Manufacturing artificial bone allografts: a perspective
Bone grafts have traditionally come from four sources: the patients’ own tissue (autograft), tissue from a living or cadaveric human donor (allograft), animal donors (xenograft) and synthetic artificial biomaterials (ceramics, cement, polymers, and metal). However, all of these have advantages and drawbacks. The most commercially successful bone grafts so far are allografts, which hold 57% of the current bone graft market; however, disease transmission and scarcity are still significant drawbacks limiting their use. Tissue-engineered grafts have great potential, in which human stem cells and synthetical biomaterials are combined to produce bone-like tissue in vitro, but this is yet to be approved for widespread clinical practice. It is hypothesised that artificial bone allografts can be mass-manufactured to replace conventional bone allografts through refined bone tissue engineering prior to decellularisation. This review article aims to review current literature on (1) conventional bone allograft preparation; (2) bone tissue engineering including the use of synthetic biomaterials as bone graft substitute scaffolds, combined with osteogenic stem cells in vitro; (3) potential artificial allograft manufacturing processes, including mass production of engineered bone tissue, osteogenic enhancement, decellularisation, sterilisation and safety assurance for regulatory approval. From these assessments, a practical route map for mass production of artificial allografts for clinical use is proposed.
Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.
以下是您提供的文献引用的完整列表：
1. Dimitriou, R.; Jones, E.; McGonagle, D.; Giannoudis, P. V. Bone regeneration: current concepts and future directions. *BMC Med*. 2011, 9, 66.
2. Brydone, A. S.; Meek, D.; Maclaine, S. Bone grafting, orthopaedic biomaterials, and the clinical need for bone engineering. *Proc Inst Mech Eng H*. 2010, 224, 1329-1343.
3. Bracey, D. N.; Jinnah, A. H.; Willey, J. S.; Seyler, T. M.; Hutchinson, I. D.; Whitlock, P. W.; Smith, T. L.; Danelson, K. A.; Emory, C. L.; Kerr, B. A. Investigating the osteoinductive potential of a decellularized xenograft bone substitute. *Cells Tissues Organs*. 2019, 207, 97-113.
4. Albrektsson, T.; Johansson, C. Osteoinduction, osteoconduction and osseointegration. *Eur Spine J*. 2001, 10 Suppl 2, S96-101.
5. Weber, F. E. Reconsidering osteoconduction in the era of additive manufacturing. *Tissue Eng Part B Rev*. 2019, 25, 375-386.
6. Qi, L.; Liu, Y.; Li, H.; Zhang, Y. Results of 10-year follow-up of the iliac donor site of graft patients. *J Int Med Res*. 2014, 42, 1348-1352.
7. Matsuura, T.; Hashimoto, Y.; Kinoshita, T.; Nishino, K.; Nishida, Y.; Takigami, J.; Katsuda, H.; Shimada, N. Donor site evaluation after osteochondral autograft transplantation for capitellar osteochondritis dissecans. *Am J Sports Med*. 2019, 47, 2836-2843.
8. Lomas, R.; Chandrasekar, A.; Board, T. N. Bone allograft in the U.K.: perceptions and realities. *Hip Int*. 2013, 23, 427-433.
9. McNamara, I. R. Impaction bone grafting in revision hip surgery: past, present and future. *Cell Tissue Bank*. 2010, 11, 57-73.
10. Enneking, W. F.; Campanacci, D. A. Retrieved human allografts: a clinicopathological study. *J Bone Joint Surg Am*. 2001, 83, 971-986.
11. Conrad, E. U.; Gretch, D. R.; Obermeyer, K. R.; Moogk, M. S.; Sayers, M.; Wilson, J. J.; Strong, D. M. Transmission of the hepatitis-C virus by tissue transplantation. *J Bone Joint Surg Am*. 1995, 77, 214-224.
