The temporomandibular joint (TMJ) disc is a structurally heterogeneous fibrocartilaginous tissue characterized by sparse vascularity and inherently limited regenerative capacity. Although tissue engineering strategies have made significant progress in promoting TMJ disc regeneration, the resulting neotissue often fails to fully recapitulate the native tissue’s biomechanical properties and ultrastructure. To enhance the functional integration of cells with scaffolds and engineer fibrocartilage that closely mimics native structure of the TMJ disc, the development of biomimetic scaffolds capable of recapitulating both structural heterogeneity and anisotropy has emerged as a pivotal focus in tissue regeneration research. This article presents a systematic overview of the current state of application and challenges of biological scaffolds in fibrocartilage regeneration research, focusing on five key domains: micro-mechanically guided anisotropic biomimetic scaffolds, functionally modified decellularized extracellular matrix (dECM), immunomodulatory composite scaffolds, scaffold pore architecture, and spatiotemporally controlled delivery systems. Collectively, these advances lay a robust theoretical foundation and experimental framework for the rational design of biomimetic scaffolds in TMJ disc tissue engineering.
WerncuiCShipinZTimothyJS, et al.Distribution of pericellular matrix molecules in the temporomandibular joint and their chondroprotective effects against inflammation. Int J Oral Sci2017; 9: 43–52.
2.
LeeJDBeckerJILarkinLM, et al.Morphologic and histologic characterization of sheep and porcine TMJ as large animal models for tissue engineering applications. Clin Oral Invest2022; 26(7): 5019–5027. https://doi.org/10.1007/s00784-022-04472-3
3.
TalaatWMAdelOIAl BayattiS. Prevalence of temporomandibular disorders discovered incidentally during routine dental examination using the research diagnostic criteria for temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol2017; 125(3): 250–259. https://doi.org/10.1016/j.oooo.2017.11.012
4.
LiuXXingL. Classification of the temporomandibular joint disc displacement without reduction using MRI in the mouth-opening position. Clin Oral Invest2025; 29(6): 322. https://doi.org/10.1007/s00784-025-06408-z
5.
BuenoSSanovichR. Superficial musculoaponeurotic system interpositional graft after temporomandibular joint discectomy. Int J Oral Maxillofac Surg2024; 53(12): 1062–1064. https://doi.org/10.1016/j.ijom.2024.06.004
6.
WangXLiuFWangT, et al.Applications of hydrogels in tissue-engineered repairing of temporomandibular joint diseases. Biomater Sci2024; 12(10): 2579–2598. https://doi.org/10.1039/d3bm01687k
7.
MercuriLG. Costochondral graft versus total alloplastic joint for temporomandibular joint reconstruction. Oral Maxillofac Surg Clin2018; 30: 335–342. https://doi.org/10.1016/j.coms.2018.05.003
ZhaoYLiCHuS, et al.In vitro differentiation of human induced pluripotent stem cells into temporomandibular joint disc-like cells. Heliyon2023; 10(1): e23937. https://doi.org/10.1016/j.heliyon.2023.e23937
10.
TrindadeDCordeiroRJoseHC, et al.Biological treatments for temporo-Mandibular joint disc disorders: strategies in tissue engineering biomolecules. Biomolecules2021; 11(7): 933. https://doi.org/10.3390/biom11070933
11.
HuSYiYYeC, et al.Advances in 3D printing techniques for cartilage regeneration of temporomandibular joint disc and mandibular condyle. Int J Bioprint2023; 9(5): 761. https://doi.org/10.18063/ijb.761
12.
JiangNChenHZhangJ, et al.Decellularized-disc based allograft and xenograft prosthesis for the long-term precise reconstruction of temporomandibular joint disc. Acta Biomater2023; 159: 173–187. https://doi.org/10.1016/j.actbio.2023.01.042
13.
ZiqiGYifanZYekeW, et al.Three-dimensional, biomimetic electrospun scaffolds reinforced with carbon nanotubes for temporomandibular joint disc regeneration. Acta Biomater2022; 147: 221–234.
14.
VapniarskyNAryaeiAArziB, et al.The Yucatan minipig temporomandibular joint disc structure-function relationships support its suitability for human comparative studies. Tissue Eng C Methods2017; 23(11): 700–709. https://doi.org/10.1089/ten.TEC.2017.0149
15.
