Skeletal organoids
The skeletal system, composed of bones, muscles, joints, ligaments, and tendons, serves as the foundation for maintaining human posture, mobility, and overall biomechanical functionality. However, with ageing, chronic overuse, and acute injuries, conditions such as osteoarthritis, intervertebral disc degeneration, muscle atrophy, and ligament or tendon tears have become increasingly prevalent and pose serious clinical challenges. These disorders not only result in pain, functional loss, and a marked reduction in patients’ quality of life but also impose substantial social and economic burdens. Current treatment modalities, including surgical intervention, pharmacotherapy, and physical rehabilitation, often do not effectively restore the functionality of damaged tissues and are associated with high recurrence rates and long–term complications, highlighting significant limitations in their efficacy. Thus, there is a strong demand to develop novel and more effective therapeutic and reparative strategies. Organoid technology, as a three–dimensional micro–tissue model, can replicate the structural and functional properties of native tissues in vitro, providing a novel platform for in–depth studies of disease mechanisms, optimisation of drug screening, and promotion of tissue regeneration. In recent years, substantial advancements have been made in the research of bone, muscle, and joint organoids, demonstrating their broad application potential in personalised and regenerative medicine. Nonetheless, a comprehensive review of current research on skeletal organoids is still lacking. Therefore, this article aims to present an overview of the definition and technological foundation of organoids, systematically summarise the progress in the construction and application of skeletal organoids, and explore future opportunities and challenges in this field, offering valuable insights and references for researchers.
Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.
1. Abraham DM, Herman C, Witek L, Cronstein BN, Flores RL, Coelho PG. Self - assembling human skeletal organoids for disease modeling and drug testing. J Biomed Mater Res B Appl Biomater. 2022;110:871 - 884.
2. Shahriyari M, Islam MR, Sakib SM, Rinn M, Rika A, Krüger D, Kaurani L, Gisa V, Winterhoff M, Anandakumar H, Shomroni O, Schmidt M, Salinas G, Unger A, Linke WA, Zschüntzsch J, Schmidt J, Bassel - Duby R, Olson EN, Fischer A, Zimmermann WH, Tiburcy M. Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy. J Cachexia Sarcopenia Muscle. 2022;13:3106 - 3121.
3. Davies JA. Chapter 1 - Organoids and mini - organs: Introduction, history, and potential. In Organoids and Mini - Organs, Davies JA, Lawrence ML, eds. Academic Press: 2018; pp 3 - 23.
4. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663 - 676.
5. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Single Lgr5 stem cells build crypt - villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262 - 265.
6. Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T, Sasai Y. Self - organizing optic - cup morphogenesis in three - dimensional culture. Nature. 2011;472:51 - 56.
7. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373 - 379.
8. Post Y, Puschhof J, Beumer J, Kerkkamp HM, de Bakker MAG, Slagboom J, de Barbanson B, Wevers NR, Spijkers XM, Olivier T, Kazandjian TD, Ainsworth S, Iglesias CL, van de Wetering WJ, Heinz MC, van Ineveld RL, van Kleef R, Begthel H, Korving J, Bar - Ephraim YE, Getreuer W, Rios AC, Westerink RHS, Snippert HJG, van Oudenaarden A, Peters PJ, Vonk FJ, Kool J, Richardson MK, Casewell NR, Clevers H. Snake venom gland organoids. Cell. 2020;180:233 - 247.e21.
9. Tam WL, Freitas Mendes L, Chen X, Lesage R, Van Hoven I, Leysen E, Kerckhofs G, Bosmans K, Chai YC, Yamashita A, Tsumaki N, Geris L, Roberts SJ, Luyten FP. Human pluripotent stem cell - derived cartilaginous organoids promote scaffold - free healing of critical size long bone defects. Stem Cell Res Ther. 2021;12:513.
10. Wang J, Wu Y, Li G, Zhou F, Wu X, Wang M, Liu X, Tang H, Bai L, Geng Z, Song P, Shi Z, Ren X, Su J. Engineering large - scale self - mineralizing bone organoids with bone matrix - inspired hydroxyapatite hybrid bioinks. Adv Mater. 2024;36:e2309875.
11. Cable J, Fuchs E, Weissman I, Jasper H, Glass D, Rando TA, Blau H, Debnath S, Oliva A, Park S, Passegué E, Kim C, Krasnow MA. Adult stem cells and regenerative medicine - a symposium report. Ann N Y Acad Sci. 2020;1462:27 - 36.
