCrossRefGoogle Scholar
  120. 120.
    Yang L, Fitie CF, van der Werf, Kees O, Bennink ML, Dijkstra PJ, Feijen J. Mechanical properties of single electrospun collagen type I fibers. Biomaterials. 2008;29:955–62.PubMedCrossRefGoogle Scholar
  121. 121.
    Zhou Y, Yao H, Wang J, Wang D, Liu Q, Li Z. Greener synthesis of electrospun collagen/hydroxyapatite composite fibers with an excellent microstructure for bone tissue engineering. Int J Nanomedicine. 2015;10:3203–15.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Qiao X, Russell SJ, Yang X, Tronci G, Wood DJ. Compositional and in vitro evaluation of nonwoven type I collagen/poly-dl-lactic acid scaffolds for bone regeneration. J Funct Biomater. 2015;6:667–86.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Shojaee, M, Bashur, CA. Compositions including synthetic and natural blends for integration and structural integrity: engineered for different vascular graft applications. Adv Healthc Mater 2017;6(12). https://doi.org/10.1002/adhm.201700001.Google Scholar
  124. 124.
    Ngiam M, Liao S, Patil AJ, Cheng Z, Yang F, Gubler MJ, Ramakrishna S, Chan CK. Fabrication of mineralized polymeric nanofibrous composites for bone graft materials. Tissue Eng A. 2008;15:535–46.CrossRefGoogle Scholar
  125. 125.
    Raghavendran HRB, Puvaneswary S, Talebian S, Murali MR, Naveen SV, Krishnamurithy G, McKean R, Kamarul T. A comparative study on in vitro osteogenic priming potential of electron spun scaffold PLLA/HA/Col, PLLA/HA, and PLLA/Col for tissue engineering application. PLoS One. 2014;9:e104389.CrossRefGoogle Scholar
  126. 126.
    Ekaputra AK, Zhou Y, Cool SM, Hutmacher DW. Composite electrospun scaffolds for engineering tubular bone grafts. Tissue Eng A. 2009;15:3779–88.CrossRefGoogle Scholar
  127. 127.
    Wei K, Li Y, Mugishima H, Teramoto A, Abe K. Fabrication of core‐sheath structured fibers for model drug release and tissue engineering by emulsion electrospinning. Biotechnol J. 2012;7:677–85.PubMedCrossRefGoogle Scholar
  128. 128.
    Su Y, Su Q, Liu W, Lim M, Venugopal JR, Mo X, Ramakrishna S, Al-Deyab SS, El-Newehy M. Controlled release of bone morphogenetic protein 2 and dexamethasone loaded in core–shell PLLACL–collagen fibers for use in bone tissue engineering. Acta Biomater. 2012;8:763–71.PubMedCrossRefGoogle Scholar
  129. 129.
    Wang J, Cui X, Zhou Y, Xiang Q. Core-shell PLGA/collagen nanofibers loaded with recombinant FN/CDHs as bone tissue engineering scaffolds. Connect Tissue Res. 2014;55:292–8.PubMedCrossRefGoogle Scholar
  130. 130.
    Venugopal J, Low S, Choon AT, Sampath Kumar TS, Ramakrishna S. Mineralization of osteoblasts with electrospun collagen/hydroxyapatite nanofibers. J Mater Sci Mater Med. 2008;19:2039–46.PubMedCrossRefGoogle Scholar
  131. 131.
    Song J, Kim H, Kim H. Electrospun fibrous web of collagen–apatite precipitated nanocomposite for bone regeneration. J Mater Sci Mater Med. 2008;19:2925–32.PubMedCrossRefGoogle Scholar
  132. 132.
    Ribeiro N, Sousa SR, Van Blitterswijk CA, Moroni L, Monteiro FJ. A biocomposite of collagen nanofibers and nanohydroxyapatite for bone regeneration. Biofabrication. 2014;6:035015.PubMedCrossRefGoogle Scholar
  133. 133.
    Phipps MC, Clem WC, Grunda JM, Clines GA, Bellis SL. Increasing the pore sizes of bone-mimetic electrospun scaffolds comprised of polycaprolactone, collagen I and hydroxyapatite to enhance cell infiltration. Biomaterials. 2012;33:524–34.PubMedCrossRefGoogle Scholar
  134. 134.
    Yeo MG, Kim GH. Preparation and characterization of 3D composite scaffolds based on rapid-prototyped PCL/β-TCP struts and electrospun PCL coated with collagen and HA for bone regeneration. Chem Mater. 2011;24:903–13.CrossRefGoogle Scholar
  135. 135.
    Hild N, Schneider OD, Mohn D, Luechinger NA, Koehler FM, Hofmann S, Vetsch JR, Thimm BW, Müller R, Stark WJ. Two-layer membranes of calcium phosphate/collagen/PLGA nanofibres: in vitro biomineralisation and osteogenic differentiation of human mesenchymal stem cells. Nanoscale. 2011;3:401–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Sharifi E, Ebrahimi‐Barough S, Panahi M, Azami M, Ai A, Barabadi Z, Kajbafzadeh A, Ai J. In vitro evaluation of human endometrial stem cell‐derived osteoblast‐like cells’ behavior on gelatin/collagen/bioglass nanofibers’ scaffolds. J Biomed Mater Res A. 2016;104:2210–9.PubMedCrossRefGoogle Scholar
  137. 137.