12. Simonds, R. J.; Holmberg, S. D.; Hurwitz, R. L.; Coleman, T. R.; Bottenfield, S.; Conley, L. J.; Kohlenberg, S. H.; Castro, K. G.; Dahan, B. A.; Schable, C. A.; et al. Transmission of human immunodeficiency virus type 1 from a seronegative organ and tissue donor. *N Engl J Med*. 1992, 326, 726-732.
13. Campana, V.; Milano, G.; Pagano, E.; Barba, M.; Cicione, C.; Salonna, G.; Lattanzi, W.; Logroscino, G. Bone substitutes in orthopaedic surgery: from basic science to clinical practice. J Mater Sci Mater Med 2014, 25, 2445-2461.
14. Perić Kačarević, Z.; Kavehei, F.; Houshmand, A.; Franke, J.; Smeets, R.; Rimashevskiy, D.; Wenisch, S.; Schnettler, R.; Jung, O.; Barbeck, M. Purification processes of xenogeneic bone substitutes and their impact on tissue reactions and regeneration. *Int J Artif Organs*. 2018, 41, 789-800.
15. Herliansyah, M. K.; Hamdi, M.; Ide-Ektessabi, A.; Wildan, M. W.; Toque, J. A. The influence of sintering temperature on the properties of compacted bovine hydroxyapatite. *Mater Sci Eng C*. 2009, 29, 1674-1680.
16. Charalambides, C.; Beer, M.; Cobb, A. G. Poor results after augmenting autograft with xenograft (Surgibone) in hip revision surgery: a report of 27 cases. *Acta Orthop*. 2005, 76, 544-549.
17. Savolainen, S.; Usenius, J. P.; Hernesniemi, J. Iliac crest versus artificial bone grafts in 250 cervical fusions. *Acta Neurochir (Wien)*. 1994, 129, 54-57.
18. Siqueira, E. B.; Kranzler, L. I. Cervical Interbody fusion using calf bone. *Surg Neurol*. 1982, 18, 37-39.
19. Shi, Y.; He, R.; Deng, X.; Shao, Z.; Deganello, D.; Yan, C.; Xia, Z. Three-dimensional biofabrication of an aragonite-enriched self-hardening bone graft substitute and assessment of its osteogenicity in vitro and in vivo. *Biomater Transl*. 2020, 1, 69-81.
20. Ripamonti, U. Osteoinduction in porous hydroxyapatite implanted in heterotopic sites of different animal models. *Biomaterials*. 1996, 17, 31-35.
21. Reeve, L.; Baldrick, P. Biocompatibility assessments for medical devices - evolving regulatory considerations. *Expert Rev Med Devices*. 2017, 14, 161-167.
22. Westas, E.; Gillstedt, M.; Lönn-Stensrud, J.; Bruzell, E.; Andersson, M. Biofilm formation on nanostructured hydroxyapatite-coated titanium. *J Biomed Mater Res A*. 2014, 102, 1063-1070.
23. Grand View Research Inc. Bone grafts and substitutes market size, share & trends analysis report by material type (allograft, synthetic), by application (spinal fusion, foot & ankle, joint reconstruction), by region, and segment forecasts, 2022 - 2030. [https://www.grandviewresearch.com/industry-analysis/bone-grafts-and-substitutes-market](https://www.grandviewresearch.com/industry-analysis/bone-grafts-and-substitutes-market)
23. Grand View Research Inc. Bone grafts and substitutes market size, share & trends analysis report by material type (allograft, synthetic), by application (spinal fusion, foot & ankle, joint reconstruction), by region, and segment forecasts, 2022 - 2030. https://www.grandviewresearch. com/industry-analysis/bone-grafts-substitutes-market. Accessed Marth 7, 2022
24. Martin, T. J.; Ng, K. W.; Nicholson, G. C. Cell biology of bone. *Baillieres Clin Endocrinol Metab*. 1988, 2, 1-29.
25. Brink, O. The choice between allograft or demineralized bone matrix is not unambiguous in trauma surgery. *Injury*. 2021, 52 Suppl 2, S23-s28.
