Open access peer-reviewed chapter - ONLINE FIRST
Abstract
The temporomandibular joint (TMJ) is a vital component of the body’s complex joint system, characterized by its unique biomechanical properties. As a movable synovial joint, it plays a crucial role in executing functional activities such as chewing and speech. The condyle and articular disc work in concert to accommodate dynamic mechanical loads. However, many clinical conditions, such as osteoarthritis (OA), can cause joint damage, and the joint’s self-repair capacity after injury is limited. In its advanced stages, OA may severely compromise the structural integrity of the TMJ, leading to irreversible mechanical deterioration. The progressive degeneration of the condyle and TMJ disc weakens their load-bearing capacity, ultimately resulting in joint dysfunction and loss of mobility. Given the TMJ’s limited self-repair capacity, developing effective therapeutic strategies is crucial for preserving joint function and delaying OA progression. In this chapter, we explore the biomechanical characteristics of the TMJ, the mechanical property changes induced by OA, and emerging strategies for joint repair, reconstruction, and regeneration.
Keywords
- temporomandibular joint
- biomechanical properties
- osteoarthritis
- microscopic analysis
- therapeutic strategies
1. Introduction
The temporomandibular joint (TMJ) is a vital component of the body’s complex joint system, characterized by its unique biomechanical properties. As a movable synovial joint, it plays a crucial role in executing functional activities such as chewing and swallowing [1]. The articular disc within the TMJ provides cushioning, distributes load, and reduces friction, while enduring various forms of complex stress, including compression, tension, and shear during joint movement [2]. The condyle is involved in complex joint movements, including protrusion, retrusion, lateral excursions, and mouth opening and closing [3]. It adapts to dynamic loading during movement through the combined function of the overlying cartilage and underlying bone [4]. Unlike other synovial joints, the condyle exhibits high-frequency, low-stress activity characteristics, and unique adaptive remodeling behavior [5].
However, many clinical conditions, such as osteoarthritis (OA), can cause joint damage, and the joint’s self-repair capacity after injury is limited [6]. This often leads to secondary changes in anatomical morphology, structural composition, and biomechanical properties, ultimately affecting joint function [7]. Osteoarthritis has a high incidence in the TMJ, and its progression to advanced stages results in irreversible damage to joint components [8]. This deterioration disrupts the stress-bearing function of the condyle and articular disc, ultimately leading to a complete loss of TMJ mobility, severely impacting patients’ quality of life [9].
In clinical practice, timely repair or reconstruction should be considered for damaged TMJ structures [10]. The continuous advancements in tissue engineering technologies have provided more options for the repair, reconstruction, and regeneration of joint structures [11]. This review discusses the biomechanical characteristics of the TMJ, the impact of osteoarthritis on joint mechanical properties (Figure 1), joint replacement materials, and the use of cells, growth factors, and scaffolds for TMJ repair.
Figure 1.
Biomechanical characteristics of the healthy TMJ and the impact of OA.
2. Biomechanical characteristics of the TMJ
2.1 Condyle
The condylar cartilage is classified into four distinct layers based on its cellular and matrix composition: the fibrous zone, proliferative zone, mature zone, and hypertrophic zone [12]. Due to the specific composition and arrangement of each layer, these four structural regions exhibit different mechanical properties [13]. In the zonal testing by Gologorsky et al. [14], variations in collagen and glycosaminoglycan (GAG) content led to higher hardness in the proliferative and hypertrophic zones, while the fibrous and mature zones exhibited the greatest compliance. The fibrous zone contains a high density of type I collagen fibers that are tightly arranged in parallel to the condylar surface, exhibiting the highest tensile modulus [15]. This structure provides resistance to shear stress and reduces friction through interstitial fluid pressurization. The proliferative and mature zones are primarily composed of a three-dimensional (3D) network of type II collagen fibers and glycosaminoglycans (GAGs), with compressive modulus increasing with depth [16]. At the interface with the fibrous zone, vertically aligned collagen fibers help reduce interfacial shear stress. The hypertrophic zone contains abundant hydroxyapatite crystals and serves as a transitional tissue between bone and cartilage [17]. Its intermediate hardness enables a smooth stress transition, reducing stress concentration and facilitating the conversion of shear stress into compressive and tensile stress during loading and joint movement [18]. Beneath the cartilage, the subchondral bone is composed of the periosteum, endosteum, cortical bone, and cancellous bone from the outer to the inner layers [19]. The cortical bone consists of multiple layers of collagen fibers and hydroxyapatite crystals, exhibiting high strength and stiffness. It serves as the primary structure in the condylar bone that withstands compressive and tensile forces [20]. In contrast, the trabecular structure of cancellous bone is more porous and heterogeneous in both composition and architecture, playing a crucial role in energy dissipation [21]. The anatomical structure and histological characteristics of the condyle provide it with inherent advantages in adapting to various stresses generated during joint movement [22]. Moreover, to better accommodate individual movement patterns, the condyle is capable of growth and remodeling under appropriate mechanical stimulation, which contributes to maintaining joint health [23]. This mechanosensitive response mechanism primarily relies on the presence of fibrocartilage stem cells (FCSCs) in the fibrous zone of the condylar cartilage, whose chondrogenic differentiation potential provides a cellular basis for the adaptive changes of the condyle [24]. Additionally, cells within the bone tissue can also respond to mechanical forces by generating osteoclasts and releasing degradative enzymes to facilitate remodeling [25].
