Extracellular Matrix-based Materials for Bone Regeneration

  • Sheng Zhou
  • Shichao Zhang
  • Qing JiangEmail author


Decellularized extracellular matrix (ECM)-based scaffolds are rapidly expanding in regenerative medicine. The ECM is an intricate microenvironment with excellent biochemical, biophysical, and biomechanical properties, which can regulate cell adhesion, proliferation, migration, and differentiation, as well as drive tissue homeostasis and regeneration. Decellularized tissue-derived ECMs have been reported to be successful in clinical application of cardiovascular, respiratory, and gastrointestinal surgery. In bone tissue engineering, decellularized ECMs derived either from tissues such as bone, cartilage, and small intestinal submucosa or from cells such as stem cells, osteoblasts, and chondrocytes have shown promising results. We begin this chapter with a brief description of the composition of the ECM and its changes during osteogenesis in vivo and in vitro. Next, the decellularization methods are summarized, followed by the latest development in matrices from native tissues, or cultured cells and their application in bone tissue engineering. Finally, we investigated the different engineering strategies for the design of ECM-based scaffolds in bone regenerative medicine. With this information, we hope to better understand the ECM-based materials and to develop biomaterials more close to the clinical needs in bone tissue engineering.


Extracellular matrix Decellularization Tissue-derived extracellular matrix Cell-derived extracellular matrix Electrospinning Three-dimensional printing Hydrogel Bone regeneration 


Conflicts of Interest

The authors declare that they have no competing financial interest.


  1. 1.
    Friedlaender GE et al (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A(Suppl 1):S151–S158Google Scholar
  2. 2.
    Bucholz RW (2002) Nonallograft osteoconductive bone graft substitutes. Clin Orthop Relat Res (395):44–52Google Scholar
  3. 3.
    Fernandez de Grado G et al (2018) Bone substitutes: a review of their characteristics, clinical use, and perspectives for large bone defects management. J Tissue Eng 9:2041731418776819. Scholar
  4. 4.
    Finkemeier CG (2002) Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am 84-A:454–464CrossRefGoogle Scholar
  5. 5.
    Van Heest A, Swiontkowski M (1999) Bone-graft substitutes. Lancet 353(Suppl 1):SI28–SI29CrossRefGoogle Scholar
  6. 6.
    Kane R, Ma PX (2013) Mimicking the nanostructure of bone matrix to regenerate bone. Mater Today 16:418–423. Scholar
  7. 7.
    Pape HC, Evans A, Kobbe P (2010) Autologous bone graft: properties and techniques. J Orthop Trauma 24(Suppl 1):S36–S40. Scholar
  8. 8.
    Zimmermann G, Moghaddam A (2011) Allograft bone matrix versus synthetic bone graft substitutes. Injury 42(Suppl 2):S16–S21. Scholar
  9. 9.
    Habibovic P, de Groot K (2007) Osteoinductive biomaterials—properties and relevance in bone repair. J Tissue Eng Regen Med 1:25–32. Scholar
  10. 10.
    Langer R, Vacanti JP (1993) Tissue engineering. Science 260:920–926CrossRefGoogle Scholar
  11. 11.
    Griffith LG, Naughton G (2002) Tissue engineering—current challenges and expanding opportunities. Science 295:1009–1014. Scholar
  12. 12.
    Yuan H et al (2010) Osteoinductive ceramics as a synthetic alternative to autologous bone grafting. Proc Natl Acad Sci U S A 107:13614–13619. Scholar
  13. 13.
    Parikh SN (2002) Bone graft substitutes in modern orthopedics. Orthopedics 25:1301–1309. ; quiz 1301–1310PubMedGoogle Scholar
  14. 14.
    Chan G, Mooney DJ (2008) New materials for tissue engineering: towards greater control over the biological response. Trends Biotechnol 26:382–392. Scholar
  15. 15.
    Shekaran A, Garcia AJ (2011) Extracellular matrix-mimetic adhesive biomaterials for bone repair. J Biomed Mater Res A 96A:261–272. Scholar
  16. 16.
    Lind M et al (1996) Transforming growth factor-beta 1 stimulates bone ongrowth to weight-loaded tricalcium phosphate coated implants: an experimental study in dogs. J Bone Joint Surg Br 78:377–382CrossRefGoogle Scholar
  17. 17.
    Inzana JA et al (2014) 3D printing of composite calcium phosphate and collagen scaffolds for bone regeneration. Biomaterials 35:4026–4034. Scholar
  18. 18.
    Hussey GS, Dziki JL, Badylak SF (2018) Extracellular matrix-based materials for regenerative medicine. Nat Rev Mater 3:159–173. Scholar
  19. 19.
    Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326:1216–1219. Scholar
  20. 20.
    da Anunciacao A et al (2017) Extracellular matrix in epitheliochorial, endotheliochorial and haemochorial placentation and its potential application for regenerative medicine. Reprod Domest Anim 52:3–15. Scholar
  21. 21.
    Ott HC et al (2010) Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 16:927–933. Scholar
  22. 22.