KalpakciKNWillardVPWongME, et al.An interspecies comparison of the temporomandibular joint disc. J Dent Res2011; 90(2): 193–198. https://doi.org/10.1177/0022034510381501
16.
DonahueRPKallinsEGHuJC, et al.Characterization of the temporomandibular joint disc complex in the Yucatan minipig. Tissue Eng2023; 29(15-16): 439–448. https://doi.org/10.1089/ten.TEA.2023.0011
17.
AlmarzaAJBeanACBaggettLS, et al.Biochemical analysis of the porcine temporomandibular joint disc. Br J Oral Maxillofac Surg2006; 44: 124–128. https://doi.org/10.1016/j.bjoms.2005.05.002
18.
FazaeliSGhazanfariSEvertsV, et al.The contribution of collagen fibers to the mechanical compressive properties of the temporomandibular joint disc. Osteoarthr Cartil2016; 24(7): 1292–1301. https://doi.org/10.1016/j.joca.2016.01.138
19.
FazaeliSGhazanfariSMirahmadiF, et al.The dynamic mechanical viscoelastic properties of the temporomandibular joint disc: the role of collagen and elastin fibers from a perspective of polymer dynamics. J Mech Behav Biomed Mater2019; 100: 103406. https://doi.org/10.1016/j.jmbbm.2019.103406
20.
MillsDKFiandacaDJScapinRP. Morphologic, microscopic, and immunohisto-chemical investigations into the function of the primate TMJ disc. J Orofac Pain1994; 8: 136–154.
21.
PrashantCAbdulazizABryanK, et al.Type V collagen exhibits distinct regulatory activities in TMJ articular disc versus condylar cartilage during postnatal growth and remodeling. Acta Biomater2024; 189: 192–207.
22.
ShibataSTakahashiMShibuiT, et al.Structural features of the articular disc of the rat temporomandibular joint: fibrocartilage or dense fibrous lamina?J Oral Biosci2025; 67(4): 100694. https://doi.org/10.1016/j.job.2025.100694
23.
BroweDCDíaz-PaynoPJFreemanFE, et al.Bilayered extracellular matrix derived scaffolds with anisotropic pore architecture guide tissue organization during osteochondral defect repair. Acta Biomater2022; 143: 266–281. https://doi.org/10.1016/j.actbio.2022.03.009
24.
KazemiMMahboobiSSMaralbashiS. Design and evaluation of anisotropic octet-truss scaffolds for mimicking the mechanical behavior of human jawbone. Sci Rep2025; 15(1): 39097. https://doi.org/10.1038/s41598-025-27136-0
25.
Puiggalí-JouAHuiIBaldiL, et al.Biofabrication of anisotropic articular cartilage based on decellularized extracellular matrix. Biofabrication2025; 17(1). https://doi.org/10.1088/1758-5090/ad9cc2
26.
BowesACollinsAOakleyF, et al.Bioprinted high-cell-density laminar scaffolds stimulate extracellular matrix production in osteochondral Co-Cultures. Int J Mol Sci2024; 25(20): 11131. https://doi.org/10.3390/ijms252011131
27.
PingYJiadiLFutingH, et al.Composite system of 3D-printed polymer and acellular matrix hydrogel to repair temporomandibular joint disc. Front Mater2021; 8: 621416.
28.
WangCHWangSZhangB, et al.Layering poly (lactic-co-glycolic acid)-based electrospun membranes and co-culture cell sheets for engineering temporomandibular joint disc. J Biol Regul Homeost Agents2018; 32(1): 55–61.
29.
ZhifaWZhiyeLZhijinL, et al.Cartilaginous extracellular matrix derived from decellularized chondrocyte sheets for the reconstruction of osteochondral defects in rabbits. Acta Biomater2018; 81: 129–145.
30.
ÂngeloDFWangYMorouçoP, et al.A randomized controlled preclinical trial on interposal temporomandibular joint disc implants: TEMPOJIMS-phase 2. J Tissue Eng Regen Med2021; 15(10): 852–868. https://doi.org/10.1002/term.3230
31.