2.2 TMJ disc
The unique spatial distribution of cells and extracellular matrix (ECM) within the TMJ disc determines its complex mechanical properties [26]. The elastic collagen fiber network and the glycosaminoglycans within it contribute to its viscoelastic mechanical behavior, enabling the disc to adapt to stress under physiological loading conditions [27]. In the actual in vivo environment, the loading conditions of the temporomandibular joint disc are complex and difficult to measure directly. When analyzed, these forces can be simplified into tensile, compressive, and shear forces [28]. Through extensive interspecies comparative studies, it has been demonstrated that the mechanical properties of the porcine TMJ disc exhibit the closest resemblance to those of humans, making it a highly suitable biological model for studying joint biomechanics and pathological mechanisms [29]. However, due to cost constraints, small and medium-sized animal models, such as rabbits and rodents, are also frequently used in research [30]. The tensile behavior of the TMJ disc occurs in two distinct phases. Initially, the disc undergoes elastic deformation, characterized by its ability to completely recover its original dimensions upon the removal of applied stress. The second stage is the plastic deformation phase, where the disc cannot return to its original length after the removal of external force. If the external force exceeds its ultimate strength, the disc will undergo structural failure. The tensile characteristics of the TMJ disc are largely influenced by the orientation and organization of its internal collagen fiber network [31, 32]. Histological and scanning electron microscopy (SEM) results have demonstrated that collagen fibers in the TMJ disc exhibit a circumferential arrangement in the peripheral region and an anteroposterior orientation in the central region [33]. When the shape of collagen fibers in a specific area aligns parallel to the applied tensile force, the tissue can withstand greater tensile stress [34]. In the anteroposterior direction, the central band exhibits the highest tensile modulus, surpassing that of the medial band, whereas the lateral band demonstrates the lowest modulus among the three regions. In the mediolateral direction, the tensile modulus of the posterior and anterior bands is greater than that of the central band. The articular disc is considered to have typical viscoelastic properties. When the tissue is subjected to pressure, the binding force of GAGs to water restricts fluid flow, enhancing the tissue’s resistance to deformation and exhibiting elastic behavior [35]. However, when pressure is sustained for a certain period, leading to the extrusion of most of the fluid from the tissue, its mechanical properties significantly decrease, demonstrating viscous behavior. Its compressive properties are closely related to the distribution of glycosaminoglycans (GAGs), meaning that regions with higher GAG content exhibit greater relaxed compressive modulus [36]. Currently, it is believed that in the anteroposterior direction, the intermediate zone demonstrates a higher compressive modulus compared to the medial and lateral zones. Along the mediolateral axis, the posterior zone exhibits the greatest compressive modulus, exceeding that of the anterior zone, while the central zone shows the lowest values. Additionally, collagen fibers also influence the compressive properties of the articular disc to a certain extent [27].
3. Impact of osteoarthritis on TMJ mechanical properties
In condylar cartilage, due to its inherent remodeling ability, the early stages of OA are characterized by a reparative thickening of the fibrocartilage zone. Simultaneously, there is an increase in type II and type X collagen, as well as GAGs in the extracellular matrix. These changes help slow down or even reverse OA progression, contributing to the restoration of the condyle’s biological function [37]. However, under the continuous stimulation of pathogenic factors and inflammatory responses, chondrocyte metabolic disorders, senescence, and inhibited chondrogenic differentiation or dedifferentiation occur [38]. These changes accelerate the degradation of normal extracellular matrix components, leading to cartilage thinning and a persistent decline in the condyle’s load-bearing capacity. The resulting mechanical stress imbalance further exacerbates OA progression as a reinforcing factor [39]. In the mid-to-late stages of OA, chondrocyte apoptosis increases while autophagy is inhibited through mechanisms such as endoplasmic reticulum stress and ferroptosis [40]. This results in an accumulation of inflammatory factors in the extracellular matrix and the deposition of mineralized crystals, ultimately leading to a complete loss of cartilage load-bearing and lubrication functions [41]. In the condylar bone tissue, OA initially activates osteoclasts, leading to degenerative changes characterized by localized osteoporosis and reduced load-bearing capacity [42]. Subsequent repair mechanisms result in abnormal hyperplasia and sclerosis, accompanied by cystic degeneration and osteophyte formation, which obstruct the normal trajectory of joint movement and reduce joint stability [43]. Additionally, due to TMJ mechanical dysfunction and pain, the surrounding soft tissues undergo protective contraction, limiting mouth opening while reducing the load on the condyle [44].
The TMJ disc, which interacts with the condyle, also undergoes degenerative changes due to OA, disrupting its originally coordinated biomechanical relationship with the condyle [45]. The fibrocartilage layer of the articular disc contains a significant number of FCSCs. As the disc degenerates, the expression of type II collagen genes increases, indicating an attempt at repair. However, due to the relatively low cell density, the articular disc typically does not exhibit fibrocartilage layer hyperplasia similar to that observed in the condyle [46]. Incomplete repair leads to disorganized collagen fiber arrangement in the matrix and uneven interstitial fluid flow, resulting in functional disorders of the articular disc. As matrix degradation progresses, the reduction of collagen, glycosaminoglycans, and water content disrupts its inherent energy dissipation and lubrication functions, thereby increasing the stress burden on the condyle [47]. During matrix degradation, the articular disc gradually thins and takes on a more rounded shape, disrupting its stable relationship with the abnormally shaped condyle. As a result, the disc becomes prone to displacement and loses its ability to evenly distribute loads across the condylar surface [48]. In advanced stages of OA, with the elevated levels of vascular endothelial growth factor (VEGF), neovascularization invades the articular disc, leading to perforation and tearing, ultimately resulting in the complete loss of its cushioning function [49]. In anterior disc displacement, the posterior disc attachment’s loose connective tissue may transition into fibrocartilaginous tissue through metaplastic changes, partially compensating for the lost disc function and alleviating clinical symptoms to some extent [50].