    D’Onofrio A et al (2011) Clinical and hemodynamic outcomes after aortic valve replacement with stented and stentless pericardial xenografts: a propensity-matched analysis. J Heart Valve Dis 20:319–326PubMedGoogle Scholar
  23. 23.
    Macchiarini P et al (2008) Clinical transplantation of a tissue-engineered airway. Lancet 372:2023–2030. Scholar
  24. 24.
    Cheng CW, Solorio LD, Alsberg E (2014) Decellularized tissue and cell-derived extracellular matrices as scaffolds for orthopaedic tissue engineering. Biotechnol Adv 32:462–484. Scholar
  25. 25.
    Clarke B (2008) Normal bone anatomy and physiology. Clin J Am Soc Nephrol 3(Suppl 3):S131–S139. Scholar
  26. 26.
    Boskey AL (2013) Bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep 2:447. Scholar
  27. 27.
    Wang Y et al (2012) The predominant role of collagen in the nucleation, growth, structure and orientation of bone apatite. Nat Mater 11:724–733. Scholar
  28. 28.
    Nudelman F et al (2010) The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors. Nat Mater 9:1004–1009. Scholar
  29. 29.
    Barradas AM, Yuan H, van Blitterswijk CA, Habibovic P (2011) Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms. Eur Cell Mater 21:407–429. ; discussion 429CrossRefGoogle Scholar
  30. 30.
    Legate KR, Wickstrom SA, Fassler R (2009) Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev 23:397–418. Scholar
  31. 31.
    Sasano Y et al (2000) Immunohistochemical localization of type I collagen, fibronectin and tenascin C during embryonic osteogenesis in the dentary of mandibles and tibias in rats. Histochem J 32:591–598CrossRefGoogle Scholar
  32. 32.
    Kamiya N, Shigemasa K, Takagi M (2001) Gene expression and immunohistochemical localization of decorin and biglycan in association with early bone formation in the developing mandible. J Oral Sci 43:179–188CrossRefGoogle Scholar
  33. 33.
    Nakamura M et al (2005) Expression of versican and ADAMTS1, 4, and 5 during bone development in the rat mandible and hind limb. J Histochem Cytochem 53:1553–1562. Scholar
  34. 34.
    Hoshiba T, Kawazoe N, Tateishi T, Chen G (2009) Development of stepwise osteogenesis-mimicking matrices for the regulation of mesenchymal stem cell functions. J Biol Chem 284:31164–31173. Scholar
  35. 35.
    Papadimitropoulos A, Scotti C, Bourgine P, Scherberich A, Martin I (2015) Engineered decellularized matrices to instruct bone regeneration processes. Bone 70:66–72. Scholar
  36. 36.
    Al-Abedalla K et al (2015) Bone augmented with allograft onlays for implant placement could be comparable with native bone. J Oral Maxillofac Surg 73:2108–2122. Scholar
  37. 37.
    Gilbert TW, Sellaro TL, Badylak SF (2006) Decellularization of tissues and organs. Biomaterials 27:3675–3683. Scholar
  38. 38.
    Hoshiba T, Lu H, Kawazoe N, Chen G (2010) Decellularized matrices for tissue engineering. Expert Opin Biol Ther 10:1717–1728. Scholar
  39. 39.
    Keane TJ, Swinehart IT, Badylak SF (2015) Methods of tissue decellularization used for preparation of biologic scaffolds and in vivo relevance. Methods 84:25–34. Scholar
  40. 40.
    Hashimoto Y et al (2011) The effect of decellularized bone/bone marrow produced by high-hydrostatic pressurization on the osteogenic differentiation of mesenchymal stem cells. Biomaterials 32:7060–7067. Scholar
  41. 41.
    Kabirian F, Mozafari M (2019) Decellularized ECM-derived bioinks: prospects for the future. Methods.
  42. 42.
    Seddon AM, Curnow P, Booth PJ (2004) Membrane proteins, lipids and detergents: not just a soap opera. Biochim Biophys Acta 1666:105–117. Scholar
  43. 43.
    Hwang J et al (2017) Molecular assessment of collagen denaturation in decellularized tissues using a collagen hybridizing peptide. Acta Biomater 53:268–278. Scholar
  44. 44.
    Fitzpatrick JC, Clark PM, Capaldi FM (2010) Effect of decellularization protocol on the mechanical behavior of porcine descending aorta. Int J Biomater 2010:620503. Scholar
  45. 45.
    He M, Callanan A (2013) Comparison of methods for whole-organ decellularization in tissue engineering of bioartificial organs. Tissue Eng B Rev 19:194–208. Scholar
  46. 46.
    Petersen TH et al (2010) Tissue-engineered lungs for in vivo implantation. Science 329:538–541. Scholar
  47. 47.
    Woods T, Gratzer PF (2005) Effectiveness of three extraction techniques in the development of a decellularized bone-anterior cruciate ligament-bone graft. Biomaterials 26:7339–7349. Scholar
  48. 48.
    Boer U et al (2011) The effect of detergent-based decellularization procedures on cellular proteins and immunogenicity in equine carotid artery grafts. Biomaterials 32:9730–9737. Scholar
  49. 49.