JiangNYangYZhangL, et al.3D-printed polycaprolactone reinforced hydrogel as an artificial TMJ disc. J Dent Res2021; 100(8): 839–846. https://doi.org/10.1177/00220345211000629
32.
StoccoTDMoreiraSMCCoratMAF, et al.Towards bioinspired meniscus-regenerative scaffolds: engineering a novel 3D bioprinted patient-specific construct reinforced by biomimetically aligned nanofibers. Int J Nanomed2022; 17: 1111–1124. https://doi.org/10.2147/IJN.S353937
33.
LiuZWangHYuanZ, et al.High-resolution 3D printing of angle-ply annulus fibrosus scaffolds for intervertebral disc regeneration. Biofabrication2022; 15(1). https://doi.org/10.1088/1758-5090/aca71f
34.
ShiSYujieLMingxueC, et al.Bionic scaffolds with integrated structural components based on low-temperature deposition manufacturing 3D printing technology for the treatment of meniscus defects. Bioeng Transl Med2025; 10(5): e70022.
35.
ChaeSLeeSSChoiYJ, et al.3D cell-printing of biocompatible and functional meniscus constructs using meniscus-derived bioink. Biomaterials2021; 267: 120466. https://doi.org/10.1016/j.biomaterials.2020.120466
36.
WeiminGMingxueCZhenyongW, et al.3D-printed cell-free PCL-MECM scaffold with biomimetic micro-structure and micro-environment to enhance in situ meniscus regeneration. Bioact Mater2021; 6(10): 3620–3633.
37.
QiaoYJianfengLWeiweiS, et al.Electrospun aligned poly(ε-caprolactone) nanofiber yarns guiding 3D organization of tendon stem/progenitor cells in tenogenic differentiation and tendon repair. Front Bioeng Biotechnol2022; 10: 960694.
38.
SandraCEHuipinYPieterJE, et al.Mimicking the graded wavy structure of the anterior cruciate ligament. Adv Healthcare Mater2023; 12(17): e2203023.
39.
GrasaJUrbiolaAFlandes-IparraguirreM, et al.Modeling and fabrication of MEW-3D tubular scaffolds with tendon mechanical behavior for tenocyte differentiation. Acta Biomater2025; 197: 226–239. https://doi.org/10.1016/j.actbio.2025.03.006
XiaoLLiuHHuangH, et al.3D nanofiber scaffolds from 2D electrospun membranes boost cell penetration and positive host response for regenerative medicine. J Nanobiotechnol2024; 22(1): 322. https://doi.org/10.1186/s12951-024-02578-2
42.
JuranCMDolwickMFMcFetridgePS. Engineered 36 microporosity: enhancing the early regenerative potential of decellularized temporomandibular joint discs. Tissue Eng2015; 21(3): 829839.
43.
LiangJYiPWangX, et al.Acellular matrix hydrogel for repair of the temporomandibular joint disc. J Biomed Mater Res B Appl Biomater2020; 108(7): 2995–3007. https://doi.org/10.1002/jbm.b.34629
44.
ZhenYHaoLYueT, et al.Biofunctionalized structure and ingredient mimicking scaffolds achieving recruitment and chondrogenesis for staged cartilage regeneration. Front Cell Dev Biol2021; 9: 655440.
45.
BrownBNChungWLLoweJ, et al.Inductive remodeling of extracellular matrix scaffolds in the temporomandibular joint of pigs. Tissue Eng2022; 28(9-10): 447–457. https://doi.org/10.1089/ten.TEA.2021.0123
ZhenglunWBoLYongshengL, et al.Influence of structural parameters of 3D-printed triply periodic minimal surface gyroid porous scaffolds on compression performance, cell response, and bone regeneration. J Biomed Mater Res B Appl Biomater2024; 112(1): e35337.
48.
LiangZLiJLinH, et al.Understanding the multi-functionality and tissue-specificity of decellularized dental pulp matrix hydrogels for endodontic regeneration. Acta Biomater2024; 181: 202–221. https://doi.org/10.1016/j.actbio.2024.04.040
49.
KuiWYuanyuanWHongY, et al.Injectable decellularized extracellular matrix hydrogel containing stromal cell-derived factor 1 promotes transplanted cardiomyocyte engraftment and functional regeneration after myocardial infarction. ACS Appl Mater Interfaces2023; 15(2): 2578–2589.