4. Recent advances in strategies for restoration and improvement
4.1 Tissue engineering
The emergence and development of tissue engineering have brought new hope for its application in the repair and regeneration of the TMJ [51]. The following section provides an overview of the relevant strategies in the field of the temporomandibular joint, focusing on three key aspects: seed cells, growth factors, and scaffolds (Figure 2).
Figure 2.
Key aspects for tissue engineering in TMJ.
4.1.1 Seed cells
In the OA state, tissue cell density decreases, and cellular function is impaired, making self-repair difficult. As a source of repair, seed cells can be seeded onto scaffolds in combination with growth factors to proliferate and secrete matrix components for the reconstruction of the condyle and articular disc [52]. Based on their origin, seed cells are mainly classified into two categories: stem cells and somatic cells.
4.1.1.1 Stem cells
Mesenchymal stem cells (MSCs), derived from both adult and embryonic tissues, possess low immunogenicity and maintain the capacity to differentiate into specific cell types when stimulated by appropriate growth factors [53]. Stem cells extracted from different tissues not only undergo osteogenic or chondrogenic differentiation under growth factor induction but also improve the inflammatory environment by secreting anti-inflammatory factors, reducing cell apoptosis at the implantation site, and preventing cartilage matrix degradation [54]. These characteristics make MSCs suitable for TMJ condyle and disc tissue engineering applications. Bone marrow mesenchymal stem cells (BMSCs) represent the most widely utilized source of seed cells for bone and cartilage regeneration. Their exosomes can promote the expression of type I and type II collagen in condylar chondrocytes. Wang et al. [55] compared BMSCs from different sources and found that those obtained from the subchondral bone of the condyle exhibited superior proliferation, osteogenic differentiation, and mineralization capabilities. Hypoxia-inducible factor-1α (HIF-1α) serves as a critical transcriptional regulator, facilitating cellular adaptation to low-oxygen conditions. Cheng et al. [56] enhanced BMSC activity in the condylar environment by inducing its overexpression, effectively reconstructing fibrocartilage. Kobayashi et al. [57] developed a rabbit model of TMJ disc perforation, isolating autologous BMSCs from the femur and culturing them on a collagen-based scaffold. Eight weeks after implantation into the perforation site, the scaffold-seeded cell group demonstrated the formation of dense connective tissue at the defect, whereas the scaffold-only group showed only a reduction in perforation diameter, with the defect still present.
Adipose stem cells (ADSCs) share a similar immunophenotype with BMSCs but have the advantages of abundant sources, easy extraction, and higher proliferation capacity, making them a potential alternative to BMSCs. In a hypoxic environment, ADSCs can maintain high proliferative activity and mimic the surrounding collagen types for tissue repair, offering potential for the regeneration of condylar bone, cartilage, and interface reconstruction [58]. Yang et al. [59, 60] have explored various gene transfection approaches and scaffold materials to optimize the reparative potential of ADSCs in the condyle. When comparing the gene expression of ADSCs after 6 weeks of chondrogenic induction with transforming growth factor-β1 (TGF-β1) in vitro, it was found that ADSCs seeded on polylactic acid (PLA) expressed similar levels of type I collagen as TMJ disc cells. However, the expression levels of type II collagen, type X collagen, and proteoglycans were significantly lower. Additionally, staining results confirmed the adhesion and growth of ADSCs within the PLA fibers, as well as the aggregation and formation of GAGs. An in vivo study based on a rabbit model utilized differentiated adipose-derived mesenchymal stem cells (ADMSCs) seeded onto a PLA scaffold, which was sutured to the zygomatic arch after rabbit disc removal surgery to ensure unrestricted mandibular movement. The results showed that, compared to the control group, the experimental group with differentiated ADMSCs exhibited a more regular and smoother condylar morphology.
Other suitable seed cells for joint tissue engineering include human embryonic stem cells (hESCs), synovial-derived stem cells (SDSCs), and dental pulp stem cells (DPSCs). Hoben et al.’s study [61] demonstrated that hESCs have the potential to differentiate into fibrocartilage-like cells and, with the addition of growth factors such as transforming growth factor-β3 (TGF-β3) and bone morphogenetic protein 4 (BMP-4), can promote the secretion and formation of more collagen and glycosaminoglycans. Shirakawa et al. [62] conducted an in vitro study on SDSCs and found that a cell density of 8 × 105 was optimal for cartilage spheroid formation in vitro. After 42 days of induction, the cartilage spheroids reached a diameter of 3 mm, with volume increase primarily driven by newly deposited extracellular matrix rather than cell proliferation. Subcutaneous implantation of SDSC-seeded TMJ scaffolds in mice resulted in significantly higher production of GAGs and collagen relative to unseeded scaffold controls. DPSCs are considered a potential stem cell source for disc repair due to their ease of acquisition and chondrogenic differentiation capability [63]. When DPSCs were seeded onto a 3D scaffold and cultured in chondrogenic medium for 8 weeks, quantitative polymerase chain reaction (qPCR) and histological results showed upregulation of cartilage-related markers and the formation of cartilage extracellular matrix. However, when Monteiro et al. [64] loaded DPSCs into a hydrogel and implanted them for a certain period, only dense fibrous connective tissue was observed at the condylar defect site, with no successful regeneration of bone or cartilage. However, the exosomes derived from DPSCs effectively inhibited OA progression in the condyle and significantly restored the structure of both the condylar cartilage and subchondral bone, demonstrating their potential in condylar tissue engineering through paracrine mechanisms [65]. In the TMJ, the abundantly present SDSCs and FCSCs have also been experimentally proven to contribute to condylar regeneration. SDSCs exhibit superior chondrogenic capacity compared to BMSCs and ADSCs, successfully reconstructing both cartilage and bone tissues in the condyle. FCSCs are considered the most chondrogenic MSCs, capable of spontaneously forming cartilage and further developing into bone through either endochondral or intramembranous ossification [66].
