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    Remaining Hurdles for Tissue-Engineering the Temporomandibular Joint Disc. Donahue Ryan P,Hu Jerry C,Athanasiou Kyriacos A Trends in molecular medicine The temporomandibular joint (TMJ) disc, a fibrocartilaginous structure between the mandible and temporal bone, is implicated in temporomandibular disorders (TMDs). TMDs symptomatically affect approximately 25% of the population, of which 70% have internal derangement of the disc. Treatments lack efficiency, motivating novel therapies, including tissue-engineering toward TMJ disc regeneration. Recent developments in scaffold-based or scaffold-free approaches, cell sources, and biochemical and mechanical stimulation have resulted in constructs exhibiting native tissue mechanics. Safety and efficacy of tissue-engineered implants have shown promising results in orthotopic animal studies. However, many hurdles need to be overcome in tissue-engineering approaches, and clinical and regulatory pathways. Future studies present an opportunity for clinicians and researchers to work together toward safe and effective clinical trials. 10.1016/j.molmed.2018.12.007
    Engineering Human TMJ Discs with Protein-Releasing 3D-Printed Scaffolds. Legemate K,Tarafder S,Jun Y,Lee C H Journal of dental research The temporomandibular joint (TMJ) disc is a heterogeneous fibrocartilaginous tissue positioned between the mandibular condyle and glenoid fossa of the temporal bone, with important roles in TMJ functions. Tissue engineering TMJ discs has emerged as an alternative approach to overcoming limitations of current treatments for TMJ disorders. However, the anisotropic collagen orientation and inhomogeneous fibrocartilaginous matrix distribution present challenges in the tissue engineering of functional TMJ discs. Here, we developed 3-dimensional (3D)-printed anatomically correct scaffolds with region-variant microstrand alignment, mimicking anisotropic collagen alignment in the TMJ disc and corresponding mechanical properties. Connective tissue growth factor (CTGF) and transforming growth factor beta 3 (TGFβ3) were then delivered in the scaffolds by spatially embedding CTGF- or TGFβ3-encapsulated microspheres (µS) to reconstruct the regionally variant fibrocartilaginous matrix in the native TMJ disc. When cultured with human mesenchymal stem/progenitor cells (MSCs) for 6 wk, 3D-printed scaffolds with CTGF/TGFβ3-µS resulted in a heterogeneous fibrocartilaginous matrix with overall distribution of collagen-rich fibrous structure in the anterior/posterior (AP) bands and fibrocartilaginous matrix in the intermediate zone, reminiscent of the native TMJ disc. High dose of CTGF/TGFβ3-µS (100 mg µS/g of scaffold) showed significantly more collagen II and aggrecan in the intermediate zone than a low dose (50 mg µS/g of scaffold). Similarly, a high dose of CTGF/TGFβ3-µS yielded significantly higher collagen I expression in the AP bands compared with the low-dose and empty µS. From stress relaxation tests, the ratio of relaxation modulus to instantaneous modulus was significantly smaller with CTGF/TGFβ3-µS than empty µS. Similarly, a significantly higher coefficient of viscosity was achieved with the high dose of CTGF/TGFβ3-µS compared with the low-dose and empty µS, suggesting the dose effect of CTGF and TGFβ3 on fibrocartilage formation. Together, our findings may represent an efficient approach to engineering the TMJ disc graft with anisotropic scaffold microstructure, heterogeneous fibrocartilaginous matrix, and region-dependent viscoelastic properties. 10.1177/0022034516642404
    Injectable scaffolds: Preparation and application in dental and craniofacial regeneration. Chang Bei,Ahuja Neelam,Ma Chi,Liu Xiaohua Materials science & engineering. R, Reports : a review journal Injectable scaffolds are appealing for tissue regeneration because they offer many advantages over pre-formed scaffolds. This article provides a comprehensive review of the injectable scaffolds currently being investigated for dental and craniofacial tissue regeneration. First, we provide an overview of injectable scaffolding materials, including natural, synthetic, and composite biomaterials. Next, we discuss a variety of characteristic parameters and gelation mechanisms of the injectable scaffolds. The advanced injectable scaffolding systems developed in recent years are then illustrated. Furthermore, we summarize the applications of the injectable scaffolds for the regeneration of dental and craniofacial tissues that include pulp, dentin, periodontal ligament, temporomandibular joint, and alveolar bone. Finally, our perspectives on the injectable scaffolds for dental and craniofacial tissue regeneration are offered as signposts for the future advancement of this field. 10.1016/j.mser.2016.11.001
