Review Article

Engineering Osteo-Mucosal Constructs: A Review of Adhesion Mechanisms and Innovations

Osteo-Mucosal Constructs and Adhesion Strategies

Abstract

Developing a laboratory-grown construct integrating viable bone and oral mucosal tissues with strong adhesion between the hard and soft tissue layers presents a significant challenge. This engineered tissue construct holds promise as a versatile graft material for diverse oral surgeries and as an in vitro model for evaluating dental materials, dental implants, and oral healthcare products, potentially replacing the need for in vivo studies. Additionally, it offers a valuable tool for investigating various aspects of oral diseases and evaluating the efficacy of different treatments, eliminating the need for animal models. The success of such osteo-mucosal constructs depends on achieving proper adhesion between the bone and connective tissue layers, prompting researchers to conduct studies exploring interlayer adhesion mechanisms. This review provides a comprehensive overview of advances in osteo-mucosal models, conducted through a search of articles published in journals indexed in PubMed, ScienceDirect, Scopus, and Google Scholar databases from January 2010 to January 2024. First, we outline the methods used to construct various components of osteo-mucosal models, including the materials and fabrication techniques. Next, we provide a detailed discussion of the adhesion methods employed. Lastly, we compare the effectiveness of each adhesion method by summarizing the results of cell viability studies, which are crucial for the success of tissue regeneration. This review provides a comprehensive understanding of recent advancements in osteo-mucosal models and their interfacial adhesion, paving the way for promising clinical applications.

