The repair and reconstruction of oral mucosal defects are critical for restoring both function and aesthetics of the oral cavity. Tissue engineering, which integrates principles from engineering and life sciences, has enabled the development of biological substitutes that closely mimic the native structure and function of oral mucosa, significantly reducing the risks and complications associated with autologous transplantation. With the rapid advancement of tissue-engineered oral mucosa (TEOM) technology, its applications in regenerative medicine and oral disease modeling have become increasingly prominent. In recent years, innovative strategies such as the development of organoids, prevascularization, immunomodulation, and dermal–epidermal junction biomimicry have emerged, providing effective solutions to challenges related to inadequate vascularization, immune dysregulation, and mechanical performance in TEOM constructs. In addition, the application of cutting-edge manufacturing technologies such as 3D bioprinting has accelerated the translation of TEOM toward clinical use. This review outlines the fundamental principles, design strategies, and potential applications of TEOM, and discusses novel approaches and challenges that must be addressed to facilitate its clinical implementation.
Impact Statement
This review provides a critical synthesis of recent advances in tissue-engineered oral mucosa, emphasizing cutting-edge methodologies in biomaterial development, cell engineering, and microenvironment modulation. By identifying unresolved challenges such as vascularization and immunomodulation, and proposing innovative strategies, including organoids and smart biomaterials, this article provides a valuable framework for researchers and clinicians striving to translate laboratory breakthroughs into effective regenerative therapies. This integrative perspective is poised to accelerate progress in oral mucosal repair across a variety of clinical applications.
PereiraD, SequeiraI. A scarless healing tale: Comparing homeostasis and wound healing of oral mucosa with skin and oesophagus. Front Cell Dev Biol, 2021; 9:682143.
2.
GroegerS, MeyleJ. Oral mucosal epithelial cells. Front Immunol, 2019; 10:208.
3.
HaP, LiuTP, LiC, et al.Novel strategies for orofacial soft tissue regeneration. Adv Wound Care (New Rochelle), 2023; 12(6):339–360.
4.
ŞenelS. An overview of physical, microbiological and immune barriers of oral mucosa. Int J Mol Sci, 2021; 22(15):7821.
5.
WangSS, TangYL, PangX, et al.The maintenance of an oral epithelial barrier. Life Sci, 2019; 227:129–136.
6.
FangJ, ChenF, LiuD, et al.Adipose tissue-derived stem cells in breast reconstruction: A brief review on biology and translation. Stem Cell Res Ther, 2021; 12(1):8.
7.
SculeanA, GruberR, BosshardtDD. Soft tissue wound healing around teeth and dental implants. J Clin Periodontol, 2014; 41(Suppl 15):S6–S22.
8.
ZhengZ, AoX, XieP, et al.The biological width around implant. J Prosthodont Res, 2021; 65(1):11–18.
9.
GibbsS, RoffelS, MeyerM, et al.Biology of soft tissue repair: Gingival epithelium in wound healing and attachment to the tooth and abutment surface. Eur Cell Mater, 2019; 38:63–78.
10.
GilbertRW. Reconstruction of the oral cavity; past, present and future. Oral Oncol, 2020; 108:104683.
IzumiK, YortchanW, AizawaY, et al.Recent trends and perspectives in reconstruction and regeneration of intra/extra-oral wounds using tissue-engineered oral mucosa equivalents. Jpn Dent Sci Rev, 2023; 59:365–374.
13.
HellerM, BauerHK, SchwabR, et al.The impact of intercellular communication for the generation of complex multicellular prevascularized tissue equivalents. J Biomed Mater Res A, 2020; 108(3):734–748.
14.
KnoedlerL, KnoedlerS, PanayiAC, et al.Cellular activation pathways and interaction networks in vascularized composite allotransplantation. Front Immunol, 2023; 14:1179355.
15.
SaghebK, NoelkenR, SchrögerS, et al.Biomechanical analysis of the human derived soft tissue graft Epiflex for use in oral soft tissue augmentation. Int J Implant Dent, 2024; 10(1):16.
16.
Kauke-NavarroM, TchiloembaB, HaugV, et al.Pathologies of oral and sinonasal mucosa following facial vascularized composite allotransplantation. J Plast Reconstr Aesthet Surg, 2021; 74(7):1562–1571.
17.
McGuireMK, TavelliL, FeinbergSE, et al.Living cell-based regenerative medicine technologies for periodontal soft tissue augmentation. J Periodontol, 2020; 91(2):155–164.
