Orthobiologics Primer: What Practitioners Need to Know About This Exciting Field

Orthobiologics can be broadly categorized as blood-derived or cell-based products.

by Samuel P. Franklin, DVM, PhD, MS, DACVS-SA, DACVSMR (Canine)

What Are Orthobiologics?

To most veterinarians, the term orthobiologics refers to products such as platelet-rich plasma (PRP) or “stem cells” that are used to treat injuries or diseases affecting the musculoskeletal system. From the perspective of the federal government, these treatments are typically referred to as “cell-based therapies” and are regulated by the Center for Veterinary Medicine of the US Food and Drug Administration (FDA).

At the time of this writing, there are no FDA-approved cell-based therapies for use in veterinary medicine. Conversely, the federal government considers “biologics” to be products that influence the immune system. The best example of a biologic is a vaccine. Biologics are regulated by the US Department of Agriculture. For the purposes of this article, I will use the term orthobiologics to refer to products such as platelet-rich plasma. Furthermore, I will only discuss products, their clinical application, and data supporting use in dogs.

Orthobiologics Products and Systems

Orthobiologics can be broadly categorized as blood-derived or cell-based products. The blood-derived products are all made by collecting and processing peripheral blood. The cell-based products are produced from obtaining either bone marrow or adipose tissue. The following are some basic definitions of some of the available canine orthobiologics.

Blood-Derived Products

Platelet-rich plasma involves the acquisition of blood and centrifugation to isolate the platelet-rich fraction of plasma. The premise behind the use of PRP is that activated platelets release a suite of anabolic growth factors that can mitigate inflammation and promote cellular proliferation. Importantly, the cellular composition of different PRPs can vary widely, so the term platelet-rich plasma is not specific. Some provide dramatic platelet concentration over that in the whole blood, while others do not. In addition, some systems result in leukoreduction or elimination, while others result in leukoconcentration. Veterinarians should know what the typical cellular composition is of the PRP they use.

Autologous conditioned serum, also frequently referred to as IRAP (interleukin 1-β receptor antagonist protein), is produced by incubating blood in a proprietary system with glass or borosilicate beads that activate monocytes to release IRAP. Typically, incubation occurs overnight and the IRAP-rich serum is harvested the following day. The IRAP in the serum blocks IL-1β at associated receptors, minimizing the effects of this proinflammatory cytokine.

Autologous protein solution (APS) is a blood-derived product that is prepared with an initial centrifugation cycle to isolate a leukocyte-concentrated platelet-rich plasma. This plasma is then incubated briefly with polymer beads and undergoes a second centrifugation to desiccate and concentrate the anabolic and anti-inflammatory proteins, including IRAP, in a small volume for clinical application.

Cellular-Based Products

It is worth noting that all of the following cell-based products contain some stem cells. However, for some of these products, only a very small percentage of such cells could be stem cells. Consequently, knowledgeable and detail-oriented veterinarians should refer to these products by their specific name, provided here, rather than broadly referring to them as “stem cells.”

Stromal vascular fraction (SVF) involves the mechanical and enzymatic degradation of adipose tissue followed by centrifugation to stratify the components of adipose tissue based on their size and specific gravity. Following centrifugation, the pellet at the bottom of the associated tube is referred to as the SVF. A small portion of the SVF includes adipose-derived progenitor cells.

Bone marrow aspirate (BMA) involves aspirating bone marrow for direct injection. BMA includes a milieu of cells, some of which are erythroid cells or erythroid precursors, while a small percentage are likely stem cells. Bone marrow aspirate concentrate (BMAC) involves the aspiration of a larger volume of bone marrow (and blood) from the bone marrow followed by centrifugation to eliminate some of the unwanted erythroid fraction and concentrate the desired progenitor cell fraction in a smaller volume.

Cultured stem cells, whether autologous or allogeneic, or bone marrow derived or adipose derived, are cultured in a laboratory to homogenize and expand the cellular population. One characteristic of mesenchymal stem cells is that they adhere to the plastic of tissue culture flasks. Consequently, with changing (removal) of tissue culture media, any cells that are not adhered to the flasks are discarded, thus homogenizing the remaining cellular population, all of which are adhered to the plastic. These remaining cells, many of which might meet other criteria of being a mesenchymal stem cell, expand and multiply. Hence, with repeated cycles of culture (known as passages), the number of cells increases. When the desired passage or number of cells is obtained, the cells can then be removed from the flasks and resuspended for clinical application.

