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The increasing prevalence of degenerative cartilage disorders in young patients is a growing public concern worldwide. Cartilage’s poor innate regenerative capacity has inspired the exploration and development of cartilage replacement treatments such as tissue-engineered cartilages and osteochondral implants as potential solutions to cartilage loss. The clinical application of tissue-engineered implants is hindered by the lack of long-term follow-up demonstrating efficacy, biocompatibility, and bio-integration. The historically reported immunological privilege of cartilage tissue was based on histomorphological observations pointing out the lack of vascularity and the presence of a tight extracellular matrix. However, clinical studies in humans and animals do not unequivocally support the immune-privilege theory. More in-depth studies on cartilage immunology are needed to make clinical advances such as tissue engineering more applicable. This review analyzes the literature that supports and opposes the concept that cartilage is an immune-privileged tissue and provides insight into mechanisms conferring various degrees of immune privilege to other, more in-depth studied tissues such as testis, eyes, brain, and cancer.

Feline chronic gingivostomatitis is a frustrating disease to manage owing to its elusive etiopathogenesis and its subsequently suboptimal treatment options. Nevertheless, efforts to shed light on the disease over the past few decades have advanced the knowledge on its potential etiopathogenesis and the success rates of available treatment options. Further research is ongoing, with promising attempts to better understand and treat this, likely, multifactorial disease.

There is a paucity of in vivostudies that investigate the safety and efficacy of temporomandibular joint (TMJ) tissue regeneration approaches, in part due to the lack of established animal models. Review of disease models for study of TMJ is presented herein with an attempt to identify relevant preclinical animal models for TMJ tissue engineering, with emphasis on the disc and condyle. Although degenerative joint disease models have been mainly performed on mice, rats, and rabbits, preclinical regeneration approaches must employ larger animal species. There remains controversy regarding the preferred choice of larger animal models between the farm pig, minipig, goat, sheep, and dog. The advantages of the pig and minipig include their well characterized anatomy, physiology, and tissue properties. The advantages of the sheep and goat are their easier surgical access, low cost per animal, and its high tissue availability. The advantage of the dog is that the joint space is confined, so migration of interpositional devices should be less likely. However, each species has limitations as well. For example, the farm pig has continuous growth until about 18 months of age, and difficult surgical access due to the zygomatic arch covering the lateral aspect of joint. The minipig is not widely available and somewhat costly. The sheep and the goat are herbivores, and their TMJs mainly function in translation. The dog is a carnivore, and the TMJ is a hinge joint that can only rotate. Although no species provides the gold standard for all preclinical TMJ tissue engineering approaches, the goat and sheep have emerged as the leading options, with the minipig as the choice when cost is less of a limitation; and with the dog and farm pig serving as acceptable alternatives. Finally, naturally occurring TMJ disorders in domestic species may be harnessed on a preclinical trial basis as a clinically relevant platform for translation.

Frequent involvement of the disc in temporomandibular joint (TMJ) disorders warrants attempts to tissue engineer TMJ disc replacements. Physiologically, a great degree of similarity is seen between humans and farm pigs (FPs), but the pig's rapid growth confers a significant challenge for in vivoexperiments. Minipigs have a slower growth rate and are smaller than FPs, but minipig TMJ discs have yet to be fully characterized. The objective of this study was to determine the suitability of the minipig for TMJ studies by extensive structural and functional characterization. The properties of minipig TMJ discs closely reproduced previously reported morphological, biochemical, and biomechanical values of human and FP discs. The width/length dimension ratio of the minipig TMJ disc was 1.95 (1.69 for human and 1.94 for FP). The biochemical evaluation revealed, on average per wet weight, 24.3% collagen (22.8% for human and 24.9% for FP); 0.8% glycosaminoglycan (GAG; 0.5% for human and 0.4% for FP); and 0.03% DNA (0.008% for human and 0.02% for FP). Biomechanical testing revealed, on average, compressive relaxation modulus of 50 kPa (37 kPa for human and 32 kPa for FP), compressive instantaneous modulus of 1121 kPa (1315 kPa for human and 1134 kPa for FP), and coefficient of viscosity of 13 MPa·s (9 MPa·s for human and 3 MPa·s for FP) at 20% strain. These properties also varied topographically in accordance to those of human and FP TMJ discs. Anisotropy, quantified by bidirectional tensile testing and histology, again was analogous among minipig, human, and FP TMJ discs. The minipig TMJ's ginglymoarthrodial nature was verified through cone beam computer tomography. Collectively, the similarities between minipig and human TMJ discs support the use of minipig as a relevant model for TMJ research; considering the practical advantages conferred by its growth rate and size, the minipig may be a preferred model over FP.

