Regenerative Medicine

regenerative medicine, equine musculoskeletal injuries, inflammatory protein Interleukin-1, Interleukin-1 receptor antagonist protein, platelet rich plasma, hypoxic-ischemic-based injuries, extracorporeal shock wave therapy, modern equine medicine

regenerative medicine, equine musculoskeletal injuries, inflammatory protein Interleukin-1, Interleukin-1 receptor antagonist protein, platelet rich plasma, hypoxic-ischemic-based injuries, extracorporeal shock wave therapy, modern equine medicine

A new way forward?

By Margaret Evans

What exactly is regenerative medicine? It’s been a buzz phrase for a while now, yet it remains somewhat of a mystery to many horse owners as an application in the treatment of musculoskeletal injuries suffered by performance horses in particular.

regenerative medicine, equine musculoskeletal injuries, inflammatory protein Interleukin-1, Interleukin-1 receptor antagonist protein, platelet rich plasma, hypoxic-ischemic-based injuries, extracorporeal shock wave therapy, modern equine medicine

Regenerative medicine is opening up more options for the treatment of musculoskeletal injuries suffered by horses, particularly those in high performance careers. Photo: Shutterstock/Jennay Hitesman

Regenerative medicine is based on therapies that use blood products or stem cells harvested directly from the horse, then returned to the patient in a targeted therapeutic form. Since they are produced by the horse and returned to it, they are deemed to be natural, safe, and effective. Their applications treat a variety of ligament and tendon injuries, and there are a number of regenerative regimes including IRAP, PRP, stem cells and ESWT.

regenerative medicine, equine musculoskeletal injuries, inflammatory protein Interleukin-1, Interleukin-1 receptor antagonist protein, platelet rich plasma, hypoxic-ischemic-based injuries, extracorporeal shock wave therapy, modern equine medicine

Platelet rich plasma, or PRP, has been found to be extremely effective for ligament and tendon injuries. Stem cells, with their considerable anti-inflammatory properties, have shown great promise in helping tendons heal, and have been associated with a 50 percent risk of tendon re-injury. Photo: Shutterstock/Osetrik

IRAP

IRAP stands for “Interleukin-1 receptor antagonist protein.”

When a horse injures a joint, the trauma promotes the release of an inflammatory protein called Interleukin-1. This protein actually speeds up the joint’s inflammation and cartilage damage, resulting in pain. IRAP is an anti-inflammatory protein that counteracts Interleukin-1. The IRAP therapy stimulates the horse’s own white blood cells to produce anti-inflammatory properties contained in the Interleukin-1 receptor antagonist protein. 

Harvesting IRAP is a process requiring the veterinarian to collect blood from the horse, then incubate the blood for 24 hours in syringes that contain special glass beads. These beads prompt the white cells in the blood to produce the therapeutic protein. The blood is then centrifuged in a machine with a rapidly rotating container, which uses centrifugal force to separate the plasma from the red blood cells (Figure 1). This protein-rich serum is processed into multiple syringes, one of which can be utilized the following day and the rest frozen for future use. It is administered in doses by being injected directly into the affected joint according to the vet’s protocol.

regenerative medicine, equine musculoskeletal injuries, inflammatory protein Interleukin-1, Interleukin-1 receptor antagonist protein, platelet rich plasma, hypoxic-ischemic-based injuries, extracorporeal shock wave therapy, modern equine medicine

IRAP’s action on the joint brings the needed pain relief, and it has shown success in post-surgical joint therapies and in treating osteoarthritis and suspensory injuries.

PRP

PRP stands for “platelet rich plasma.” 

This therapy uses the horse’s own platelets to promote the healing of tendon and ligament injuries. Platelets are responsible for the clotting mechanism in blood. Like the IRAP therapy, blood is collected from the horse and spun in the centrifuge machine to separate out the platelets. When activated, this platelet-rich plasma releases a concentration of growth factors that contribute significantly to wound healing by aiding in the formation of new blood vessels and connective tissue to repair the injured area. It differs from IRAP in that the separated concentrated solution can be injected into the horse the same day it is collected.

