Regenerative Medicine and Treatment Modalities

Regenerative Medicine entered into our lexicon years ago when discussing such novel therapies as Stem Cells. Currently the use of stem cells and a growing number of other blood derived therapies get discussed for a variety of conditions on the human side as well as for horses. On this page we’ll delve into the range of options available to us and ones that are being employed in this practice on a more routine basis as there has been a movement away from just steroid based intra-joint therapies. The term that best describes these therapies is orthobiologic. This refers to the fact that their source is the horse’s own blood which goes through several steps such as filtration and centrifuging in order to concentrate the material needed for the treatment. We’ll discuss their applications in sports related injuries and which structures and conditions may respond best.

A sports related injury can affect all horses from the serious athletes down to the lightly used pleasure horse. The injuries can be sustained during a competition, while in training or just “horsing around” in the field. Quite a few fall into the latter camp and can be difficult to sort out their origin as they are often not witnessed. Some of the conditions can range from career ending and/or potentially modifying the manner in which a horse is used and others can be more short term in nature. An example of these injuries could be the following and it’s worth bearing in my mind they may occur as a single entity or in combination with others:

• Ligament Injury (Desmitis)

• Tendon Injury (Tendonitis) and Tendon Sheath Injuries (Tenosynovitis)

• Joint Inflammation - Cartilage damage, Joint capsule trauma, Joint swelling/effusion (Synovitis, Arthritis)

• Stifle Joint Disease-Inflammation associated with Injury to a Meniscus

• Muscle Trauma (Myositis)

• Bone Trauma and Fractures

Regarding regenerative therapies and orthobiologics, we need to expand our list beyond Stem Cells as we now have more choices. Fortunately our options to rehabilitate damaged tissues has improved and newer approaches are constantly being explored. Early intervention with an injury is best and structuring treatments along with periodic monitoring into the treatment and rehabilitation phases for our patients work best. List of commonly used regenerative therapies:

• Stem Cells - can be derived from fat, bone marrow and fetal dental pulp tissue

• Platelet Rich Plasma (PRP) - collected from processed and centrifuged blood

• Pro-Stride - collected from processed and centrifuged blood

• Alpha2-EQ or Alpha2-Macroglobulins - collected from processed and centrifuged blood.

• Interleukin-1 Receptor Antagonist Protein (IRAP) - collected from processed and centrifuged blood

• Class IV Laser Therapy - not all lasers applicable, the following article from this website describes the one utilized by Burlington Equine and its advantages: https://www.bevet.com/laser-therapy

Stem Cells can be acquired from the 3 methods described in the above list. Over the years I have done most by surgically collecting a small sample of fat taken from the rump area of a horse that’s sent on to a lab in California which processes the sample so that stem cells are returned that are ready to implant - typically into a damaged tendon or ligament. This process all happens within a 3-4 day period. The newer method to acquire stem cells is from companies that take sterile dental pulp, recovered from gum tissue of otherwise healthy foals that perish during foaling, and process the tissue to produce mechanically manipulated, unexpanded pulp tissue particles containing viable stem cells surrounded in extracellular matrix. Research by Equine Veterinarian surgeon and researcher Dr. Alicia Bertone from Ohio State University stated the following: “The dental pulp is a ball of tissue that is below the gumline in newborn foals. It is the most primitive form of stem cell tissue and has the greatest potential for developing into bone, ligaments, blood vessels and more. Studies in human medicine using dental pulp have used tissue generated from the wisdom teeth and the results have been very encouraging.” In the cases I have used this in it’s by far the simplest, least invasive way to use stem cells. Although the source is not from the horse’s own blood or tissue it is not recognized as foreign material when injected. Bone marrow is the 3rd source and one that’s a bit more cumbersome to go through in order to collect stem cells and not one that I routinely use. The reason Stem Cells are considered a valuable method to treat damaged or altered tissue is their ability to be incorporated into and regenerate the structures that are affected and because they are a natural source product i.e. no medications utilized. Disadvantages often are methods of collecting and the expense.

In the following group of orthobiologics: PRP, Pro-Stride, and Alpha2-EQ they go through similar a processes to get the final product. Essentially blood is collected from the patient, it is then centrifuged and filtered then may have a second centrifuging which results in the product that will be used. All of this can happen on the same visit to the barn and injected within an hour’s time.

If PRP will be used in the treatment, then the same initial processing of blood along with the same chamber above is utilized and results in a concentration of the platelets that will be injected into the damaged tendon or ligament tissue. So in cases such as a bowed tendon or fiber damage involving either tendons or ligaments PRP is remarkably effective in providing growth factors that help to regenerate the damaged tissue. As far as the mechanism for what platelets do: once PRP is inserted into an injury site, the platelets activate, and growth factors are released, which help in healing, repair and regeneration of soft and hard tissue including tendons, ligaments, muscles and bones. The processing of the blood in the PRP system will activate the platelets. After doing this growth factors (TGF-β, PDGF, IGF and EGF), white blood cells and anti-inflammatories are released, and they play a primary role in the natural healing, repair, and regeneration of the tissues being treated. Another area that can be difficult to heal, which is the meniscus in a stifle, is an area where there has been success using either PRP alone or in the Pro-Stride product.

