Letha Y. Griffin, MD, leads a focused roundtable
Chronic overuse conditions such as Achilles tendinopathy (tendinosis) are not uncommon, but are extremely difficult sports injuries to treat. The pathophysiology of tendinopathy—the term used to refer to chronic inflammation of the tendon (as distinguished from tendinitis, which refers to the acute inflammatory state)—continues to elude physicians studying the issue.
Oral and topical anti-inflammatory medications, copper bracelets, high- or low-intensity pulsed ultrasound, extracorporeal shock wave therapy (ESWT), and injected platelet-rich plasma (PRP) have all been used to speed recovery.
Dr. Griffin: What about the recent trend of using PRP to treat tendinopathy? Is this just another fad or does PRP actually affect healing in this disease entity?
Dr. Cole: Basic science studies seem to support the application of PRP for the treatment of problems related to tendons. Several limitations exist in these models, and healthy tendon cultures exposed to an agent may respond differently than an intact chronically diseased tendon. Thus, drawing clinical conclusions from these studies is difficult.
Unfortunately, a chronic tendon injury model is difficult to reproduce and is not likely to have identical pathophysiology compared to tendinosis. PRP has been studied clinically mostly in the elbow and Achilles tendon, and some studies seem to show it has some benefit. Based upon clinical study alone, we cannot yet categorically conclude that PRP is beneficial for all conditions related to tendinopathy.
Also, combined therapy (such as using ESWT with PRP) may actually be more effective than a single modality therapy. PRP makes sense intuitively and, other than cost, has very little downside.
In addition, I believe PRP may have some anti-nocioceptive effect that is still poorly defined. Many of our patients have rapid resolution of symptoms that cannot possibly be explained by resolution of the pathologic findings associated with a diseased tendon.
Dr. Mandelbaum: In our clinic, we follow a specific algorithm for using PRP in chronic Achilles tendinopathy. Based on the gross and histologic properties of Achilles tendinosis, an opportunity theoretically exists for improvement by injecting PRP to stimulate angiogenic infiltration and remodeling by tenocytes.
PRP therapy may also facilitate healing in patellar tendinopathy—but it is critical to distinguish patellar tendinosis from other common causes of anterior knee pain, particularly in the adolescent athlete.
Our indications for PRP treatment for patellar tendinosis in adults are severe symptoms present for more than 3 months that are unresponsive to physical therapy and clinical findings corroborated by changes on magnetic resonance images or ultrasound. The athlete must stop using nonsteroidal anti-inflammatory drugs (NSAIDs) for at least 1 week prior to the injection and avoid NSAID use for 3 to 4 weeks postinjection. The postinjection protocol includes standard rehabilitation for strength and functional progress and gradual return to activities over 6 to 8 weeks. Frequent and liberal use of ice, particularly in the early stages, has been helpful in controlling any discomfort from the injection. Criteria for return to sport include full painless range of motion, ability to tolerate going up and down stairs, and no discomfort as sports progression proceeds.
Dr. Griffin: Dr. Arnoczky and Dr. Andrews, could you summarize your thoughts on the effectiveness of PRP injections in treating tendinopathy?
Dr. Arnoczky: First of all, it is important to determine what, precisely, you are ‘asking’ PRP preparations to do in the treatment of tendinopathy. That is, what aspect(s) of the wound healing process are you trying to stimulate? In chronic tendinopathy, the tissue repair process has been ‘stalled’ and treatments have been based on inciting an inflammatory response to allow the body’s natural repair process to start over.
Although the increase in growth factor concentration associated with PRP has been used to justify its application in the treatment of tendinopathy, platelets also have the ability to store and rapidly release a variety of other bioactive molecules, including proteases and anti-proteases, adhesion proteins, and inflammatory cytokines. Thus, the PRP injection may provide the inflammatory cytokines needed to incite an acute inflammatory response and kick-start the healing process in a compromised tissue.
In addition, the proteins (albumin and globulins) and clotting factors (fibrinogen) present in the plasma portion of PRP are critical components in the early stages of wound healing, such as in creating a provisional fibrin scaffold and stimulating the inflammatory response. Although PRP contains all the elements needed to initiate and support wound repair, the precise indication (timing, dosage, and proposed mechanism of action) has yet to be precisely unraveled.
