Surgery STAT: Stem cell therapy in canine medicine

This is the first article of a two-part dvm360 series focusing on stem cells and platelet rich plasma. We will explain the basics of these therapies and briefly cover the existing literature reporting their efficacy.

Stem cells and platelet rich plasma (PRP) are two therapies that hold potential for modulating inflammation and repairing or regenerating damaged tissues. These treatments are familiar to many of us because of increasing media attention and interest in human and veterinary medicine. Their methodologies and efficacy, however, are not widely known. This article explores what constitutes stem cell therapy (SCT) and briefly reviews the evidence available regarding its use in treating canine orthopedic disease. Part two of this series will similarly explore the topic of PRP for treatment of orthopedic diseases in dogs.

Terminology and preparation of stem cells

There are two general categories of cellular products that are often referred to as SCT. One product requires the surgical harvest of fat, which is then sent to a laboratory, minced, washed, digested by collagenase and centrifuged. The cellular pellet is re-suspended and shipped back to the practitioner for administration without cellular expansion (i.e. culture) or homogenization of the cells.

This heterogenous product likely includes adipose-derived stromal cells with multipotent differentiation capabilities, among a milieu of other cells. Because there is no homogenization or expansion of a specific cellular lineage, this product is most accurately referred to as stromal vascular fraction (SVF) rather than stem cells.

Alternatively, bone marrow cells or adipose tissue is acquired and subsequently washed and centrifuged, similar to the process described above. The sample is then cultured to achieve cellular expansion and greater homogeneity. Only those cells that adhere to plastic tissue culture flasks remain after such process, one of many characteristics of stem cells. The more uniform and culture-expanded population of cells can then be removed from the culture flasks, concentrated and re-suspended for use.

Whether these cells can be referred to as stem cells has been debated. However, it is accepted that without characterization of the cell surface markers and demonstration that they meet the specific criteria used to define stem cells, these cells are most accurately referred to as mesenchymal stromal (MCS) cells rather than stem cells.

Measuring treatment effectiveness

Three studies have demonstrated some efficacy of SVF for treatment of osteoarthritis (OA) in dogs. One study was a prospective, blinded, randomized trial in which dogs with coxofemoral OA were randomly allocated to receive either a saline injection (control) or treatment with autologous SVF.1 The owners and veterinarians subjectively evaluated the dogs. There was significantly greater improvement in dogs treated with SVF than the control dogs in several variables evaluated by the veterinarians. Owners observed no significant differences.

The same group performed a similar study assessing response of dogs with elbow OA, but without a control group.2 There was improvement in dogs noted over time by both the veterinarians and owners.

The first of these two studies was well-designed in that there was a comparative control group, random allocation to treatment groups and blinding of the assessors (veterinarians and owners). However, the results should not be interpreted as definitive justification for widespread treatment of OA with SVF because relatively few dogs completed the study, and researchers used unvalidated subjective outcome measures. In addition, although SVF appeared superior to the sham treatment (saline), this initial study didn’t compare SVF with less invasive and less expensive treatments. For example, intra-articular hyaluronan, PRP and corticosteroids can all be used to treat OA. None of these treatments require general anesthesia and surgery to acquire the product, and each costs the owner a fraction of the price of SVF therapy.

Most recently, a study assessing changes in weight bearing over time using a force plate showed that dogs with coxofemoral OA had significant improvements in peak vertical force and vertical impulse when treated with SVF and PRP concurrently.3 However, because dogs had been treated with both SVF and PRP it is unclear whether the SVF therapy is superior to the less invasive, less expensive PRP therapy.

There are also a couple reports of culture-expanded stromal cells for treatment of orthopedic disease in canine medicine. There is a single published case report that describes injection of culture-expanded, bone marrow-derived stromal cells into a core lesion of an injured canine Achilles tendon.4 The dog showed improvement but without a comparison group, it’s hard to conclude that the improvement was from the stromal cell injection rather than the rest and supportive orthotic that were also prescribed.

Most recently, an abstract from the 2013 American College of Veterinary Surgeons Annual Symposium described use of stromal vascular fraction as well as culture-expanded stromal cells as an adjunct to arthroscopic surgery in dogs with medial coronoid disease.5 The study included randomization of dogs to numerous treatment groups and use of objective outcome measures. Beneficial results were reported in dogs treated with allogeneic culture-expanded stromal cells when compared with groups treated by SVF and those not treated with the cells. Many of us eagerly await the publication of these results with more detailed information.

Conclusion

The use of SVF and stromal cells is alluring for their potential to mitigate inflammation or facilitate healing. However, additional data from existing studies and additional controlled studies should be gathered and published, enabling further evaluation of such treatments and comparison to less expensive and less invasive treatments before widespread clinical application is accepted. According to a 2011 stromal cell review in Veterinary Surgery, “Additional investigations and clinical trials to establish safety and efficacy are also necessary before routine clinical application.”6 Fortunately it appears that interest is great and studies are underway. Stem cell therapy may ultimately prove beneficial, but, at this time, further work is needed to optimize its potential and clarify its benefits.

Dr. Sam Franklin is a surgeon and sports medicine and rehabilitation specialist at the University of Georgia. He is actively pursuing research on use of absorbable scaffolds with stem cells to replace or regenerate damaged articular cartilage.

References

1. Black LL, Gaynor J, Gahring D, et al. Effect of adipose-derived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized, double-blinded, multicenter, controlled trial. Vet Ther 2007;8(4):272-284.

2. Black LL, Gaynor J, Adams C, et al. Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs. Vet Ther 2008;9(3):192-200.

3. Vilar JM, Morales M, Santana A, et al. Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs. BMC Vet Res 2013;9(131):1-6.

4. Case JB, Palmer R, Valdes-Martinez A, et al. Gastrocnemius tendon strain in a dog treated with autologous mesenchymal stem cells and a custom orthosis. Vet Surg 2013;42(4):355-360.

5. Kiefer K. Outcome assessment measures for evaluating clinical effectiveness of canine adipose derived stem cell therapy of osteoarthritis. ACVS Veterinary Symposium, San Antonio, Texas, 2013.

6. Spencer ND, Gimble JM, Lopez MJ. Mesenchymal stromal cells: past, present, and future. Vet Surg 2011;40(2):129-139.

Suggested reading

Jeffery ND, Granger N. Is ‘stem cell therapy’ becoming 21st century snake oil? Vet Surg 2012;41(2):189-190.