    Bourgine PE, Pippenger BE, Todorov A Jr, Tchang L, Martin I (2013) Tissue decellularization by activation of programmed cell death. Biomaterials 34:6099–6108. Scholar
  50. 50.
    Bourgine PE et al (2014) Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis. Proc Natl Acad Sci U. S. A 111:17426–17431. Scholar
  51. 51.
    van Engeland M, Kuijpers HJ, Ramaekers FC, Reutelingsperger CP, Schutte B (1997) Plasma membrane alterations and cytoskeletal changes in apoptosis. Exp Cell Res 235:421–430. Scholar
  52. 52.
    Raff M (1998) Cell suicide for beginners. Nature 396:119–122. Scholar
  53. 53.
    Bruyneel AAN, Carr CA (2017) Ambiguity in the presentation of decellularized tissue composition: the need for standardized approaches. Artif Organs 41:778–784. Scholar
  54. 54.
    Chen XD, Dusevich V, Feng JQ, Manolagas SC, Jilka RL (2007) Extracellular matrix made by bone marrow cells facilitates expansion of marrow-derived mesenchymal progenitor cells and prevents their differentiation into osteoblasts. J Bone Miner Res Off 22:1943–1956. Scholar
  55. 55.
    Laurencin CT, Khan Y (2012) Regenerative engineering. Sci Transl Med 4:160–169. Scholar
  56. 56.
    Esses SI, Halloran PF (1983) Donor marrow-derived cells as immunogens and targets for the immune response to bone and skin allografts. Transplantation 35:169–174CrossRefGoogle Scholar
  57. 57.
    Campana V et al (2014) Bone substitutes in orthopaedic surgery: from basic science to clinical practice. J Mater Sci Mater Med 25:2445–2461. Scholar
  58. 58.
    Rosenberg E, Rose LF (1998) Biologic and clinical considerations for autografts and allografts in periodontal regeneration therapy. Dent Clin N Am 42:467–490PubMedGoogle Scholar
  59. 59.
    Freiberg RA, Ray RD (1964) Studies of devitalized bone implants. Arch Surg 89:417–427CrossRefGoogle Scholar
  60. 60.
    Frohlich M et al (2010) Bone grafts engineered from human adipose-derived stem cells in perfusion bioreactor culture. Tissue Eng PartA 16:179–189. Scholar
  61. 61.
    Marcos-Campos I et al (2012) Bone scaffold architecture modulates the development of mineralized bone matrix by human embryonic stem cells. Biomaterials 33:8329–8342. Scholar
  62. 62.
    Hesse E et al (2010) Repair of a segmental long bone defect in human by implantation of a novel multiple disc graft. Bone 46:1457–1463. Scholar
  63. 63.
    Drosos GI, Kazakos KI, Kouzoumpasis P, Verettas DA (2007) Safety and efficacy of commercially available demineralised bone matrix preparations: a critical review of clinical studies. Injury 38(Suppl 4):S13–S21CrossRefGoogle Scholar
  64. 64.
    Schwartz Z et al (1998) Ability of commercial demineralized freeze-dried bone allograft to induce new bone formation is dependent on donor age but not gender. J Periodontol 69:470–478. Scholar
  65. 65.
    Munting E, Wilmart JF, Wijne A, Hennebert P, Delloye C (1988) Effect of sterilization on osteoinduction. Comparison of five methods in demineralized rat bone. Acta Orthop Scand 59:34–38CrossRefGoogle Scholar
  66. 66.
    Iwata H, Sakano S, Itoh T, Bauer TW (2002) Demineralized bone matrix and native bone morphogenetic protein in orthopaedic surgery. Clin Orthop Relat Res (395):99–109Google Scholar
  67. 67.
    Chen L et al (2010) Loading of VEGF to the heparin cross-linked demineralized bone matrix improves vascularization of the scaffold. J Mater Sci Mater Med 21:309–317. Scholar
  68. 68.
    Lee JH et al (2011) Combined effects of porous hydroxyapatite and demineralized bone matrix on bone induction: in vitro and in vivo study using a nude rat model. Biomed Mater 6:015008. Scholar
  69. 69.
    Jayasuriya AC, Ebraheim NA (2009) Evaluation of bone matrix and demineralized bone matrix incorporated PLGA matrices for bone repair. J Mater Sci Mater Med 20:1637–1644. Scholar
  70. 70.
    Park BW et al (2012) In vitro and in vivo osteogenesis of human mesenchymal stem cells derived from skin, bone marrow and dental follicle tissues. Differentiation 83:249–259. Scholar
  71. 71.
    Liu G et al (2010) In vitro and in vivo evaluation of osteogenesis of human umbilical cord blood-derived mesenchymal stem cells on partially demineralized bone matrix. Tissue Eng Part A 16:971–982. Scholar
  72. 72.
    Kang EJ et al (2010) In vitro and in vivo osteogenesis of porcine skin-derived mesenchymal stem cell-like cells with a demineralized bone and fibrin glue scaffold. Tissue Eng Part A 16:815–827. Scholar
  73. 73.
    Sawkins MJ et al (2013) Hydrogels derived from demineralized and decellularized bone extracellular matrix. Acta Biomater 9:7865–7873. Scholar
  74. 74.