    Tissue engineering toward temporomandibular joint disc regeneration. Vapniarsky Natalia,Huwe Le W,Arzi Boaz,Houghton Meghan K,Wong Mark E,Wilson James W,Hatcher David C,Hu Jerry C,Athanasiou Kyriacos A Science translational medicine Treatments for temporomandibular joint (TMJ) disc thinning and perforation, conditions prevalent in TMJ pathologies, are palliative but not reparative. To address this, scaffold-free tissue-engineered implants were created using allogeneic, passaged costal chondrocytes. A combination of compressive and bioactive stimulation regimens produced implants with mechanical properties akin to those of the native disc. Efficacy in repairing disc thinning was examined in minipigs. Compared to empty controls, treatment with tissue-engineered implants restored disc integrity by inducing 4.4 times more complete defect closure, formed 3.4-fold stiffer repair tissue, and promoted 3.2-fold stiffer intralaminar fusion. The osteoarthritis score (indicative of degenerative changes) of the untreated group was 3.0-fold of the implant-treated group. This tissue engineering strategy paves the way for developing tissue-engineered implants as clinical treatments for TMJ disc thinning. 10.1126/scitranslmed.aaq1802
    Tissue engineered autologous cartilage-bone grafts for temporomandibular joint regeneration. Chen David,Wu Josephine Y,Kennedy Kelsey M,Yeager Keith,Bernhard Jonathan C,Ng Johnathan J,Zimmerman Brandon K,Robinson Samuel,Durney Krista M,Shaeffer Courtney,Vila Olaia F,Takawira Catherine,Gimble Jeffrey M,Guo X Edward,Ateshian Gerard A,Lopez Mandi J,Eisig Sidney B,Vunjak-Novakovic Gordana Science translational medicine Joint disorders can be detrimental to quality of life. There is an unmet need for precise functional reconstruction of native-like cartilage and bone tissues in the craniofacial space and particularly for the temporomandibular joint (TMJ). Current surgical methods suffer from lack of precision and comorbidities and frequently involve multiple operations. Studies have sought to improve craniofacial bone grafts without addressing the cartilage, which is essential to TMJ function. For the human-sized TMJ in the Yucatan minipig model, we engineered autologous, biologically, and anatomically matched cartilage-bone grafts for repairing the ramus-condyle unit (RCU), a geometrically intricate structure subjected to complex loading forces. Using image-guided micromilling, anatomically precise scaffolds were created from decellularized bone matrix and infused with autologous adipose-derived chondrogenic and osteogenic progenitor cells. The resulting constructs were cultured in a dual perfusion bioreactor for 5 weeks before implantation. Six months after implantation, the bioengineered RCUs maintained their predefined anatomical structure and regenerated full-thickness, stratified, and mechanically robust cartilage over the underlying bone, to a greater extent than either autologous bone-only engineered grafts or acellular scaffolds. Tracking of implanted cells and parallel bioreactor studies enabled additional insights into the progression of cartilage and bone regeneration. This study demonstrates the feasibility of TMJ regeneration using anatomically precise, autologous, living cartilage-bone grafts for functional, personalized total joint replacement. Inclusion of the adjacent tissues such as soft connective tissues and the TMJ disc could further extend the functional integration of engineered RCUs with the host. 10.1126/scitranslmed.abb6683
    Knee orthopedics as a template for the temporomandibular joint. Bielajew Benjamin J,Donahue Ryan P,Espinosa M Gabriela,Arzi Boaz,Wang Dean,Hatcher David C,Paschos Nikolaos K,Wong Mark E K,Hu Jerry C,Athanasiou Kyriacos A Cell reports. Medicine Although the knee joint and temporomandibular joint (TMJ) experience similar incidence of cartilage ailments, the knee orthopedics field has greater funding and more effective end-stage treatment options. Translational research has resulted in the development of tissue-engineered products for knee cartilage repair, but the same is not true for TMJ cartilages. Here, we examine the anatomy and pathology of the joints, compare current treatments and products for cartilage afflictions, and explore ways to accelerate the TMJ field. We examine disparities, such as a 6-fold higher article count and 2,000-fold higher total joint replacement frequency in the knee compared to the TMJ, despite similarities in osteoarthritis incidence. Using knee orthopedics as a template, basic and translational research will drive the development and implementation of clinical products for the TMJ. With more funding opportunities, training programs, and federal guidance, millions of people afflicted with TMJ disorders could benefit from novel, life-changing therapeutics. 10.1016/j.xcrm.2021.100241