12. Doss MX, Sachinidis A. Current challenges of iPSC - based disease modeling and therapeutic implications. Cells. 2019;8:403.
13. Omole AE, Fakoya AOJ. Ten years of progress and promise of induced pluripotent stem cells: historical origins, characteristics, mechanisms, limitations, and potential applications. PeerJ. 2018;6:e4370.
14. Qian S, Mao J, Liu Z, Zhao B, Zhao Q, Lu B, Zhang L, Mao X, Cheng L, Cui W, Zhang Y, Sun X. Stem cells for organoids. Smart Med. 2022;1:e20220007.
15. Wu S, Wu X, Wang X, Su J. Hydrogels for bone organoid construction: From a materiobiological perspective. J Mater Sci Technol. 2023;136:21 - 31.
16. Ma P, Chen Y, Lai X, Zheng J, Ye E, Loh XJ, Zhao Y, Parikh BH, Su X, You M, Wu YL, Li Z. The translational application of hydrogel for organoid technology: challenges and future perspectives. Macromol Biosci. 2021;21:e2100191.
17. Catoira MC, Fusaro L, Di Francesco D, Ramella M, Boccafoschi F. Overview of natural hydrogels for regenerative medicine applications. J Mater Sci Mater Med. 2019;30:115.
18. Kozlowski MT, Crook CJ, Ku HT. Towards organoid culture without Matrigel. Commun Biol. 2021;4:1387.
19. Jee JH, Lee DH, Ko J, Hahn S, Jeong SY, Kim HK, Park E, Choi SY, Jeong S, Lee JW, Cho HJ, Kwon MS, Yoo J. Development of collagen - based 3D matrix for gastrointestinal tract - derived organoid culture. Stem Cells Int. 2019;2019:8472712.
20. Ye W, Luo C, Li C, Huang J, Liu F. Organoids to study immune functions, immunological diseases and immunotherapy. Cancer Lett. 2020;477:31 - 40.
21. Li C, Zhang Y, Du Y, Hou Z, Zhang Y, Cui W, Chen W. A review of advanced biomaterials and cells for the production of bone organoid. Small Sci. 2023;3:2370015.
22. Madduma - Bandarage USK, Madihally SV. Synthetic hydrogels: synthesis, novel trends, and applications. J Appl Polym Sci. 2021;138:50376.
23. Aisenbrey EA, Murphy WL. Synthetic alternatives to Matrigel. Nat Rev Mater. 2020;5:539 - 551.
24. Wilson RL, Swaminathan G, Ettayebi K, Bomidi C, Zeng XL, Blutt SE, Estes MK, Grande - Allen KJ. Protein - functionalized poly(ethylene glycol) hydrogels as scaffolds for monolayer organoid culture. Tissue Eng Part C Methods. 2021;27:12 - 23.
25. Jin S, Xia X, Huang J, Yuan C, Zuo Y, Li Y, Li J. Recent advances in PLGA - based biomaterials for bone tissue regeneration. Acta Biomater. 2021;127:56 - 79.
26. Wozney JM, Rosen V, Byrne M, Celeste AJ, Moutsatsos I, Wang EA. Growth factors influencing bone development. J Cell Sci Suppl. 1990;13:149 - 156.
27. Tortorella I, Argentati C, Emiliani C, Martino S, Morena F. The role of physical cues in the development of stem cell - derived organoids. Eur Biophys J. 2022;51:105 - 117.
28. Farokhi M, Mottaghitalab F, Shokrgozar MA, Ou KL, Mao C, Hosseinkhani H. Importance of dual delivery systems for bone tissue engineering. J Control Release. 2016;225:152 - 169.
29. Olszta MJ, Cheng X, Jee SS, Kumar R, Kim YY, Kaufman MJ, Douglas EP, Gower LB. Bone structure and formation: A new perspective. Mater Sci Eng R Rep. 2007;58:77 - 116.
30. Buckwalter JA, Glimcher MJ, Cooper RR, Recker R. Bone biology. JBJS. 1995;77:1276 - 1289.
31. Buck DW 2nd, Dumanian GA. Bone biology and physiology: Part I. The fundamentals. Plast Reconstr Surg. 2012;129:1314 - 1320.