Finally, even though the natural history of tendinopathy has been extensively studied and prescribed treatments have been guided by clinical signs, the level of tissue pathology and the ability of the tissue to respond to PRP (or for that matter any therapeutic intervention) could vary greatly, even in patients with similar clinical signs. A chronic condition such as tendinopathy may display a varying subset of cellular pathologies that subtly change over time, which may explain the varied results that have been reported.
Dr. Andrews: We have had success using PRP injections for tendinosis patients. The discomfort to patients and the cost are issues, but athletes are often frustrated with the chronic discomfort associated with tendinosis.
PRP injections should be used in conjunction with other treatments, such as rest, ice, anti-inflammatory medication, and physical therapy in a multimodal plan to promote symptom relief and tendon healing.
The effectiveness of PRP in treating tendinosis has not been scientifically proven in human trials. Growth factors associated with certain cells can help promote healing; what sort of cell differentiation PRP promotes is unclear. Our experience is anecdotal. More randomized, double-blind studies are needed with human trials.
Dr. Griffin: Dr. Rodeo, you have used PRP to augment surgical repair of chronic rotator cuff tears. What about the use of PRP in treating chronic rotator cuff pathology in the absence of a full- or partial-thickness tear?
Dr. Rodeo: We have recently completed a prospective, randomized trial examining the effect of platelet-rich fibrin matrix (PRFM) in 67 patients undergoing arthroscopic rotator cuff tendon repair (36 with PRFM at the tendon-bone interface and 31 without). The PRFM was attached to the suture at the interface between the tendon and the greater tuberosity. The postoperative rehabilitation protocol was the same in both groups. The primary outcome was tendon healing evaluated by ultrasound (intact versus defect at repair site) at 6 and 12 weeks.
We found that PRFM had no demonstrable effect on tendon healing, tendon vascularity, manual muscle strength, or clinical rating scales. Several reasons can be postulated for the lack of an effect, such as variability in platelet recovery, platelet activation, and kinetics of cytokine release from the PRFM. A weakness of our study was the absence of information about the number of platelets actually delivered in patients who received the PRFM, as well as the relatively small number of patients studied. Further study is clearly required to evaluate the role of PRFM in rotator cuff repair.
As far as PRP treatment of rotator cuff tendinopathy in the absence of a partial- or full-thickness tear, little data are available. Recently published randomized trials on PRP in treating tendinosis have demonstrated variable and conflicting results, making it difficult to extrapolate to rotator cuff tendinosis. I think we need to answer the following important questions:
- What is the best time for injection?
- Are there different effects on acutely injured tendon versus degenerative tendon?
- Is there a risk of increasing inflammation?
- Would serial injections be more effective?
- What is the effect of pH on cytokine release?
- What are the kinetics of cytokine release?
Dr. Griffin: What do you see as the role of PRP in treating entities such as patellar tendinopathy, Achilles tendinopathy, plantar fasciitis, lateral epicondylitis, and shin splints?
Dr. Maffulli: PRP is increasingly being used, with excellent results being reported. But a systematic review of the literature found that results could not be substantiated when closely scrutinized. A study published in the January issue of the Journal of the American Medical Association showed that PRP in Achilles tendinopathy does not work. We just finished a randomized, controlled trial of PRP in repair of small and moderate rotator cuff tears and found no effect. The studies on tennis elbow are a bit more comforting, and it is possible that the effect changes according to the tendon being treated.
Dr. Mandelbaum: We have used PRP in treating patellar tendinopathy, Achilles tendinopathy, plantar fasciitis, and medial and lateral epicondylitis. We have had no experience with shin splints. Over the last 4 years, we have developed algorithms for the treatments of these disorders. It is imperative and essential to follow clinical pathways at all times. In my experience, global use of PRP for tendinopathy is not recommended.
Dr. Griffin: Several variations of PRP preparations exist. Can they be used interchangeably? Do some have unique characteristics that make them more advantageous in certain situations?
Dr. Arnoczky: All PRP preparations are not created equal. Broadly, PRP can be defined as an increase in the concentration of platelets (and their associated contents) in a given volume of plasma that is greater than that found in whole blood. However, the commercial methods by which the final PRP product is made vary markedly.