26. Blaudez, F.; Ivanovski, S.; Hamlet, S.; Vaquette, C. An overview of decellularisation techniques of native tissues and tissue engineered products for bone, ligament and tendon regeneration. *Methods*. 2020, 171, 28-40.
27. Rasch, A.; Naujokat, H.; Wang, F.; Seekamp, A.; Fuchs, S.; Klüter, T. Evaluation of bone allograft processing methods: Impact on decellularization efficacy, biocompatibility and mesenchymal stem cell functionality. *PLoS One*. 2019, 14, e0218404.
28. Seebach, C.; Schultheiss, J.; Wilhelm, K.; Frank, J.; Henrich, D. Comparison of six bone-graft substitutes regarding to cell seeding efficiency, metabolism and growth behaviour of human mesenchymal stem cells (MSC) in vitro. *Injury*. 2010, 41, 731-738.
29. Moon, K. N.; Kim, S. G.; Oh, J. S.; Kim, C. S.; Lim, S. C.; Jeong, M. A. Evaluation of bone formation after grafting with deproteinized bovine bone and mineralized allogenic bone. *Implant Dent*. 2015, 24, 101-105.
30. Gruskin, E.; Doll, B. A.; Futrell, F. W.; Schmitz, J. P.; Hollinger, J. O. Demineralized bone matrix in bone repair: history and use. *Adv Drug Deliv Rev*. 2012, 64, 1063-1077.
31. Servin-Trujillo, M. A.; Reyes-Esparza, J. A.; Garrido-Fariña, G.; Flores-Gazca, E.; Osuna-Martinez, U.; Rodriguez-Fragoso, L. Use of a graft of demineralized bone matrix along with TGF-β1 leads to an early bone repair in dogs. *J Vet Med Sci*. 2011, 73, 1151-1161.
32. Grgurevic, L.; Pecina, M.; Vukicevic, S. Marshall R. Urist and the discovery of bone morphogenetic proteins. *Int Orthop*. 2017, 41, 1065-1069.
33. McDonald, N. M.; Woodell-May, J. E.; Pietrzak, W. S. Bone morphogenetic protein concentration in human demineralized bone matrix. In *51st Annual Meeting of the Orthopaedic Research Society*, 2005.
34. Hunziker, E. B.; Liu, Y.; Muff, M.; Haegi, T.; Shintani, N.; Lippuner, K. The slow release of BMP-7 at a low dose accelerates dental implant healing in an osteopenic environment. *Eur Cell Mater*. 2021, 41, 170-183.
35. Cahill, K. S.; McCormick, P. C.; Levi, A. D. A comprehensive assessment of the risk of bone morphogenetic protein use in spinal fusion surgery and postoperative cancer diagnosis. *J Neurosurg Spine*. 2015, 23, 86-93.
36. Shehadi, J. A.; Elzein, S. M. Review of commercially available demineralized bone matrix products for spinal fusions: A selection paradigm. *Surg Neurol Int*. 2017, 8, 203.
37. Zhang, H.; Yang, L.; Yang, X. G.; Wang, F.; Feng, J. T.; Hua, K. C.; Li, Q.; Hu, Y. C. Demineralized bone matrix carriers and their clinical applications: an overview. *Orthop Surg*. 2019, 11, 725-737.
38. Kainer, M. A.; Linden, J. V.; Whaley, D. N.; Holmes, H. T.; Jarvis, W. R.; Jernigan, D. B.; Archibald, L. K. Clostridium infections associated with musculoskeletal-tissue allografts. *N Engl J Med*. 2004, 350, 2564-2571.
39. Singh, R.; Singh, D.; Singh, A. Radiation sterilization of tissue allografts: a review. *World J Radiol*. 2016, 8, 355-369.