    Zhang S, Zhang X, Cai Q, Wang B, Deng X, Yang X. Microfibrous β-TCP/collagen scaffolds mimic woven bone in structure and composition. Biomed Mater. 2010;5:065005.PubMedCrossRefGoogle Scholar
  138. 138.
    Cheng X, Gurkan UA, Dehen CJ, Tate MP, Hillhouse HW, Simpson GJ, Akkus O. An electrochemical fabrication process for the assembly of anisotropically oriented collagen bundles. Biomaterials. 2008;29:3278–88.PubMedCrossRefGoogle Scholar
  139. 139.
    Uquillas JA, Akkus O. Modeling the electromobility of type-I collagen molecules in the electrochemical fabrication of dense and aligned tissue constructs. Ann Biomed Eng. 2012;40:1641–53.PubMedCrossRefGoogle Scholar
  140. 140.
    Younesi M, Islam A, Kishore V, Anderson JM, Akkus O. Tenogenic induction of human MSCs by anisotropically aligned collagen biotextiles. Adv Funct Mater. 2014;24:5762–70.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Younesi M, Goldberg VM, Akkus O. A micro-architecturally biomimetic collagen template for mesenchymal condensation based cartilage regeneration. Acta Biomater. 2016;30:212–21.PubMedCrossRefGoogle Scholar
  142. 142.
    Kishore V, Iyer R, Frandsen A, Nguyen T. In vitro characterization of electrochemically compacted collagen matrices for corneal applications. Biomed Mater. 2016;11:055008.PubMedCrossRefGoogle Scholar
  143. 143.
    Abu-Rub MT, Billiar K, van Es MH, Knoght A, Rodriguez BJ, Zeugolis DI, McMahon S, Windebank AJ, Pandit A. Nano-textured self-assembled aligned collagen hydrogels promote directional neurite guidance and overcome inhibition by myelin associated glycoprotein. Soft Matter. 2011;7:2770–81.CrossRefGoogle Scholar
  144. 144.
    Nguyen TU, Bashur CA, Kishore V. Impact of elastin incorporation into electrochemically aligned collagen fibers on mechanical properties and smooth muscle cell phenotype. Biomed Mater. 2016;11:025008.PubMedCrossRefGoogle Scholar
  145. 145.
    Younesi M, Islam A, Kishore V, Panit S, Akkus O. Fabrication of compositionally and topographically complex robust tissue forms by 3D-electrochemical compaction of collagen. Biofabrication. 2015;7:035001.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Kishore V, Paderi JE, Akkus A, Smith KM, Balachandran D, Beaudoin S, Panitch A, Akkus O. Incorporation of a decorin biomimetic enhances the mechanical properties of electrochemically aligned collagen threads. Acta Biomater. 2011;7:2428–36.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Nijsure MP, Pastakia M, Spano J, Fenn MB, Kishore V. Bioglass incorporation improves mechanical properties and enhances cell‐mediated mineralization on electrochemically aligned collagen threads. J Biomed Mater Res A. 2017;105(9):2429–40.PubMedCrossRefGoogle Scholar
  148. 148.
    Kokubo T, Takadama H. How useful is SBF in predicting in vivo bone bioactivity? Biomaterials. 2006;27:2907–15.PubMedCrossRefGoogle Scholar
  149. 149.
    Mizuno M, Shindo M, Kobayashi D, Tsuruga E, Amemiya A, Kuboki Y. Osteogenesis by bone marrow stromal cells maintained on type I collagen matrix gels in vivo. Bone. 1997;20:101–7.PubMedCrossRefGoogle Scholar
  150. 150.
    Kokubo S, Fujimoto R, Yokota S, Fukushima S, Nozaki K, Takahashi K, Miyata K. Bone regeneration by recombinant human bone morphogenetic protein-2 and a novel biodegradable carrier in a rabbit ulnar defect model. Biomaterials. 2003;24:1643–51.PubMedCrossRefGoogle Scholar
  151. 151.
    Visser R, Arrabal PM, Becerra J, Rinas U, Cifuentes M. The effect of an rhBMP-2 absorbable collagen sponge-targeted system on bone formation in vivo. Biomaterials. 2009;30:2032–7.PubMedCrossRefGoogle Scholar
  152. 152.
    Geiger M, Li R, Friess W. Collagen sponges for bone regeneration with rhBMP-2. Adv Drug Deliv Rev. 2003;55:1613–29.PubMedCrossRefGoogle Scholar
  153. 153.