    Micro-precise spatiotemporal delivery system embedded in 3D printing for complex tissue regeneration. Tarafder Solaiman,Koch Alia,Jun Yena,Chou Conrad,Awadallah Mary R,Lee Chang H Biofabrication Three dimensional (3D) printing has emerged as an efficient tool for tissue engineering and regenerative medicine, given its advantages for constructing custom-designed scaffolds with tunable microstructure/physical properties. Here we developed a micro-precise spatiotemporal delivery system embedded in 3D printed scaffolds. PLGA microspheres (μS) were encapsulated with growth factors (GFs) and then embedded inside PCL microfibers that constitute custom-designed 3D scaffolds. Given the substantial difference in the melting points between PLGA and PCL and their low heat conductivity, μS were able to maintain its original structure while protecting GF's bioactivities. Micro-precise spatial control of multiple GFs was achieved by interchanging dispensing cartridges during a single printing process. Spatially controlled delivery of GFs, with a prolonged release, guided formation of multi-tissue interfaces from bone marrow derived mesenchymal stem/progenitor cells (MSCs). To investigate efficacy of the micro-precise delivery system embedded in 3D printed scaffold, temporomandibular joint (TMJ) disc scaffolds were fabricated with micro-precise spatiotemporal delivery of CTGF and TGFβ3, mimicking native-like multiphase fibrocartilage. In vitro, TMJ disc scaffolds spatially embedded with CTGF/TGFβ3-μS resulted in formation of multiphase fibrocartilaginous tissues from MSCs. In vivo, TMJ disc perforation was performed in rabbits, followed by implantation of CTGF/TGFβ3-μS-embedded scaffolds. After 4 wks, CTGF/TGFβ3-μS embedded scaffolds significantly improved healing of the perforated TMJ disc as compared to the degenerated TMJ disc in the control group with scaffold embedded with empty μS. In addition, CTGF/TGFβ3-μS embedded scaffolds significantly prevented arthritic changes on TMJ condyles. In conclusion, our micro-precise spatiotemporal delivery system embedded in 3D printing may serve as an efficient tool to regenerate complex and inhomogeneous tissues. 10.1088/1758-5090/8/2/025003
    Histological analysis of regeneration of temporomandibular joint discs in rabbits by using a reconstituted collagen template. Lai W-F T,Tsai Y-H,Su S-J,Su C-Y,Stockstill J W,Burch J G International journal of oral and maxillofacial surgery The aim of this study was to design a biodegradable implant, in the form of a reconstituted collagen template in order to promote and support regeneration of the temporomandibular joint disc. Bovine collagen (Major Type I) was pepsinized, reduced by beta-mercaptoethanol, and reconstituted by glutaraldehyde. The reconstitution of the collagen increased the resistance to biological degradation by collagenase, optimized the pore size and possessed maximum biological activity for tissue regeneration. Forty-four New Zealand rabbits underwent either sham surgical procedures or partial temporomandibular joint discectomy. In animals that underwent partial discectomy, the discs were replaced by either reconstituted collagen templates or subdermal grafts. Some of the surgerized animals did not receive any type of implant or disc substitute. Gross and histological examination of the surgerized temporomandibular joints was carried out at 1-, 2-, and 3-month intervals after surgery on the selected groups of animals. Marked arthritic changes were observed after 3 months in the partially discectomized joints without implantation. In contrast, the discs, which received a reconstituted collagen template or subdermal graft exhibited regeneration and nearly normal morpology. No foreign body response was observed in experimental groups 3 months after implantation. This study demonstrated that the reconstituted collagen did as well as subdermal grafts in supporting and facilitating regeneration of the disc and the former was found to have some advantages over the latter. 10.1016/j.ijom.2004.05.003
