Platelet-rich plasma: For now, more questions than answers

It is controversial, diverse and potentially revolutionary. But what do we know about it?

Though much has been made of treatment involving platelet-rich plasma – from efficacy to formulations, hype, uses and potential – relatively little data exists to firmly support or refute its capabilities.

The very nature of platelet-rich plasma (PRP) is one problem: As the autologous PRP for every patient is different, it is difficult to create any one particular formulation for study that would properly apply to all patients. These differences pose a large problem for physicians and scientists, who have found that the work is not necessarily in the study of PRP but rather the development of the studies.

Furthermore, said Steven P. Arnoczky, DVM, since PRP is being used in so many ways on such a wide variety of pathologies, consistent results have been difficult to acquire.

These are only some of the problems surrounding the further development and use of PRP, and while answers may be on the way, many questions are lingering.

Stephen P. Arnoczky, DVM, said the ease of use and lack of fear of using PRP by physicians has been both a benefit and a detriment. Image: Arnoczky SP

How can PRP be defined?

Though the efficacy of PRP is possibly the largest point of contention among physicians, some suggest the larger question is that of what is PRP, actually.

“The lay press does not understand the complexity of PRP,” Allan Mishra, MD, said. “As more data emerge, it will become clear to both physicians and surgeons that the specific formulation of PRP matters significantly in terms of bioactivity.”

“The thing I would emphasize is that we have got to get a better understanding of the formulations in order to figure out whether PRP is valuable or not,” he added. “What is missing in the lay press – but also in the medical literature – is the discussion of what PRP is.”

Mishra pointed out that a formulation of PRP containing only concentrated platelets differs greatly from a formulation composed of concentrated platelets and white blood cells.

Arnoczky said that indications, benefits and limitations of PRP would be best determined through extensive trial, but stressed that such studies are “an onerous task” due to PRP’s lack of definition. Among the issues, he said, are:

• variations in preparation techniques: platelet harvest efficiency, the presence or absence of white and/or red blood cells, the use of thrombin to activate platelets;
• the biologic variability among donors, such as individual variation in platelet count; and
• absence of a standard dosing protocol: Is it 1cc or 2cc of a given PRP preparation administered? What level of cytokine concentration does that present?

Nicholas A. Sgaglione, MD, said that while the definition has been a hurdle in the creation of efficacy studies, it is a problem that could soon be solved.

“It is very variable, so investigators are not always clear about what to study and how to study it,” he said. “Dosing, application, schedule, two injections vs. one – all of that produces a problem. I think we are already in the phase where that is changing and the data will start to accrue.”

What is the best use for PRP?

Thus far, physicians are finding that the best indication for the use of PRP is tendinopathy. According to Mishra – who published a study in 2006 which found a 93% reduction in pain after 1-year follow-up for patients of chronic lateral epicondylar tendinopathy treated by PRP – forms of chronic severe tendinopathy in the Achilles, patellar and quadriceps could be sufficient indications.

“A study of partial rotator cuff tears would also be interesting,” he added.

Sgaglione said that he is “very limited and narrow” in terms of how he uses PRP.

“I have selected and chosen to treat patients with isolated meniscal tears who are biologically at risk for failure of meniscus repair,” he said, adding that he places the PRP arthroscopically using a fibrin-rich matrix to add to the meniscus repair construct and augment or increase the healing rates of those tears.

Though PRP has shown promise in the area of tendinopathy, Mishra noted that it should not be seen as the go-to treatment without more data to back up its use.

“Patients with mild or moderate tendinopathy that has not been treated with other means such as rest, physical therapy and activity modification should not be given PRP unless they fail these modalities,” he said.

What defines a good result?

Arnoczky, an Orthopedics Today Editorial Board member said one major issue with determining the efficacy of PRP is that of physicians expecting “the home run” – clear, large-scale improvements in functional outcome.