The goal with this therapy is to facilitate healing to return the site to original strength with minimal scarring. PRP has been found to be extremely effective for ligament and tendon injuries, structures that often do not return to their original strength and integrity with traditional treatments. PRP can also be used for joint injuries and wounds, and for granulation of tissue defects.  

STEM CELLS

Stem cells, harvested from the newborn or adult horse’s body, are referred to as mesenchymal stem cells (MSCs). They are commonly taken either from bone marrow or fat (adipose) tissue but can also be taken from a foal’s umbilical cord or cord blood following birth.

regenerative medicine, equine musculoskeletal injuries, inflammatory protein Interleukin-1, Interleukin-1 receptor antagonist protein, platelet rich plasma, hypoxic-ischemic-based injuries, extracorporeal shock wave therapy, modern equine medicine

A - Equine umbilical cord blood mesenchymal stem cells growing on plastic. B - Same cells after introduction of a gene coding for a green fluorescent protein that allows identification of the cells after in-tissue samples of experimental horses. Photo: Ritesh Briah, University of Guelph, Koch Lab. 

Stem cells have shown enormous promise to aid in the healing of a variety of conditions including damaged cartilage, fractures, and ligament injuries. While a great deal of research continues to be done on the benefits of stem cell therapy, it is known that they have significant anti-inflammatory properties, particularly when it comes to helping tendons heal.  

ESWT

ESWT stands for “extracorporeal shock wave therapy” and uses non-invasive, high intensity shock waves to stimulate healing. The waves are not actual electrical shocks but a rise in pressure generated by electricity. The waves promote energy to the site through pressure and density which, in turn, stimulates a biological response in the release of growth factors and blood vessel formation. It has been used in conjunction with IRAP, PRP, and stem cell therapies.

Clearly, regenerative medicine has opened up new, exciting modalities for healing, taking technologies to a whole new level beyond the days of cortisone. 

“The old standard for controlling pain in a region was always cortisone,” says Dr. Nick Kleider, owner of Kleider Veterinary Services, Langley, BC. “We still frequently use it as a primary treatment since one injection rarely hurts and it is very effective for decreasing inflammation. The problem with cortisone is that it decreases the metabolism of the area, and therefore can decrease the strength and integrity of the tissue with long-term use. By adding regenerative medicine to our treatment regime, we can pick and choose some of the healing qualities we’re looking for. For example, autologous conditioned serum (ACS) or IRAP has some of the anti-inflammatory qualities similar to cortisone, but also has some growth factors and other mediators that potentiate the healing response. Traditionally, it has been used to treat arthritis - so mainly for joints - but can be used in soft tissue structures as well. We use PRP for most of our soft tissue injections since it is high in the growth factor needed to kick-start the healing process in many tendon and ligament injuries.”

Kleider says that in the human field, PRP is utilized in North America to a greater extent than IRAP for legal reasons. IRAP requires an overnight incubation period, which means it is out of the surgeon’s sight for a period of time. There is a potential for a sample mix-up with another patient, making IRAP less appealing.

“Obtaining PRP requires taking blood from the patient, spinning it down in a special centrifuge, separating off the platelet fraction and injecting it,” says Kleider. “This can all be done under the direct supervision of the surgeon, which satisfies the legal issue. In human medicine, PRP is used frequently for joint therapy. In horses, we use both PRP and IRAP depending on the situation. If the condition seems to require only one injection and the horse is being seen as a day patient, then PRP is more convenient and economical. If the horse may need repetitive treatments and is available for repeat visits, then IRAP can be used. With IRAP, administration cannot be done until the following day since the sample needs to be incubated first. The frequency of IRAP injections can vary anywhere from weekly through monthly to bi-annually depending on the horse’s condition and the degree of injury.”

Each horse and its medical condition are different, requiring unique therapies according to its needs. The collection and preparation of the different serums takes time and several injections may be required, which is why regenerative medicine tends to be more expensive than a conservative approach. But the track record showing successful outcomes makes the technology very promising. 

regenerative medicine, equine musculoskeletal injuries, inflammatory protein Interleukin-1, Interleukin-1 receptor antagonist protein, platelet rich plasma, hypoxic-ischemic-based injuries, extracorporeal shock wave therapy, modern equine medicine

Ultrasound guided intralesional stem cell treatment of the superficial digital flexor tendon at the Ontario Veterinary College by Drs. Heather Chalmers, Judith Koenig and Thomas Koch. Photo: Prof. Judith Koenig, Dept. of Clinical Studies, Ontario Veterinary College.