    Histological and Immunohistochemical Analyses of Repair of the Disc in the Rabbit Temporomandibular Joint Using a Collagen Template. Wang Kuo-Hwa,Chan Wing P,Chiu Li-Hsuan,Tsai Yu-Hui,Fang Chia-Lang,Yang Charn-Bing,Chen Kuan-Chou,Tsai Hung-Li,Lai Wen-Fu Materials (Basel, Switzerland) A previous study demonstrated that the reconstituted type I collagen matrix extracted from rabbit tendons enabled the TMJ disc to regenerate in the rabbit. The aim of this study was to investigate changes in the extracellular matrix (ECM) and mechanisms of regeneration in the TMJ disc. In 36 New Zealand rabbits that underwent a partial discectomy, discs were replaced with reconstituted collagen templates for 3 months. A histological analysis showed that moderate to severe degeneration appeared in partially discectomized joints without implantation. In contrast, discs experienced regeneration of reconstituted collagen template implantation and the joint returned to normal function. Cells in the regenerative tissue expressed ECM, and fibers became regular and compact due to tissue remodeling over time. Reparative cells differentiated into chondroblasts, and showed highly dense pericellular fibers. The morphology and collagen composition of the disc and condyle in the 3-month experimental group were similar to those of normal tissues. In conclusion, the reconstituted collagen template facilitated the regeneration of surgically discectomized discs. Type I and type II collagens play a crucial role in the regeneration of articular discs. 10.3390/ma10080924
    Autologous adipose stem cells and polylactide discs in the replacement of the rabbit temporomandibular joint disc. Ahtiainen Katja,Mauno Jari,Ellä Ville,Hagström Jaana,Lindqvist Christian,Miettinen Susanna,Ylikomi Timo,Kellomäki Minna,Seppänen Riitta Journal of the Royal Society, Interface The temporomandibular joint (TMJ) disc lacks functional replacement after discectomy. We investigated tissue-engineered bilayer polylactide (PLA) discs and autologous adipose stem cells (ASCs) as a potential replacement for the TMJ disc. These ASC discs were pre-cultured either in control or in differentiation medium, including transforming growth factor (TGF)-β1 for one week. Prior to implantation, expression of fibrocartilaginous genes was measured by qRT-PCR. The control and differentiated ASC discs were implanted, respectively, in the right and left TMJs of rabbits for six (n = 5) and 12 months (n = 5). Thereafter, the excised TMJ areas were examined with cone beam computed tomography (CBCT) and histology. No signs of infection, inflammation or foreign body reactions were detected at histology, whereas chronic arthrosis and considerable condylar hypertrophy were observed in all operated joints at CBCT. The left condyle treated with the differentiated ASC discs appeared consistently smoother and more sclerotic than the right condyle. The ASC disc replacement resulted in dislocation and morphological changes in the rabbit TMJ. The ASC discs pre-treated with TGF-β1 enhanced the condylar integrity. While adverse tissue reactions were not shown, the authors suggest that with improved attachment and design, the PLA disc and biomaterial itself would hold potential for TMJ disc replacement. 10.1098/rsif.2013.0287
    Inductive, scaffold-based, regenerative medicine approach to reconstruction of the temporomandibular joint disk. Brown Bryan N,Chung William L,Almarza Alejandro J,Pavlick Matthew D,Reppas Serafim N,Ochs Mark W,Russell Alan J,Badylak Stephen F Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons PURPOSE:A device composed of extracellular matrix (ECM) was investigated as an inductive template in vivo for reconstruction of the temporomandibular joint (TMJ) disk after discectomy. MATERIALS AND METHODS:A scaffold material composed of porcine-derived ECM was configured to mimic the shape and size of the TMJ. This device was implanted in a canine model of bilateral TMJ discectomy. After discectomy, 1 side was repaired with an ECM scaffold material and the contralateral side was left empty as a control. At 6 months after implantation, the joint space was opened, the joints were evaluated for signs of gross pathologic degenerative changes, and newly formed tissue was excised for histologic, biochemical, and biomechanical analysis. RESULTS:The results showed that implantation of an initially acellular material supported the formation of site-appropriate, functional host tissue that resembled that of the native TMJ disk. Furthermore, this prevented gross degenerative changes in the temporal fossa and mandibular condyle. No tissue formation and mild to severe gross pathologic changes were observed in the contralateral controls. CONCLUSIONS:These results suggest that an ECM-based bioscaffold could represent an off-the-shelf solution for TMJ disk replacement. 10.1016/j.joms.2011.12.030
