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Regenerative therapy: ‘as good as new’...

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01 November 2010, at 12:00am

MARION McCULLAGH continues her reports on the sessions at this year’s BEVA congress

FRIDAY’s “state-of-the-art” session at the BEVA congress was opened by Lisa Fortier of Cornell University who posed the question: “Regenerative therapy for equine joint disease – where are we at?”

Regenerative therapies use preparations made from the body itself, known as biologics. These enhance the body’s own potential for healing. The required tissue is collected from the injured animal, treated to increase the desired part of it and put back into the patient’s site of injury. 

Three examples are platelet-rich plasma (PRP), autologous conditioned serum (ACS), and bone marrow concentrate (BMC). 

Biologics give a scaffold for healing and they are a source of cells and growth factors. The rationale of using them is to get the injured tissue to replace itself, rather than repair itself by adding scar tissue. These treatments for joints are still in development but the experimental results are very encouraging. 

ACS was probably the first one to be tested in horses. It seems to act by blocking the receptor of interleukin -1 (IL-1) which is a cytokine, a soluble protein messenger that is part of the inflammatory process.

Experiment

In an experiment, lesions of synovitis or early arthritis were created and ACS was injected into the damaged joints. The horses responded with a reduction of lameness and synovial hyperplasia. This effect was not seen in the placebo- treated controls.

PRP is made by taking some of the patient’s blood and concentrating it so that the final platelet concentration is between two and eight times higher than normal.

There are several different methods of making PRP and so the products differ in volume and in their concentration of platelets and growth factor.

PRP contains all the elements of blood, about 1,500 proteins, and we do not know the function of these taken individually. PRP is injected into the injured joint using ultrasound guidance.

Platelets modulate the inflammatory response and induce blood vessel development at the site of injury. Fibroblasts and local stem cells are attracted to the site and nearby uninjured cells are stimulated to produce autocrine growth factor.

Bovine thrombin can be added to the PRP when it is being injected or just before. This initiates the clotting cascade so that the clotted PRP acts as a scaffold for tissue repair. Also, growth factors are stored and released slowly. PRP is given in two or three treatments a week apart. Clinical observation established that pain relief preceded repair.

Improving chondroprotection

Experimental PRP treatment increases proliferation of chondrocytes and the synthesis of proteoglycans and collagen type 2 by the cartilage extracellular matrix.

In cell culture, synoviocytes from human arthritic patients cultured in PRP gave increased hyaluronic acid production. This suggests that PRP could be used to improve chondroprotection and joint lubrication.

BMC is made by centrifuging the patient’s own bone marrow aspirate. BMC performs better than PRP in the regeneration of cartilage and the tissues of the musculoskeletal system. Like BMC it contains platelets which are a good source of growth factors.

If it is administered in the clotted form, it functions as a scaffold for the regeneration. It gives better cartilage repair than microfracture. This gain was present at 12 weeks and eight months after the treatment of the experimentally-created defects.

The regenerated tissue was thicker, had a smoother surface and was more coherent with the surrounding tissue than the control.

Regenerative therapies are showing great promise for the future treatment of equine joint problems but they are still in their youth as regards clinical application. Regeneration therapy needs to be followed by a programme of rehabilitation that is tailored to each individual animal.

Increase exercise

Exercise needs to be increased gradually, a 10% increase in either intensity or duration each week is a good guideline. Corrective shoeing and maintaining an optimum bodyweight are also important.

Professor Roger Smith of the RVC outlined the use of “Bone marrow-derived stem cells for tendon and ligament injuries”. The aim of regenerative medicine is to replace the injured tissue by tissue which is as close as possible to the original healthy tissue. If left to nature, these injuries repair by scar tissue formation which is less efficient in function so the athletic ability of the horse is reduced and there is high risk of re-injury. Mesenchymal progenitor cells (MPCs) are good for regenerative therapy because they differentiate into cell lines that lead to the formation of new matrix.

MCPs are probably present in small numbers in most tissues and take part in normal repair, but by adding them in far greater number tissue regeneration is improved.

Bone marrow is a good source of MCPs. This is convenient to obtain, can be taken from the patient under standing sedation and the multipotency of bone-marrow derived MPCs appears to be better than that of MPCs taken from other sites.

Common injuries

Flexor tendon injuries in horses are common and the nature of the lesion lends itself to repair by regeneration therapy. The lesion is located in the core of the tendon, so the implanted cells are surrounded by tendon cells.

It is also an advantage that these are highly vascularised, and at about one month post injury, when the treatment is carried out, the defect is filled with granulation tissue. This acts as a scaffold for the stem cells. The mechanical environment is significant too, as are local cytokines and the bone marrow supernatant has been shown to have an anabolic effect.

Implanting autologous MCPs supplies the healing tendon with many more stem cells than would be present naturally and the tendons treated in this manner are mechanically stronger and the treated horses are less susceptible to re- injury.

Full training

World-wide, over 1,500 horses have been treated using this method. In one analysis which involved 113 National Hunt horses, those horses which had returned to full training and had been followed up for two years showed a re-injury rate of 28.9% for the stem cell-treated horses compared to a re-injury rate of 56% for conventionally-treated horses. So, both experimentally and clinically, MCP treatment appears to be achieving its aim of replacing injured tendon tissue with something very nearly as good as new both in structure and function.