J Korean Assoc Oral Maxillofac Surg Journal of the Korean Association of Oral and Maxillofacial Surgeons J Korean Assoc Oral Maxillofac Surg 2234-7550 2234-5930 The Korean Association of Oral and Maxillofacial Surgeons 10.5125/jkaoms.2025.51.6. jkaoms-51-6-331 Editorial Is tissue engineering finally ready? The second wave of tissue engineering and its implications for oral and maxillofacial reconstruction surgery https://orcid.org/0000-0002-0333-6349 ParkJoo-Young DDS, PhD 1 2 Department of Oral and Maxillofacial Surgery, School of Dentistry, Seoul National University, Seoul, Korea Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital, Seoul, Korea Joo-Young Park, Department of Oral and Maxillofacial Surgery, School of Dentistry, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea, TEL: +82-2-6256-3133, E-mail: bbyoung1@snu.ac.kr, ORCID: https://orcid.org/0000-0002-0333-6349 31 12 2025 31 12 2025 51 6 331 332 Copyright © 2025 The Korean Association of Oral and Maxillofacial Surgeons. All rights reserved. 2025 This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. <p>Tissue engineering has experienced a significant revitalization in recent years across scientific, clinical, and industrial fields. This renewal reflects the convergence of major technological breakthroughs, rising clinical demand, and growing regulatory and investment support. While early tissue engineering faced challenges with inconsistent results and limited clinical application, recent advancements, especially in biomaterials science, immunomodulation technologies, and the digital fabrication of scaffolds, have changed the field as a key driver of next-generation regenerative medicine. This editorial summarizes those second waves of tissue engineering and describes its future application in the field of oral and maxillofacial surgery (OMFS).</p> <p>Modern tissue engineering was conceptualized in the early 1990s, when Langer and Vacanti<sup><xref rid="ref1" ref-type="bibr">1</xref></sup> first proposed the now-foundational triad of scaffolds, cells, and signaling molecules for tissue regeneration. Conventional tissue engineering approaches in the following 20 years relied on biodegradable scaffolds seeded with cells and growth factors, but translation to routine clinical use was limited due to insufficient vascularization, insufficient mechanical durability, and unpredictable host immune responses<sup><xref rid="ref2" ref-type="bibr">2</xref><xref rid="ref3" ref-type="bibr"/>-<xref rid="ref4" ref-type="bibr">4</xref></sup>. Since the 2010s, these limitations were overcoming one by one, the emergence of high-resolution three-dimensional (3D) bioprinting (2013-2016) enabled spatially controlled deposition of biomaterials and living cells, reproducing complex microenvironments that mimic native tissue structures<sup><xref rid="ref5" ref-type="bibr">5</xref></sup>. Most recently, imaging-guided workflow innovation allows patient-specific scaffold fabrication based on computed tomography (CT) data, particularly relevant in OMFS reconstruction<sup><xref rid="ref6" ref-type="bibr">6</xref></sup>. In parallel, the development of organoids, first demonstrated for intestinal crypts in 2009, and the rise of organ-on-a-chip platforms around 2010-2012, have provided advanced physiologic models for disease simulation, drug evaluation, and preclinical validation prior to clinical translation<sup><xref rid="ref7" ref-type="bibr">7</xref><xref rid="ref8" ref-type="bibr"/>-<xref rid="ref9" ref-type="bibr">9</xref></sup>.</p> <p>Another major recent advancement is the deeper understanding of the immune–biomaterial interface, especially the role of macrophage polarization in wound healing and foreign body reactions<sup><xref rid="ref10" ref-type="bibr">10</xref>,<xref rid="ref11" ref-type="bibr">11</xref></sup>. This has led to the development of immune-informed scaffolds that actively promote regenerative rather than inflammatory responses, improving graft stability and integration<sup><xref rid="ref12" ref-type="bibr">12</xref>,<xref rid="ref13" ref-type="bibr">13</xref></sup>. Parallel to scientific progress, global regulatory systems have become increasingly supportive. The U.S. Food and Drug Administration’s Regenerative Medicine Advanced Therapy (RMAT) program accelerates approval for regenerative therapies<sup><xref rid="ref14" ref-type="bibr">14</xref></sup>, and Europe’s Advanced Therapy Medicinal Products (ATMP) framework provides clear standards for cell- and tissue-based products<sup><xref rid="ref15" ref-type="bibr">15</xref></sup>. In South Korea, the 2019 Advanced Regenerative Medicine and Advanced Biological Products (ARMAB) Act, updated in 2024 to expand patient eligibility from February 2025, strengthened safety monitoring and facilitated application of advanced regenerative technologies. Combined with increasing industry investment and translational funding, these factors create a robust ecosystem for clinical adoption and commercialization of new tissue engineering technologies.</p> <p>In summary, innovations in biomaterials, immune-responsive scaffold engineering, and patient-specific digital fabrication are propelling the second wave of tissue engineering into clinical relevance. As regulatory systems mature and translational pipelines expand, engineered tissues are expected to transition from experimental constructs to practical surgical tools—particularly in maxillofacial bone, soft-tissue, and temporomandibular joint regeneration.(<xref rid="T1" ref-type="table">Table 1</xref>) Sustained progress may ultimately shift OMFS from reconstruction toward true biological restoration, enabling grafts that integrate, remodel, and function as living replacements.</p> </sec> </body> <back> <fn-group> <fn fn-type="coi-statement"> <p><bold>Conflict of Interest</bold></p> <p>No potential conflict of interest relevant to this article was reported.</p> </fn> <fn fn-type="supported-by"> <p><bold>Funding</bold></p> <p>No funding to declare.</p> </fn> </fn-group> <ref-list> <title>References LangerR VacantiJP 1993 Tissue engineering Science 260 920 6 https://doi.org/10.1126/science.8493529 10.1126/science.8493529 8493529 GriffithLG NaughtonG 2002 Tissue engineering--current challenges and expanding opportunities Science 295 1009 14 https://doi.org/10.1126/science.1069210 10.1126/science.1069210 11834815 JainRK AuP TamJ DudaDG FukumuraD 2005 Engineering vascularized tissue Nat Biotechnol 23 821 3 https://doi.org/10.1038/nbt0705-821 10.1038/nbt0705-821 16003365 AndersonJM RodriguezA ChangDT 2008 Foreign body reaction to biomaterials Semin Immunol 20 86 100 https://doi.org/10.1016/j.smim.2007.11.004 10.1016/j.smim.2007.11.004 18162407 PMC2327202 MurphySV AtalaA 2014 3D bioprinting of tissues and organs Nat Biotechnol 32 773 85 https://doi.org/10.1038/nbt.2958 10.1038/nbt.2958 25093879 SearsNA SeshadriDR DhavalikarPS Cosgriff-HernandezE 2016 A review of three-dimensional printing in tissue engineering Tissue Eng Part B Rev 22 298 310 https://doi.org/10.1089/ten.teb.2015.0464 10.1089/ten.teb.2015.0464 26857350 SatoT VriesRG SnippertHJ van de WeteringM BarkerN StangeDE 2009 Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche Nature 459 262 5 https://doi.org/10.1038/nature07935 10.1038/nature07935 19329995 HuhDD 2015 A human breathing lung-on-a-chip Ann Am Thorac Soc 12 Suppl 1 S42 4 https://doi.org/10.1513/annalsats.201410-442mg 10.1513/AnnalsATS.201410-442MG 25830834 PMC5467107 BhatiaSN IngberDE 2014 Microfluidic organs-on-chips Nat Biotechnol 32 760 72 https://doi.org/10.1038/nbt.2989 10.1038/nbt.2989 25093883 MurrayPJ WynnTA 2011 Protective and pathogenic functions of macrophage subsets Nat Rev Immunol 11 723 37 https://doi.org/10.1038/nri3073 10.1038/nri3073 21997792 PMC3422549 FaulkDM LondonoR WolfMT RanalloCA CarruthersCA WildemannJD 2014 ECM hydrogel coating mitigates the chronic inflammatory response to polypropylene mesh Biomaterials 35 8585 95 https://doi.org/10.1016/j.biomaterials. 2014.06.057 10.1016/j.biomaterials.2014.06.057 25043571 PMC5942585 SadtlerK EstrellasK AllenBW WolfMT FanH TamAJ 2016 Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells Science 352 366 70 https://doi.org/10.1126/science.aad9272 10.1126/science.aad9272 27081073 PMC4866509 SalthouseD NovakovicK HilkensCMU FerreiraAM 2023 Interplay between biomaterials and the immune system: challenges and opportunities in regenerative medicine Acta Biomater 155 1 18 https://doi.org/10.1016/j.actbio.2022.11.003 10.1016/j.actbio.2022.11.003 36356914 U.S. Food and Drug Administration (FDA) Regenerative medicine advanced therapy designation [Internet] FDA Silver Spring (MD) Available from: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/regenerative-medicine-advanced-therapy-designation cited 2025 Dec 24 European Medicines Agency (EMA) Advanced therapy medicinal products [Internet] EMA Amsterdam Available from: https://www.ema.europa.eu/en/human-regulatory-overview/advanced-therapy-medicinal-products-overview cited 2025 Dec 24 Table