    Epstein N. Pros, cons, and costs of INFUSE in spinal surgery. Surg Neurol Int. 2011;2:10.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Arrabal PM, Visser R, Santos-Ruiz L, Becerra J, Cifuentes M. Osteogenic molecules for clinical applications: improving the BMP-collagen system. Biol Res. 2013;46:421–9.PubMedCrossRefGoogle Scholar
  155. 155.
    Hou J, Wang J, Cao L, Qian X, Xing W, Lu J, Liu C. Segmental bone regeneration using rhBMP-2-loaded collagen/chitosan microspheres composite scaffold in a rabbit model. Biomed Mater. 2012;7:035002.PubMedCrossRefGoogle Scholar
  156. 156.
    Quinlan E, Thompson EM, Matsiko A, O’brien FJ, López-Noriega A. Long-term controlled delivery of rhBMP-2 from collagen–hydroxyapatite scaffolds for superior bone tissue regeneration. J Control Release. 2015;207:112–9.PubMedCrossRefGoogle Scholar
  157. 157.
    Calabrese G, Giuffrida R, Forte S, Salvatorelli L, Fabbi C, Figallo E, Gulisano M, Parenti R, Magro G, Colarossi C, Memeo L, Gulino R. Bone augmentation after ectopic implantation of a cell-free collagen-hydroxyapatite scaffold in the mouse. Sci Rep. 2016;6:36399.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Ren X, Tu V, Bischoff D, Weisgerber DW, Lewis MS, Yamaguchi DT, Miller TA, Harley BA, Lee JC. Nanoparticulate mineralized collagen scaffolds induce in vivo bone regeneration independent of progenitor cell loading or exogenous growth factor stimulation. Biomaterials. 2016;89:67–78.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Lyons FG, Al-Munajjed AA, Kieran SM, Toner ME, Murphy CM, Duffy GP, O’Brien FJ. The healing of bony defects by cell-free collagen-based scaffolds compared to stem cell-seeded tissue engineered constructs. Biomaterials. 2010;31:9232–43.PubMedCrossRefGoogle Scholar
  160. 160.
    Quinlan E, López‐Noriega A, Thompson EM, Hibbitts A, Cryan SA, O’Brien FJ. Controlled release of vascular endothelial growth factor from spray‐dried alginate microparticles in collagen–hydroxyapatite scaffolds for promoting vascularization and bone repair. J Tissue Eng Regen Med. 2017;11:1097–109.PubMedCrossRefGoogle Scholar
  161. 161.
    Villa MM, Wang L, Rowe DW, Wei M. Effects of cell-attachment and extracellular matrix on bone formation in vivo in collagen-hydroxyapatite scaffolds. PLoS One. 2014;9:e109568.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Gao C, Harvey E, Chua M, Chen B, Jiang F, Liu Y, Li A, Wang H, Henderson J, Education P. MSC-seeded dense collagen scaffolds with a bolus dose of VEGF promote healing of large bone defects. Metab Clin Exp. 2013;500:10–5.Google Scholar
  163. 163.
    Chamieh F, Collignon AM, Coyac BR, Lesieur J, Ribes S, Sadoine J, Llorens A, Nicoletti A, Letourneur D, Colombier ML, Nazhat SN, Bouchard P, Chaussain C, Rochefort GY. Accelerated craniofacial bone regeneration through dense collagen gel scaffolds seeded with dental pulp stem cells. Sci Rep. 2016;6:38814.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Ducheyne P, Healy K, Hutmacher DE, Grainger DW, Kirkpatrick CJ. Comprehensive biomaterials. Oxford: Newnes; 2015.Google Scholar
  165. 165.
    James AW, LaChaud G, Shen J, Asatrian G, Nguyen V, Zhang X, Ting K, Soo C. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng B Rev. 2016;22:284–97.CrossRefGoogle Scholar
  166. 166.
    Kaigler D, Wang Z, Horger K, Mooney DJ, Krebsbach PH. VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects. J Bone Miner Res. 2006;21:735–44.PubMedCrossRefGoogle Scholar
  167. 167.
    Burdick JA, Vunjak-Novakovic G. Engineered microenvironments for controlled stem cell differentiation. Tissue Eng A. 2008;15:205–19.CrossRefGoogle Scholar
  168. 168.
    Ghasemi-Mobarakeh L, Prabhakaran MP, Tian L, Shamirzaei-Jeshvaghani E, Dehghani L, Ramakrishna S. Structural properties of scaffolds: crucial parameters towards stem cells differentiation. World J Stem Cells. 2015;7:728–44.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Almarza AJ, Yang G, Woo SL, Nguyen T, Abramowitch SD. Positive changes in bone marrow–derived cells in response to culture on an aligned bioscaffold. Tissue Eng A. 2008;14:1489–95.CrossRefGoogle Scholar
  170. 170.
    Wang JH, Jia F, Gilbert TW, Woo SL. Cell orientation determines the alignment of cell-produced collagenous matrix. J Biomech. 2003;36:97–102.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Chemical EngineeringFlorida Institute of TechnologyMelbourneUSA
  2. 2.Department of Biomedical EngineeringFlorida Institute of TechnologyMelbourneUSA

Personalised recommendations