Mesenchymal stem cells (MSCs) have potent immunomodulatory functions and are a promising therapy for immune‐mediated inflammatory disorders. We previously demonstrated the efficacy of fresh, autologous, adipose‐derived MSCs (ASCs) to treat feline chronic gingivostomatitis (FCGS), a chronic oral mucosal inflammatory disease similar to human oral lichen planus. Here, we investigate the use of fresh allogeneic ASCs for treatment of FCGS in seven cats. Radiolabeled ASCs were also tracked systemically. Each cat received two intravenous injections of 20 million ASCs, 1 month apart. Oral inflammation, blood lymphocyte subsets, anti‐fetal bovine serum antibody levels, ASC crossmatching and serum proteins and cytokine concentrations were determined. Four of the 7 cats (57%) responded to treatment [complete clinical remission (n= 2) or substantial clinical improvement (n= 2)]. Three cats were nonresponders. Prior to therapy, most cats had increased circulating CD8+ T cells, decreased CD8locells, and a decreased CD4/CD8 ratio, however clinical resolution was not associated with normalization of these parameters. Nonresponders showed more severe systemic inflammation (neutrophilia, hyperglobulinemia and increased interferon gamma and tumor necrosis factor alpha concentration) prior to ASC therapy. Clinical remission took up to 20 months and no clinical relapse has occurred. A higher fraction of radiolabeled ASCs were identified in the oral cavity of FCGS affected cats than the control cat. The administration of fresh, allogenic ASCs appeared to have lower clinical efficacy with a delayed response as compared to the fresh, autologous ASCs. In addition, the mechanism(s) of action for autologous and allogenic ASCs may differ in this model of oral inflammation. StemCellsTranslationalMedicine2017;6:1710–1722 In this study, we investigated the use of fresh allogeneic ASCs for the treatment of a naturally occurring chronic oral mucosal inflammatory disease of cats similar to human oral lichen planus. Through a series of immune system assays, clinical and histological assessments, we demonstrated that the administration of fresh, allogenic ASCs appeared to be safe and resulted in clinical cure in 57% of the cats. However, the administration of allogenic ASCs may have a lower clinical efficacy with a delayed response as compared to the administration of fresh, autologous ASCs for chronic oral inflammation.

The study of past pathologies by means of quantitative reports is an underexplored approach to deal with the biology and ecology of extinct taxa. In the present study, we assessed the prevalence rate of primary osteoarthritis in a large sample of Prolagus sardus(Mammalia, Lagomorpha) from Medusa Cave (also known as Grotta Dragonara, Sardinia, Italy; Late Pleistocene) to shed light on the evolutionary history of small mammals under isolation regimes. The hip and knee joints of 246 femora were examined grossly, microscopically, and using advanced radiology, recording essential biological features such as age or weight. We noted that 27.7% of skeletally mature sample had degenerative disorder of the joints, with higher frequency in adults (p-value < 0.05), regardless of their body mass (p-value > 0.05). Histologically, affected joints displayed changes in subchondral plate potentially reflecting adaptive modeling. Our analysis revealed ageing (the extended lifespan) as the main driver of this prevalence rate, whereas mechanical factors (caused by a particular lifestyle) were considered of significantly lesser importance. Our results provide additional empirical support to the analytical framework of life history theory from a new perspective, according to which, under low extrinsic mortality regimes, selection should favor slow-strategies (extended lifespan) in small-sized mammals.

Clefts of the primary palate in the dog are uncommon, and their repair can be challenging. The aims of this article are to provide information regarding pathogenesis and convey practical information for the repair of these defects.

Osteoarthritis affects one in eight American adults over the age of 25 y and is a leading cause of chronic disability in the US. Translational research to investigate treatments for this naturally occurring joint disease requires an appropriate animal model. The authors conducted a retrospective study to assess the potential of naturally occurring osteoarthritis in the domestic rabbit as a model of the human disease. Analysis of radiographic images showed that the presence and severity of osteoarthritis were significantly influenced by both age and body weight. The most commonly affected joints were the knee and the hip. The findings reported here suggest that the rabbit is an excellent model of spontaneously arising osteoarthritis that may be useful in translational research pertaining to the human disease.

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.

Tissue-engineered implants integrate with native tissue, are capable of adaptive remodeling, and improve healing of temporomandibular joint disc defects in minipigs.

Naturally occurring diseases in companion animals represent an underused resource that holds promise for providing predictive proof of efficacy in the evaluation of new therapeutics and devices.

Integration of engineered musculoskeletal tissues with adjacent native tissues presents a significant challenge to the field. Specifically, the avascularity and low cellularity of cartilage elicit the need for additional efforts in improving integration of neocartilage within native cartilage. Self-assembled neocartilage holds significant potential in replacing degenerated cartilage, though its stabilization and integration in native cartilage require further efforts. Physical and enzymatic stabilization methods were investigated in an in vitromodel for temporomandibular joint (TMJ) disc degeneration. First, in phase 1, suture, glue and press-fit constructs were compared in TMJ disc intermediate zone defects. In phase 1, suturing enhanced interfacial shear stiffness and strength immediately; after four weeks, a 15-fold increase in stiffness and a ninefold increase in strength persisted over press-fit. Neither suture nor glue significantly altered neocartilage properties. In phase 2, the effects of the enzymatic stabilization regimen composed of lysyl oxidase, CuSO4and hydroxylysine were investigated. A full factorial design was employed, carrying forward the best physical method from phase 1, suturing. Enzymatic stabilization significantly increased interfacial shear stiffness after eight weeks. Combined enzymatic stabilization and suturing led to a fourfold increase in shear stiffness and threefold increase in strength over press-fit. Histological analysis confirmed the presence of a collagen-rich interface. Enzymatic treatment additionally enhanced neocartilage mechanical properties, yielding a tensile modulus over 6 MPa and compressive instantaneous modulus over 1200 kPa at eight weeks. Suturing enhances stabilization of neocartilage, and enzymatic treatment enhances functional properties and integration of neocartilage in the TMJ disc. Methods developed here are applicable to other orthopaedic soft tissues, including knee meniscus and hyaline articular cartilage.