    Supronowicz P et al (2011) Human adipose-derived side population stem cells cultured on demineralized bone matrix for bone tissue engineering. Tissue Eng Part A 17:789–798. Scholar
  75. 75.
    Kurkalli BG, Gurevitch O, Sosnik A, Cohn D, Slavin S (2010) Repair of bone defect using bone marrow cells and demineralized bone matrix supplemented with polymeric materials. Curr Stem Cell Res Ther 5:49–56CrossRefGoogle Scholar
  76. 76.
    Brighton CT, Sugioka Y, Hunt RM (1973) Cytoplasmic structures of epiphyseal plate chondrocytes. Quantitative evaluation using electron micrographs of rat costochondral junctions with special reference to the fate of hypertrophic cells. J Bone Joint Surg Am 55:771–784CrossRefGoogle Scholar
  77. 77.
    Brighton CT, Hunt RM (1986) Histochemical localization of calcium in the fracture callus with potassium pyroantimonate. Possible role of chondrocyte mitochondrial calcium in callus calcification. J Bone Joint Surg Am 68:703–715CrossRefGoogle Scholar
  78. 78.
    Gerber HP et al (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5:623–628. Scholar
  79. 79.
    Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423:332–336. Scholar
  80. 80.
    Krych AJ, Harnly HW, Rodeo SA, Williams RJ 3rd (2012) Activity levels are higher after osteochondral autograft transfer mosaicplasty than after microfracture for articular cartilage defects of the knee: a retrospective comparative study. J Bone Joint Surg Am 94:971–978. Scholar
  81. 81.
    Pallante AL et al (2012) Treatment of articular cartilage defects in the goat with frozen versus fresh osteochondral allografts: effects on cartilage stiffness, zonal composition, and structure at six months. J Bone Joint Surg Am 94:1984–1995. Scholar
  82. 82.
    Pallante AL et al (2012) The in vivo performance of osteochondral allografts in the goat is diminished with extended storage and decreased cartilage cellularity. Am J Sports Med 40:1814–1823. Scholar
  83. 83.
    Townsend JM et al (2017) Colloidal gels with extracellular matrix particles and growth factors for bone regeneration in critical size rat calvarial defects. AAPS J 19:703–711. Scholar
  84. 84.
    Gupta V et al (2017) Microsphere-based osteochondral scaffolds carrying opposing gradients of decellularized cartilage and demineralized bone matrix. ACS Biomater Sci Eng 3:1955–1963. Scholar
  85. 85.
    Gawlitta D et al (2015) Decellularized cartilage-derived matrix as substrate for endochondral bone regeneration. Tissue Eng Part A 21:694–703. Scholar
  86. 86.
    Cunniffe GM et al (2017) Growth plate extracellular matrix-derived scaffolds for large bone defect healing. Eur Cell Mater 33:130–142. Scholar
  87. 87.
    Badylak SF, Freytes DO, Gilbert TW (2009) Extracellular matrix as a biological scaffold material: structure and function. Acta Biomater 5:1–13. Scholar
  88. 88.
    Kim KS et al (2010) Small intestine submucosa sponge for in vivo support of tissue-engineered bone formation in the presence of rat bone marrow stem cells. Biomaterials 31:1104–1113. Scholar
  89. 89.
    Li M, Zhang C, Cheng M, Gu Q, Zhao J (2017) Small intestinal submucosa: a potential osteoconductive and osteoinductive biomaterial for bone tissue engineering. Mater Sci Eng C Mater Biol Appl 75:149–156. Scholar
  90. 90.
    Sun T et al (2018) Composite scaffolds of mineralized natural extracellular matrix on true bone ceramic induce bone regeneration through Smad1/5/8 and ERK1/2 pathways. Tissue Eng Part A 24:502–515. Scholar
  91. 91.
    Sun TF et al (2018) Guided osteoporotic bone regeneration with composite scaffolds of mineralized ECM/heparin membrane loaded with BMP2-related peptide. Int J Nanomed 13:791–804. Scholar
  92. 92.
    Zhang C, Li M, Zhu J, Luo F, Zhao J (2017) Enhanced bone repair induced by human adipose-derived stem cells on osteogenic extracellular matrix ornamented small intestinal submucosa. Regen Med 12:541–552. Scholar
  93. 93.
    Li M, Zhang C, Mao YX, Zhong Y, Zhao JY (2018) A cell-engineered small intestinal submucosa-based bone mimetic construct for bone regeneration. Tissue Eng Part A 24:1099–1111. Scholar
  94. 94.
    Moore DC, Pedrozo HA, Crisco JJ 3rd, Ehrlich MG (2004) Preformed grafts of porcine small intestine submucosa (SIS) for bridging segmental bone defects. J Biomed Mater Res A 69:259–266. Scholar
  95. 95.
    Zhao L, Zhao J, Wang S, Wang J, Liu J (2011) Comparative study between tissue-engineered periosteum and structural allograft in rabbit critical-sized radial defect model. J Biomed Mater Res B Appl Biomater 97:1–9. Scholar
  96. 96.