40. Nguyen, H.; Morgan, D. A.; Forwood, M. R. Sterilization of allograft bone: effects of gamma irradiation on allograft biology and biomechanics. *Cell Tissue Bank*. 2007, 8, 93-105.
41. American Association of Tissue Banks. *Standards for Tissue Banking*. 14th ed.; 2016.
42. Akkus, O.; Belaney, R. M. Sterilization by gamma radiation impairs the tensile fatigue life of cortical bone by two orders of magnitude. *J Orthop Res*. 2005, 23, 1054-1058.
43. Grieb, T. A.; Forng, R. Y.; Stafford, R. E.; Lin, J.; Almeida, J.; Bogdansky, S.; Ronholdt, C.; Drohan, W. N.; Burgess, W. H. Effective use of optimized, high-dose (50 kGy) gamma irradiation for pathogen inactivation of human bone allografts. *Biomaterials*. 2005, 26, 2033-2042.
44. Ijiri, S.; Yamamuro, T.; Nakamura, T.; Kotani, S.; Notoya, K. Effect of sterilization on bone morphogenetic protein. *J Orthop Res*. 1994, 12, 628-636.
45. Puolakkainen, P. A.; Ranchalis, J. E.; Strong, D. M.; Twardzik, D. R. The effect of sterilization on transforming growth factor beta isolated from demineralized human bone. *Transfusion*. 1993, 33, 679-685.
46. Arizono, T.; Iwamoto, Y.; Okuyama, K.; Sugioka, Y. Ethylene oxide sterilization of bone grafts. Residual gas concentration and fibroblast toxicity. *Acta Orthop Scand*. 1994, 65, 640-642.
47. Pekkarinen, T.; Hietala, O.; Lindholm, T. S.; Jalovaara, P. Influence of ethylene oxide sterilization on the activity of native reindeer bone morphogenetic protein. *Int Orthop*. 2004, 28, 97-101.
48. Ernst, R. R. Ethylene oxide sterilization kinetics. Biotechnol Bioeng Symp. 1974, 0, 865-878.
49. Munting, E.; Wilmart, J. F.; Wijne, A.; Hennebert, P.; Delloye, C.Effect of sterilization on osteoinduction. Comparison of five methods in demineralized rat bone. Acta Orthop Scand. 1988, 59, 34-38
以下是您提供的文献引用的完整列表，包括第50条及后续条目：
50. Aspenberg, P.; Johnsson, E.; Thorngren, K. G. Dose-dependent reduction of bone inductive properties by ethylene oxide. *J Bone Joint Surg Br*. 1990, 72, 1036-1037.
51. Aspenberg, P.; Lindqvist, S. B. Ethene oxide and bone induction. Controversy remains. *Acta Orthop Scand*. 1998, 69, 173-176.
52. Zhang, Q.; Cornu, O.; Delloye, C. Ethylene oxide does not extinguish the osteoinductive capacity of demineralized bone. A reappraisal in rats. *Acta Orthop Scand*. 1997, 68, 104-108.
53. Solheim, E.; Pinholt, E. M.; Bang, G.; Sudmann, E. Ethylene oxide gas sterilization does not reduce the osteoinductive potential of demineralized bone in rats. *J Craniofac Surg*. 1995, 6, 195-198.
54. Lin, C.; Zhang, N.; Waldorff, E. I.; Punsalan, P.; Wang, D.; Semler, E.; Ryaby, J. T.; Yoo, J.; Johnstone, B. Comparing cellular bone matrices for posterolateral spinal fusion in a rat model. *JOR Spine*. 2020, 3, e1084.
55. Skovrlj, B.; Guzman, J. Z.; Al Maaieh, M.; Cho, S. K.; Iatridis, J. C.; Qureshi, S. A. Cellular bone matrices: viable stem cell-containing bone graft substitutes. *Spine J*. 2014, 14, 2763-2772.