18.
TavelliL, BarootchiS, RasperiniG, et al.Clinical and patient-reported outcomes of tissue engineering strategies for periodontal and peri-implant reconstruction. Periodontol 2000, 2023; 91(1):217–269.
19.
LiuY, GuoL, LiX, et al.Challenges and tissue engineering strategies of periodontal-guided tissue regeneration. Tissue Eng Part C Methods, 2022; 28(8):405–419.
20.
WaasdorpM, KromBP, BikkerFJ, et al.The bigger picture: Why oral mucosa heals better than skin. Biomolecules, 2021; 11(8):1165.
21.
MachlaF, MonouPK, BekiariC, et al.Tissue-Engineered oral epithelium for dental material testing: Toward in vitro biomimetic models. Tissue Eng Part C Methods, 2024; 30(12):555–568.
22.
LohanaP, SuryaprawiraA, WoodsEL, et al.Role of Enzymic antioxidants in mediating oxidative stress and contrasting wound healing capabilities in oral mucosal/skin fibroblasts and tissues. Antioxidants (Basel), 2023; 12(7):1374.
23.
GopalarethinamJ, NairAP, IyerM, et al.Advantages of mesenchymal stem cell over the other stem cells. Acta Histochem, 2023; 125(4):152041.
24.
TianZ, YuT, LiuJ, et al.Introduction to stem cells. Prog Mol Biol Transl Sci, 2023; 199:3–32.
25.
XuZ, XuW, ZhangT, et al.Mechanisms of tendon-bone interface healing: Biomechanics, cell mechanics, and tissue engineering approaches. J Orthop Surg Res, 2024; 19(1):817.
26.
PanZ, SunW, ChenY, et al.Extracellular vesicles in tissue engineering: Biology and engineered strategy. Adv Healthc Mater, 2022; 11(21):e2201384.
27.
GriffinMF, FahyEJ, KingM, et al.Understanding scarring in the oral mucosa. Adv Wound Care (New Rochelle), 2022; 11(10):537–547.
28.
FiorilloL, CervinoG, Galindo-MorenoP, et al.Growth factors in oral tissue engineering: New perspectives and current therapeutic options. Biomed Res Int, 2021; 2021:8840598.
29.
Ruiz-AlonsoS, Lafuente-MerchanM, CirizaJ, et al.Tendon tissue engineering: Cells, growth factors, scaffolds and production techniques. J Control Release, 2021; 333:448–486.
30.
XuK, YuE, WuM, et al.Cells, growth factors and biomaterials used in tissue engineering for hair follicles regeneration. Regen Ther, 2022; 21:596–610.
31.
QuM, JiangX, ZhouX, et al.Stimuli-Responsive delivery of growth factors for tissue engineering. Adv Healthc Mater, 2020; 9(7):e1901714.
32.
DinhT, BraunagelS, RosenblumBI. Growth factors in wound healing: The present and the future. Clin Podiatr Med Surg, 2015; 32(1):109–119.
33.
BrownM, LiJ, MoraesC, et al.Decellularized extracellular matrix: New promising and challenging biomaterials for regenerative medicine. Biomaterials, 2022; 289:121786.
34.
GuanN, LiuZ, ZhaoY, et al.Engineered biomaterial strategies for controlling growth factors in tissue engineering. Drug Deliv, 2020; 27(1):1438–1451.
35.
Martin-PiedraMA, Albendin-MorenoM, Olivares-AbrilA, et al.Tissue engineering for oral mucosa biofabrication: A systematic review and meta-analysis. Tissue Eng Part B Rev, 2025:10.1177/19373341251359112.
36.
GelinA, Masson-MeyersD, AminiF, et al.Collagen: The superior material for full-thickness oral mucosa tissue engineering. J Oral Biosci, 2024; 66(3):511–518.
37.
Blanco-ElicesC, España-GuerreroE, Mateu-SanzM, et al.In vitro generation of novel functionalized biomaterials for use in oral and dental regenerative medicine applications. running title: Fibrin-agarose functionalized scaffolds. Materials (Basel), 2020; 13(22):5205.
38.
WuDT, Munguia-LopezJG, ChoYW, et al.Polymeric scaffolds for dental, oral, and craniofacial regenerative medicine. Molecules, 2021; 26(22):7043.
39.
YangS, ChenR, ZhangP, et al.Fabrication and characterization of poly(lactic acid-trimethylene carbonate) based biodegradable composite films. Int J Biol Macromol, 2024; 262(Pt 2):130148.