32. Huang J, Zhang L, Lu A, Liang C. Organoids as innovative models for bone and joint diseases. Cells. 2023;12:1590.
33. Grabowski P. Physiology of bone. In Calcium and bone disorders in children and adolescents. Allgrove J, Shaw N, eds. Karger Publishers: 2009; Vol. 16, pp 32 - 48.
34. Porter JR, Ruckh TT, Popat KC. Bone tissue engineering: a review in bone biomimetics and drug delivery strategies. Biotechnol Prog. 2009;25:1539 - 1560.
35. Li B, Shi Y, Liu M, Wu F, Hu X, Yu F, Wang C, Ye L. Attenuates of NAD(+) impair BMSC osteogenesis and fracture repair through OXPHOS. Stem Cell Res Ther. 2022;13:77.
36. Vallmajo-Martin Q, Broguiere N, Millan C, Zenobi-Wong M, Ehrbar M. PEG/HA hybrid hydrogels for biologically and mechanically tailorable bone marrow organoids. Adv Funct Mater. 2020;30:1910282.
37. Li M, Liu W, Sun J, Xianyu Y, Wang J, Zhang W, Zheng W, Huang D, Di S, Long YZ, Jiang X. Culturing primary human osteoblasts on electrospun poly(lactic-co-glycolic acid) and poly(lactic-co-glycolic acid)/nanohydroxyapatite scaffolds for bone tissue engineering. ACS Appl Mater Interfaces. 2013;5:5921 - 5926.
38. Schmidt-Bleek K, Willie BM, Schwabe P, Seemann P, Duda GN. BMPs in bone regeneration: less is more effective, a paradigm - shift. Cytokine Growth Factor Rev. 2016;27:141 - 148.
39. Akiva A, Melke J, Ansari S, Liv N, van der Meijden R, van Erp M, Zhao F, Stout M, Nijhuis WH, de Heus C, Muñiz Ortera C, Fermie J, Klumperman J, Ito K, Sommerdijk N, Hofmann S. An organoid for woven bone. Adv Funct Mater. 2021;31:2010524.
40. Hospodiuk M, Dey M, Sosnoski D, Ozbolat IT. The bioink: a comprehensive review on bioprintable materials. Biotechnol Adv. 2017;35:217 - 239.
41. Papadimitropoulos A, Scherberich A, Güven S, Theilgaard N, Crooijmans HJ, Santini F, Scheffler K, Zallone A, Martin I. A 3D in vitro bone organ model using human progenitor cells. Eur Cell Mater. 2011;21:445 - 458; discussion 458.
42. Han Y, Wu Y, Wang F, Li G, Wang J, Wu X, Deng A, Ren X, Wang X, Gao J, Shi Z, Bai L, Su J. Heterogeneous DNA hydrogel loaded with Apt02 modified tetrahedral framework nucleic acid accelerated critical - size bone defect repair. Bioact Mater. 2024;35:1 - 16.
43. Yuasa M, Yamada T, Taniyama T, Masaoka T, Xuetao W, Yoshii T, Horie M, Yasuda H, Uemura T, Okawa A, Sotome S. Dexamethasone enhances osteogenic differentiation of bone marrow - and muscle - derived stromal cells and augments ectopic bone formation induced by bone morphogenetic protein - 2. PLoS One. 2015;10:e0116462.
44. Park Y, Cheong E, Kwak JG, Carpenter R, Shim JH, Lee J. Trabecular bone organoid model for studying the regulation of localized bone remodeling. Sci Adv. 2021;7:eabd6495.
45. Xie C, Liang R, Ye J, Peng Z, Sun H, Zhu Q, Shen X, Hong Y, Wu H, Sun W, Yao X, Li J, Zhang S, Zhang X, Ouyang H. High - efficient engineering of osteo - callus organoids for rapid bone regeneration within one month. Biomaterials. 2022;288:121741.
46. Visconti RJ, Kolaja K, Cottrell JA. A functional three - dimensional microphysiological human model of myeloma bone disease. J Bone Miner Res. 2021;36:1914 - 1930.
47. Iordachescu A, Hughes EAB, Joseph S, Hill EJ, Grover LM, Metcalfe AD. Trabecular bone organoids: a micron - scale ‘humanised’ prototype designed to study the effects of microgravity and degeneration. NPJ Microgravity. 2021;7:17.
48. Gupta N, Liu JR, Patel B, Solomon DE, Vaidya B, Gupta V. Microfluidics - based 3D cell culture models: Utility in novel drug discovery and delivery research. Bioeng Transl Med. 2016;1:63 - 81.