“Our devices focus around joints, soft tissue, and wound injuries,” says Mark Schindel, CEO, Owl Manor Veterinary in Warsaw, Indiana. “There continues to be new development/innovation, including new opportunities where existing technologies may be leveraged. That may include combinations of IRPA and PRP in our product line-up. The veterinarian’s expertise and intimate knowledge of a given horse, including injury history, prior treatments, response to treatments, types of injury (soft tissue, joint, etc), discipline of the horse, and related activities all factor into what type of treatment may be best to consider. Drug testing requirements, costs, short- vs. long-term benefits are also a consideration.”

The use of stem cells has had its challenges in the past, driven by economics, practicality, subjective choice and even politics, and the therapy continues to be the focus of much research. But it is widely accepted that stem cells have anti-inflammatory properties, influence cell-signaling factors, and can stimulate the formation of tendon-like tissue. 

“At the turn of the century, one of the therapies I used for treatment of high suspensory disease in the hind limb (a hard-to-heal ligament injury) was to inject raw bone marrow, collected from the sternum, into the affected ligament,” says Kleider. “In spite of the high volume and poor refinement of the technique, it seemed to help a high percentage of horses that were otherwise destined to stay perpetually lame. Theories why this worked varied from injecting the area with mesenchymal stem cells that the bone marrow provided, or the growth factors that were also present. In the following years, the bone marrow was sent away to be cultured along lines required for the injury, such as cartilage or tendon. This process took about three weeks so there was a necessary delay in treatment.”

He says the difficulties that were encountered involved cross-border shipping of the biological material that had to be maintained at a cold temperature. At the time, only American university labs were doing the cultures and, after the 9/11 terrorist attack, many stem cell cultures were ruined because of a hold-up at Customs when samples were deemed suspicious. Canadian labs acquired the technology, but errors still occurred with courier services across the country.

“Then someone published a paper that showed that many of these stem cells were dead by three months after implantation, so questions arose as to what benefits they provided,” says Kleider. “The stimulus for healing was definitely there, so many felt that they turn on or stimulate the local stem cell population. But most stem cells are suspended in a medium of platelet rich plasma (PRP) so what is really doing the trick? Until more research is done, whether to use one type of regenerative medicine over another will remain subjective and dependent on economics, practicality, and what is validated by current research. I think all forms of regenerative medicine are good, but it will remain difficult to predict which is best without properly controlled blind studies. Papers from the last American Association of Equine Practitioners (AAEP) [conference] compared a few PRP systems and acellular bone marrow for treatment of tendon injuries, and I was pleased to discover that the PRP system that we are presently using was deemed the most beneficial. Another paper comparing different systems for joint therapy summarized that ‘Regenerative therapies are showing tremendous promise but the therapies are too new to draw any firm conclusions regarding specific indications, contraindications, or prognosis after their use.’ In our practice, we now use PRP for most of our tendon and ligament injuries, and reserve mesenchymal stem cells in the form of processed bone marrow aspirate for obstinate cases. Most joint therapies receive multiple therapeutic injections of IRAP but PRP is popular for occasional therapy.”

The take-home message is that regenerative therapies hold promise for effective and enduring treatment of joint, tendon, and ligament injuries. Going forward, though, it is important to document long-term outcomes of treated horses and the precise benefits gained from each procedure. It is also important to have safeguard mechanisms in place as much more research into biological treatments continues.

“Scientists are increasingly exploring stem cells’ utility in treating inflammation-based and hypoxic-ischemic-based injuries,” says Thomas Koch, assistant professor with the Ontario Veterinary College, University of Guelph. “Laminitis, RAO/COPD [recurrent airway obstruction/chronic obstructive pulmonary disease] and uveitis [inflammatory condition of the eye] fall within these categories. Mesenchymal stem cells derived from the patient itself have been used for more than 10 years now and no major adverse reactions have been reported, so these so-called autologous cells appear safe to use. Cells from a different individual of the same species (allogeneic) are increasingly used and again, no major adverse reactions have been noted. The cells appear to be efficacious, but they do not go unnoticed by the body and some horses develop antibodies towards the cells. The clinical significance of these antibodies is currently unknown and under investigation.”