40.
PhanTV, PimpakanT, SuwanchaikasemP, et al.Decellularized matrix-hyaluronic acid-alginate hybrid hydrogels to enable a multi-layered full-thickness oral mucosa-on-a-chip. J Dent, 2025; 163:106115.
41.
LiB, ShuY, MaH, et al.Three-dimensional printing and decellularized-extracellular-matrix based methods for advances in artificial blood vessel fabrication: A review. Tissue Cell, 2024; 87:102304.
42.
NamH, JeongH, JoY, et al.Multi-layered free-form 3D cell-printed tubular construct with decellularized inner and outer esophageal tissue-derived bioinks. Sci Rep, 2020; 10(1):7255.
43.
ŠpiljakB, Somogyi ŠkocM, Rezić MeštrovićI, et al.Targeting the oral mucosa: Emerging drug delivery platforms and the therapeutic potential of Glycosaminoglycans. Pharmaceutics, 2025; 17(9):1212.
RaviM, ParameshV, KaviyaSR, et al.3D cell culture systems: Advantages and applications. J Cell Physiol, 2015; 230(1):16–26.
46.
KorolevaA, DeiwickA, El-TamerA, et al.In vitro development of human iPSC-Derived functional neuronal networks on laser-fabricated 3D scaffolds. ACS Appl Mater Interfaces, 2021; 13(7):7839–7853.
47.
SunT, JacksonS, HaycockJW, et al.Culture of skin cells in 3D rather than 2D improves their ability to survive exposure to cytotoxic agents. J Biotechnol, 2006; 122(3):372–381.
48.
ColleyHE, EvesPC, PinnockA, et al.Tissue-engineered oral mucosa to study radiotherapy-induced oral mucositis. Int J Radiat Biol, 2013; 89(11):907–914.
49.
ChaiWL, BrookIM, PalmquistA, et al.The biological seal of the implant-soft tissue interface evaluated in a tissue-engineered oral mucosal model. J R Soc Interface, 2012; 9(77):3528–3538.
50.
RahimiC, RahimiB, PadovaD, et al.Oral mucosa-on-a-chip to assess layer-specific responses to bacteria and dental materials. Biomicrofluidics, 2018; 12(5):54106.
51.
DaimsH, WagnerM. In situ techniques and digital image analysis methods for quantifying spatial localization patterns of nitrifiers and other microorganisms in biofilm and flocs. Methods Enzymol, 2011; 496:185–215.
52.
TabatabaeiF, MoharamzadehK, TayebiL. Three-Dimensional in vitro oral mucosa models of fungal and bacterial infections. Tissue Eng Part B Rev, 2020; 26(5):443–460.
53.
BarbagliG, HeidenreichA, ZugorV, et al.Urothelial or oral mucosa cells for tissue-engineered urethroplasty: A critical revision of the clinical outcome. Asian J Urol, 2020; 7(1):18–23.
54.
SchwabR, HellerM, PfeiferC, et al.Full-thickness tissue engineered oral mucosa for genitourinary reconstruction: A comparison of different collagen-based biodegradable membranes. J Biomed Mater Res B Appl Biomater, 2021; 109(4):572–583.
55.
HuD, LiX, LiJ, et al.The preclinical and clinical progress of cell sheet engineering in regenerative medicine. Stem Cell Res Ther, 2023; 14(1):112.
56.
NishidaK, YamatoM, HayashidaY, et al.Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med, 2004; 351(12):1187–1196.
57.
NakamuraT, TakedaK, InatomiT, et al.Long-term results of autologous cultivated oral mucosal epithelial transplantation in the scar phase of severe ocular surface disorders. Br J Ophthalmol, 2011; 95(7):942–946.
58.
OsmanNI, HillaryC, BullockAJ, et al.Tissue engineered buccal mucosa for urethroplasty: Progress and future directions. Adv Drug Deliv Rev, 2015; 82–83:69–76.
59.
ŁawkowskaK, RosenbaumC, PetraszP, et al.; Trauma and Reconstructive Urology Working Party of the European Association of Urology Young Academic Urologists. Tissue engineering in reconstructive urology-The current status and critical insights to set future directions-critical review. Front Bioeng Biotechnol, 2022; 10:1040987.
60.
AmemiyaT, NakamuraT, YamamotoT, et al.Autologous transplantation of oral mucosal epithelial cell sheets cultured on an amniotic membrane substrate for intraoral mucosal defects. PLoS One, 2015; 10(4):e0125391.