    Roberts SJ, van Gastel N, Carmeliet G, Luyten FP (2015) Uncovering the periosteum for skeletal regeneration: the stem cell that lies beneath. Bone 70:10–18. Scholar
  97. 97.
    Zhang X et al (2005) Periosteal progenitor cell fate in segmental cortical bone graft transplantations: implications for functional tissue engineering. J Bone Miner Research 20:2124–2137. Scholar
  98. 98.
    Lin XF et al (2018) Periosteum extracellular-matrix-mediated acellular mineralization during bone formation. Adv Healthc Mater 7:1700660. Scholar
  99. 99.
    Wang XY et al (2017) Preparation and characterization of a chitosan/gelatin/extracellular matrix scaffold and its application in tissue engineering. Tissue Eng Part C Methods 23:169–179. Scholar
  100. 100.
    Schonmeyr B, Clavin N, Avraham T, Longo V, Mehrara BJ (2009) Synthesis of a tissue-engineered periosteum with acellular dermal matrix and cultured mesenchymal stem cells. Tissue Eng Part A 15:1833–1841. Scholar
  101. 101.
    Kim HJ et al (2012) Effect of acellular dermal matrix as a delivery carrier of adipose-derived mesenchymal stem cells on bone regeneration. J Biomed Mater Res Part B Appl Biomater 100:1645–1653. Scholar
  102. 102.
    Hwang JW, Kim S, Kim SW, Lee JH (2016) Effect of extracellular matrix membrane on bone formation in a rabbit tibial defect model. Biomed Res Int 2016:6715295. Scholar
  103. 103.
    Li W et al (2015) Investigating the potential of amnion-based scaffolds as a barrier membrane for guided bone regeneration. Langmuir 31:8642–8653. Scholar
  104. 104.
    Penolazzi L et al (2012) Human mesenchymal stem cells seeded on extracellular matrix-scaffold: viability and osteogenic potential. J Cell Physiol 227:857–866. Scholar
  105. 105.
    Beachley V et al (2018) Extracellular matrix particle-glycosaminoglycan composite hydrogels for regenerative medicine applications. J Biomed Mater Res A 106:147–159. Scholar
  106. 106.
    Wainwright D et al (1996) Clinical evaluation of an acellular allograft dermal matrix in full-thickness burns. J Burn Care Rehabil 17:124–136CrossRefGoogle Scholar
  107. 107.
    Badylak SF (2007) The extracellular matrix as a biologic scaffold material. Biomaterials 28:3587–3593. Scholar
  108. 108.
    Trelford JD, Trelford-Sauder M (1979) The amnion in surgery, past and present. Am J Obstet Gynecol 134:833–845CrossRefGoogle Scholar
  109. 109.
    Wei W et al (2017) In vitro osteogenic induction of bone marrow mesenchymal stem cells with a decellularized matrix derived from human adipose stem cells and in vivo implantation for bone regeneration. J Mater Chem B 5:2468–2482. Scholar
  110. 110.
    Ravindran S et al (2012) Biomimetic extracellular matrix-incorporated scaffold induces osteogenic gene expression in human marrow stromal cells. Tissue Eng Part A 18:295–309. Scholar
  111. 111.
    Lai Y et al (2010) Reconstitution of marrow-derived extracellular matrix ex vivo: a robust culture system for expanding large-scale highly functional human mesenchymal stem cells. Stem Cells Dev 19:1095–1107. Scholar
  112. 112.
    Zhang Z et al (2015) Bone marrow stromal cell-derived extracellular matrix promotes osteogenesis of adipose-derived stem cells. Cell Biol Int 39:291–299. Scholar
  113. 113.
    Zeitouni S et al (2012) Human mesenchymal stem cell-derived matrices for enhanced osteoregeneration. Sci Transl Med 4:132–155. Scholar
  114. 114.
    Antebi B et al (2015) Stromal-cell-derived extracellular matrix promotes the proliferation and retains the osteogenic differentiation capacity of mesenchymal stem cells on three-dimensional scaffolds. Tissue Eng Part C Methods 21:171–181. Scholar
  115. 115.
    Sadr N et al (2012) Enhancing the biological performance of synthetic polymeric materials by decoration with engineered, decellularized extracellular matrix. Biomaterials 33:5085–5093. Scholar
  116. 116.
    Baroncelli M et al (2018) Human osteoblast-derived extracellular matrix with high homology to bone proteome is osteopromotive. Tissue Eng Part A 24:1377–1389. Scholar
  117. 117.
    Cunniffe GM et al (2015) Porous decellularized tissue engineered hypertrophic cartilage as a scaffold for large bone defect healing. Acta Biomater 23:82–90. Scholar
  118. 118.
    Takeshita K et al (2017) Xenotransplantation of interferon-gamma-pretreated clumps of a human mesenchymal stem cell/extracellular matrix complex induces mouse calvarial bone regeneration. Stem Cell Res Ther 8:101. Scholar
  119. 119.
    Clough BH et al (2015) Bone regeneration with osteogenically enhanced mesenchymal stem cells and their extracellular matrix proteins. J Bone Miner Res 30:83–94. Scholar
  120. 120.