Other available cell types include umbilical cord mesenchymal stromal cells (UCMSCs) and induced pluripotent stem cells (iPSCs) [67, 68]. iPSCs are easily accessible cells with the potential to differentiate into components of the articular disc. A study on the repair of articular cartilage defects using iPSCs demonstrated the formation of fibrocartilage during the process. UCMSCs are a young type of MSCs with excellent proliferation and differentiation potential, as well as low immunogenicity. They are also abundant, easily accessible, and do not cause donor site damage. Although UCMSCs have not yet been applied in TMJ disc tissue engineering, their chondrogenic potential and successful use in other fibrocartilage repair strategies offer promising prospects for future research. Kim et al. [69] evaluated the therapeutic effects of different concentrations of human UCMSCs in TMJ OA and found that a moderate concentration (5 × 105 cells/200 μL saline) exhibited superior chondrogenic potential. This effect, combined with the excellent secretion of growth factors and anti-inflammatory properties, contributed to the repair of the condyle. However, there have been no attempts to incorporate UCMSCs into scaffolds to date.
4.1.1.2 Somatic cells
Autologous chondrocytes can be isolated from the patient, cultured for expansion, and subsequently reintroduced into the damaged area using a supportive scaffold. Nevertheless, the clinical use of autologous cells is hindered by challenges such as donor site morbidity, dedifferentiation, and limitations in cell expansion [70]. Previous studies have shown that primary cell isolation from the TMJ disc is technically challenging, with a very limited number of cells obtainable. Moreover, during in vitro culture, it is difficult to achieve both cell proliferation and extracellular matrix formation simultaneously, making disc-derived cells an unsuitable option for tissue engineering [71]. Comparative studies on the differences in collagen formation and proliferative capacity among TMJ disc-derived cells, fibroblasts, and costal chondrocytes have demonstrated that costal chondrocytes exhibit superior performance over other cell types [72]. To resolve the challenge of cellular dedifferentiation, Anderson et al. [73] compared passage 5 costal chondrocytes with freshly isolated cells and found that both exhibited comparable abilities in collagen and GAGs synthesis. To biomimic the complex morphology and intrinsic molecular structure of the native TMJ disc, MacBarb et al. [74] cocultured meniscus cells and articular chondrocytes extracted from the distal femoral condyle in a 1:1 ratio within an agarose-supplemented biconcave mold. Under passive axial compression and stimulation with chondroitinase and TGF-β1, the engineered constructs were cultured for 5 weeks. The self-assembled tissue exhibited functionally anisotropic fibrocartilage characteristics, with significant improvements in collagen content (dry weight ratio) and mechanical properties compared to monolayer cultures. The Athanasiou research group [75] employed a scaffold-free culture technique, utilizing an aggregate redifferentiation method to expand costal chondrocytes and construct cartilage-like implants for TMJ disc defect repair in minipigs. After in vitro culture, once the self-assembled constructs achieved mechanical properties similar to those of the native TMJ disc, they were implanted into the animal model for 8 weeks. Histological analysis, defect closure assessment, mechanical testing, and osteoarthritis scoring all indicated successful repair, demonstrating the potential of this approach for TMJ disc regeneration.
Mandibular condylar cartilage (MCC) cells are the most abundant cell type in the condylar cartilage and are considered the primary choice for mandibular condyle cartilage regeneration due to their ease of isolation and culture. Moderate mechanical loading can activate their proliferative activity and extracellular matrix secretion through multiple signaling pathways [76]. However, in vitro culture fails to fully replicate the complex mechanical stimuli experienced by the mandibular condyle, resulting in reduced MCC activity. Additionally, with increasing passage numbers in vitro, MCCs tend to undergo dedifferentiation, leading to a shift in extracellular matrix production from type II collagen and glycosaminoglycans to type I and type III collagen [77]. To address this issue, researchers employed three-dimensional cell culture techniques, maintaining MCCs in suspension, which helped preserve their phenotypic characteristics even after multiple passages, thereby partially mitigating the dedifferentiation problem.
4.1.2 Growth factors
Multiple growth factors have been identified to promote bone and cartilage formation, including transforming growth factor-β1 (TGF-β1), bone morphogenetic proteins (BMPs), platelet-derived growth factor (PDGF), fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF). These factors can be incorporated into scaffolds or directly injected into the TMJ to significantly slow down or even reverse condylar degradation [78]. In tissue engineering, growth factors not only recruit and enhance the activity of resident cells but also act on stem cells to promote their differentiation into target phenotypes.
