Case StudyTreatment of Bilateral Medial Femoral Condyle Articular Cartilage Fissures in a Horse Using Bone Marrow-Derived Multipotent Mesenchymal Stromal Cells
Introduction
Joint pathology has been reported to be a major cause of lameness in horses and is estimated to account for 42%-60% [1], [2] of lameness cases. The relatively avascular and hypoxic nature of cartilage as a tissue, in addition to the nonproliferative characteristics of mature chondrocytes, often results in a poor prognosis for complete recovery. In addition, these cartilage injuries present with highly variable clinical signs and recovery outcomes. Factors that determine the extent of healing include the depth, location, size, and weight-bearing environment of the lesion(s), in addition to patient age and conformation [3], [4]. Current treatments for injuries related to articular cartilage in horses are ever evolving. A diagnosis is generally confirmed through arthroscopic examination and treatments include partial meniscectomy, curettage or drilling into the subchondral bone, cartilage flap/fragment fixation, and surgical debridement and microfracture [5], [6], [7], [8], [9], [10], [11], [12]. In horses with lameness localized to the medial femorotibial joint having subtle radiographic changes of the medial femoral condyles, it was found that only two of six horses with generalized cartilage lesions were reported as being sound and without any evidence of joint effusion after arthroscopic-guided abrasion arthroplasty and microfracture [12]. Prognosis depends on the severity and location of the lesion(s), among other factors, and it is generally accepted that the percentage of patients making a complete recovery decreases with increasing severity of injury [13]. In another series, 86% of horses with focal lesions of the medial femoral condyle treated with arthroscopic curettage and debridement returned to normal function, whereas none of the horses that presented with extensive and diffuse damage, in which arthroscopic treatment was not performed, recovered completely [6]. Both studies highlight a guarded prognosis for horses with moderate to extensive damage to the cartilage of the medial femoral condyle.
With limited options available for articular cartilage repair and the efficacy of such options being variable, especially for extensive injuries, clinicians and researchers in both human and veterinary medicine have, over the past decade, looked into the potential of progenitor or stem cells to aid in tissue regeneration and repair. Currently, only one cell-based therapy has been approved by the Food and Drug Administration for use in human beings (Carticel, Genzyme). This uses autologous chondrocytes harvested from a non- or low load-bearing location that are then expanded in vitro, implanted into articular defects, and covered by a periosteal flap. The efficacy of such therapy, as measured by a combination of function and pain [14], has been reported to be >80% in human beings [15], with comparable results in horses using a similar technique for the repair of manufactured full-thickness defects in minor load-bearing areas of the tibiotarsal joint [16]. However, induction of defects to harvest chondrocytes is a concern with this type of cell therapy and comparable clinical results have been obtained with microfracture [17]. Thus, other tissue sources for cellular therapy as well as implantation methods are being considered.
Mesenchymal stromal cells (MSCs) are a multipotent adult stem cell population capable of differentiating into tissues of the mesenchymal lineages including bone, cartilage, and fat, and may also serve as trophic mediators aiding in attenuating the inflammatory response [18], [19], [20]. These cells have been referred to in the published data and by industry by a variety of names including mesenchymal stem cells and bone marrow stromal cells; we have chosen to use the name multipotent MSCs, as recommended by the International Society for Cellular Therapy [21]. With the relative abundance and accessibility of MSCs for clinical harvest, many clinicians and researchers have begun looking at the use of MSCs for cartilage [22], tendon [23], [24], ligament [23], [24], and bone repair [25]. Recently, there was a report of the use of autologous MSCs in a fibrin glue enhancing the early repair of manufactured full-thickness articular cartilage/subchondral bone defect in the equine femoropatellar joint [26]. Although the report noted that long-term healing at 8 months was not significantly different between individuals receiving MSC-laden fibrin glue or control (MSC-free fibrin glue), the study did not compare an untreated control, thus it is difficult to determine whether the fibrin glue alone may have played a role in healing. There is evidence in the published data that fibrin may serve as a scaffold for tissue repair, including that of cartilage, thereby contributing to the healing process [27], [28]. The apparent benefits of MSCs on early healing should not be disregarded and may provide a foundation for additional intra-articular cellular therapy to improve overall joint health. Although experimental studies are limited, there is less evidence for the efficacy of such treatment in naturally occurring superficial lesions in which the subchondral bone is intact. In this case report, we describe the use of arthroscopically delivered autologous MSCs in a partially autologous fibrin glue to treat bilateral diffuse fissure fractures of the medial femoral condyles of a horse.