    Deutsch ER, Guldberg RE (2010) Stem cell-synthesized extracellular matrix for bone repair. J Mater Chem 20:8942–8951CrossRefGoogle Scholar
  121. 121.
    Kang YQ, Kim S, Bishop J, Khademhosseini A, Yang YZ (2012) The osteogenic differentiation of human bone marrow MSCs on HUVEC-derived ECM and beta-TCP scaffold. Biomaterials 33:6998–7007. Scholar
  122. 122.
    Tour G, Wendel M, Tcacencu I (2013) Human fibroblast-derived extracellular matrix constructs for bone tissue engineering applications. J Biomed Mater Res A 101:2826–2837. Scholar
  123. 123.
    Xing Q, Qian Z, Kannan B, Tahtinen M, Zhao F (2015) Osteogenic differentiation evaluation of an engineered extracellular matrix based tissue sheet for potential periosteum replacement. ACS Appl Mater Interfaces 7:23239–23247. Scholar
  124. 124.
    Kim IG et al (2015) Bioactive cell-derived matrices combined with polymer mesh scaffold for osteogenesis and bone healing. Biomaterials 50:75–86. Scholar
  125. 125.
    Pati F et al (2015) Ornamenting 3D printed scaffolds with cell-laid extracellular matrix for bone tissue regeneration. Biomaterials 37:230–241. Scholar
  126. 126.
    Shtrichman R et al (2014) The generation of hybrid electrospun nanofiber layer with extracellular matrix derived from human pluripotent stem cells, for regenerative medicine applications. Tissue Eng Part A 20:2756–2767. Scholar
  127. 127.
    Narayanan K, Leck KJ, Gao S, Wan AC (2009) Three-dimensional reconstituted extracellular matrix scaffolds for tissue engineering. Biomaterials 30:4309–4317. Scholar
  128. 128.
    Lee HJ et al (2015) A new approach for fabricating collagen/ECM-based bioinks using preosteoblasts and human adipose stem cells. Adv Healthcare Mater 4:1359–1368. Scholar
  129. 129.
    Ma JX et al (2017) Biomimetic matrix fabricated by LMP-1 gene-transduced MC3T3-E1 cells for bone regeneration. Biofabrication 9:045010. Scholar
  130. 130.
    Gao CY et al (2018) Directing osteogenic differentiation of BMSCs by cell-secreted decellularized extracellular matrixes from different cell types. J Mater Chem B 6:7471–7485. Scholar
  131. 131.
    Fu Y, Liu LL, Cheng RY, Cui WG (2018) ECM decorated electrospun nanofiber for improving bone tissue regeneration. Polymers (Basel) 10:272. Scholar
  132. 132.
    Kumar A, Nune KC, Misra RDK (2016) Biological functionality and mechanistic contribution of extracellular matrix-ornamented three dimensional Ti-6Al-4V mesh scaffolds. J Biomed Mater Res A 104:2751–2763. Scholar
  133. 133.
    Kumar A, Nune KC, Misra RDK (2016) Biological functionality of extracellular matrix-ornamented three-dimensional printed hydroxyapatite scaffolds. J Biomed Mater Res A 104:1343–1351. Scholar
  134. 134.
    Pham QP et al (2008) The influence of an in vitro generated bone-like extracellular matrix on osteoblastic gene expression of marrow stromal cells. Biomaterials 29:2729–2739. Scholar
  135. 135.
    Datta N et al (2006) In vitro generated extracellular matrix and fluid shear stress synergistically enhance 3D osteoblastic differentiation. Proc Natl Acad Sci U S A 103:2488–2493. Scholar
  136. 136.
    Datta N, Holtorf HL, Sikavitsas VI, Jansen JA, Mikos AG (2005) Effect of bone extracellular matrix synthesized in vitro on the osteoblastic differentiation of marrow stromal cells. Biomaterials 26:971–977. Scholar
  137. 137.
    Kwon SH et al (2013) Modulation of BMP-2-induced chondrogenic versus osteogenic differentiation of human mesenchymal stem cells by cell-specific extracellular matrices. Tissue Eng Part A 19:49–58. Scholar
  138. 138.
    Lau TT, Lee LQP, Vo BN, Su K, Wang DA (2012) Inducing ossification in an engineered 3D scaffold-free living cartilage template. Biomaterials 33:8406–8417. Scholar
  139. 139.
    Bourgine PE et al (2017) Engineered extracellular matrices as biomaterials of tunable composition and function. Adv Funct Mater 27:1605486CrossRefGoogle Scholar
  140. 140.
    Fu CC et al (2018) Embryonic-like mineralized extracellular matrix/stem cell microspheroids as a bone graft substitute. Adv Healthc Mater 7:1800705. Scholar
  141. 141.
    Choudhery MS, Badowski M, Muise A, Pierce J, Harris DT (2014) Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. J Transl Med 12:8. Scholar
  142. 142.
    Carlson ME, Conboy IM (2007) Loss of stem cell regenerative capacity within aged niches. Aging Cell 6:371–382. Scholar
  143. 143.