    Osteochondral interface regeneration of rabbit mandibular condyle with bioactive signal gradients. Dormer Nathan H,Busaidy Kamal,Berkland Cory J,Detamore Michael S Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons PURPOSE:Tissue engineering solutions focused on the temporomandibular joint (TMJ) have expanded in number and variety during the past decade to address the treatment of TMJ disorders. The existing data on approaches for healing small defects in the TMJ condylar cartilage and subchondral bone, however, are sparse. The purpose of the present study was thus to evaluate the performance of a novel gradient-based scaffolding approach to regenerate osteochondral defects in the rabbit mandibular condyle. MATERIALS AND METHODS:Miniature bioactive plugs for regeneration of small mandibular condylar defects in New Zealand white rabbits were fabricated. The plugs were constructed from poly(D,L-lactic-co-glycolic acid) microspheres with a gradient transition between cartilage-promoting and bone-promoting growth factors. RESULTS:At 6 weeks of healing, the results suggested that the implants provided support for the neosynthesized tissue as evidenced by the histologic and 9.4 T magnetic resonance imaging findings. CONCLUSION:The inclusion of bioactive factors in a gradient-based scaffolding design is a promising new treatment strategy for focal defect repair in the TMJ. 10.1016/j.joms.2010.12.049
    Regeneration of articular cartilage defects in the temporomandibular joint of rabbits by fibroblast growth factor-2: a pilot study. Takafuji H,Suzuki T,Okubo Y,Fujimura K,Bessho K International journal of oral and maxillofacial surgery The purpose of this study was to investigate the therapeutic usefulness of fibroblast growth factor-2 (FGF-2) in rabbit temporomandibular joints (TMJ) with osteoarthritis. A 10-mm(3) defect was bored in the surface of the mandibular condyle head. The animals were divided into four groups: two test groups in which the defect was filled with lyophilized collagen containing 0.1 or 1.0microg of FGF-2, and two control groups, in which the defects were filled with lyophilized collagen without FGF-2 or left empty. The defective sites were examined under a light microscope 3 weeks after surgery. Initiation of cartilage formation was observed in the defects filled with 0.1microg of FGF-2, but only a small amount of cartilage was found in the defects of the 1.0-mug FGF-2- treated group. In the control groups, soft-tissue repair only or no tissue repair was found. In vivo, a dose of 0.1microg of FGF-2 can stimulate articular cartilage restoration in defects of the TMJ in rabbits, although determining the effective concentration range of FGF-2 may be difficult. The present results suggest that an optimum concentration of FGF-2 could restore defects of TMJ articular cartilage clinically. 10.1016/j.ijom.2007.06.007
    Regeneration of defects in the articular cartilage in rabbit temporomandibular joints by bone morphogenetic protein-2. Suzuki T,Bessho K,Fujimura K,Okubo Y,Segami N,Iizuka T The British journal of oral & maxillofacial surgery The purpose of this study was to investigate the therapeutic use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in internally deranged temporomandibular joints (TMJ). Defects (2 mm in diameter) were created in the surface of the condylar head. Lyophilized rhBMP-2 with collagen as the carrier was implanted in the defects in different doses: rhBMP-2 15 microg (n = 5); rhBMP-2 3 microg (n = 5); rhBMP-2 0.6 microg (n = 5). In the two control groups, the defects were either filled with collagen alone (n = 5) or left untreated (n = 5). Three weeks postoperatively the sites of defects were examined under light microscopy. In the 15 micromg and the 3 microg groups, new cartilage had filled the defects; endochondral ossification was also found deep within the defect. In the 0.6 microg group, fibrous tissue was proliferating in most areas of the defect, although cartilage was also found in some parts. In the two control groups, there was either soft tissue repair only or no evidence of tissue repair. These findings suggest that BMP-2 could stimulate the repair of defects in the articular cartilage of the mandibular condyle head during the 3 weeks postoperatively. To observe the progress of endochondral ossification in more detail, it may be necessary to extend the experiment for a longer period of time. However, this study supports the contention that BMP-2 may be useful in the regeneration of cartilage in TMJ disease. 10.1054/bjom.2001.0720