56. Le, B. Q.; Nurcombe, V.; Cool, S. M.; van Blitterswijk, C. A.; de Boer, J.; LaPointe, V. L. S. The components of bone and what they can teach us about regeneration. *Materials (Basel)*. 2017, 11, 14.
57. Hayashi, T.; Lord, E. L.; Suzuki, A.; Takahashi, S.; Scott, T. P.; Phan, K.; Tian, H.; Daubs, M. D.; Shiba, K.; Wang, J. C. A comparison of commercially available demineralized bone matrices with and without human mesenchymal stem cells in a rodent spinal fusion model. *J Neurosurg Spine*. 2016, 25, 133-137.
58. Hart, N. H.; Nimphius, S.; Rantalainen, T.; Ireland, A.; Siafarikas, A.; Newton, R. U. Mechanical basis of bone strength: influence of bone material, bone structure and muscle action. *J Musculoskelet Neuronal Interact*. 2017, 17, 114-139.
59. Xia, Z.; Shi, Y.; He, H.; Pan, Y.; Liu, C. Development of biodegradable bone graft substitutes using 3D printing. In Developments and applications of calcium phosphate bone cements, Liu, C.; He, H., eds.; Springer Singapore: Singapore, 2018; pp 517-545.
60. Triffitt, J. T. A brief history of the development of stromal stem cells (stem cells of the skeleton). Biomater Transl. 2021, 2, 287-293.
61. Triffitt, J. T. Orthopaedic tissue engineering and stem cells - an unfulfilled promise. Biomater Transl. 2021, 2, 89-90.
62. Wright, A.; Arthaud-Day, M. L.; Weiss, M. L. Therapeutic use of mesenchymal stromal cells: the need for inclusive characterization guidelines to accommodate all tissue sources and species. Front Cell Dev Biol. 2021, 9, 632717.
63. Pereira Chilima, T. D.; Moncaubeig, F.; Farid, S. S. Impact of allogeneic stem cell manufacturing decisions on cost of goods, process robustness and reimbursement. Biochem Eng J. 2018, 137, 132-151.
64. Levy, O.; Kuai, R.; Siren, E. M. J.; Bhere, D.; Milton, Y.; Nissar, N.; De Biasio, M.; Heinelt, M.; Reeve, B.; Abdi, R.; Alturki, M.; Fallatah, M.; Almalik, A.; Alhasan, A. H.; Shah, K.; Karp, J. M. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. 2020, 6, eaba6884.
65. Fu, K.; Xu, Q.; Czernuszka, J.; Triffitt, J. T.; Xia, Z. Characterization of a biodegradable coralline hydroxyapatite/calcium carbonate composite and its clinical implementation. Biomed Mater. 2013, 8, 065007.
66. Koëter, S.; Tigchelaar, S. J.; Farla, P.; Driessen, L.; van Kampen, A.; Buma, P. Coralline hydroxyapatite is a suitable bone graft substitute in an intra-articular goat defect model. J Biomed Mater Res B Appl Biomater. 2009, 90, 116-122.
67. Ripamonti, U.; Crooks, J.; Khoali, L.; Roden, L. The induction of bone formation by coral-derived calcium carbonate/hydroxyapatite constructs. Biomaterials. 2009, 30, 1428-1439.
68. Viateau, V.; Manassero, M.; Sensébé, L.; Langonné, A.; Marchat, D.; Logeart-Avramoglou, D.; Petite, H.; Bensidhoum, M. Comparative study of the osteogenic ability of four different ceramic constructs in an ectopic large animal model. J Tissue Eng Regen Med. 2016, 10, E177-187.
69. Gao, T. J.; Lindholm, T. S.; Kommonen, B.; Ragni, P.; Paronzini, A.; Lindholm, T. C.; Jalovaara, P.; Urist, M. R. The use of a coral composite implant containing bone morphogenetic protein to repair a segmental tibial defect in sheep. Int Orthop. 1997, 21, 194-200.