50.
JinglveZWenqingXYutianX, et al.Accurate delivery of mesenchymal stem cell spheroids with platelet-rich fibrin shield: enhancing survival and repair functions of Sp-MSCs in diabetic wound healing. Adv Sci2025; 12(25): e2413430.
51.
MohamedSAwadREsamM, et al.Reinforcement of osteochondoral defects repair with leukocyte platelet-rich fibrin and bone marrow-derived mononuclear cells in a rabbit model. BMC Muscoskelet Disord2025; 26(1): 707.
52.
KeyaGAayushiRSayanDD, et al.Fluid shear-controlled Pro/anti-inflammatory osteomodulatory construct for drug-free immune activation through cationic ion channel activation. Adv Healthcare Mater2025; 7: e00404.
ZahraALidaMMoosaJ, et al.Characterization of macroporous polycaprolactone/Silk Fibroin/Gelatin/ascorbic acid composite scaffolds and in vivo results in a rabbit model for meniscus cartilage repair. Cartilage2021; 13(2): 1583–1601.
55.
ZihangCYoujieLTianxiangL, et al.Enhanced rotator cuff tendon-bone interface regeneration with injectable manganese-based mesoporous silica nanoparticle-loaded dual crosslinked hydrogels. Front Bioeng Biotechnol2025; 13: 1645970.
56.
PengYChenXZhangQ, et al.Enzymatically bioactive nucleus pulposus matrix hydrogel microspheres for exogenous stem cells therapy and endogenous repair strategy to achieve disc regeneration. Adv Sci (Weinh)2024; 11(10): e2304761. https://doi.org/10.1002/advs.202304761
57.
BeiHPHungPMYeungHL, et al.Bone-a-Petite: engineering exosomes towards bone, osteochondral, and cartilage repair. Small2021; 17(50): e2101741. https://doi.org/10.1002/smll.202101741
58.
LiuYZhangZWangB, et al.Inflammation-stimulated MSC-derived small extracellular vesicle miR-27b-3p regulates macrophages by targeting CSF-1 to promote temporomandibular joint condylar regeneration. Small2022; 18(16): e2107354. https://doi.org/10.1002/smll.202107354
59.
QiLHui-leiYFeng-yuanZ, et al.3D printing of microenvironment-specific bioinspired and exosome-reinforced hydrogel scaffolds for efficient cartilage and subchondral bone regeneration. Adv Sci (Weinh)2023; 10(26): e2303650.
60.
YangYLiJXiaZ, et al.Mesenchymal stem cells-derived exosomes alleviate temporomandibular joint disc degeneration in temporomandibular joint disorder. Biochem Biophys Res Commun2024; 726: 150278. https://doi.org/10.1016/j.bbrc.2024.150278
61.
ChenWHuangFChenB, et al.BMSC derived exosomes attenuate apoptosis of temporomandibular joint disc chondrocytes in TMJOA via PI3K/AKT pathway. Stem Cell Rev Rep2025; 21(2): 491–508. https://doi.org/10.1007/s12015-024-10810-7
62.
YueWJi-ZhengQChao-YuX, et al.Kartogenin-loaded exosomes derived from bone marrow mesenchymal stem cells enhance chondrogenesis and expedite tendon enthesis healing in a rat model of rotator cuff injury. Am J Sports Med2024; 52(14): 3520–3535.
63.
YiyunGPengleiCMuliH, et al.Biomimetic triphasic silk fibroin scaffolds seeded with tendon-derived stem cells for tendon-bone junction regeneration. Biomater Sci2024; 12(5): 1239–1248.
64.
HongyuanXZengjieZQijiangM, et al.Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration. J Nanobiotechnol2021; 19(1): 264.
65.
MathildeMColinePMatthieuS, et al.Biodegradable tyramine functional Gelatin/6 Arms-PLA inks compatible with 3D two photon-polymerization printing and meniscus tissue regeneration. Biomacromolecules2024; 25(8): 5098–5109.
66.
MarshallSLJacobsenTDEmsboE, et al.Three-dimensional-printed flexible scaffolds have tunable biomimetic mechanical properties for intervertebral disc tissue engineering. ACS Biomater Sci Eng2021; 7(12): 5836–5849. https://doi.org/10.1021/acsbiomaterials.1c01326
67.