    Mesenchymal stem cells and platelet gel improve bone deposition within CAD-CAM custom-made ceramic HA scaffolds for condyle substitution. Ciocca L,Donati D,Ragazzini S,Dozza B,Rossi F,Fantini M,Spadari A,Romagnoli N,Landi E,Tampieri A,Piattelli A,Iezzi G,Scotti R BioMed research international PURPOSE:This study evaluated the efficacy of a regenerative approach using mesenchymal stem cells (MSCs) and CAD-CAM customized pure and porous hydroxyapatite (HA) scaffolds to replace the temporomandibular joint (TMJ) condyle. METHODS:Pure HA scaffolds with a 70% total porosity volume were prototyped using CAD-CAM technology to replace the two temporomandibular condyles (left and right) of the same animal. MSCs were derived from the aspirated iliac crest bone marrow, and platelets were obtained from the venous blood of the sheep. Custom-made surgical guides were created by direct metal laser sintering and were used to export the virtual planning of the bone cut lines into the surgical environment. Sheep were sacrificed 4 months postoperatively. The HA scaffolds were explanted, histological specimens were prepared, and histomorphometric analysis was performed. RESULTS:Analysis of the porosity reduction for apposition of newly formed bone showed a statistically significant difference in bone formation between condyles loaded with MSC and condyles without (P < 0.05). The bone ingrowth (BI) relative values of split-mouth comparison (right versus left side) showed a significant difference between condyles with and without MSCs (P < 0.05). Analysis of the test and control sides in the same animal using a split-mouth study design was performed; the condyle with MSCs showed greater bone formation. CONCLUSION:The split-mouth design confirmed an increment of bone regeneration into the HA scaffold of up to 797% upon application of MSCs. 10.1155/2013/549762
    In vivo ultrasound-assisted tissue-engineered mandibular condyle: a pilot study in rabbits. El-Bialy Tarek,Uludag Hasan,Jomha Nadr,Badylak Stephen F Tissue engineering. Part C, Methods CONTEXT:Tissue engineering of mandibular articular condyles encounters many challenges, especially restoring adequate mechanical strength that is correlated to matrix production by the tissue-engineered mandibular condyles (TEMCs). Low-intensity pulsed ultrasound (LIPUS) has been shown to enhance cell expansion, differentiation, and matrix production by different cells. OBJECTIVE:This study evaluated effect of daily LIPUS treatment (in vitro and in a pilot in vivo study) for 4 weeks on matrix production and functional integration of the TEMCs in rabbits. METHODS:Bone marrow stromal cells were isolated from the femoral bones of skeletally mature New Zealand rabbits, expanded, and differentiated into chondrogenic and osteogenic lineages. Animals employed in the in vivo study were divided into four groups: (1) TEMCs and LIPUS treatment; (2) TEMCs without LIPUS treatment; (3) empty scaffold and LIPUS treatment, and (4) empty scaffolds without LIPUS treatment. RESULTS:In vitro results showed that LIPUS enhanced chondrogenic and osteogenic differentiation of bone marrow stromal cells. The in vivo study showed that LIPUS led to better structural formation (namely, new osteogenic and chondrogenic tissue formation) and integration of the newly formed tissues and original condylar bone than those without LIPUS treatment. LIPUS resulted in a small amount of tissue regeneration in the empty scaffolds, whereas empty scaffolds without LIPUS treatment showed no signs of repair. CONCLUSIONS:The preliminary results of this pilot study suggest that LIPUS can enhance TEMCs both in vitro and in vivo. 10.1089/ten.TEC.2009.0564
    The use of polylactic acid/polyglycolic acid copolymer and gelatin sponge complex containing human recombinant bone morphogenetic protein-2 following condylectomy in rabbits. Ueki Koichiro,Takazakura Daisuke,Marukawa Kohei,Shimada Mayumi,Nakagawa Kiyomasa,Takatsuka Shigeyuki,Yamamoto Etsuhide Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery PURPOSE:To examine the results of a polylactic acid/polyglycolic acid copolymer and gelatin sponge complex (PGS) with or without recombinant human bone morphogenetic protein-2 (rhBMP-2) used to treat condylar defects in rabbits. MATERIAL AND METHODS:Adult male Japanese white rabbits (n=60; 3kg; 12-16 weeks old) were divided into three groups of 20 each. All rabbits underwent condylectomy. In