Unlike ‘off-the-shelf’ pharmaceuticals, where the exact concentration and character of a product are guaranteed, the precise ‘potency’ of a given PRP concoction cannot always be predicted a priori. For example, the inclusion of white blood cells in some PRP preparations may increase the inflammatory cytokine profile of the final product, while the addition of thrombin has been shown to induce platelet activation and the rapid secretion of the growth factor contents of the a-granules. This is significant, as growth factor half-life is very short, ranging from minutes to a few hours.
A recent study has shown that the creation of a PRFM can increase the duration of increased concentrations of growth factor availability when compared to a naturally occurring clot. It is important to note that the ability to concentrate platelets (and growth factors) several fold via a given PRP preparation may not always be a positive attribute, because the dose-response curve of most growth factors is not linear (and often cell-type dependent). Indeed, higher concentrations of some growth factors have been shown to be inhibitory to connective tissue cells. Because PRP preparations are not the same, we cannot summarily conclude that the failure or success of one product is invariably applicable to all others.
Dr. Cole: In general, the PRP paradigm is shifting away from “more platelets are better” to “it’s not just about platelets.” Where and when the other cellular components within a PRP preparation will actually matter is probably pathology-specific.
Our recent research in collaboration with Lisa A. Fortier, DVM, PhD, at the Cornell University College of Veterinary Medicine demonstrated that the more white blood cells present, the more matrix metalloproteinases that were produced in tendon culture and the lower the ratio of collagen 1 to collagen 3 becomes, which is consistent with scar formation rather than healthy tissue formation.
Donor variability is also significant, both between individuals and between same donor PRP preparations. Adding to the complexity is the role of pH and anti-coagulation. Independent of the presence of an anti-coagulant, platelets will degranulate as soon as they come into contact with a cellular basement membrane.
Finally, we really do not yet understand the proper dose, frequency, and timing of PRP application for any specific condition.
Dr. Griffin: Dr. Andrews, hearing these responses, how would you summarize our knowledge of the use of PRP to treat tendinosis or tendinopathy?
Dr. Andrews: Our knowledge of PRP is just beginning. We know it is safe, but the long-term effectiveness is still in question. I believe that the growth factors do play a valuable role on the cells in poorly vascularized tendinous tissue, but whether they make a difference clinically is still up for debate.
Disclosure information: Dr. Griffin—Piedmont Hospital Board of Directors; AOSSM; AAOS Now; Dr. Andrews—Biomet Sports Medicine; Biomet; Bauerfiend; MiMedx; Theralase; Physiotherapy Associates; Patient Connection; Connective Orthopaedics; FastHealth Corp; AOSSM; Dr. Arnoczky—Musculoskeletal Transplant Foundation; Wright Medical Technology, Inc; Regeneration Technologies, Inc.; Smith & Nephew; NovaLign Orthopaedics, Inc.; Active Implants Corp.; Journal of Bone and Joint Surgery-American (JBJS); Osteoarthritis and Cartilage; Journal of Orthopaedic Research; Orthopaedics Today; American Journal of Sports Medicine (AJSM); Scandinavian Journal of Medicine and Science in Sports; Journal of Knee Surgery; Dr. Cole—Arthrex, Inc.; DJ Orthopaedics; Lippincott; Elsevier; Genzyme; Zimmer; Carticept; Biomimmetic Therapeutics; Allosource; Regentis; Smith & Nephew; JBJS, AJSM; Cartilage; Journal of Shoulder and Elbow Surgery; American Journal of Orthopaedics; Dr. Mandelbaum—Exacted, Inc.; Johnson & Johnson; Genzyme; Zimmer; Smith & Nephew; AJSM; International Cartilage Repair Society; Dr. Maffuli—ISAKOS; Dr. Rodeo—Musculoskeletal Transplant Foundation; Wyeth; Cayenne.
Editor’s note: As identified in “Platelet-rich plasma: Clarifying the issues”, platelet-rich plasma (PRP) therapy is frequently applied in sports medicine, particularly in treating tendinopathy. AAOS Now editorial board member Letha Y. Griffin, MD, recently conducted a focused roundtable on the treatment of tendinopathy with James R. Andrews, MD; Steven P. Arnoczky, DVM; Brian J. Cole, MD; Nicola Maffulli, MD, PhD; Bert Mandelbaum, MD; and Scott A. Rodeo, MD.
This is the first of a two-part report on that roundtable. Next month, the discussion continues with a broader look at treatments and specific treatment tips from each of the participants.