70. Liang, X.; Song, E. The role of bone marrow stromal cells in blood diseases and clinical significance as a crucial part of the hematopoietic microenvironment. Ann Blood. 2020, 5, 2.
71. Mankani, M. H.; Kuznetsov, S. A.; Fowler, B.; Kingman, A.; Robey, P. G. In vivo bone formation by human bone marrow stromal cells: effect of carrier particle size and shape. Biotechnol Bioeng. 2001, 72, 96-107.
72. Zhou, Y. F.; Sae-Lim, V.; Chou, A. M.; Hutmacher, D. W.; Lim, T. M. Does seeding density affect in vitro mineral nodules formation in novel composite scaffolds? J Biomed Mater Res A. 2006, 78, 183-193.
73. Adamzyk, C.; Kachel, P.; Hoss, M.; Gremse, F.; Modabber, A.; Hölzle, F.; Tolba, R.; Neuss, S.; Lethaus, B. Bone tissue engineering using polyetherketoneketone scaffolds combined with autologous mesenchymal stem cells in a sheep calvarial defect model. J Craniomaxillofac Surg. 2016, 44, 985-994.
74. Caterson, E. J.; Nesti, L. J.; Danielson, K. G.; Tuan, R. S. Human marrow-derived mesenchymal progenitor cells: isolation, culture expansion, and analysis of differentiation. Mol Biotechnol. 2002, 20, 245-256.
75. Day, A. G. E.; Francis, W. R.; Fu, K.; Pieper, I. L.; Guy, O.; Xia, Z. Osteogenic potential of human umbilical cord mesenchymal stem cells on coralline hydroxyapatite/calcium carbonate microparticles. Stem Cells Int. 2018, 2018, 4258613.
76. Squillaro, T.; Peluso, G.; Galderisi, U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant. 2016, 25, 829-848.
77. Kern, S.; Eichler, H.; Stoeve, J.; Klüter, H.; Bieback, K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006, 24, 1294-1301.
78. Rebelatto, C. K.; Aguiar, A. M.; Moretão, M. P.; Senegaglia, A. C.; Hansen, P.; Barchiki, F.; Oliveira, J.; Martins, J.; Kuligovski, C.; Mansur, F.; Christofis, A.; Amaral, V. F.; Brofman, P. S.; Goldenberg, S.; Nakao, L. S.; Correa, A. Dissimilar differentiation of mesenchymal stem cells from bone marrow, umbilical cord blood, and adipose tissue. Exp Biol Med (Maywood). 2008, 233, 901-913.
79. Mohamed-Ahmed, S.; Fristad, I.; Lie, S. A.; Suliman, S.; Mustafa, K.; Vindenes, H.; Idris, S. B. Adipose-derived and bone marrow mesenchymal stem cells: a donor-matched comparison. Stem Cell Res Ther. 2018, 9, 168.
80. Zeddou, M.; Briquet, A.; Relic, B.; Josse, C.; Malaise, M. G.; Gothot, A.; Lechanteur, C.; Beguin, Y. The umbilical cord matrix is a better source of mesenchymal stem cells (MSC) than the umbilical cord blood. Cell Biol Int. 2010, 34, 693-701.
81. Mennan, C.; Garcia, J.; Roberts, S.; Hulme, C.; Wright, K. A comprehensive characterisation of large-scale expanded human bone marrow and umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 2019, 10, 99.
82. Zhang, Z. Y.; Teoh, S. H.; Chong, M. S.; Schantz, J. T.; Fisk, N. M.; Choolani, M. A.; Chan, J. Superior osteogenic capacity for bone tissue engineering of fetal compared with perinatal and adult mesenchymal stem cells. Stem Cells. 2009, 27, 126-137.
83. Mennan, C.; Wright, K.; Bhattacharjee, A.; Balain, B.; Richardson, J.; Roberts, S. Isolation and characterisation of mesenchymal stem cells from different regions of the human umbilical cord. Biomed Res Int. 2013, 2013, 916136.