the two implanted groups, PGS with or without 5 microg of rhBMP-2 was implanted to the condylar defect without fixation. No material was implanted into the control group. Animals were sacrificed at 2, 4, 8, 12 and 24 weeks postoperatively, and the temporomandibular joints (TMJs) were examined histologically. RESULTS:Four weeks after implantation, growth of bone and cartilage-like tissue was observed in all rabbits that received PGS implants (with and without rhBMP-2). A cartilage-like layer was derived from the bone marrow at the operated surface. There was no growth of bone tissue in the control rabbits, but they also had a cartilage-like layer directly derived from the operated surface. CONCLUSION:This study demonstrated that PGS with or without rhBMP-2 could induce regeneration of new bone and cartilage-like tissue in the TMJ. 10.1016/s1010-5182(02)00187-7
    NEL-like molecule-1-modified bone marrow mesenchymal stem cells/poly lactic-co-glycolic acid composite improves repair of large osteochondral defects in mandibular condyle. Zhu S,Zhang B,Man C,Ma Y,Hu J Osteoarthritis and cartilage OBJECTIVE:Articular cartilage of the mandibular condyle has limited ability to regenerate itself after injury. This study was to investigate whether osteochondral defects in mandibular condyle could be repaired by NELL-1(NEL-like molecule-1)-modified autogenous bone marrow mesenchymal stem cells (BMMSCs) and poly lactic-co-glycolic acid (PLGA) composite. METHODS:Osteochondral defects of 3mm-diameter × 5mm-depth were created unilaterally in the central part of the condyle in 50 adult goats. The injury sites were treated with NELL-1-modified BMMSCs/PLGA, BMMSCs/PLGA, PLGA alone, or left empty. The defect area was monitored using gross examination, histology, immunohistochemistry, and micro-computed tomography (μ-CT). Implanted BMMSCs were tracked using Adeno-LacZ labeling. RESULTS:The NELL-1-modified BMMSCs/PLGA group showed vigorous and rapid repair leading to regeneration of fibrocartilage at 6 weeks and to complete repair of native articular cartilage and subchondral bone at 24 weeks. The BMMSCs/PLGA group also completely repaired the defect with fibrocartilage at 24 weeks, but the cartilage in the BMMSCs/PLGA group was less well-organized than the NELL-1-modified BMMSCs/PLGA. The osteochondral defects in the PLGA and empty defect groups were poorly repaired, and no cartilage in the empty defect group or only small portion of cartilage in the PLGA group was found. In vivo viability of implanted cells was demonstrated by the retention for 6 weeks in the defects. CONCLUSION:These findings demonstrated that NELL-1-modified BMMSCs/PLGA composite can rapidly repair large osteochondral defect in the mandibular condyle with regeneration of native fibrocartilage and subchondral bone. 10.1016/j.joca.2011.02.015
    A bilayered scaffold with segregated hydrophilicity-hydrophobicity enables reconstruction of goat hierarchical temporomandibular joint condyle cartilage. Yu Xi,Hu Yihui,Zou Luxiang,Yan Shifeng,Zhu Huimin,Zhang Kunxi,Liu Wenguang,He Dongmei,Yin Jingbo Acta biomaterialia Temporomandibular joint (TMJ) supports chewing, talking or other daily oral activities. So far, it still remains a great challenge to treat the defected TMJ condyle cartilage through tissue engineering technology. Herein, a bilayered scaffold is designed to fully reconstruct the different cartilage matrices of TMJ condyle under same induction condition. The bilayered scaffold with segregated hydrophobicity-hydrophilicity in top and bottom layer is prepared from a low and high content of polyethylene glycol (PEG) crosslinked poly (L-glutamic acid)-g-polycaprolactone (PLGA-g-PCL). The hydrophobic aggregates in top layer support the adhesion and spread of bone mesenchymal stem cells (BMSCs), thus inducing the differentation towards fibrocartilage; while aggregates (spheroids) are formed on the hydrophlic bottom layer, showing a preferable hyaline differentiation pathway under same chondrogenic induction in vitro. After 14 d in vitro induction, the scaffold/BMSCs construct is implanted in goat TMJ condyle defects. The post-operative outcome after 2 months demonstrates that the defects are fully covered by neo-cartilage. And the regenerated hierarchical TMJ condyle cartilage perfectly consist of ordered fibrocartilage and hyaline cartilage, which is same as natural condyle cartilage. These results corroborate that this bilayered scaffold with segregated hydrophilicity-hydrophobicity carrying induced BMSCs is a promising for treatment of TMJ condyle cartilage defects. 10.1016/j.actbio.2020.11.031