    Sun Y et al (2011) Rescuing replication and osteogenesis of aged mesenchymal stem cells by exposure to a young extracellular matrix. FASEB J 25:1474–1485. Scholar
  144. 144.
    Ng CP et al (2014) Enhanced ex vivo expansion of adult mesenchymal stem cells by fetal mesenchymal stem cell ECM. Biomaterials 35:4046–4057. Scholar
  145. 145.
    Bilousova G et al (2011) Osteoblasts derived from induced pluripotent stem cells form calcified structures in scaffolds both in vitro and in vivo. Stem Cells 29:206–216. Scholar
  146. 146.
    Rohanizadeh R, Swain MV, Mason RS (2008) Gelatin sponges (Gelfoam) as a scaffold for osteoblasts. J Mater Sci Mater Med 19:1173–1182. Scholar
  147. 147.
    Pham QP et al (2009) Analysis of the osteoinductive capacity and angiogenicity of an in vitro generated extracellular matrix. J Biomed Mater Res A 88:295–303. Scholar
  148. 148.
    Garcia P et al (2012) Temporal and spatial vascularization patterns of unions and nonunions: role of vascular endothelial growth factor and bone morphogenetic proteins. J Bone Joint Surg Am 94A:49–58. Scholar
  149. 149.
    Cricchio G, Lundgren S (2003) Donor site morbidity in two different approaches to anterior iliac crest bone harvesting. Clin Implant Dent Relat Res 5:161–169CrossRefGoogle Scholar
  150. 150.
    Ventura RD, Padalhin AR, Min YK, Lee BT (2015) Bone regeneration using hydroxyapatite sponge scaffolds with in vivo deposited extracellular matrix. Tissue Eng Part A 21:2649–2661. Scholar
  151. 151.
    Kusuma GD et al (2018) Transferable matrixes produced from decellularized extracellular matrix promote proliferation and osteogenic differentiation of mesenchymal stem cells and facilitate scale-up. ACS Biomater Sci Eng 4:1760–1769. Scholar
  152. 152.
    Lin H, Yang G, Tan J, Tuan RS (2012) Influence of decellularized matrix derived from human mesenchymal stem cells on their proliferation, migration and multi-lineage differentiation potential. Biomaterials 33:4480–4489. Scholar
  153. 153.
    Decaris ML, Mojadedi A, Bhat A, Leach JK (2012) Transferable cell-secreted extracellular matrices enhance osteogenic differentiation. Acta Biomater 8:744–752. Scholar
  154. 154.
    Decaris ML, Binder BY, Soicher MA, Bhat A, Leach JK (2012) Cell-derived matrix coatings for polymeric scaffolds. Tissue Eng Part A 18:2148–2157. Scholar
  155. 155.
    Keane TJ et al (2015) Tissue-specific effects of esophageal extracellular matrix. Tissue Eng Part A 21:2293–2300. Scholar
  156. 156.
    Shegarfi H, Reikeras O (2009) Review article: bone transplantation and immune response. J Orthop Surg 17:206–211. Scholar
  157. 157.
    Bose S, Roy M, Bandyopadhyay A (2012) Recent advances in bone tissue engineering scaffolds. Trends Biotechnol 30:546–554. Scholar
  158. 158.
    Kittaka M et al (2015) Clumps of a mesenchymal stromal cell/extracellular matrix complex can be a novel tissue engineering therapy for bone regeneration. Cytotherapy 17:860–873. Scholar
  159. 159.
    Motoike S et al (2018) Cryopreserved clumps of mesenchymal stem cell/extracellular matrix complexes retain osteogenic capacity and induce bone regeneration. Stem Cell Res Ther 9:73. Scholar
  160. 160.
    Onishi T et al (2018) Osteogenic extracellular matrix sheet for bone tissue regeneration. Eur Cell Mater 36:68–80. Scholar
  161. 161.
    Akahane M et al (2010) Scaffold-free cell sheet injection results in bone formation. J Tissue Eng Regen Med 4:404–411. Scholar
  162. 162.
    Nakamura A et al (2010) Cell sheet transplantation of cultured mesenchymal stem cells enhances bone formation in a rat nonunion model. Bone 46:418–424. Scholar
  163. 163.
    Akahane M et al (2008) Osteogenic matrix sheet-cell transplantation using osteoblastic cell sheet resulted in bone formation without scaffold at an ectopic site. J Tissue Eng Regen Med 2:196–201. Scholar
  164. 164.
    Gao Z et al (2009) Vitalisation of tubular coral scaffolds with cell sheets for regeneration of long bones: a preliminary study in nude mice. Br J Oral Maxillofac Surg 47:116–122. Scholar
  165. 165.
    Kang Y, Ren L, Yang Y (2014) Engineering vascularized bone grafts by integrating a biomimetic periosteum and beta-TCP scaffold. ACS Appl Mater Interfaces 6:9622–9633. Scholar
  166. 166.
    Liu SK et al (2018) Off-the-shelf biomimetic graphene oxide-collagen hybrid scaffolds wrapped with osteoinductive extracellular matrix for the repair of cranial defects in rats. ACS Appl Mater Inter 10:42948–42958. Scholar
  167. 167.
