TMJ subcondylar and adjacent bone and cartilage

The temporomandibular joint (TMJ) is one of the most complex joints in the human body. In TMJ disorders (TMD) - chronic syndromes consisting of masticatory dysfunction and/or orofacial pain - articular disc displacement, osteoarthritis or ankylosis may occur. About 1% of patients with TMD undergo invasive procedures. In case of extensive traumatic or tumor-related bone defects, alloplastic prosthetic total TMJ reconstruction (TJR) can improve function and range of motion (RoM). In spite of good success rates, little is known on long-term function and durability of alloplastic TJR. In particular, mandibular function has been analyzed biomechanically only by simple measurements. Dynamic stereometry yields in real time and in vivo the 3D-relationship between skull and mandible, and to date permits to most accurately assess mandibular biomechanics. Aim of this study is the analysis of long-term outcome of alloplastic TJR by dynamic stereometry, correlating its parameters to patients‘ satisfaction and self-management. A maximum of 30 patients with alloplastic TJR from the cranio-maxillofacial centers of Zurich and Basle will be examined clinically and by questionnaires on subjective well-being, pain, quality of life and of sleep. They will receive instructions on home exercises for improving mandibular kinematics and will be measured by dynamic stereometry before and after regime of self-management. Measurements will be performed 3× bilaterally for jaw opening/closing, mandibular protrusion, laterotrusions, border movements and unilateral chewing. For RoM assessment, trajectories and velocities of condylar poles and interincisal points will be measured as well as parameters defining spatial position/orientation of the instantaneous axis of rotation. Joint loading will be analyzed by determining stress-fields. Results from clinical examination, psychological dimensions, and parameters from dynamic stereometry will be correlated and possible group and treatment differences will be explored using t-tests and ANOVA at an α-level of p<0.05. Results from this study will provide new and useful information on a) the impact of alloplastic TJR on patients‘ quality of life and loading of the remaining natural TMJs, b) how TMJ prostheses design can be improved biomechanically also minimizing material failure and c) how much patients‘ self-management by active physical therapy can symmetrize mandibular range of motion, thus better restoring masticatory system function.

Published articles:

Wojczynska A, Leiggener CS, Bredell M, Ettlin DA, Erni S, Gallo LM, Golombo V "Alloplastic total temporomandibular joint replacements: do they perform like natural joints? Prospective cohort study with a historical control" Int. J. Oral Maxillofac. Surg. 2016; 45: 1213–1221. doi:
10.1016/j.ijom.2016.04.022

Craniofacial microsomia (CFM) includes a spectrum of malformations primarily involving structures derived from the first and second branchial arches. The mandible, maxilla, zygoma, external and middle ear, facial and trigeminal nerves, muscles of mastication, and overlying soft tissue can be affected. Reported incidence rates vary from 1:3500 to 1:20000, making it the most frequently seen craniofacial malformation following clefts. Although the deformity normally is unilateral, in 7 - 10 % of the cases CFM is bilateral.

Published articles:

de Jong MA, Gül A, de Gijt JP, Koudstaal MJ, Kayser M, Wolvius EB, Böhringer S. "Automated human skull landmarking with 2D gabor wavelets" Phys Med Biol. 2018 May 16;63(10):105011. doi: 10.1088/1361-6560/aabfa0. PMID: 29676286

de Jong MA, Hysi P, Spector T, Niessen W, Koudstaal MJ, Wolvius EB, Kayser M, Böhringer S. Ensemble landmarking of 3D facial surface scans. Sci Rep. 2018 Jan 8;8(1):12. doi: 10.1038/s41598-017-18294-x. PMID: 29311563 Free PMC Article

de Jong MA, Wollstein A, Ruff C, Dunaway D, Hysi P, Spector T, Fan Liu, Niessen W, Koudstaal MJ, Kayser M, Wolvius EB, Bohringer S. "An Automatic 3D Facial Landmarking Algorithm Using 2D Gabor Wavelets" IEEE Trans Image Process. 2016 Feb;25(2):580-8. doi: 10.1109/TIP.2015.2496183

Gül A, de Jong MA, de Gijt JP, Wolvius EB, Kayser M, Böhringer S, Koudstaal MJ: Three-dimensional soft tissue effects of mandibular midline distraction and surgically assisted rapid maxillary expansion: an automatic stereophotogrammetry landmarking analysis. Int J Oral Maxillofac Surg. 2019 May;48(5):629-634. doi: 10.1016/j.ijom.2018.10.016. Epub 2018 Nov 17. PMID: 30459065

