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In recent years, extracellular vesicles (EVs) have emerged as prominent mediators of the homeostasis, repair, and regeneration of musculoskeletal tissues including bone, skeletal muscle, and cartilage. Accordingly, the therapeutic potential of EVs for regenerative medicine applications has not gone unnoticed. The use of EVs for the treatment of musculoskeletal injury and disease in veterinary species is a nascent but rapidly expanding area of research. Recent studies in this area have demonstrated the safety and feasibility of EV products in dogs and horses. While early clinical responses to EV-based therapeutics in companion animals have been favorable, more rigorously designed, sufficiently powered, and placebo-controlled clinical trials are required to fully elucidate the clinical benefits and best-use scenarios for EV therapeutics in veterinary medicine. Additionally, clinical translation of EV-based therapeutics will require Good Manufacturing Practice–compliant methods to scale up and purify EV products. Despite these challenges, EVs hold great promise in the regenerative medicine landscape, particularly in the treatment of musculoskeletal injury and disease in companion animals.

Open access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To document effects of cisplatin on regenerate bone formation during the distraction and consolidation phases of bone transport osteogenesis.

Animals—10 skeletally mature hounds.

Procedure—Bone transport osteogenesis was performed to reconstruct a 3-cm defect in the radius of each dog. Five dogs were randomly selected to receive cisplatin (70 mg/m2, IV, q 21 d for 4 cycles), and 5 were administered saline (0.9% NaCl) solution. Bone mineral density was measured by use of dual-energy x-ray absorptiometry (DEXA) on days 24, 55, and 90 after surgery. Dogs were euthanatized 90 days after surgery. Histomorphometry was performed on nondecalcified sections of regenerate bone. Bone mineral density and histomorphometric indices of newly formed bone were compared between groups.

Results—Densitometric differences in regenerate bone mineral density were not detected between groups at any time period. Cisplatin-treated dogs had decreased mineralized bone volume, decreased percentage of woven bone volume, decreased percentage of osteoblast-covered bone, increased porosity, and increased percentage of osteoblast-covered surfaces, compared with values for control dogs. Lamellar bone volume and osteoid volume did not differ significantly between groups.

Conclusions and Clinical Relevance—Regenerate bone will form and remodel during administration of cisplatin. Results of histomorphometric analysis suggest that bone formation and resorption may be uncoupled in cisplatin-treated regenerate bone as a result of increased osteoclast activity or delayed secondary bone formation during remodeling. These histomorphometric differences were modest in magnitude and did not result in clinically observable complications or decreased bone mineral density as measured by use of DEXA. (Am J Vet Res 2002;63:703–711)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether sustained release of transforming growth factor (TGF)-β1 from a gelatin hydrogel would enhance bone regeneration in critical-sized long-bone defects and overcome inhibitory effects of preoperative irradiation.

Animals—24 adult New Zealand White rabbits.

Procedure—Rabbits were allocated to 2 groups. Twelve rabbits received localized megavoltage radiation to the right ulna by use of a cobalt 60 teletherapy unit, and 12 rabbits received no irradiation. Then, a 1.5-cm defect was aseptically created in the right ulna of each rabbit. Gelatin hydrogel that contained 5 µg of adsorbed recombinant-human (rh) TGF-β1 was placed in the defect of 12 rabbits (6 irradiated and 6 nonirradiated), and the other 12 rabbits received hydrogel without rhTGF-β1. Rabbits were euthanatized 10 weeks after surgery. New bone formation within the defect was analyzed by use of nondecalcified histomorphometric methods. A 1-way ANOVA was used to compare differences among groups.

Results—New bone formation within the defect was significantly greater in TGF-β1–treated rabbits than in rabbits treated with hydrogel carrier alone. Local delivery of rhTGF-β1 via a hydrogel carrier in irradiated defects resulted in amounts of bone formation similar to those for nonirradiated defects treated by use of rhTGF-β1.

Conclusions and Clinical Relevance—Local delivery of TGF-β1 by use of a hydrogel carrier appears to have therapeutic potential for enhancing bone formation in animals after radiation treatments.

Impact for Human Medicine—This technique may be of value for treating human patients at risk for delayed bone healing because of prior radiation therapy. (Am J Vet Res 2005;66:1039–1045)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To develop an orthotopic model of canine osteosarcoma in athymic rats as a model for evaluating the effects of stereotactic radiotherapy (SRT) on osteosarcoma cells.

Animals—26 athymic nude rats.

Procedures—3 experiments were performed. In the first 2 experiments, rats were injected with 1 × 106 Abrams canine osteosarcoma cells into the proximal aspect of the tibia (n = 12) or distal aspect of the femur (6). Tumor engraftment and progression were monitored weekly via radiography, luciferase imaging, and measurement of urine pyridinoline concentration for 5 weeks and histologic evaluation after euthanasia. In the third experiment, 8 rats underwent canine osteosarcoma cell injection into the distal aspect of the femur and SRT was administered to the affected area in three 12-Gy fractions delivered on consecutive days (total radiation dose, 36 Gy). Percentage tumor necrosis and urinary pyridinoline concentrations were used to assess local tumor control. The short-term effect of SRT on skin was also evaluated.

Results—Tumors developed in 10 of 12 tibial sites and all 14 femoral sites. Administration of SRT to rats with femoral osteosarcoma was feasible and successful. Mean tumor necrosis of 95% was achieved histologically, and minimal adverse skin effects were observed.

Conclusions and Clinical Relevance—The orthotopic model of canine osteosarcoma in rats developed in this study was suitable for evaluating the effects of local tumor control and can be used in future studies to evaluate optimization of SRT duration, dose, and fractionation schemes. The model could also allow evaluation of other treatments in combination with SRT, such as chemotherapy or bisphosphonate, radioprotectant, or parathyroid hormone treatment.

Full access
in American Journal of Veterinary Research

Abstract

In collaboration with the American College of Veterinary Pathologists

Open access
in Journal of the American Veterinary Medical Association