49. Frontera WR, Ochala J. Skeletal muscle: a brief review of structure and function. Calcif Tissue Int. 2015;96:183 - 195.
50. Au Y. The muscle ultrastructure: a structural perspective of the sarcomere. Cell Mol Life Sci. 2004;61:3016 - 3033.
51. Vandenburgh H, Shansky J, Del Tatto M, Chromiak J. Organogenesis of skeletal muscle in tissue culture. Methods Mol Med. 1999;18:217 - 225.
52. Sinacore DR, Gulve EA. The role of skeletal muscle in glucose transport, glucose homeostasis, and insulin resistance: implications for physical therapy. Phys Ther. 1993;73:878 - 891.
53. Powell CA, Smiley BL, Mills J, Vandenburgh HH. Mechanical stimulation improves tissue - engineered human skeletal muscle. Am J Physiol Cell Physiol. 2002;283:C1557 - 1565.
54. Kindler U, Zaehres H, Mavrommatis L. Generation of skeletal muscle organoids from human pluripotent stem cells. Bio Protoc. 2024;14:e4984.
55. Otto A, Schmidt C, Luke G, Allen S, Valasek P, Muntoni F, Lawrence - Watt D, Patel K. Canonical Wnt signalling induces satellite - cell proliferation during adult skeletal muscle regeneration. J Cell Sci. 2008;121:2939 - 2950.
56. Vandenburgh H, Del Tatto M, Shansky J, Lemaire J, Chang A, Payumo F, Lee P, Goodyear A, Raven L. Tissue - engineered skeletal muscle organoids for reversible gene therapy. Hum Gene Ther. 1996;7:2195 - 2200.
57. Shin MK, Bang JS, Lee JE, Tran HD, Park G, Lee DR, Jo J. Generation of skeletal muscle organoids from human pluripotent stem cells to model myogenesis and muscle regeneration. Int J Mol Sci. 2022;23:5108.
58. Shahriyari M, Rinn M, Hofemeier AD, Babych A, Zimmermann WH, Tiburcy M. Protocol to develop force - generating human skeletal muscle organoids. STAR Protoc. 2024;5:102794.
59. Borok MJ, Mademtzoglou D, Relaix F. Bu - M - P - ing iron: how BMP signaling regulates muscle growth and regeneration. J Dev Biol. 2020;8:4.
60. Sartori R, Schirwis E, Blaauw B, Bortolanza S, Zhao J, Enzo E, Stantzou A, Mouisel E, Toniolo L, Ferry A, Stricker S, Goldberg AL, Dupont S, Piccolo S, Amthor H, Sandri M. BMP signaling controls muscle mass. Nat Genet. 2013;45:1309 - 1318.
61. Pawlikowski B, Vogler TO, Gadek K, Olwin BB. Regulation of skeletal muscle stem cells by fibroblast growth factors. Dev Dyn. 2017;246:359 - 367.
62. Mavrommatis L, Jeong HW, Kindler U, Gomez - Giro G, Kienitz MC, Stehling M, Psathaki OE, Zeuschner D, Bixel MG, Han D, Morosan - Puopolo G, Gerovska D, Yang JH, Kim JB, Arauzo - Bravo MJ, Schwamborn JC, Hahn SA, Adams RH, Schöler HR, Vorgerd M, Brand - Saberi B, Zaehres H. Human skeletal muscle organoids model fetal myogenesis and sustain uncommitted PAX7 myogenic progenitors. Elife. 2023;12:RP87081.
63. Pinton L, Khedr M, Lionello VM, Sarcar S, Maffioletti SM, Dastidar S, Negroni E, Choi S, Khokhar N, Bigot A, Counsell JR, Bernardo AS, Zammit PS, Tedesco FS. 3D human induced pluripotent stem cell - derived bioengineered skeletal muscles for tissue, disease and therapy modeling. Nat Protoc. 2023;18:1337 - 1376.
64. Wang J, Zhou CJ, Khodabukus A, Tran S, Han SO, Carlson AL, Madden L, Kishnani PS, Koeberl DD, Bursac N. Three - dimensional tissue - engineered human skeletal muscle model of Pompe disease. Commun Biol. 2021;4:524.
65. Gholobova D, Gerard M, Decroix L, Desender L, Callewaert N, Annaert P, Thorrez L. Human tissue - engineered skeletal muscle: a novel 3D in vitro model for drug disposition and toxicity after intramuscular injection. Sci Rep. 2018;8:12206.