1. Young S, Kasper FK, Melville J, Donahue R, A Athanasiou K, G. Mikos A, et al. Tissue engineering in oral and maxillofacial surgery. Principles of Tissue Engineering: Elsevier; 2020. p. 1201-20.
2. Ferraz MP. Bone grafts in dental medicine: an overview of autografts, allografts and synthetic materials. Materials. 2023 May;16(11):4117.
3. Tabatabaei F, Rasoulianboroujeni M, Yadegari A, Tajik S, Moharamzadeh K, Tayebi L. Osteo-mucosal engineered construct: In situ adhesion of hard-soft tissues. Mater Sci Eng C Mater Biol Appl. 2021 Sep;128:112255.
4. He Z, Zhou X, Wang Y, Lin J, Huang S, Hu R, et al. Asymmetric barrier membranes based on polysaccharide micro-nanocomposite hydrogel: Synthesis, characterization, and their antibacterial and osteogenic activities. Carbohydr Polym. 2021 Dec;273:118525.
5. Aldana AA, Abraham GA. Current advances in electrospun gelatin-based scaffolds for tissue engineering applications. Int J Pharm. 2017 May;523(2):441-53.
6. Koons GL, Diba M, Mikos AG. Materials design for bone-tissue engineering. Nat Rev Mater. 2020 Aug;5(8):584-603.
7. Matichescu A, Ardelean LC, Rusu LC, Craciun D, Bratu EA, Babucea M, et al. Advanced biomaterials and techniques for oral tissue engineering and regeneration-A review. Materials (Basel). 2020 Nov;13(22):5303.
8. Iviglia G, Kargozar S, Baino F. Biomaterials, current strategies, and novel nano-technological approaches for periodontal regeneration. J Funct Biomater. 2019 Jan;10(1):3.
9. Toledano M, Toledano-Osorio M, Carrasco-Carmona Á, Vallecillo C, Lynch CD, Osorio MT, et al. State of the art on biomaterials for soft tissue augmentation in the oral cavity. Part I: natural polymers-based biomaterials. Polymers (Basel). 2020 Aug;12(8):1850.
10. Gou L, Yang W, Qiao X, Ye L, Yan K, Li L, et al. Marginal or segmental mandibulectomy: treatment modality selection for oral cancer: a systematic review and meta-analysis. Int J Oral Maxillofac Surg. 2018 Jan;47(1):1-10.
11. Pilipchuk SP, Plonka AB, Monje A, Taut AD, Lanis A, Kang B, et al. Tissue engineering for bone regeneration and osseointegration in the oral cavity. Dent Mater. 2015 Apr;31(4):317-38.
12. Sun L, Zhang L, Wang J, Liu Y, Guo Y. Fabrication of novel multilayer core-shell structured nanofibers network reinforced carbon matrix composites for bone tissue engineering. Mater Lett. 2023 Feb;333:133634.
13. Almela T, Al-Sahaf S, Bolt R, Brook IM, Moharamzadeh K. Characterization of multilayered tissue-engineered human alveolar bone and gingival mucosa. Tissue Eng Part C Methods. 2018 Feb;24(2):99-107.
14. Almela T, Al-Sahaf S, Brook IM, Khoshroo K, Rasoulianboroujeni M, Fahimipour F, et al. 3D printed tissue engineered model for bone invasion of oral cancer. Tissue Cell. 2018 Jun;52:71-7.
15. Abdelaziz D, Hefnawy A, Al-Wakeel E, El-Fallal A, El-Sherbiny IM. New biodegradable nanoparticles-in-nanofibers based membranes for guided periodontal tissue and bone regeneration with enhanced antibacterial activity. J Adv Res. 2020 Jun;28:51-62.
16. Yunus Basha R, Sampath Kumar TS, Doble M. Design of biocomposite materials for bone tissue regeneration. Mater Sci Eng C Mater Biol Appl. 2015 Dec;57:452-63.
17. Mittwede PN, Gottardi R, Alexander PG, Tarkin IS, Tuan RS. Clinical applications of bone tissue engineering in orthopedic trauma. Curr Pathobiol Rep. 2018 Jun;6(2):99-108.
18. Tang G, Liu Z, Liu Y, Yu J, Wang X, Tan Z, et al. Recent trends in the development of bone regenerative biomaterials. Front Cell Dev Biol. 2021 May;9:665813.
19. Montoya C, Du Y, Gianforcaro AL, Orrego S, Yang M, Lelkes PI. On the road to smart biomaterials for bone research: definitions, concepts, advances, and outlook. Bone Res. 2021 Feb;9(1):12.
20. Ha P, Liu TP, Li C, Zheng Z. Novel strategies for orofacial soft tissue regeneration. Adv Wound Care (New Rochelle). 2023 Jun;12(6):339-60.
21. Patel S, Caldwell JM, Doty SB, Levine WN, Rodeo S, Soslowsky LJ, et al. Integrating soft and hard tissues via interface tissue engineering. J Orthop Res. 2018 Apr;36(4):1069-77.
22. Lu HH, Thomopoulos S. Functional attachment of soft tissues to bone: development, healing, and tissue engineering. Annu Rev Biomed Eng. 2013;15:201-26.
23. Armitage OE, Oyen ML. Hard-soft tissue interface engineering. Engineering mineralized and load bearing tissues. 2015. p.187-204.
24. Jenkins LE, Davis LS. Comprehensive review of tissue adhesives. Dermatol Surg. 2018 Nov;44(11):1367-72.
25. Bouten PJ, Zonjee M, Bender J, Yauw ST, van Goor H, van Hest JC, et al. The chemistry of tissue adhesive materials. Prog Polym Sci. 2014 Jul;39(7):1375-405.
26. Liu Y, Cheong Ng S, Yu J, Tsai WB. Modification and crosslinking of gelatin-based biomaterials as tissue adhesives. Colloids Surf B Biointerfaces. 2019 Feb;174:316-23.
27. Tayebi L, Masaeli R, Zandsalimi K, Tayebi L, Masaeli R, Zandsalimi K. Application of 3D printing in reconstruction of oral and maxillofacial multi-and interfacial tissue defects. 3D printing in oral and maxillofacial surgery, 2021. p.167-217.
28. Fuchs A, Youssef A, Seher A, Hartmann S, Brands RC, Müller-Richter UDA, et al. A new multilayered membrane for tissue engineering of oral hard- and soft tissue by means of melt electrospinning writing and film casting - An in vitro study. J Craniomaxillofac Surg. 2019 Apr;47(4):695-703.