84. Schneider, S.; Unger, M.; van Griensven, M.; Balmayor, E. R. Adipose-derived mesenchymal stem cells from liposuction and resected fat are feasible sources for regenerative medicine. Eur J Med Res. 2017, 22, 17.
85. Markarian, C. F.; Frey, G. Z.; Silveira, M. D.; Chem, E. M.; Milani, A. R.; Ely, P. B.; Horn, A. P.; Nardi, N. B.; Camassola, M. Isolation of adipose-derived stem cells: a comparison among different methods. Biotechnol Lett. 2014, 36, 693-702.
86. Choudhery, M. S.; Badowski, M.; Muise, A.; Pierce, J.; Harris, D. T. Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. J Transl Med. 2014, 12, 8.
87. Hasegawa, T.; Miwa, M.; Sakai, Y.; Niikura, T.; Lee, S. Y.; Oe, K.; Iwakura, T.; Kurosaka, M.; Komori, T. Efficient cell-seeding into scaffolds improves bone formation. J Dent Res. 2010, 89, 854-859.
88. Wilson, C. E.; Dhert, W. J.; Van Blitterswijk, C. A.; Verbout, A. J.; De Bruijn, J. D. Evaluating 3D bone tissue engineered constructs with different seeding densities using the alamarBlue assay and the effect on in vivo bone formation. J Mater Sci Mater Med. 2002, 13, 1265-1269.
89. Vunjak-Novakovic, G.; Obradovic, B.; Martin, I.; Bursac, P. M.; Langer, R.; Freed, L. E. Dynamic cell seeding of polymer scaffolds for cartilage tissue engineering. Biotechnol Prog. 1998, 14, 193-202.
90. Lode, A.; Bernhardt, A.; Gelinsky, M. Cultivation of human bone marrow stromal cells on three-dimensional scaffolds of mineralized collagen: influence of seeding density on colonization, proliferation and osteogenic differentiation. J Tissue Eng Regen Med. 2008, 2, 400-407.
91. Martin, I.; Wendt, D.; Heberer, M. The role of bioreactors in tissue engineering. Trends Biotechnol. 2004, 22, 80-86.
92. Grayson, W. L.; Bhumiratana, S.; Cannizzaro, C.; Vunjak-Novakovic, G. Bioreactor cultivation of functional bone grafts. Methods Mol Biol. 2011, 698, 231-241.
93. Gooch, K. J.; Kwon, J. H.; Blunk, T.; Langer, R.; Freed, L. E.; Vunjak-Novakovic, G. Effects of mixing intensity on tissue-engineered cartilage. Biotechnol Bioeng. 2001, 72, 402-407.
94. Temple, J. P.; Yeager, K.; Bhumiratana, S.; Vunjak-Novakovic, G.; Grayson, W. L. Bioreactor cultivation of anatomically shaped human bone grafts. Methods Mol Biol. 2014, 1202, 57-78.
95. Botchwey, E.; Ferrante, E.; Humphrey, J. Bioreactor-based bone tissue engineering. J Biomech. 2006, 39, S218.
96. O’Dea, R. D.; Byrne, H. M.; Waters, S. L. Continuum modelling of in vitro tissue engineering: a review. In Computational modeling in tissue engineering, Geris, L., ed. Springer Berlin Heidelberg: Berlin, Heidelberg, 2013; pp 229-266.
97. Burova, I.; Wall, I.; Shipley, R. J. Mathematical and computational models for bone tissue engineering in bioreactor systems. J Tissue Eng. 2019, 10, 2041731419827922.
98. Garg, P.; Mazur, M. M.; Buck, A. C.; Wandtke, M. E.; Liu, J.; Ebraheim, N. A. Prospective review of mesenchymal stem cells differentiation into osteoblasts. Orthop Surg. 2017, 9, 13-19.