66. Vandenburgh H, Shansky J, Benesch - Lee F, Barbata V, Reid J, Thorrez L, Valentini R, Crawford G. Drug - screening platform based on the contractility of tissue - engineered muscle. Muscle Nerve. 2008;37:438 - 447.
67. Duan D, Goemans N, Takeda S, Mercuri E, Aartsma - Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7:13.
68. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC. Amyotrophic lateral sclerosis. Lancet. 2011;377:942 - 955.
69. Bombieri C, Corsi A, Trabetti E, Ruggiero A, Marchetto G, Vattemi G, Valenti MT, Zipeto D, Romanelli MG. Advanced cellular models for rare disease study: exploring neural, muscle and skeletal organoids. Int J Mol Sci. 2024;25:1014.
70. Osaki T, Uzel SGM, Kamm RD. Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS - derived muscle cells and optogenetic motor neurons. Sci Adv. 2018;4:eaat5847.
71. Chen Z, Li B, Zhan RZ, Rao L, Bursac N. Exercise mimetics and JAK inhibition attenuate IFN - γ - induced wasting in engineered human skeletal muscle. Sci Adv. 2021;7:eabd9502.
72. Makris EA, Gomoll AH, Malizos KN, Hu JC, Athanasiou KA. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol. 2015;11:21 - 34.
73. Zhu J, Lun W, Feng Q, Cao X, Li Q. Mesenchymal stromal cells modulate YAP by verteporfin to mimic cartilage development and construct cartilage organoids based on decellularized matrix scaffolds. J Mater Chem B. 2023;11:7442 - 7453.
74. Zhang Y, Li G, Wang J, Zhou F, Ren X, Su J. Small joint organoids 3D bioprinting: construction strategy and application. Small. 2024;20:e2302506.
75. Ralphs JR, Benjamin M. The joint capsule: structure, composition, ageing and disease. J Anat. 1994;184 (Pt 3):503 - 509.
76. Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: structure, composition, and function. Sports Health. 2009;1:461 - 468.
77. Forrester DM. Diagnosis of Bone and Joint Disorders. Donald Resnick, MD and Gen Niwayama, MD. 3 Volumes. Philadelphia, W. B. Saunders, 1981. 3277 pages, 2670 illustrations, $295. Arthritis Rheum. 1982;25:480.
78. O’Connor SK, Katz DB, Oswald SJ, Groneck L, Guilak F. Formation of osteochondral organoids from murine induced pluripotent stem cells. Tissue Eng Part A. 2021;27:1099 - 1109.
79. Lin W, Wang M, Xu L, Tortorella M, Li G. Cartilage organoids for cartilage development and cartilage - associated disease modeling. Front Cell Dev Biol. 2023;11:1125405.
80. Sun Y, Wu Q, Dai K, You Y, Jiang W. Generating 3D - cultured organoids for pre - clinical modeling and treatment of degenerative joint disease. Signal Transduct Target Ther. 2021;6:380.
81. Sun Y, You Y, Wu Q, Hu R, Dai K. Senescence - targeted MicroRNA/Organoid composite hydrogel repair cartilage defect and prevention joint degeneration via improved chondrocyte homeostasis. Bioact Mater. 2024;39:427 - 442.
82. Rothbauer M, Byrne RA, Schobesberger S, Olmos Calvo I, Fischer A, Reihs EI, Spitz S, Bachmann B, Sevelda F, Holinka J, Holnthoner W, Redl H, Toegel S, Windhager R, Kiener HP, Ertl P. Establishment of a human three - dimensional chip - based chondro - synovial coculture joint model for reciprocal cross - talk studies in arthritis research. Lab Chip. 2021;21:4128 - 4143.
83. Kleuskens MWA, Crispim JF, van Doeselaar M, van Donkelaar CC, Janssen RPA, Ito K. Neo - cartilage formation using human non - degenerate versus osteoarthritic chondrocyte - derived cartilage organoids in a viscoelastic hydrogel. J Orthop Res. 2023;41:1902 - 1915.
84. Hall GN, Tam WL, Andrikopoulos KS, Casas - Fraile L, Voyiatzis GA, Geris L, Luyten FP, Papantoniou I. Patterned, organoid - based cartilaginous implants exhibit zone specific functionality forming osteochondral - like tissues in vivo. Biomaterials. 2021;273:120820.