Summary of the recent emerging tissue engineering advances and related OMFS-specific innovations

Emerging technology OMFS-specific innovation (2022-2025 published articles)
Smart, immunomodulatory biomaterials • Anti-inflammatory / M2-polarizing scaffolds for peri-implant bone healing
• Infection-responsive hydrogels for GBR and sinus augmentation
• Anti-fibrotic coatings to reduce foreign-body reaction in facial implants
Advanced 3D bioprinting and bioinks • Patient-specific mandibular body/ramus/condyle scaffolds from CT segmentation
• Osteochondral printing for mandible, maxilla, including TMJ disc–cartilage interface Organoids and organ-on-chip models
• Tooth germ organoids for periodontal regeneration research
• TMJ joint-on-a-chip for chondrocyte–synovium interaction studies
• Mucosa-on-chip for oral drug permeation and infection models
Vascularization and perfusion bioengineering • Microchannel bioprinting for mandibular reconstruction (fibula-free-flap alternatives)
• Perfused bone constructs for irradiated jaw osteonecrosis models
AI-assisted digital bio-design • AI-guided porosity/topology optimization for mandibular plates & scaffolds
• CT-MRI fusion for patient-specific TMJ geometry
• Virtual surgical planning integrated with regenerative scaffold design

(OMFS: oral and maxillofacial surgery, GBR: guided bone regeneration, 3D: three-dimensional, CT: computed tomography, TMJ: temporomandibular joint, AI: artificial intelligence, MRI: magnetic resonance imaging)