“I think in contrast to other orthopedic therapies like [total knee arthroplasty] or [total hip arthroplasty] where functional outcomes are more ‘clear cut,’ clinical studies looking at the efficacy of biologics like PRP in heterogeneous populations such as tendinopathy and rotator cuff repair will require a more nuanced study design,” he said.

Arnoczky added that biologic agents could bring forth an early response that becomes less pronounced over the long-term, or vice-versa.

Freddie H. Fu, MD, DSc, DPs. (Hon), cited mixed results from several studies that questioned the value of PRP treatment as compared to alternatives – or, in some cases, placebos.

“[In the de Vos study], the use of PRP in Achilles tendon injury was compared with regular saline injection and no difference could be found,” he said. “Another study by Peerbooms et al. compared platelet injections with injections of a steroid in patients with tennis elbow and 73% of the platelet-treated group saw improvement at 1 year, compared with 51% with the steroid injections. But can we consider 73% a real ‘success’?”

According to Sgaglione, improvement may not be a question of huge gain so much as incremental success.

“Augmentation of healing is the key phrase,” he said. “If you have certain tissues that heal 60% of the time, and you are able to increase it by 10% to15%? That is significant.”

Evaluating the improvement offered by this therapy is also tricky. “We need to go beyond ‘do you feel better’ to ‘are you really better,’” Mishra said. He added, ultrasound evaluation of tendon or ligament thickness can be used as an objective measure of improvement, as well as the monthly evaluation of hypoechoic signal as compared to the patient’s pain scores and functional outcome.

“It is variable, so investigators are not always clear about what to study and how to study it.” — Nicholas A. Sgaglione, MD

Growth factors: Too much of a good thing?

When PRP has been efficacious, many have attributed this success to the growth factors it can add to the healing process. Even that is viewed with hesitancy, however, as too many growth factors can potentially be detrimental.

“Studies have shown too high a concentration of growth factors can actually inhibit cellular responses,” Arnoczky said. “Thus, the idea that the more platelets you inject the better the healing response is [is] not supported by basic science.”

“It is easy, and fashionable, to say ‘well, I am putting in a lot of growth factors and growth factors are good, therefore something beneficial is going to happen,’” he added. “That may or may not be the case. We have some data to suggest that a little bit of growth factor is good and a lot is not necessarily better. We do not know if it is the growth factors themselves that make the big difference in muscle injury or tendinopathy. That is the problem. We have clinical outcomes, but we do not understand what the science is.”

Fu, a member of the Orthopedics Today Editorial Board, cautioned that with so many unanswered questions, it is dangerous to assume growth factors have a universally beneficial effect.

“How do we know which phase of the healing process needs to be stimulated with growth factors and, moreover, how do we know that PRP or a fibrin clot are releasing those growth factors at the right time,” he said.

“In Pittsburgh, [Johnny Huard, PhD] has investigated the role of growth factors in relationship to muscle injuries during the past 10 years and come to the conclusion that not all growth factors will initially contribute to the healing process,” he added. “[Furthermore, they] can also stimulate anti-healing outcomes such as fibrosis … the good thing is that it is from your own body, so it is probably okay. But some cytokines or growth factors actually impede part of the healing process or make it worse.”

‘Autologous engineering’

One of the most appealing aspects of PRP, Mishra said, is the lack of additional engineering required to produce it. Patients and physicians feel more comfortable with the treatment knowing that it comes directly from the body.

“It is not a genetically engineered or cultured product,” Mishra said. “That is what makes it attractive … it is hard to say it is not potentially valuable, because your body is using it every day.”

“I call it autologous engineering,” he added. “We are trying to use what is in your own body to help stimulate a healing process.”

According to Arnoczky, the ease of use and lack of fear involved with PRP is both beneficial and detrimental, as this allows physicians to use it frequently but also means results are going to be difficult to track properly.

“There is nothing harmful there that we know of,” he said. “I think that is what leads physicians to be more eager to accept it, and therein lies the problem,” he added. “We have so many people doing it because there is little – if any – downside to it, as far as I can see, but because there is such variation we are going to get different levels of improvement and then it is going to be hard to interpret.”