85. Giobbe GG, Crowley C, Luni C, Campinoti S, Khedr M, Kretzschmar K, De Santis MM, Zambaiti E, Michielin F, Meran L, Hu Q, van Son G, Urbani L, Manfredi A, Giomo M, Eaton S, Cacchiarelli D, Li VSW, Clevers H, Bonfanti P, Elvassore N, De Coppi P. Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture. Nat Commun. 2019;10:5658.
86. Deng Y, Lei G, Lin Z, Yang Y, Lin H, Tuan RS. Engineering hyaline cartilage from mesenchymal stem cells with low hypertrophy potential via modulation of culture conditions and Wnt/β - catenin pathway. Biomaterials. 2019;192:569 - 578.
87. Li ZA, Sant S, Cho SK, Goodman SB, Bunnell BA, Tuan RS, Gold MS, Lin H. Synovial joint - on - a - chip for modeling arthritis: progress, pitfalls, and potential. Trends Biotechnol. 2023;41:511 - 527.
88. Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA. Osteoarthritis - an untreatable disease? Nat Rev Drug Discov. 2005;4:331 - 344.
89. Richard MJ, Driban JB, McAlindon TE. Pharmaceutical treatment of osteoarthritis. Osteoarthritis Cartilage. 2023;31:458 - 466.
90. Li ZA, Shang J, Xiang S, Li EN, Yagi H, Riewruja K, Lin H, Tuan RS. Articular tissue - mimicking organoids derived from mesenchymal stem cells and induced pluripotent stem cells. Organoids. 2022;1:135 - 148.
91. Lim WL, Liau LL, Ng MH, Chowdhury SR, Law JX. Current progress in tendon and ligament tissue engineering. Tissue Eng Regen Med. 2019;16:549 - 571.
92. Kannus P. Structure of the tendon connective tissue. Scand J Med Sci Sports. 2000;10:312 - 320.
93. Amiel D, Frank C, Harwood F, Fronek J, Akeson W. Tendons and ligaments: a morphological and biochemical comparison. J Orthop Res. 1984;1:257 - 265.
94. Koski JA, Ibarra C, Rodeo SA. Tissue - engineered ligament: cells, matrix, and growth factors. Orthop Clin North Am. 2000;31:437 - 452.
95. Xu B, Chow MJ, Zhang Y. Experimental and modeling study of collagen scaffolds with the effects of cross - linking and fiber alignment. Int J Biomater. 2011;2011:172389.
96. Randelli P, Spennacchio P, Ragone V, Arrigoni P, Casella A, Cabitza P. Complications associated with arthroscopic rotator cuff repair: a literature review. Musculoskelet Surg. 2012;96:9 - 16.
97. Laternser S, Keller H, Leupin O, Rausch M, Graf - Hausner U, Rimann M. A novel microplate 3D bioprinting platform for the engineering of muscle and tendon tissues. SLAS Technol. 2018;23:599 - 613.
98. Hsieh MS, Chen MY, Chang YS, Huang CS, Hsu TN, Huang MS, Yeh CT, Tzeng YM. Targeting the Neuropilin - 1 receptor with Ovatodiolide and progress in using periodontal ligament organoids for COVID - 19 research and therapy. Life Sci. 2024;351:122764.
99. Graça AL, Kroner - Weigl N, Reyes Alcaraz V, Müller - Deubert S, Rudert M, Docheva D. Demonstration of self - assembled cell sheet culture and manual generation of a 3d tendon/ligament - like organoid by using human dermal fibroblasts. J Vis Exp. 2024;e66047.
100. Donderwinkel I, Tuan RS, Cameron NR, Frith JE. Tendon tissue engineering: Current progress towards an optimized tenogenic differentiation protocol for human stem cells. Acta Biomater. 2022;145:25 - 42.
101. Kirkendall DT, Garrett WE. Function and biomechanics of tendons. Scand J Med Sci Sports. 1997;7:62 - 66.
102. Petrigliano FA, Arom GA, Nazemi AN, Yeranosian MG, Wu BM, McAllister DR. In vivo evaluation of electrospun polycaprolactone graft for anterior cruciate ligament engineering. Tissue Eng Part A. 2015;21:1228 - 1236.
103. Chainani A, Hippensteel KJ, Kishan A, Garrigues NW, Ruch DS, Guilak F, Little D. Multilayered electrospun scaffolds for tendon tissue engineering. Tissue Eng Part A. 2013;19:2594 - 2604.