Pro-Stride uses a dual-device system to produce a concentrated solution of cells, platelets, growth factors and anti-inflammatory cytokines. The process takes less than 20 minutes, and the resulting solution helps reduce pain and inflammation to manage equine lameness and arthritis in horses. In Pro-Stride will be the anti-inflammatory natural biologic products along with PRP resulting in management of joint inflammation as well as tissue treatment. Often I’ll use Pro-Stride in a post surgery joint, in cases where steroids may be contra-indicated or in cases where we want both the anti-inflammatory properties from the plasma along with the platelets to help heal damaged tissue. The anti-inflammatory portion of the Pro-Stride product is potent and fortunately has no negative effects such as those that can be associated with steroids. Steroids remain one of our most commonly used, effective anti-inflammatories for joint related conditions, but there exists a trade off that may be a consideration with their use and deciding between these therapies is done on a case by case basis. I have been impressed with the results using this product and will continue to do so especially where joint inflammation may be combined with some degree of soft tissue injury involving the same joint. The disadvantage is the limited supply as each process only allows for the treatment of 1-2 joints and no storage option.

Alpha2EQ is the newest member of the orthobiologic products and offers advantages similar to Pro-Stride with respect to the anti-inflammatory qualities as well as safety in that it is also an all natural blood based product. When joint inflammation is present a cascade of events can develop that lead to swelling, pain, lack of normal joint function and potentially arthritis over time as the processes can negatively impact joint tissues and cartilage. The byproducts of inflammation in the joint are products called cytokines and metalloproteases. The essential mechanism for how this product works is described in research and on their website as follows: A2EQ is a major plasma glycoprotein best known for its ability to inhibit a broad spectrum of serine, threonine and metalloproteases by a
unique bait and trap method. Essentially what does is the A2EQ molecule has receptor sites on each side that are surrounded by lobes. These receptor sites capture destructive elements in the joint space, at which point the lobes “collapse” around them. Once captured, the bound A2EQ macroglobulin and destructive enzymes are eliminated from the joint space through the body’s natural processes.

Schematically it may be best seen here:

Research on this product has been done with human, equine and canine cases. The following website will elaborate on the above information: https://alpha2eq.com/

Advantages are many:

• all natural orthobiologic - no steroids or other medications involved

• potent anti-inflammatory effects that are long lasting

• can be used in treatment of an acute or chronic joint problem also suitable for “joint maintenance”.

• benefits that can be appreciated within a week’s time

• process produces a much larger volume that we can get with Pro-Stride allowing treatment of multiple joint sites along with storage of the remaining product that can be thawed and used again within a 12 month period.

• collecting and processing of the blood and treatment can all be done at the same barn visit.

For the treatment of inflammation in a joint or tendon sheath, the orthobiologics that would be most suitable, in my opinion, would be Pro-Stride and A2EQ. Determining which of those two would be best would likely result from the information in the above list.

Next in our discussion of orthobiologic products will be IRAP and for years this was the mainstay of what most of us reached for when possible to treat cases such as ones described above. As newer treatments have become available IRAP tends to be not involved as much with post-surgical joints or with general joint inflammation. It can still have a role, but in terms of efficacy, ease of treatment and availability the aforementioned three products are superior in my opinion. IRAP is Interleukin-1 Receptor Antagonist Protein and it’s an anti-inflammatory treatment for joint disease in horses that works by addressing the inflammatory cascade triggered by the release of the interleukin-1 protein in the joint. Interleukin-1 (IL-1) is considered a pro-inflammatory protein that is found in an increased concentration in injured joints whether it’s an acute problem or a more chronic-active issue. Once IL-1 is present and active it can be a powerful signal for a number of other harmful cytokines that create inflammation. The result of all this will be inflammation and depending on duration, extent and a number of other factors can play significant roles in cartilage degradation and development of arthritis.

Somewhat different from the other collection and processing methods discussed above, IRAP requires blood to be collected, stored for a short period of time in a syringe with glass beads, cooled, then centrifuged and filtered the next day and frozen. The role of the glass beads is to induce the white blood cells that are present in the blood to produce and secrete IRAP. After freezing the product can be thawed and used on any particular day and typically there are a number of doses that will remain frozen to be used again as required. Often treatments are done in series and for some post-surgical joints the treatments may be done weekly 3-5 times. Pro-Stride is typically done 1-2 times post surgery.

We have an ever expanding ability to treat joint inflammation as well as soft tissue injuries and they run the gamut from traditional vs the now, more available and natural blood based products. Each case is different and the circumstances may make several options suitable or at times, an orthobiologic may be the best option. Another newer joint related treatment employing a Polyacrylamide Gel, otherwise known as a PAAG such as Noltrex or Arthramid, have also become invaluable additions in my opinion and some of these joints may be treated first by a product to reduce the inflammation then followed up with a PAAG to enhance and considerably improve joint motion due to its primary role in affecting lubrication of cartilage and joint surfaces. I have used all of these products discussed above and can speak in more detail if interested on suitability for any particular case.