The temporomandibular joint (TMJ) articular surface has poor self-healing capacity, which limits therapeutic options after traumatic injury or in inflammatory/degenerative conditions such as osteoarthritis (OA). Current treatment strategies for TMJ disorders aim to halt the progression of anatomical and functional derangement; however, in advanced stages, replacement of the joint with alloplastic materials remains the gold standard. The TMJ articular surface is composed of fibrocartilage, which seamlessly fuses to the underlying subchondral bone via an osteochondral interface, creating a structure that allows chewing forces to be effectively transmitted to the surrounding bone. Restoration of this important tissue, therefore, not only requires reproduction of osseous and fibrocartilaginous tissue, but also the osteochondral interface, and all three components in continuity. Previous reports in defect- and OA-induced models have been based on intra-articular injections of growth factors, transplantation of stem cells, or cell-seeded scaffolds, however, none have yielded reliable or reproducible outcomes. In this project we propose a new approach to regenerating the TMJ articular surface, including the critical osteochondral interface, in which innovative science in stem cell biology and materials engineering will be incorporated into a translational program. Hyaluronan-based hydrogels encapsulating stem cells, tissue-specific growth factors, and new scientific insights into the role of mechanosensing in controlling stem cell differentiation will be employed to engineer continuous osteochondral constructs. State-of-the-art biological and materials engineering methods will then be utilized to characterize the biological, biochemical and mechanical properties of the constructs with the aim of optimizing their properties to match those of the native tissue. An in vivo study in a sheep TMJ defect model will also be undertaken to evaluate the ability of the construct to both heal a defect in the articular condyle and preventing joint degeneration associated with OA.

Published article:

(2018) Ferreira SA, Motwani MS, Seymour A, Yu TTL, Enayati M, Taheem DK, Kania EM Oommen OP, Ahmed T, Dazzi F, Auner HW, Loaiza S, Varghese OP, Festy F, Grigoriadis AE, Bozec L, Gentleman E: “Bi-directional cell-pericellular matrix interactions direct stem cell fate" Nature Communications, 9:4049, doi: 10.1038/s41467-018-06183-4

Mandible trauma is a very common accident, and a usual consequence is condyle fracture, which could happen along with others fractures that affect the mandibular area, especially symphysis and para-symphysis. However, although some studies have provided a basis for the fixation of separate fractures, no study assesses the fixation of a combined fracture. It is known that several fractures occur simultaneously, the stress distribution could change, and it could alter the best-performing approach to mandibular fracture fixation. Moreover, actually, there is consensus of which is the best form to assess the mechanical comportment of fixation methods. Studies have assessed it through biomechanical tests (using polyurethane mandible, for example) and, more recently, finite element analysis. Thus, the present study’s aims are: to assess, through a finite element analysis and biomechanical test, different forms of condyle fixation when combined with symphysis fracture fixation in order to determine the most favorable combination of fixation protocols in regard to biomechanical comportment; and to compare both methods in order to determine if there is some influence on stress/mechanical forces distribution determination. Both tests will be used to determine the best stress distribution that occurs when a condyle is fixed using one miniplate, two miniplates, or a trapezoidal condyle trauma miniplate. Moreover, symphysis fractures will be fixed using two parallel plates, two perpendicular plates, or two lag-screw techniques. Besides the analysis of each separate fracture, the analysis will be performed while considering both fractures’ occurring simultaneously. The finite element analysis will be performed by simulating a byte force of 250 N, and the stress distribution will be determined via colored diagrams that FEMAP software version 8.3 generates. The biomechanical assay will employ polyurethane mandibles, in which will be simulated symphysis and condyle fractures, whose will be fixed following the same protocols than finite element analysis. Fixed mandibles will subjected to linear vertical loading in the molar region in an Instron 4411 servohydraulic mechanical testing unit (Instron Corporation, Norwood, MA). The load resistance values will be measured at load application displacements of 1, 3, 5, and 10 mm. Means and standard deviations will be compared with respect to statistical significance using analysis of variance (P < .05) and compared by the Tukey test.