Section snippets
Clinical Findings
A 4-year-old Thoroughbred gelding was presented for bilateral stifle arthroscopy. The horse began racing in November 2004 as a 2-year-old and raced successfully through September 2006 with 11 starts (Table 1). Although there was a clinical indication of subtle hindlimb performance-limiting lameness in July 2006, physical examination, nuclear scintigraphy, and associated stifle radiographic examination were inconclusive. However, there was slight flattening noted on the medial femoral condyles
Results
Four months after the initial stem cell treatment, arthroscopic examination of both stifles was repeated using the previously described procedure. Exploration of the left and right medial femorotibial joints showed persistent fissures of the central articular cartilage of the medial condyles. However, these fissures were more blunted and shallow than in previous exploration (Fig. 6). The area of the suspected cranial cruciate injury appeared to be moderately improved, as determined by
Discussion
This case demonstrates the use of biologics such as autologous MSCs and partially autologous fibrin glue for the treatment of bilateral articular cartilage fissures on the medial femoral condyles of a horse. Autologous chondrocyte transplants, as well as MSCs, have been used to successfully repair artificially created or enhanced full-thickness lesions that traverse the articular cartilage and/or subchondral bone boundary in both human and veterinary medicine [15], [16], [26]. It is
Acknowledgments
The authors thank Jonathan Hirsch, Bill Symm, Lisa Fortier. Location of work: The initial lameness examination and associated diagnostics (nuclear scintigraphy, and stifle radiographs) were performed at the Southern California Equine Foundation Hospital at the Santa Anita Racetrack, Arcadia, CA, whereas follow-up lameness examination, (CBC and chemistry panel screening, equine protozoal myeloencephalitis testing, and diagnostic intra-articular anesthesia) were performed at the Harris Farms
References (39)
Future directions in treatment of joint disease in horses
Vet Clin North Am Equine Pract
(2005)Diagnosis and treatment of ligamentous and meniscal injuries in the equine stifle
Vet Clin North Am Equine Pract
(2005)- et al.
Arthroscopic drilling in juvenile osteochondritis dissecans of the medial femoral condyle
Arthroscopy
(1994) - et al.
Arthroscopic surgical management of osteochondritis dissecans of the knee
Arthroscopy
(1988) - et al.
New surgical treatments for osteochondritis dissecans and subchondral bone cysts
Vet Clin North Am Equine Pract
(2005) Osteochondritis dissecans of the trochlea of the femur
Arthroscopy
(1990)- et al.
Human mesenchymal stem cells modulate allogeneic immune cell responses
Blood
(2005) Immunomodulatory effects of fetal and adult mesenchymal stem cells
Cytotherapy
(2003)- et al.
Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement
Cytotherapy
(2006) - et al.
Intra-articular injection of mesenchymal stromal cells in partially torn anterior cruciate ligaments in a rat model
Arthroscopy
(2007)
Advances in articular cartilage repair
Injury
Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects
Osteoarthritis Cartilage
Repair of full-thickness cartilage defects with cells of different origin in a rabbit model
Arthroscopy
Effects of anti-inflammatory drugs on proliferation, cytotoxicity and osteogenesis in bone marrow mesenchymal stem cells
Biochem Pharmacol
Pathophysiology of synovitis: clinical signs and examination in horses
Compendium
Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation
Instr Course Lect
Present status of and future direction for articular cartilage repair
J Bone Miner Metab
Evaluation of cartilage lesions on the medial femoral condyle as a cause of lameness in horses: 11 cases (1988-1994)
J Am Vet Med Assoc
Cartilage healing: a review with emphasis on the equine model
Can Vet J
Cited by (12)
Equine Mesenchymal Stem Cells: Properties, Sources, Characterization, and Potential Therapeutic Applications
2019, Journal of Equine Veterinary ScienceCitation Excerpt :In horses, most of the studies so far have been unable to demonstrate positive results for better cartilage repair in osteoarthritis patients [48,49,179,180]. Some of the studies, clinical as well as experimental, though have shown beneficial effects but mainly on account of reduction in pain perception [49,163,181–185]. In an equine meniscal tear model, induced chondral defects (10 mm diameter and 6 mm depth) treated with BM-MSCs or AD-MSCs laden in collagen repair patch after 12 months were repaired by fibrocartilage, whereas control group menisci were either partially repaired or not at all [183].
Biologic Strategies for Intra-articular Treatment andCartilage Repair
2015, Journal of Equine Veterinary ScienceCitation Excerpt :All groups had similar systemic and local response with minimal joint swelling and lameness but marked inflammation in synovial fluid during the first 72 hours after injection. Despite the short period of evaluation, it is important to clarify in vivo safety of allogeneic treatments, although flares can appear several days after injection or after second treatment [109]. Most clinical studies are experimental, and the main reason for this is the lack of scientific support together with elevated price of stem cell therapy.
Therapeutic Applications of Mesenchymal Stem Cells in Veterinary Medicine
2022, Therapeutic Applications of Mesenchymal Stem Cells in Veterinary MedicineEquine Mesenchymal Stem Cell Basic Research and Potential Applications
2020, Mesenchymal Stem Cell in Veterinary Sciences