29. Bae S, Sun S, Aghaloo T, Oh JE, McKenna CE, Kang MK, et al. Development of oral osteomucosal tissue constructs in vitro and localization of fluorescently-labeled bisphosphonates to hard and soft tissue. Int J Mol Med. 2014 Aug;34(2):559-63.
30. Almela T, Brook IM, Moharamzadeh K. Development of three-dimensional tissue engineered bone-oral mucosal composite models. J Mater Sci Mater Med. 2016 Apr;27(4):65.
31. Boskey AL. Bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep. 2013 Dec;2:447.
32. Panaksri A, Kuncharin P, Neerawong P, Panthong T, Thanakornkriengkrai T, Boonyagul S, et al. Novel one-pot recovery and in-situ crystallization of polyhydroxybutyrate and hydroxyapatite/tricalcium phosphate biocomposite microparticles with comparative life cycle assessment. Polymer Degrad Stabil. 2025 Jul;237:111321.
33. Wang YH, Liu TT, Guo YP, Zhu SJ, Liao ZM, Song JM, et al. Integrating melt electrospinning writing and microfluidics to engineer a human cardiac microenvironment for high-fidelity drug screening. Bioact Mater. 2024 Dec;45:551-66.
34. Jin Y, Gao Q, Xie C, Li G, Du J, Fu J, et al. Fabrication of heterogeneous scaffolds using melt electrospinning writing: Design and optimization. Mater Des. 2020 Jan;185:108274.
35. Hutmacher DW, Tandon B, Dalton PD. Scaffold design and fabrication. Tissue engineering: Elsevier; 2023. p. 355-85.
36. Bruyas A, Lou F, Stahl AM, Gardner M, Maloney W, Goodman S, et al. Systematic characterization of 3D-printed PCL/β-TCP scaffolds for biomedical devices and bone tissue engineering: influence of composition and porosity. J Mater Res. 2018 Jul;33(14):1948-59.
37. Shahverdi M, Seifi S, Akbari A, Mohammadi K, Shamloo A, Movahhedy MR. Melt electrowriting of PLA, PCL, and composite PLA/PCL scaffolds for tissue engineering application. Sci Rep. 2022 Nov;12(1):19935.
38. Skibiński S, Czechowska JP, Guzik M, Vivcharenko V, Przekora A, Szymczak P, et al. Scaffolds based on β tricalcium phosphate and polyhydroxyalkanoates as biodegradable and bioactive bone substitutes with enhanced physicochemical properties. Sustain Mater Techno
2023 Dec;38:e00722.
39. Xu J, Xu S, Hao J, Cao H. Experimental and density functional theory study of the effect of polar groups on interaction at the polyolefin-aluminum laminated film interface. J Mater Res Technol. 2023 Nov;27:5093-108.
40. Andrei G, van den Oord J, Fiten P, Opdenakker G, De Wolf-Peeters C, De Clercq E, et al. Organotypic epithelial raft cultures as a model for evaluating compounds against alphaherpesviruses. Antimicrob Agents Chemother. 2005 Nov;49(11):4671-80.
41. Dongari-Bagtzoglou A, Kashleva H. Development of a highly reproducible three-dimensional organotypic model of the oral mucosa. Nat Protoc. 2006;1(4):2012-8.
42. Yuan S, Xiong G, Roguin A, Choong C. Immobilization of gelatin onto poly(glycidyl methacrylate)-grafted polycaprolactone substrates for improved cell-material interactions. Biointerphases. 2012 Dec;7(1-4):30.
43. Shi Y, Xing TL, Zhang HB, Yin RX, Yang SM, Wei J, et al. Tyrosinase-doped bioink for 3D bioprinting of living skin constructs. Biomed Mater. 2018 Mar 6;13(3):035008.
44. Marmelstein AM, Lobba MJ, Mogilevsky CS, Maza JC, Brauer DD, Francis MB. Tyrosinase-mediated oxidative coupling of tyrosine tags on peptides and proteins. J Am Chem Soc. 2020 Mar;142(11):5078-86.
45. Connolly P, Garcia-Carpio I, Villunger A. Cell-cycle cross talk with caspases and their substrates. Cold Spring Harb Perspect Biol. 2020 Jun;12(6):a036475.
46. Ge L, Chen S. Recent advances in tissue adhesives for clinical medicine. Polymers (Basel). 2020 Apr;12(4):939.
47. Pintor AVB, Queiroz LD, Barcelos R, Primo LSG, Maia LC, Alves GG. MTT versus other cell viability assays to evaluate the biocompatibility of root canal filling materials: a systematic review. Int Endod J. 2020 Oct;53(10):1348-73.
48. Kamiloglu S, Sari G, Ozdal T, Capanoglu E. Guidelines for cell viability assays. Food frontiers. 2020 Sep;1(3):332-49.
49. Luzak B, Siarkiewicz P, Boncler M. An evaluation of a new high-sensitivity PrestoBlue assay for measuring cell viability and drug cytotoxicity using EA.hy926 endothelial cells. Toxicol In Vitro. 2022 Sep;83:105407.
50. Boncler M, Różalski M, Krajewska U, Podsędek A, Watala C. Comparison of PrestoBlue and MTT assays of cellular viability in the assessment of anti-proliferative effects of plant extracts on human endothelial cells. J Pharmacol Toxicol Methods. 2014 Jan-Feb;69(1):9-16.
51. Coyle JP, Johnson C, Jensen J, Farcas M, Derk R, Stueckle TA, et al. Variation in pentose phosphate pathway-associated metabolism dictates cytotoxicity outcomes determined by tetrazolium reduction assays. Sci Rep. 2023 May;13(1):8220.
IssueVol 23 (Continuously Published Article-Based) QRcode
SectionReview Article
Keywords
Biocompatible Materials Mucous Membrane Osteogenesis Tissue Engineering

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1.
Mihandoust S, Seyed-Monir A, Ghavami-Lahiji M, Moharamzadeh K, Tayebi L. Engineering Osteo-Mucosal Constructs: A Review of Adhesion Mechanisms and Innovations. Front Dent. 2026;23.