61.
TabatabaeiF, RasoulianboroujeniM, YadegariA, et al.Osteo-mucosal engineered construct: In situ adhesion of hard-soft tissues. Mater Sci Eng C Mater Biol Appl, 2021; 128:112255.
62.
WittM, CherriM, FerraroM, et al.Anti-inflammatory IL-8 regulation via an advanced drug delivery system at the oral mucosa. ACS Appl Bio Mater, 2023; 6(6):2145–2157.
63.
Klausner1M, HandaY, AizawaS. In vitro three-dimensional organotypic culture models of the oral mucosa. In Vitro Cell Dev Biol Anim, 2021; 57(2):148–159.
64.
LiuS, ZhuP, TianY, et al.Preparation and application of taste bud organoids in biomedicine towards chemical sensation mechanisms. Biotechnol Bioeng, 2022; 119(8):2015–2030.
65.
ShiL, XuY, LiJ, et al.Vascularized characteristics and functional regeneration of three-dimensional cell reconstruction of oral mucosa equivalents based on vascular homeostasis phenotypic modification. J Tissue Eng, 2024; 15:20417314241268912.
66.
ShafieeS, ShariatzadehS, ZafariA, et al.Recent advances on cell-based co-culture strategies for Prevascularization in tissue engineering. Front Bioeng Biotechnol, 2021; 9:745314.
67.
ZhouM, ChenX, QiuY, et al.Study of tissue engineered vascularised oral mucosa-like structures based on ACVM-0.25% HLC-I scaffold in vitro and in vivo. Artif Cells Nanomed Biotechnol, 2020; 48(1):1167–1177.
68.
HellerM, Frerick-OchsEV, BauerHK, et al.Tissue engineered pre-vascularized buccal mucosa equivalents utilizing a primary triculture of epithelial cells, endothelial cells and fibroblasts. Biomaterials, 2016; 77:207–215.
69.
IqbalMZ, RiazM, BiedermannT, et al.Breathing new life into tissue engineering: Exploring cutting-edge vascularization strategies for skin substitutes. Angiogenesis, 2024; 27(4):587–621.
70.
WangY, LiuM, ZhangW, et al.Mechanical strategies to promote vascularization for tissue engineering and regenerative medicine. Burns Trauma, 2024; 12:tkae039.
71.
TraWM, SpiegelbergL, TukB, et al.Hyperbaric oxygen treatment of tissue-engineered mucosa enhances secretion of angiogenic factors in vitro. Tissue Eng Part A, 2014; 20(9–10):1523–1530.
72.
WebbBCW, GlogauerM, SanterreJP. The structure and function of next-generation gingival graft substitutes-a perspective on multilayer Electrospun constructs with consideration of vascularization. Int J Mol Sci, 2022; 23(9):5256.
73.
ZhangY, ZhangXM. [Potential of three-dimensional bioprinting in oral soft tissue engineering applications]. Zhonghua Kou Qiang Yi Xue Za Zhi, 2021; 56(7):613–619.
74.
DasguptaI, RangineniDP, AbdelsaidH, et al.Tiny organs, big impact: How microfluidic organ-on-chip technology is revolutionizing mucosal tissues and vasculature. Bioengineering (Basel), 2024; 11(5):476.
75.
DingS, ZhangX, WangG, et al.Promoting diabetic oral mucosa wound healing with a light-responsive hydrogel adaptive to the microenvironment. Heliyon, 2024; 10(19):e38599.
76.
ChenY, HuangX, LiuA, et al.Lactobacillus Reuteri vesicles regulate mitochondrial function of macrophages to promote mucosal and cutaneous wound healing. Adv Sci (Weinh), 2024; 11(24):e2309725.
77.
WenX, XiK, TangY, et al.Immunized microspheres engineered hydrogel membrane for reprogramming macrophage and mucosal repair. Small, 2023; 19(15):e2207030.
78.
ZhangK, JagannathC. Crosstalk between metabolism and epigenetics during macrophage polarization. Epigenetics Chromatin, 2025; 18(1):16.
79.
DaskalakiMG, TsatsanisC, KampranisSC. Histone methylation and acetylation in macrophages as a mechanism for regulation of inflammatory responses. J Cell Physiol, 2018; 233(9):6495–6507.
80.
HennD, ZhaoD, SivarajD, et al.Cas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing. Nat Commun, 2023; 14(1):4729.
81.