Since tissue regeneration requires a certain period and follows a sequential process, achieving sustained and controlled release of growth factors is crucial for their successful function. Zhang et al. [79] designed scaffolds with different sequential release patterns of bone morphogenetic protein 2 (BMP-2) and VEGF using microencapsulation techniques. Their study revealed that BMP-2 initiates osteogenesis, while VEGF promotes angiogenesis and bone tissue maturation. The best synergistic effect was observed when BMP-2 was released first. Similarly, Li et al. [80] embedded bone morphogenetic protein 7 (BMP-7) within a scaffold while coating the exterior with BMP-2 to mimic the natural sequence of growth factor action during fracture healing. This design enabled both BMPs to work together, achieving rapid and high-quality bone tissue repair. Additionally, Wu et al. [81] demonstrated that the sequential release of fibroblast growth factor 2 (FGF-2) followed by TGF-β1 successfully induced the chondrogenic differentiation and maturation of ADSCs, leading to optimal cartilage formation.
By comparing the effects of TGF-β1 and insulin-like growth factor 1 (IGF-I) on fibrocartilage cells and articular chondrocytes cultured in agarose, TGF-β1 was shown to enhance collagen deposition and improve the biomechanical performance of the cell-agarose construct, bringing it closer to the properties of the native TMJ disc. However, IGF-I did not significantly improve the composite properties. In three-dimensional culture, studies have shown that both TGF-β1 and IGF-I can promote collagen formation by porcine TMJ disc cells on polyglycolic acid (PGA) scaffolds, but on poly-L-lactic acid (PLLA) scaffolds, TGF-β1 uniquely improved both the biochemical composition and mechanical strength of the secreted extracellular matrix. This result may be attributed to the faster degradation rate of PGA compared to PLLA, demonstrating that the effects of growth factors on cells are synergistic with scaffold materials. To achieve sustained release of TGF-β1, polylactic-co-glycolic acid (PLGA) microparticles were embedded in polycaprolactone (PCL) powder and fabricated using melt extrusion. As PLGA dissolves, it gradually releases growth factors over an extended period. Additionally, PLGA acts as a thermal insulator, protecting TGF-β1 during the high-temperature extrusion process required for melt deposition. When fluorescent PLGA particles were embedded within the PCL scaffold, confocal imaging confirmed spatially controlled particle distribution. This concept can also be applied to the 3D printing of an integrated TMJ disc: microparticles loaded with connective tissue growth factor (CTGF) can be uniformly implanted into the scaffold, while TGF-β3 is localized in the central region. Since TGF-β3 induces GAGs formation, this design enables region-specific deposition of GAGs to mimic the native TMJ disc composition and structure.
Except for direct loading onto scaffolds, gene transfection can also enable seed cells to express growth factors for sustained release. Jiang et al. [82] transfected BMSCs with BMP-2 and VEGF genes using a lentiviral vector, resulting in the prolonged expression of both growth factors in mice for up to 8 weeks. Similarly, researchers transfected ADSCs with various growth factor genes, including bone morphogenetic protein 9 (BMP-9), hepatocyte growth factor (HGF), and TGF-β1, significantly enhancing the osteogenic and chondrogenic differentiation efficiency of ADSCs in the condyle. Mechanical stimulation, apart from growth factors, is an essential signal that influences cellular metabolism, ECM secretion, and the biomechanical properties of tissue-engineered constructs. Studies have reported that hydrostatic pressure can promote ECM formation by enhancing chondrogenic differentiation and upregulating specific ECM gene expression. However, research on mechanical stimulation in TMJ disc tissue engineering remains limited. Almarza et al. [83] reported that hydrostatic pressure could promote type I collagen formation, but the optimal mechanical stimulation parameters for TMJ discs and their potential synergy with growth factors require further investigation.
4.1.3 Scaffolds
Scaffolds used in TMJ tissue engineering should not only support cell adhesion and maintain cellular biological functions but also possess sufficient mechanical strength to meet the demands of joint movement after implantation. Additionally, they must exhibit biocompatibility and long-term stability to ensure proper formation of newly generated tissue. Based on their origin, TMJ scaffolds can be categorized as natural materials and synthetic materials.
4.1.3.1 Natural materials
Various materials have been explored for disc tissue engineering, including collagen, alginate, fibrin, chitosan, and decellularized extracellular matrix (dECM). Collagen, the most abundant component of the TMJ disc extracellular matrix, is widely available and features a porous structure that facilitates cell infiltration. Additionally, GAGs readily deposit on collagen surfaces, and implanting BMSCs onto collagen scaffolds has successfully repaired disc perforations in rabbit models. Alginate hydrogels can maintain chondrocyte viability and morphology, promoting collagen and GAG secretion. Their ease of modification further enhances their potential as scaffold materials. Fibrin gel has also been applied in soft tissue regeneration; however, its weak mechanical strength, fast degradation rate, and significant volume contraction during gelation limit its application in TMJ disc reconstruction unless combined with other materials. A study demonstrated the use of a composite scaffold combining fibrin gel with freeze-dried chitosan, when loaded with SDSCs, supported cell proliferation and chondrogenic differentiation in vitro. In vivo experiments demonstrated more pronounced extracellular matrix deposition in the composite material group compared to the chitosan-only group, suggesting enhanced regenerative potential.
ECM scaffolds for TMJ disc reconstruction are currently derived from either porcine bladder or directly from the TMJ disc. Porcine bladder-based scaffold is fabricated using a sandwich-like structure, where powdered decellularized porcine bladder is placed between two hydrated decellularized bladder sheets. In a canine model with bilateral disc resection, the implanted scaffold supported new tissue formation, and after 24 weeks, the regenerated tissue exhibited morphology similar to that of the native TMJ disc. Quantitative analysis revealed that the implanted scaffold contained GAGs and collagen at concentrations comparable to those of the native disc, with similar mechanical properties. Additionally, studies have reported the decellularization of porcine TMJ discs followed by laser micropatterning to enhance permeability. The purpose of microporization is to enhance scaffold-cell attachment and promote higher cell density through enhanced porosity; however, this technique remains at the in vitro research stage. Liang et al. [84] processed porcine TMJ discs into small fragments and performed decellularization using a combination of physical, biological, and chemical methods. They then digested the material with pepsin to create a flowable, viscous solution. Both in vitro and in vivo experiments demonstrated the biocompatibility of the gelled decellularized material, providing a novel injectable approach for TMJ disc defect repair.