Intra-Articular Injections for Osteoarthritis

At this time, there are two common applications for use of orthobiologics in canine medicine: (1) intra-articular injection (IA) for symptomatic treatment of osteoarthritis (OA), and (2) intralesional, percutaneous injection into injured tendons to try to stimulate healing. With regard to IA injections for treating OA, there are some data in dogs, of variable quality, supporting the use of PRP, APS, SVF, and cultured stem cells.

The greatest number of studies in both research dogs and dogs with naturally occurring disease support the use of PRP, including at least eight prospective, randomized controlled trials in which PRP is compared with some other treatment group, with four of these studies using objective kinetic outcome data.

There are also two prospective, randomized controlled trials with objective outcome data supporting use of APS for treating OA in client-owned dogs when compared with saline controls. There are a few prospective studies comparing SVF with saline controls, some of which provide positive data, while others do not, and some of the positive studies lack objective kinetic outcome data. There are numerous studies on cultured stem cells in dogs with some using autologous and others using allogeneic cells, but they are all adipose derived. None of these studies provides a controlled trial comparing the cells with a control group while demonstrating superiority of the cultured cells to the control group based on objective kinetic outcome data.

There are numerous ways to interpret these data, and each veterinarian is going to need to make their own decisions based on the available data. I use the blood-derived products and PRP and APS specifically because they are easier to prepare, less likely to be scrutinized by the FDA given that they involve relatively minimal manipulation of autologous blood, less expensive, and have more data supporting their use in dogs—specifically when compared with the more involved products, such as BMAC, SVF, and cultured stem cells. Nonetheless, with additional research, we may ultimately find that cellular-based products are superior. My use of biologics may change over time as additional data are generated delineating which orthobiologics are most efficacious for specific applications.

There are no FDA-approved cell-based therapies for use in veterinary medicine.

Intralesional Injections for Tendon Injury

It is difficult to draw conclusions about use of orthobiologics for treating tendon injury in dogs because there are only three studies evaluating dogs with naturally occurring tendinopathy, with each focusing on dogs with supraspinatus tendinopathy. None of these studies is a randomized controlled trial; all are case series. One study used a single injection of PRP and objective force plate data. The researchers found an improved ultrasonographic appearance of the tendons, but they did not document improvement in weight bearing based on force plate data. The second study combined cultured, autologous adipose-derived cells combined with PRP. The researchers did find improvement over time based on objective, pressure-sensitive walkway data. The third study used PRP combined with BMAC. The study suggested that there was improvement in the tendons based on ultrasound evaluation.

Of those aforementioned treatments that have been used to treat tendinopathy in dogs, cultured stem cells are more likely scrutinized by the FDA and will cost substantially more. Consequently, for the foreseeable future, it is more likely that veterinarians will use PRP or BMA/BMAC or the combination of PRP and BMAC for tendinopathy. While eagerly awaiting more robust studies on the subject, I currently tend to offer owners injection with PRP while being forthright about the lack of data supporting percutaneous injections of PRP to treat tendinopathy in dogs.

Orthobiologics remains an area of great research interest, and there will continue to be new data generated routinely. Practitioners should stay tuned for such work, as our understanding of orthobiologics in dogs will likely change as more information becomes available.

Samuel P. Franklin obtained his DVM from Colorado State University and completed his surgical residency and a PhD investigating the use of stem cells and bioabsorbable materials for replacing arthritic canine hips, at the University of Missouri. He is a diplomate of the American College of Veterinary Surgeons and the American College of Veterinary Sports Medicine and Rehabilitation. His areas of clinical and research interest include noninvasive imaging of the musculoskeletal system, minimally invasive orthopedic surgery, joint replacement, and sports medicine, including use of orthobiologics. He has published 10 peer-reviewed articles on canine biologics and has an ongoing study assessing the use of autologous protein solution for treating hip osteoarthritis in dogs. He currently practices at Colorado Canine Orthopedics and Rehab in Colorado Springs.

Photo credits: ©iStock.com/deliormanli, ©iStock.com/Elkhophoto