Published articles:

Oliveira T, Kemmoku D, Lopes da Silva J, Noritomi P, Passeri P: Finite element evaluation of stable fixation in combined mandibular fractures Journal of Oral & Maxillofacial Surgery: 1-12, 2017. doi: 10.1016/j.joms.2017.06.021

Autologous bone transplantation remains the gold standard for the treatment of large bone defects in the craniomaxillofacial regions as well as appendicular skeleton. This is despite the accompanying donor site morbidity, lack of large quantities of available tissue and requirement for a second surgery for the patient. The promise of tissue engineered bone has yet to be realised. Generating new bone using adult mesenchymal stem cells via endochondral ossification has shown great promise in animal models to date. This involves the generation of a cartilage intermediate, either in vitro or in vivo which is eventually vascularised, mineralised and converted into mature bone. This solves the issue of core necrosis due to lack of vascularisation that is often seen when MSCs are directly differentiated into osteoblasts. However, in order to bring such a therapy to the clinic the approach must be scaled up, with respect to both size of constructs generated and numbers of constructs. This requires large numbers of cells. Ideally these cells would be allogeneic rather than autologous in nature, thereby enabling their harvesting, storage, characterisation and quality control to be performed well in advance of treatment. While adult human MSCs have been shown to be able to modulate the immune system there is some concern and evidence that upon differentiation they lose the ability to do so and come under attack from the host immune system. We hypothesise that chondrogenic differentiation of adult MSCs does not result in these cells being attacked by the immune system. Rather, we aim to demonstrate that chondrogenically primed MSCs recruit cells from the immune system to support bone formation in vivo. We will also assess the effects of using a biomaterial in combination with MSCs has on bone formation. These constructs will be implanted in syngeneic and allogeneic animals and bone formation will be assessed. We will also investigate the interactions between these constructs and cells of the immune system. Assuming our hypothesis is proven we will proceed to heal a critical sized bone defect in the rat. If no bone formation is observed we will investigate the possibility of shielding the MSCs from the immune system and again assess bone formation by endochondral ossification in the allogeneic setting. Generation of vascularised bone in the allogeneic setting will solve many of the problems associated with translation of bone tissue engineering to the clinic.

Published articles:

Kiernan CH, Hoogduijn MJ, Franquesa M, Wolvius EB, Brama PAJ, Farrell E "Allogeneic chondrogenically differentiated human mesenchymal stromal cells do not induce immunogenic responses fromT lymphocytes in vitro", Cytotherapy, 2016, 18:957-969. doi: 10.1016/j.jcyt.2016.05.002

Autologous bone transplantation is the current gold standard for the repair of congenital or trauma-induced bone defects. The disadvantages of this treatment are the donor site morbidity and the limited availability of transplantable bone. Alternatively, bone forming constructs can be generated in vitro from mesenchymal stem cells (MSCs). These constructs can be made of the patient’s own MSCs, but retrieval and culture of the cells causes a significant delay in the time to treatment. Furthermore cells from older diseased patients can have reduced potency. The use of MSCs from healthy young donors creates the possibility of generating off-the-shelf constructs. Allogeneic bone-forming constructs may however induce immune responses in the recipient. In the present study we propose to examine endochondral bone formation by MSCs from a highly potent source of paediatric MSCs in the presence of an allogeneic (donor mismatched) human immune system in vivo using a humanised mouse model. In this model, human bone-forming constructs will be transplanted in immunocompromised mice, followed by administration of human immune cells. The capability of the constructs to form bone will be assessed and if bone formation is hampered by undesired immune responses, cellular immune therapy will be used to dampen these responses, with the aim of inducing stable bone formation over the long term. The ability to generate stable bone using allogeneic MSCs, derived from surplus biological material from healthy young donors, presents the possibility to use a new source of potent cells to treat not only large bone defects but also other diseases.

Published articles:

Kiernan CH, Hoogduijn Mj, Franquesa M, Wolvius EB, Brama PAJ, Farrell E "Allogeneic chondrogenically differentiated human mesenchymal stromal cells do not induce immunogenic responses from T lymphocytes in vitro". Cytotherapy, 18;8, 2016, 957-969. doi: 10.1016/j.jcyt.2016.05.002

(2018, Apr 10): Knuth C, Kiernan C, Palomares C, Lehmann J, Witte-Buoma J, Berge D, Brama P, Wolvius E et al. Isolating paediatric mesenchymal stem cells with enhanced expansion and differentiation capabilities, Tissue Engineering, doi: 10.1089/ten.TEC.2018.0031 (Epub ahead of print)