99. Friedlaender, G. E.; Perry, C. R.; Cole, J. D.; Cook, S. D.; Cierny, G.; Muschler, G. F.; Zych, G. A.; Calhoun, J. H.; LaForte, A. J.; Yin, S. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001, 83-A Suppl 1, S151-158.
100. Fujioka-Kobayashi, M.; Kobayashi, E.; Schaller, B.; Mottini, M.; Miron, R. J.; Saulacic, N. Effect of recombinant human bone morphogenic protein 9 (rhBMP9) loaded onto bone grafts versus barrier membranes on new bone formation in a rabbit calvarial defect model. J Biomed Mater Res A. 2017, 105, 2655-2661.
101. Paralkar, V. M.; Grasser, W. A.; Mansolf, A. L.; Baumann, A. P.; Owen, T. A.; Smock, S. L.; Martinovic, S.; Borovecki, F.; Vukicevic, S.; Ke, H. Z.; Thompson, D. D. Regulation of BMP-7 expression by retinoic acid and prostaglandin E(2). J Cell Physiol. 2002, 190, 207-217.
102. Zhao, J.; Ohba, S.; Shinkai, M.; Chung, U. I.; Nagamune, T. Icariin induces osteogenic differentiation in vitro in a BMP- and Runx2-dependent manner. Biochem Biophys Res Commun. 2008, 369, 444-448.
103. Cao, H.; Ke, Y.; Zhang, Y.; Zhang, C. J.; Qian, W.; Zhang, G. L. Icariin stimulates MC3T3-E1 cell proliferation and differentiation through up-regulation of bone morphogenetic protein-2. Int J Mol Med. 2012, 29, 435-439.
104. Xie, L.; Liu, N.; Xiao, Y.; Liu, Y.; Yan, C.; Wang, G.; Jing, X. In vitro and in vivo osteogenesis induced by icariin and bone morphogenetic protein-2: a dynamic observation. Front Pharmacol. 2020, 11, 1058.
105. Loozen, L. D.; Kruyt, M. C.; Kragten, A. H. M.; Schoenfeldt, T.; Croes, M.; Oner, C. F.; Dhert, W. J. A.; Alblas, J. BMP-2 gene delivery in cell-loaded and cell-free constructs for bone regeneration. PLoS One. 2019, 14, e0220028.
106. Park, S. Y.; Kim, K. H.; Kim, S.; Lee, Y. M.; Seol, Y. J. BMP-2 gene delivery-based bone regeneration in dentistry. Pharmaceutics. 2019, 11, 393.
107. Loozen, L. D.; Vandersteen, A.; Kragten, A. H.; Öner, F. C.; Dhert, W. J.; Kruyt, M. C.; Alblas, J. Bone formation by heterodimers through non-viral gene delivery of BMP-2/6 and BMP-2/7. Eur Cell Mater. 2018, 35, 195-208.
108. Rose, L. C.; Kucharski, C.; Uludağ, H. Protein expression following non-viral delivery of plasmid DNA coding for basic FGF and BMP-2 in a rat ectopic model. Biomaterials. 2012, 33, 3363-3374.
109. Nie, X.; Wang, D. A. Decellularized orthopaedic tissue-engineered grafts: biomaterial scaffolds synthesised by therapeutic cells. Biomater Sci. 2018, 6, 2798-2811.
110. Shi, Y. Allografts combined with tissue derived stem cells for bone healing. Patent No. US20100124776A1. 2017.
112. Office of the Federal Register. 21 CFR 872.3930 - Bone grafting material. National Archives and Records Administration. 2012.
113. ISO 10993-1:2018. Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process.
114. Hu, Y.; Zhao, Q. W.; Wang, Z. C.; Fang, Q. Q.; Zhu, H.; Hong, D. S.; Liang, X. G.; Lou, D.; Tan, W. Q. Co-transfection with BMP2 and FGF2 via chitosan nanoparticles potentiates osteogenesis in human adipose-derived stromal cells in vitro. J Int Med Res. 2021, 49, 300060521997679.
