Osteoarthritis (OA) of the temporomandibular joint (TMJ) is an inflammatory and degen-erative disease that frequently leads to limited mandibular function and chronic pain. This chronic condition is usually, but not always, generated by excessive mechanical stress applied to or sustained by joint structures, to the extent that exceeds its ability to adapt. The process usually begins with low intensity synovial inflammation and progresses to cartilage degrada-tion, with subsequent remodeling of the subchondral bone tissue. However, it has been ob-served that bone marrow and subchondral cortical plate structural changes occur in early stages of this disease. Further destruction of the condylar cartilage and underlying subchondral bone may lead to a more invasive condylar resorption that precipitates the development of skeletal and occlusion changes. Recently, OA has been defined as “an organ” pathology, where resident cells play an important role in joint homeostasis and pathogenesis. Intra-articular structures of TMJ are cov-ered by a synovial membrane, except for the articular cartilage of the fossa, mandibular condyle and articular disc, and soaked by the synovial fluid. Normal synovial fluid is a dialysate of blood plasma with the addition of components synthesized by synovial tissue and catabolic products from the surrounding tissues. Synovial cells produce and are stimulated by pro-in-flammatory cytokines, detected in the synovial fluid of patients with TMJ OA, secreting chemokines which exert further homing of monocytes and macrophages into inflamed TMJ tissues. Chondrocytes of the articular cartilage are metabolically active cells that synthesize and turnover a large volume of extra cellular matrix components. The metabolic activities of chon-drocytes are altered by many factors that are present within their chemical and mechanical en-vironment. The most important among these factors are the pro-inflammatory cytokines and growth factors that have catabolic and anabolic effects. These factors play a role in the degra-dation and synthesis of matrix macromolecules. Thus, the cell–cell interactions between in-flammatory cells and TMJ resident cells, possibly exacerbates the inflammatory symptoms and promotes its transition to a chronic and degenerative state. Adult mesenchymal stem cells (MSCs) are non-hematopoietic, self-renewing cells that are capable of clone-forming and multilineage differentiation. MSCs have been detected in numerous adult articular tissues, including articular cartilage and synovial membrane. The physiological role of MSCs is to ensure that when cells within tissues expire naturally, these can be easily replaced to provide physiological balance, but also to serve as a reserve for damaged or compromised adult tissues requiring more extensive repair or expansion. Different studies demonstrated that MSCs also orchestrate important immunologic functions through modulation of the local inflammatory responses. It has been demonstrated that inflammation could alter the expression and function of MSCs. Articular cartilage is avascular, with limited supplies of nutrients and without the free access to blood-born or perivascular progenitor cells, with a limited ability to promote healing and repair. Regenerative medicine is a promising approach that can benefit patients with le-sions that are difficult to cure, such as TMJ OA, and it should regenerate or fully replace the damaged tissues. Trauma and degenerative lesions have been the major targets of regenera-tive therapies in the musculoskeletal system. While bone regeneration has gained rather broad success using cells, scaffolds, and/or growth factors, cartilage regeneration has not been fully successful despite the fact that the first cell therapies were proposed for cartilage repair more than two decades ago. MSCs show an intense and immediate release of mediators that control inflammation through the secretion of cytokines, release of regulatory epigenetic factors in exosomes, or induction of resident macrophages expressing pro-inflammatory phenotype towards the anti- inflammatory phenotype. Mesenchymal cells can thus simultaneously control the inflammatory environment and provide the progenitor cell population required for the repair and regeneration of chondrogenesis in the condylar apical perichondrium, promoting the subsequent endochon-dral ossification and bone repair. The nasal septum structure is similar to the condylar cartilage. It is covered by a peri-chondrium with a dense external fibrous layer and a subjacent layer containing proliferating progenitor cells. We previously showed that cartilage progenitors were present in this peri-chondrium and that they were highly proliferative and able to differentiate into chondrocytes and osteoblasts, required for endochondral ossification. These autologous fibrocartilage MSCs derived from the nasal septum can be easily harvested. The obtained cell populations have been shown to be highly proliferative and able to promote regeneration of both cartilage and bone. Posteriorly, we proposed a new treatment of TMJ OA consisted of an intra-articular in-jection, on inferior joint space, of autologous in-vitro expanded MSCs from the nasal septum. The proof-of-concept treatment of a selected patient that had no alternative therapeutic pro-posal has given promising results, reaching full regeneration of both the condylar cartilage and bone at 6 months after the therapy, which was fully maintained after 1 year. Current intra-articular injection therapies have usually been directed to the superior rather than inferior joint space because of the simplicity of the technique. As the target of these innovative regenerative therapies is the entire joint “organ”, including the synovial membrane and the articular cartilage in both hermetic spaces, simultaneous injection into the upper and lower compartments seems to be the ideal method to obtain better therapeutic efficacy. Ultra-sound-guided injections have shown to be safe and efficient for this purpose but lacks to pro-vide a direct and clear view of the joint structures and macroscopic representations of the pathological process. Arthroscopy of the TMJ has been established as a reliable and pre-dictable technique for the diagnosis and visually-guided lysis, lavage and injections into the superior joint space. However, the greater invasiveness and the risks of adverse effects related to this technique, associated to the tissue damage caused in the joint capsule, making it diffi-cult for the injected therapies to remain within the joint spaces, prevent their routine use in these scenarios. Thus, we also proposed a minimally invasive arthroscopic technique, using a thinner scope of only 1.0mm diameter, to access and deposit cellular therapies in both TMJ compartments.

Ricardo Tesch holds a Degree in Dentistry – Federal University of Rio de Janeiro; Post-graduation in Ortho- dontics – Association of Dental Surgeons of Campinas; Master’s Degree in Medicine in the area of Head and Neck Surgery – Heliópolis Hospital São Paulo; PhD in Clinical Medicine in the area of Neurology – Federal University of Rio de Janeiro (thesis defense scheduled for November 2018). Associate Professor of the Faculty of Medicine of Petrópolis, where he is the Chief of Temporomandibular Disorders and Orofacial Pain Clinic. Invited Professor of the Pontifícia Universidad Católica Madre y Maestra of Dominican Republic. Researcher with special interest in the areas of Orthodontics and Dentofacial Orthopedics, TMD and Orofacial Pain, Headaches, Genetics and Regenerative Medicine, the latter area with emphasis on Cell Therapies for Cartilage and Bone Regeneration. Currently, Mr. Tesch is the principal investigator in the first in-human clinical trial for temporomandibular joint (TMJ) regeneration using transplantation of autologous nasal septum chondrocytes (UTN – U1111–1194-6997).