104. Yang G, Rothrauff BB, Lin H, Yu S, Tuan RS. Tendon - derived extracellular matrix enhances transforming growth factor - β3 - induced tenogenic differentiation of human adipose - derived stem cells. Tissue Eng Part A. 2017;23:166 - 176.
105. Ker DFE, Tan C, Cartmell S. Editorial: Tendons and ligaments: development, pathogenesis, tissue engineering, and regenerative medicine. Front Bioeng Biotechnol. 2024;12:1489256.
106. Lejard V, Blais F, Guerquin MJ, Bonnet A, Bonnin MA, Havis E, Malbouyres M, Bidaud CB, Maro G, Gilardi - Hebenstreit P, Rossert J, Ruggiero F, Duprez D. EGR1 and EGR2 involvement in vertebrate tendon differentiation. J Biol Chem. 2011;286:5855 - 5867.
107. Bourdón - Santoyo M, Quiñones - Uriostegui I, Martínez - López V, Sánchez - Arévalo F, Alessi - Montero A, Velasquillo C, Ibarra - Ponce de León C. Preliminary study of an in vitro development of new tissue applying mechanical stimulation with a bioreactor as an alternative for ligament reconstruction. Rev Invest Clin. 2014;66 Suppl 1:S100 - 110.
108. Zhang Y, Lei T, Tang C, Chen Y, Liao Y, Ju W, Zhang H, Zhou B, Liang R, Zhang T, Fan C, Chen X, Zhao Y, Xie Y, Ye J, Heng BC, Chen X, Hong Y, Shen W, Yin Z. 3D printing of chemical - empowered tendon stem/progenitor cells for functional tissue repair. Biomaterials. 2021;271:120722.
109. Qiu Y, Lei J, Koob TJ, Temenoff JS. Cyclic tension promotes fibroblastic differentiation of human MSCs cultured on collagen - fibre scaffolds. J Tissue Eng Regen Med. 2016;10:989 - 999.
110. Yan Z, Yin H, Brochhausen C, Pfeifer CG, Alt V, Docheva D. Aged tendon stem/progenitor cells are less competent to form 3D tendon organoids due to cell autonomous and matrix production deficits. Front Bioeng Biotechnol. 2020;8:406.
111. Fang G, Chen YC, Lu H, Jin D. Advances in spheroids and organoids on a chip. Adv Funct Mater. 2023;33:2215043.
112. Mansoorifar A, Gordon R, Bergan R, Bertassoni LE. Bone - on - a - chip: microfluidic technologies and microphysiologic models of bone tissue. Adv Funct Mater. 2021;31:2006796.
113. Perkhofer L, Frappart PO, Müller M, Kleger A. Importance of organoids for personalized medicine. Per Med. 2018;15:461 - 465.
114. Driehuis E, van Hoeck A, Moore K, Kolders S, Francies HE, Gulersonmez MC, Stigter ECA, Burgering B, Geurts V, Gracanin A, Bounova G, Morsink FH, Vries R, Boj S, van Es J, Offerhaus GJA, Kranenburg O, Garnett MJ, Wessels L, Cuppen E, Brosens LAA, Clevers H. Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. Proc Natl Acad Sci U S A. 2019;116:26580 - 26590.
115. Zhu Y, Tang S, Yuan Q, Fu J, He J, Liu Z, Zhao X, Li Y, Zhao Y, Zhang Y, Zhang X, Zhang Y, Zhu Y, Wang W, Zheng B, Wu R, Wu T, Yang S, Qiu X, Shen S, Hu J, Chen L, Wang Y, Wang H, Gao D, Chen L. Integrated characterization of hepatobiliary tumor organoids provides a potential landscape of pharmacogenomic interactions. Cell Rep Med. 2024;5:101375.
116. Wang Y, You Y, Chen H, Liu J, Wu Q, Dai K, Sun Y. 3D - bioprinted anti - senescence organoid scaffolds repair cartilage defect and prevent joint degeneration via miR - 23b/ELOVL5 - mediated metabolic rewiring. Chem Eng J. 2024;491:152049.
117. Shen C, Wang J, Li G, Hao S, Wu Y, Song P, Han Y, Li M, Wang G, Xu K, Zhang H, Ren X, Jing Y, Yang R, Geng Z, Su J. Boosting cartilage repair with silk fibroin - DNA hydrogel - based cartilage organoid precursor. Bioact Mater. 2024;35:429 - 444.