FaragVE, DeveyEA, LeongKW. The interface of gene editing with regenerative medicine. Engineering (Beijing), 2025; 46:73–100.
82.
ZhangH, HuaS, HeC, et al.Application of 4D-Printed Magnetoresponsive FOGS hydrogel scaffolds in auricular cartilage regeneration. Adv Healthc Mater, 2025; 14(9):e2404488.
83.
FengL, PengQ, MiaoL, et al.“Monitor-and-treat” that integrates bacterio-therapeutics and bio-optics for infected wound management. Bioact Mater, 2025; 48:118–134.
84.
BighamA, IslamiN, KhosraviA, et al.MOFs and MOF-Based composites as next-generation materials for wound healing and dressings. Small, 2024; 20(30):e2311903.
85.
LawlorKT, KaurP. Dermal contributions to human interfollicular epidermal architecture and self-renewal. Int J Mol Sci, 2015; 16(12):28098–28107.
86.
SuebsamarnO, KamimuraY, SuzukiA, et al.In-process monitoring of a tissue-engineered oral mucosa fabricated on a micropatterned collagen scaffold: Use of optical coherence tomography for quality control. Heliyon, 2022; 8(11):e11468.
87.
LammersG, RothG, HeckM, et al.Construction of a microstructured collagen membrane mimicking the papillary dermis architecture and guiding keratinocyte morphology and gene expression. Macromol Biosci, 2012; 12(5):675–691.
88.
SuzukiA, KodamaY, MiwaK, et al.Manufacturing micropatterned collagen scaffolds with chemical-crosslinking for development of biomimetic tissue-engineered oral mucosa. Sci Rep, 2020; 10(1):22192.
89.
JainP, RauerSB, MöllerM, et al.Mimicking the natural basement membrane for advanced tissue engineering. Biomacromolecules, 2022; 23(8):3081–3103.
90.
MancinelliE, ZushiN, TakumaM, et al.Porous polymeric nanofilms for recreating the basement membrane in an endothelial barrier-on-chip. ACS Appl Mater Interfaces, 2024; 16(10):13006–13017.
91.
TianJ, FuC, LiW, et al.Biomimetic tri-layered artificial skin comprising silica gel-collagen membrane-collagen porous scaffold for enhanced full-thickness wound healing. Int J Biol Macromol, 2024; 266(Pt 1):131233.
92.
MalaraMM, BlackstoneBN, BaumannME, et al.Cultured epithelial autograft combined with micropatterned dermal template forms rete ridges in vivo. Tissue Eng Part A, 2020; 26(21–22):1138–1146.
93.
Echeverria MolinaMI, KomvopoulosK. Influence of scaffold topography and culture duration on fibroblast morphology in tissue engineering. Tissue Eng Part A, 2025:10.1177/19373341251364544.
94.
BarzegarA, EbrahimzadehS, VahdaniV, et al.Engineering bi-layered skin-like nanopads with electrospun nanofibers and chitosan films for promoting fibroblast infiltration in tissue regeneration and wound healing. Int J Biol Macromol, 2024; 277(Pt 3):134398.
95.
VahdatiniaF, HooshyarfardA, JamshidiS, et al.3D-Printed soft membrane for periodontal guided tissue regeneration. Materials (Basel), 2023; 16(4):1364.
96.
TayebiL, RasoulianboroujeniM, MoharamzadehK, et al.3D-printed membrane for guided tissue regeneration. Mater Sci Eng C Mater Biol Appl, 2018; 84:148–158.
97.
de BrugerolleA. SkinEthic Laboratories, a company devoted to develop and produce in vitro alternative methods to animal use. Altex, 2007; 24(3):167–171.
98.
NesicD, SchaeferBM, SunY, et al.3D printing approach in dentistry: The future for personalized oral soft tissue regeneration. J Clin Med, 2020; 9(7):2238.
99.
SmiraniR, RémyM, DevillardR, et al.Engineered Prevascularization for oral tissue grafting: A systematic review. Tissue Eng Part B Rev, 2020; 26(4):383–398.
100.
GaoJ, DingX, YuX, et al.Cell-Free Bilayered porous scaffolds for osteochondral regeneration fabricated by continuous 3D-printing using nascent physical hydrogel as ink. Adv Healthc Mater, 2021; 10(3):e2001404.
101.
TuZ, ZhongY, HuH, et al.Design of therapeutic biomaterials to control inflammation. Nat Rev Mater, 2022; 7(7):557–574.