ZhangYSunNZhuM, et al.The contribution of pore size and porosity of 3D printed porous titanium scaffolds to osteogenesis. Biomater Adv2022; 133: 112651. https://doi.org/10.1016/j.msec.2022.112651
68.
WangGZiyingPDanN, et al.Chitosan microporous foam filled 3D printed polylactic acid-pearl macroporous scaffold: dual-Scale porous structure, biological and mechanical properties. Int J Biol Macromol2025; 303: 140508.
69.
RongpengDMingyangKYangQ, et al.Incorporating hydrogel (with low polymeric content) into 3D-Printed PLGA scaffolds for local and sustained release of BMP2 in repairing large segmental bone defects. Adv Healthcare Mater2025; 14(2): e2403613.
70.
WangYLingCChenJ, et al.3D-printed composite scaffold with gradient structure and programmed biomolecule delivery to guide stem cell behavior for osteochondral regeneration. Biomater Adv2022; 140: 213067. https://doi.org/10.1016/j.bioadv.2022.213067
71.
AiCLiuLGohJC. Pore size modulates in vitro osteogenesis of bone marrow mesenchymal stem cells in fibronectin/gelatin coated silk fibroin scaffolds. Mater Sci Eng C2021; 124: 112088. https://doi.org/10.1016/j.msec.2021.112088
72.
SidaLHaoyeMJunZ, et al.Injectable adipose-derived stem cells-embedded alginate-gelatin microspheres prepared by electrospray for cartilage tissue regeneration. J Orthop Transl2022; 33: 174–185.
73.
XiaoXBaiyanSXinL, et al.A bioinspired and high-strengthed hydrogel for regeneration of perforated temporomandibular joint disc: construction and pleiotropic immunomodulatory effects. Bioact Mater2022; 25: 701–715.
74.
ZhangXZhaiHZhuX, et al.Polyphenol-mediated adhesive and anti-inflammatory double-network hydrogels for repairing postoperative intervertebral disc defects. ACS Appl Mater Interfaces2024; 16(40): 53541–53554. https://doi.org/10.1021/acsami.4c11901
75.
WangXWuSLiR, et al.ROS-activated nanohydrogel scaffolds with multi-factors controlled releasefor targeted dual-lineage repair of osteochondral defects. Adv Sci2025; 12(20): e2412410. https://doi.org/10.1002/advs.202412410
76.
HaoLTianyuanZZhenY, et al.Biofabrication of cell-free dual drug-releasing biomimetic scaffolds for meniscal regeneration. Biofabrication2021; 14(1): ac2cd7. https://doi.org/10.1088/1758-5090/ac2cd7
77.
HaozheCChunpingAZixinS, et al.Microenvironment-targeted strontium delivery system reshapes redox homeostasis to halt degenerative cascades in intervertebral discs. J Contr Release2026; 389: 114449.
78.
LiuYSunXWangL, et al.Sequential targeted enzyme-instructed self-assembly supramolecular nanofibers to attenuate intervertebral disc degeneration. Adv Mater2024; 36(41): e2408678. https://doi.org/10.1002/adma.202408678
79.
BaekJLeeKIRaHJ, et al.Collagen fibrous scaffolds for sustained delivery of growth factors for meniscal tissue engineering. Nanomedicine (Lond)2022; 17(2): 77–93. https://doi.org/10.2217/nnm-2021-0313
80.
LuXCiZLiB, et al.Programmable macrophage mimics for inflammatory meniscus regeneration via nanotherapy. Research (Wash D C), 2026, 9:1056. https://doi.org/10.34133/research.1056
81.
ShantoPCParkSFahadMAA, et al.3D bio-printed proteinaceous bioactive scaffold loaded with dual growth factor enhanced chondrogenesis and in situ cartilage regeneration. Bioact Mater2024; 46: 365–385. https://doi.org/10.1016/j.bioactmat.2024.12.021
82.
ChengHGuoQZhaoH, et al.An injectable hydrogel scaffold loaded with dual-drug/sustained-release PLGA microspheres for the regulation of macrophage polarization in the treatment of intervertebral disc degeneration. Int J Mol Sci2022; 24(1): 390. https://doi.org/10.3390/ijms24010390