    Matsuda N, Shimizu T, Yamato M, Okano T (2007) Tissue engineering based on cell sheet technology. Adv Mater 19:3089–3099. Scholar
  168. 168.
    Long T et al (2014) The effect of mesenchymal stem cell sheets on structural allograft healing of critical sized femoral defects in mice. Biomaterials 35:2752–2759. Scholar
  169. 169.
    Zou B et al (2012) Electrospun fibrous scaffolds with continuous gradations in mineral contents and biological cues for manipulating cellular behaviors. Acta Biomater 8:1576–1585. Scholar
  170. 170.
    Zhang SC et al (2019) Direct electronetting of high-performance membranes based on self-assembled 2D nanoarchitectured networks. Nat Commun 10:1458. Scholar
  171. 171.
    Khorshidi S et al (2016) A review of key challenges of electrospun scaffolds for tissue-engineering applications. J Tissue Eng Regen Med 10:715–738. Scholar
  172. 172.
    Reznikov N, Shahar R, Weiner S (2014) Bone hierarchical structure in three dimensions. Acta Biomater 10:3815–3826. Scholar
  173. 173.
    Carvalho MS et al (2019) Co-culture cell-derived extracellular matrix loaded electrospun microfibrous scaffolds for bone tissue engineering. Mater Sci Eng C Mater Biol Appl 99:479–490. Scholar
  174. 174.
    Gibson M et al (2014) Tissue extracellular matrix nanoparticle presentation in electrospun nanofibers. Biomed Res Int 2014:469120. Scholar
  175. 175.
    Thibault RA, Mikos AG, Kasper FK (2013) Winner of the 2013 young investigator award for the Society for Biomaterials annual meeting and exposition, April 10-13, 2013, Boston, Massachusetts Osteogenic differentiation of mesenchymal stem cells on demineralized and devitalized biodegradable polymer and extracellular matrix hybrid constructs. J Biomed Mater Res A 101:1225–1236. Scholar
  176. 176.
    Thibault RA, Scott Baggett L, Mikos AG, Kasper FK (2010) Osteogenic differentiation of mesenchymal stem cells on pregenerated extracellular matrix scaffolds in the absence of osteogenic cell culture supplements. Tissue Eng Part A 16:431–440. Scholar
  177. 177.
    Jeon H, Lee J, Lee H, Kim GH (2016) Nanostructured surface of electrospun PCL/dECM fibres treated with oxygen plasma for tissue engineering. RSC Adv 6:32887–32896. Scholar
  178. 178.
    Jang J, Park JY, Gao G, Cho DW (2018) Biomaterials-based 3D cell printing for next-generation therapeutics and diagnostics. Biomaterials 156:88–106. Scholar
  179. 179.
    Bose S, Vahabzadeh S, Bandyopadhyay A (2013) Bone tissue engineering using 3D printing. Mater Today 16:496–504. Scholar
  180. 180.
    Hung BP et al (2016) Three-dimensional printing of bone extracellular matrix for craniofacial regeneration. ACS Biomater Sci Eng 2:1806–1816. Scholar
  181. 181.
    Nyberg E, Rindone A, Dorafshar A, Grayson WL (2017) Comparison of 3D-printed poly-varepsilon-caprolactone scaffolds functionalized with tricalcium phosphate, hydroxyapatite, bio-oss, or decellularized bone matrix<sup/>. Tissue Eng Part A 23:503–514. Scholar
  182. 182.
    Chai YC et al (2017) Harnessing the osteogenicity of in vitro stem cell-derived mineralized extracellular matrix as 3D biotemplate to guide bone regeneration. Tissue Eng Part A 23:874–890. Scholar
  183. 183.
    Kim JY et al (2018) Synergistic effects of beta tri-calcium phosphate and porcine-derived decellularized bone extracellular matrix in 3D-printed polycaprolactone scaffold on bone regeneration. Macromol Biosci 18:1800025. Scholar
  184. 184.
    Davis HE, Leach JK (2011) Designing bioactive delivery systems for tissue regeneration. Ann Biomed Eng 39:1–13. Scholar
  185. 185.
    Wang XH et al (2016) 3D bioprinting technologies for hard tissue and organ engineering. Materials (Basel) 9:802. Scholar
  186. 186.
    Mandrycky C, Wang ZJ, Kim K, Kim DH (2016) 3D bioprinting for engineering complex tissues. Biotechnol Adv 34:422–434. Scholar
  187. 187.
    Jang J et al (2016) Tailoring mechanical properties of decellularized extracellular matrix bioink by vitamin B2-induced photo-crosslinking. Acta Biomater 33:88–95. Scholar
  188. 188.
    Pati F et al (2014) Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink. Nat Commun 5:3935. Scholar
  189. 189.
    Hughes CS, Postovit LM, Lajoie GA (2010) Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics 10:1886–1890. Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Orthopaedics, School of MedicineWest Virginia UniversityMorgantownUSA
  2. 2.Department of Sports Medicine and Adult Reconstructive Surgery, School of MedicineNanjing Drum Tower Hospital, Nanjing UniversityNanjingPeople’s Republic of China

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