The use of biologics is an open field of research and application and, understandably, horse owners naturally wonder about safety and long term implications of the therapy. Koch says that several groups have done safety studies.

regenerative medicine, equine musculoskeletal injuries, inflammatory protein Interleukin-1, Interleukin-1 receptor antagonist protein, platelet rich plasma, hypoxic-ischemic-based injuries, extracorporeal shock wave therapy, modern equine medicine

Tissue engineered equine cartilage made from umbilical cord blood – derived mesenchymal stem cells. Photo: Dr. Sarah Lepage, Dept. of Biomedical Sciences, University of Guelph, Koch Lab.

“Regulatory bodies are starting to become more involved in the field. The FDA in the US has issued guidelines for the use of stem cells in horses. The Veterinary Drugs Directorate under Health Canada appears to be in an observatory position at this point in time.”

Koch agrees that it is a very exciting time to be an equine researcher in this field. 

“I think we have tremendous opportunities to improve equine welfare for a number of conditions for which we do not have adequate treatment options today,” he says. “Musculoskeletal injuries are one area, but areas of inflammation, poor perfusion, and oxygen deprivation are other conditions stem cells may be able to combat. Interesting work is also starting to be done in the area of viral and bacterial infections, and some data suggests stem cells can enhance the immune system’s ability to fight infections. Considering the challenges of antimicrobial resistance to common drugs, this is a very interesting area of study to follow in the coming years.” 

Kleider underscores the value and importance of research.

“There is extensive ongoing research into the ability to enhance healing through using the bodies’ own tissues,” says Kleider. “Identification of exactly what part of these tissues enhances the healing process leads to processing and concentration of the substance outside the body in the laboratory. These are not chemically synthesized but mostly proteins derived from biological sources. The goal should be the availability of simple and economical products with the ability to restore horses to their pre-injury state. I think most horse owners understand the cost-benefit ratio of utilizing regenerative medicine. The advantage is to promote a better quality of healing and to stimulate the healing response.” 

High performance horses are particularly at risk so the ability to apply the horse’s own resources to facilitate healing is an exciting step into the future. It may not be for every horse or every owner’s budget, but the technology is at least opening up options for consideration along with conventional treatments and the veterinarian’s guidance.

Koch says that six to twelve months is normal for recovery from tendon injuries. Costs for rehabilitation will vary considerably depending on whether it is done by a third party professional facility or at home. He says that professional rehabilitation and regular care may be in the range of $18,000 to $25,000 a year. One stem cell treatment runs around $3,000 to $4,000 which represents an extra 15 to 20 percent of cost. 

“But stem cells have been associated with a 50 percent reduction in the risk of tendon re-injury upon return to [for example] steeplechase racing in the UK,” he says. “I would encourage owners to make decisions based on a biological rationale and not a cost rationale. Patient selection and owner compliance are critical factors as well to consider. Asking the veterinarian about their experience using these therapies and the outcome of patients in their clinic will help assess the likelihood of success for their patient at that particular facility before treatment.”

Schindel agrees, adding that horse owners just want to do what is best for their horses, not just for short term benefits but long term gain. 

“It’s reasonable to assume that price remains a factor,” he says. “It is important that the overall cost considerations are understood [with a need to] consider convenience of treatment, frequency of treatments, duration of effectiveness, transportation, logistics costs, stress to the animal, and the potential for risk of transmission errors, etc.”

Clearly, there is a great deal of optimism for the future use and successful outcome of regenerative technologies in equine sports medicine. There is hope the techniques will allow horses to stay healthier and compete longer than at any time in the past. 

“Most people want the best for their horse and are willing to invest in a modality if it decreases the chance of re-injury and/or promotes the healing response,” says Kleider. 

Main article photo: Canstock/Mariait

This article was originally published in the March/April 2017 issue of Canadian Horse Journal.

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