For mandibular condyle reconstruction, incorporating hydroxyapatite significantly enhances the mechanical properties of collagen-based and other biomaterial scaffolds, mimicking the composition of natural bone tissue, making it particularly suitable for bone regeneration [85]. Additionally, platelet-rich plasma (PRP) is rich in growth factors such as TGF-β1, VEGF, and PDGF, along with anti-inflammatory factors. Numerous studies have incorporated PRP into scaffolds to promote both bone and cartilage regeneration while enabling sustained release of growth factors. Directly using PRP clots as scaffold materials has also shown effective cartilage repair in mandibular condyle applications [86].
4.1.3.2 Synthetic materials
In contrast to natural materials, synthetic alternatives lack the ability to promote cell differentiation but offer superior mechanical strength and stability. Additionally, synthetic scaffolds allow precise control over pore size, fiber dimensions, and geometric shapes. Degradable synthetic scaffolds provide high initial mechanical strength upon implantation, and ideally, they degrade at a rate comparable to tissue formation over time. PGA has been investigated for its feasibility in forming cartilage tissue by seeding chondrocytes and culturing them in vitro and in vivo. When seeded with TMJ disc cells and cultured in a bioreactor for 6 weeks, PGA scaffolds continuously produced collagen and GAGs; however, the elastic modulus did not significantly increase compared to pre-culture conditions. Additionally, post-culture absorption and shrinkage of PGA raised concerns about its in vivo application, leading researchers to focus on PLA due to its slower degradation rate. A biphasic PLA scaffold was designed with one porous side to facilitate cell seeding and a smooth PLA laminate on the opposite side to serve as an articular surface. After 12 months of implantation, the PLA scaffold remained visible; however, scaffold displacement, condylar hypertrophy, and chronic osteoarthritis indicated that it failed to adequately protect the TMJ. A scaffold fabricated by embedding PLGA microspheres into a PCL matrix has been shown to promote fibrocartilage formation, mimicking the anisotropic collagen distribution and region-specific ECM composition of the native TMJ disc. Since PCL has a lower melting point than PLGA, PLGA microspheres remain stable during PCL melting, allowing the encapsulated growth factors to remain unaffected by high temperatures. After 6 weeks of in vitro culture, this microsphere-laden scaffold demonstrated increased collagen and GAG deposition, along with enhanced mechanical properties compared to a scaffold without microspheres. Another promising elastomeric polymer with good biocompatibility, poly(glycerol sebacate) (PGS), has been shown to support continuous collagen and GAG deposition when seeded with chondrocytes. Higher initial cell seeding densities resulted in greater matrix deposition. Additionally, after 4 weeks of culture, PGS exhibited minimal degradation and a significant increase in compressive modulus compared to 24-hour post-seeding conditions.
In addition to selecting appropriate materials, optimizing the scaffold structure is essential to maximize cell infiltration, nutrient diffusion, and metabolic waste removal while simultaneously providing the necessary mechanical properties for the TMJ disc to function properly. Scaffold design requires careful consideration of multiple factors, such as pore size, porosity, structural geometry, mechanical strength under tension and compression, flexibility, and region-specific biomimetic properties. To develop scaffolds that meet these requirements, researchers have explored a wide range of fabrication techniques, from traditional approaches such as physical blending and hydrogels to advanced methods like 3D printing. Increasing porosity can compromise mechanical strength; therefore, scaffold porosity must be carefully regulated to ensure sufficient mechanical integrity for in vivo applications. Moreover, maximizing interconnectivity between pores is crucial for facilitating the effective distribution and transport of cells, nutrients, and metabolic byproducts. A combination of large (>400 μm) and small (<50 μm) pores has been shown to achieve optimal extracellular matrix deposition and material transport, ensuring both mechanical stability and biological functionality.
3D printing has emerged as a promising approach for TMJ disc tissue engineering due to its ability to achieve rapid prototyping and region-specific biomimicry of native matrix distribution. Studies have explored the use of 3D-printed PCL scaffolds to provide the necessary mechanical properties, combined with polyethylene glycol diacrylate (PEGDA) hydrogel to enhance lubrication. However, the in vitro and in vivo applications of this composite remain to be further investigated. Legemate et al. [26] incorporated PLGA microspheres loaded with TGF-β3 and CTGF into PCL powder and used melt deposition modeling to integrate these microspheres into specific regions of the PCL scaffold. The resulting scaffold enabled the sustained release of growth factors for up to 42 days. When seeded with human MSCs, the scaffold facilitated the formation of collagen-rich fibrous structures in the anterior and posterior regions, while promoting fibrocartilage-like matrix deposition in the central region, achieving desirable elastic properties. Upon implantation into a TMJ disc perforation rabbit model for 4 weeks, this regionally biomimetic artificial material demonstrated effective defect repair and successfully protected the condyle from osteoarthritic changes.