    Scaffold-Based Temporomandibular Joint Tissue Regeneration in Experimental Animal Models: A Systematic Review. Helgeland Espen,Shanbhag Siddharth,Pedersen Torbjørn Ostvik,Mustafa Kamal,Rosén Annika Tissue engineering. Part B, Reviews Reconstruction of degenerated temporomandibular joint (TMJ) structures remains a clinical challenge. Tissue engineering (TE) is a promising alternative to current treatment options, where the TMJ is either left without functional components, or replaced with autogenous, allogeneic, or synthetic grafts. The objective of this systematic review was to answer the focused question: in experimental animal models, does the implantation of biomaterial scaffolds loaded with cells and/or growth factors (GFs) enhance regeneration of the discal or osteochondral TMJ tissues, compared with scaffolds alone, without cells, or GFs? Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) guidelines, electronic databases were searched for relevant controlled preclinical in vivo studies. Thirty studies reporting TMJ TE strategies in both small (rodents, rabbits; n = 25) and large animals (dogs, sheep, goats; n = 5) reporting histological and/or radiographic outcomes were included. Twelve studies reported ectopic (subcutaneous) implantation models in rodents, whereas 18 studies reported orthotopic, surgically induced defect models in large animals. On average, studies presented with an unclear-to-high risk of bias. In most studies, mesenchymal stem cells or chondrocytes were used in combination with either natural or synthetic polymer scaffolds, aiming for either TMJ disc or condyle regeneration. In summary, the overall preclinical evidence (ectopic [n = 6] and orthotopic TMJ models [n = 6]) indicate that addition of chondrogenic and/or osteogenic cells to biomaterial scaffolds enhances the potential for TMJ tissue regeneration. Standardization of animal models and quantitative outcome evaluations (biomechanical, biochemical, histomorphometric, and radiographic) in future studies, would allow more reliable comparisons and increase the validity of the results. 10.1089/ten.TEB.2017.0429
    Biomimetic design and fabrication of multilayered osteochondral scaffolds by low-temperature deposition manufacturing and thermal-induced phase-separation techniques. Zhang Ting,Zhang Hefeng,Zhang Laquan,Jia Shuaijun,Liu Jian,Xiong Zhuo,Sun Wei Biofabrication Integrative osteochondral repair is a useful strategy for cartilage-defect repair. To mimic the microenvironment, it is necessary that scaffolds effectively mimic the extracellular matrix of natural cartilage and subchondral bone. In this study, biomimetic osteochondral scaffolds containing an oriented cartilage layer, a compact layer, and a three-dimensional (3D)-printed core-sheath structured-bone layer were developed. The oriented cartilage layer was designed to mimic the structural and material characteristics of native cartilage tissue and was fabricated with cartilage matrix-chitosan materials, using thermal-induced phase-separation technology. The 3D-printed core-sheath structured-bone layer was fabricated with poly(L-lactide-co-glycolide)/β-tricalcium phosphate-collagen materials by low-temperature deposition technology, using a specially designed core-sheath nozzle, and was designed to mimic the mechanical characteristics of subchondral bone and improve scaffold hydrophilicity. The compact layer was designed to mimic the calcified-layer structure of natural cartilage to ensure the presence of different suitable microenvironments for the regeneration of bone and cartilage. A dissolving-bonding process was developed to effectively combine the three parts together, after which the bone and cartilage scaffolds exhibited good mechanical properties and hydrophilicity. Additionally, goat autologous bone mesenchymal stem cells (BMSCs) were isolated and then seeded into the bone and cartilage layers, respectively, and following a 1 week culture in vitro, the BMSC-scaffold constructs were implanted into a goat articular-defect model. Our results indicated that the scaffolds exhibited good biocompatibility, and 24 weeks after implantation, the femoral condyle surface was relatively flat and consisted of a large quantity of hyaloid cartilage. Furthermore, histological staining revealed regenerated trabecular bone formed in the subchondral bone-defect area. These results provided a new method to fabricate biomimetic osteochondral scaffolds and demonstrated their effectiveness for future clinical applications in cartilage-defect repair. 10.1088/1758-5090/aa7078