By Jacquelyn Dietrich, BVSc and Russ Peterson, DVM, MS, DACVSMR, cert. ISELP
Regenerative Medicine is the most recent and promising area of both veterinary and human medicine exploration. It has emerging application to both disease therapy and sports medicine related injuries. Regenerative medicine focuses on stimulating (known as upregulating) the body’s inherent immune and disease mitigating capabilities rather than relying upon drugs and medications.
Unmasking (upregulating) protective portions of the patient’s genome is one key goal in addition to stimulating protective proteins which combat inflammatory agents, such as cytokines, which are produced during disease. Some approaches utilize autologous (derived from the same patient) products and others incorporate allogeneic (derived from other patients) mechanisms of action.
IRAP II
IRAP II™ is an autologous conditioned serum (ACS) and is obtained by culturing whole blood with borosilicate glass beads and harvesting the serum for treatments. IRAP stands for interleukin-1 receptor antagonist protein and is used most often in chronic, progressive osteoarthritis (or acute-on-chronic injuries). Whole blood is drawn in a syringe system containing glass beads, which is then cultured for 24-hours. The blood is then centrifuged to obtain an IRAP-enhanced serum product which can then be injected intra-articularly or intra-lesion. IRAP aims to block, or tie-up, IL-1, a potent cytokine that causes a pro-inflammatory state.
Mechanism: Aims to up-regulate Interleukin Receptor Antagonist Protein (IRAP) to block and tie-up IL-1 before it can attach to the joint capsule and initiate the “inflammatory cascade”. This helps prevent inflammation in an injured or diseased joint and allow healing to occur.
When to use:
Osteoarthritis
Joint treatment in metabolic horses/ponies
Good to use for showing horses
Post-surgical (ex. Arthroscopy) treatment
Goal of treatment: To inhibit the inflammatory cascade incited by IL-1, particularly in OA. It does not aim to directly repair or regenerate cartilage damage.
Pro-Stride
Pro-Stride® is an Autologous Protein Solution (APS) containing a high concentration of cells, platelets, growth factors, and anti-inflammatory proteins to treat inflammatory processes in joints. This all-natural, drug-free option takes 20-30 minutes to process with no incubation time and treatment can be provided in a single visit. An additional benefit to Pro-Stride is that it is not a drug or medication; therefore, has no withholding time for both FEI and USEF events.
Pro-Stride works by blocking interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha from binding to the cartilage surface. These are two major pro-inflammatory proteins, also known as cytokines (proteins which cause inflammation), which lead to the degeneration of the joints. APS is concentrated plasma with white blood cell proteins and enriched platelet growth factors derived from the horse’s own blood (ie. autologous). Specifically, Pro-Stride APS is a high concentration of interleukin-1 receptor antagonist (IRAP) that is 5.8 times more concentrated than blood. These receptor antagonists promote natural joint healing processes.
Mechanism: Aims to block IL-1 and TNF-alpha, thus helps prevent inflammation in an injured or diseased joint
When to use:
Osteoarthritis
Joint treatment in metabolic horses/ponies
Good to use for showing horses
Duration of effect is longer than IRAP products in general, due to broader spectrum of cytokine suppression and higher levels of prokinetic (healing) growth factors contained.
Goal of treatment: To inhibit the inflammatory cascade incited by IL-1, particularly in OA. It does not aim to directly repair or regenerate tissue.
PRP
Platelet-rich plasma (PRP) are high in the absolute number of platelets and therapeutically used for the platelet growth factor content. Platelet cells activation result in a pro-coagulant state, and specifically alpha granules carrying a variety of growth factors are released. The predominant growth factors in platelets are platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-b). These growth factors play a role in platelet-enhanced healing.
PRP is often used for tendon, ligament, and joint injury through percutaneous, ultrasound-guided, and intralesional injection. Often a single injection will be utilized with PRP, but repeated administrations are not uncommon. PRP also has been shown to result in some analgesic effects through stimulation of thrombin receptors (PAR-1), which increases pain threshold (ie. Decreases the patient’s perceived pain level) via opioid pathways.
PRP is an autologous biological agent, and therefore very safe. PRP is also highly utilized in treating human sports medicine injuries. Platelets are considered inflammatory cells, however, there are also leukocytes (white blood cells) present in PRP as well. Due to this, acute pain following injection may occur, especially if they are present in too high a number. PRP processing machines are specifically designed to attain the “optimal” number of cells and growth factors for therapy. Non-steroidal anti-inflammatories (NSAIDs) may help decrease this pain, however some NSAIDs or steroids may decrease the efficacy of the treatment. In horses, phenylbutazone and naproxen have shown little effect of the treatment’s efficacy and can be used to help decrease some discomfort following injection.
Mechanism: After platelet activation, numerous growth factors are released:
Large amounts: transforming growth factor beta, platelet derived growth factor
Small amounts: insulin-like growth factor, epidermal growth factor
In general, optimal response to PRP treatment of joints occurs more rapidly than in tendon and ligament injuries.
When to use: Joints, tendons, and ligament injuries; best used after acute traumatic injury to musculoskeletal tissues
Goal of treatment: Accelerate and improve the quality of healing; intended to support and enhance tissue healing as an anabolic agent
Stem Cells
Stem cell therapy has received much attention in the recent years, and their use and development is being closely monitored and regulated by the CDC and FDA. Stem cells (aka Mesenchymal Stem Cells = MSCs) have recently had a terminology change to Mesenchymal Signaling Cells, due to their lay role as “cellular healing directors” becoming actual new cell in the repair.
Stem cells were originally obtained from bone marrow or adipose tissue (fat), but over the past few years sources have included allogeneic embryonic pluripotent cells, cord blood/placental tissue, dental pulp, and peripheral blood.
Two basic types of stem cells are hematopoetic and mesenchymal. Mesenchymal cells have the best potential for regenerative medicine purposes in the tendon, ligament, cartilage, muscle and bone (ie. pluripotent). Bone marrow aspirate can be cultured for 2-3 weeks to obtain bone marrow-derived mesenchymal cells (BM-MSCs). Adipose tissue is generally taken from the tail head region or by liposuction. Processing involves a collagenase digestion and then cultured for several weeks to obtain adipose tissue-derived mesenchymal cells (AT-MSCs). The effectiveness of these sources of MSCs is highly dependent on the tissue type of the injury, and newer techniques are emerging to control the ultimate cell type which occurs (ie. bone, muscle, nerve, tendon/ligament and even entire functional organs).
Mechanism: Immature stem cells differentiate to lead to tissue regeneration
When to use: For treatment of equine musculoskeletal disorders including tendonitis, osteoarthritis, discrete core lesions, IV regional perfusion for tendon/ligament injuries
Goal of treatment: New tissue regeneration, increased ability to heal, disease conditions, organogenesis, wound healing and more. In other words, all aspects of medicine and sports medicine are striving to improve their overall outcome!