The condyle consists of bone, hyaline cartilage, and fibrocartilage, making the simultaneous regeneration of these components and their seamless integration at the interface a major challenge for complete condylar regeneration. The use of multiphasic scaffolds provides a promising strategy to address this issue. Given the differences in scaffold composition and mechanical properties, scaffold design has become the primary approach for inducing specific cellular activities to regenerate multiple condylar components. Wang et al. [87] engineered a condyle-like composite by combining a cartilage cell sheet with a bone-phase scaffold, separately seeding chondrocytes and BMSCs, and culturing the construct in vivo in nude mice, resulting in a tightly integrated bone-cartilage structure. Yu et al. [88] developed a biphasic scaffold with a hydrophobic surface layer and a hydrophilic bottom layer by modifying the scaffold with varying polyethylene glycol (PEG) contents. After seeding with BMSCs, the scaffold successfully facilitated the organized reconstruction of both the fibrocartilage and hyaline cartilage layers of the condylar surface. To further enhance interface integration and better mimic the biomechanical function of the condyle, gradient scaffold fabrication using 3D printing technology has demonstrated significant advantages in condylar tissue engineering. Xiao et al. [89] designed a scaffold with gradient pore sizes, which, upon BMSC implantation, promoted the transition between bone and cartilage. Similarly, researchers utilized gradients in hyaluronic acid concentration and pore size to achieve a well-integrated regenerated condylar cartilage and subchondral bone.
Through multi-bioactive substance modifications, scaffolds can directly recruit in situ cells or growth factors at the implantation site to facilitate tissue regeneration, thereby eliminating the need for donor site surgery, complex cell processing, and reducing immune rejection, effectively lowering overall costs. Chen et al. [90] modified silk fibroin with a calcium phosphate coating and encapsulated TGF-β1 and BMP-2 to recruit endogenous cells and promote cartilage and bone formation, respectively, while achieving controlled dual growth factor delivery over an extended period of 19 days. Mao et al. [91] successfully recruited and induced the chondrogenic differentiation of BMSCs by sequentially releasing the BMSC-specific affinity peptide E7 and TGF-β1. Similarly, Guo et al. [92] utilized a TGF-β1 recruiting peptide (HSNGLPL) to effectively harness endogenous TGF-β1, avoiding the negative impacts linked to the burst release of exogenous growth factors and enabling a simple yet effective approach for cartilage regeneration.
4.2 Joint replacement materials
When late-stage OA leads to severe condylar structural damage and conservative treatments fail to control disease progression, surgical intervention involving the removal of the affected TMJ tissues and joint replacement is often necessary [93]. Interpositional materials, including autografts, allografts, and artificial prostheses, are used to restore TMJ morphology and function.
The ability to withstand cyclic loading of the TMJ is a fundamental requirement for TMJ replacement materials. Autologous grafts offer a low-cost reconstruction approach with fewer complications but are prone to resorption. Common sources include costal cartilage and the mandible, and distraction osteogenesis can also stimulate in situ bone proliferation to regenerate a new condyle. Allogeneic costal cartilage, mandibles, or entire TMJ structures can also serve as low-immunogenic biological materials after cryopreservation, eliminating the need for donor site surgery.
The development of artificial TMJ replacement materials has evolved over time, transitioning from metal-on-metal interfaces to metal-on-nonmetal combinations. Currently, TMJ prostheses fall into four major categories: metal materials, polymer materials, bioceramics, and composite materials. Among them, titanium alloys, cobalt-chromium alloys, and ultra-high molecular weight polyethylene have become clinically preferred prosthetic materials due to their long-term stability and safety [94]. However, despite their advantages, the high cost of joint prostheses remains a significant barrier to widespread application.
5. Discussion
As the only movable joint in the human craniofacial region, the normal biomechanical function of the TMJ is essential for chewing, speech, and even overall systemic health. In orthodontic and prosthodontic treatments, there is a growing consensus that, beyond achieving esthetic outcomes, establishing proper occlusal relationships to ensure the coordinated movement of the TMJ is equally critical [95].
The TMJ has a highly intricate structure, with distinct fiber orientations and compositional variations across its osseous and cartilaginous components working in concert to transmit and distribute complex mechanical stresses [13]. Within the TMJ, the condylar cartilage exhibits a unique adaptive remodeling behavior that endows the joint with high sensitivity to dynamic loading. This allows the TMJ not only to bear mechanical loads but also to respond flexibly to mechanical stimuli, providing a specialized buffering capacity against various forms of chronic TMJ injury [96]. However, although an increasing number of studies have focused on the biomechanical properties of the healthy TMJ components, there remains a lack of clear understanding regarding their adaptive limits under various functional abnormalities. This gap hinders early diagnosis and timely intervention of TMJ disorders. As a result, many TMJ-related conditions progress without adequate treatment, ultimately leading to a complete loss of biomechanical function [4]. Future studies should focus on dynamically monitoring the repair processes and mechanical behavior of the condyle under varying cyclic mechanical loads, to further elucidate the progression of TMJ repair mechanisms. By evaluating the adaptive limits of the condyle across multiple dimensions—such as time and loading conditions—these investigations will provide critical data to support the establishment of diagnostic criteria for early stage TMJ pathologies.
In the early stages of TMJ OA, the joint retains a certain repair capacity that temporarily preserves its functional mobility. However, when abnormal disc-condyle relationships or sustained overload result in impaired stress-function matching, increased surface friction and decreased cellular activity may exceed the joint’s regulatory capacity. At this point, both the condylar surface and the TMJ disc begin to undergo degradation. By the mid-stage of OA, the TMJ enters an irreversible degenerative phase, with a gradual loss of its biomechanical function [97, 98]. One of the major challenges in treating TMJ OA lies in the fact that by the time clinical symptoms appear, the joint has often already entered a degenerative stage. At this point, structural alterations are apparent, cellular density is significantly reduced, and the tissue’s intrinsic repair capacity is inadequate. Currently, clinical treatments for early- to mid-stage TMJ OA primarily focus on anti-inflammatory approaches or improving joint lubrication to provide temporary symptom relief, but they are unable to halt or reverse disease progression. As a result, most TMJ OA patients inevitably progress to the advanced stage, characterized by condylar cartilage loss leading to subchondral bone exposure, articular disc perforation, and joint ankylosis [99, 100]. For TMJs that have undergone significant degradation, tissue engineering and joint replacement surgery remain the two most effective therapeutic strategies available in clinical practice.
Tissue engineering for TMJ reconstruction is advancing rapidly, with numerous breakthroughs achieved around its three core components. Researchers have extensively explored various aspects of seed cells from different sources, including their isolation, cultivation, implantation, post-implantation induction of differentiation, and maintenance of stable phenotypes [101]. Multiple types of MSCs have demonstrated promising applications in TMJ reconstruction. In addition, techniques, such as genetic modification and hypoxic preconditioning of seed cells, have been progressively optimized, effectively addressing issues such as the low homing efficiency and phenotypic drift of conventional MSCs within the inflammatory microenvironment of the TMJ [56, 59]. With the growing understanding of the physiological processes of cartilage and bone development, research on growth factors has advanced beyond the limitations of single-factor approaches. Guided by the concept of spatiotemporally precise delivery, multiple growth factors have been employed in TMJ reconstruction to mimic natural processes and regulate the formation of vasculature, cartilage, and bone, thereby significantly improving regenerative outcomes. As a critical component in tissue engineering, scaffolds—serving as essential carriers for seed cells and growth factors—remain at the core of technological advancements in this field. With the widespread application of composite materials capable of complementary performance enhancement, electrospinning and 3D printing have emerged as cutting-edge scaffold fabrication techniques for constructing more precise biomimetic structures. Additionally, strategies, such as dual-crosslinking and dual-network architectures, have been extensively employed to improve the mechanical properties of scaffolds and achieve sustained release of growth factors in a more cost-effective manner. Furthermore, intelligent management of scaffolds within the temporomandibular joint (TMJ) has been advanced through the incorporation of multiple stimulus-responsive mechanisms—such as temperature, pH, light, and enzyme responsiveness—which have been successfully utilized for in situ scaffold assembly and smart release of growth factors. These innovations help prevent issues associated with traditional scaffolds, including post-implantation displacement and burst release of growth factors [102].
For joint replacement surgeries involving the TMJ, the development of prosthetic materials has become increasingly refined with the growing understanding of joint structure and function. The focus has shifted from merely restoring anatomical form to simulating joint function. One of the current major directions is the use of 3D printing for structural design to replicate the energy dissipation mechanisms of the TMJ [103]. In the development of prostheses for other joints, such as the knee, further functionalization—such as biomimetic boundary lubrication, enhanced cell adhesion, drug encapsulation, antimicrobial properties, and self-healing capabilities—has provided expanded options for improving the clinical performance of joint implants [104].
The unique structure and function of the TMJ, along with current limitations in understanding its biomechanics, have hindered the development of effective clinical treatment strategies. The complex loading patterns during TMJ movement cannot be fully replicated in vitro, which not only restricts the design of scaffolds and prostheses but also provides insufficient reference for mimicking the native mechanical environment required to induce seed cell differentiation. Current reconstruction strategies generally lack precise simulation of the zonal architecture within cartilage, making it difficult for regenerated tissues to replicate the physiological biomechanical functions of different TMJ components. Although cell-laden 3D printing can spatially control the distribution of different cell types within scaffolds to better integrate bone-cartilage interfaces, this technology has not yet been applied to replicate the cellular heterogeneity across the distinct layers of TMJ condylar cartilage and regions of the TMJ disc [105]. For TMJ OA, the understanding of the interplay between cartilage and subchondral bone remains limited, and the sequence of pathological changes between the condylar bone and cartilage is still unclear. This uncertainty hinders the ability of current TMJ tissue engineering strategies to provide targeted solutions for different stages of the OA microenvironment. The future development of TMJ repair technologies will require a more comprehensive understanding of the joint’s anatomical structure, biomechanical characteristics, and pathological progression.
6. Conclusions
The TMJ possesses unique biomechanical properties, enabling it to withstand mechanical loads during complex functional activities such as mouth opening and closing. However, OA significantly compromises its structural integrity and mechanical performance, leading to progressive joint degeneration and loss of mobility. Given the limited intrinsic repair capacity of the TMJ, developing effective therapeutic strategies is crucial for preserving biomechanical properties, restoring joint function, and delaying OA progression.
In recent years, advancements in tissue engineering have provided novel solutions for TMJ repair and regeneration. The combined application of scaffolds, cells, and growth factors has demonstrated potential in reconstructing damaged joint structures and restoring biomechanical function. Concurrently, the continuous optimization of artificial joint replacement materials has enhanced their mechanical performance and in vivo compatibility, offering a more reliable solution for severe joint damage. Future research should further elucidate the micro-biomechanical characteristics of the TMJ and the pathological changes associated with OA while optimizing the physicochemical properties of biomaterials to drive the development of clinically translatable therapeutic strategies.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (No. 82301112) and the Sichuan Science and Technology Program (No. 2024NSFSC1592).
Conflict of interest
The authors declare no conflict of interest.
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