Comparing apples to apples

The variety of findings with regards to the success of PRP treatment hinges on the multitude of formulations and uses for it, Arnoczky said.

“[The positive signs] are countered by studies that say it is not efficacious,” he said. “We have to look closely at how these studies are performed to see if we are really comparing apples to apples. Not that they are wrong, but maybe we are actually comparing apples to oranges and that is why we are not seeing the same results.”

Fu noted that not all disorders within a given tissue may respond identically to PRP treatment. He pointed out that the healing processes after Achilles tendon rupture are not the same as those in Achilles tendinopathy, and that differences in the healing process could mean that PRP has different responses as well.

Mishra also said the studies may be comparing apples to oranges, and suggested that figuring out a way to make sure similar formulations are being compared is key to legitimate findings.

“I think a classification system that discusses apples to apples and oranges to oranges would be much better, and I think the very broad brush of that has two separate categories: What is the platelet concentration that you are delivering, and does the formulation have white blood cells or not,” he said.

“The third rail has to do with whether or not you activate it with something like thrombin or calcium beforehand,” he added.

Forming a proper study to figure out the ideal PRP formulation is the difficult part, Arnoczky said.

“If we go through and one technique or type of PRP turns out to be better than all the rest, obviously people are going to gravitate toward that,” he said. “All of that will shake itself out, hopefully, but it will only do that when we have these types of studies. They are underway now, both in Europe and here in the United States, so I think as time goes on we are going to get more and more information.”

Mishra is optimistic as well.

“As we go forward, what we are going to see are trials for different versions of PRP for specific indications,” he said. “One version of PRP may be very good for muscle injuries but not so good for tendon injuries, because they are different tissues. That is where I think the classification or understanding of formulation needs o be advanced before we can make definitive conclusions.”

Dealing with the hype

Almost a buzzword in the mainstream media, PRP has been touted as a panacea for numerous pathologies including hair loss.

“If we have learned anything from past experiences in science and medicine, it is that there will always be ‘hype’ about promising technologies,” Arnoczky said. “This, in turn, will always foster expectations that often exceed reality.”

Though the amount of public attention may have altered patient expectations somewhat, Sgaglione says it is ultimately up to the physicians to make sure those expectations are appropriate.

“Everybody will blame the media, and everybody will blame the fact that patients are looking for it, but ultimately the responsibility lies with the physician to be able to interpret the science, judge the proper indications and counsel the patients who come in because they read an article or saw an advertisement,” he said. “Expectations on the part of the patients and physicians are always high and, at times, unrealistic. This may prove to only augment healing – it may not be a home run, it may only be a single or double.”

Getting off of the fence

The caution from some regarding the use PRP is something that can only be assuaged with strong, consistent results from exhaustive studies.

“How can we assume that we know the entire effect of PRP on the human body after only a couple of years of research?” Fu said. “There are no good clinical studies, really. It is all [anecdotal]: ‘I injected this patient, and now they are playing better.’ I do not want to be negative, I just want to know – hey, what are you putting in? Where does it go, and how do you look at the outcome?”

Sgaglione said the hesitation is understandable, but the relatively safe nature of PRP and its potentially wide array of uses have meant a rush to the market.

“There are many different proprietary methodologies, preparations and applications,” he said. “There are many different pathologic entities being treated. All of that, along with the fact that the process is autogenous and therefore available, has limited the efforts made to study this more carefully before coming to market.”

What is PRP’s potential?

Though reliable data cultivated through large-scale studies may still be some time away, the one word that keeps coming up in the discussion of PRP is ‘potential.’

“Right now it is a hammer looking for a nail, and we are still trying to find out what that nail is and where it is going to be best utilized,” Arnoczky said. “From a basic science point of view it has great potential, but taking it from the Petri dish to the patient is a big difference.”

“I think it is something with the potential to be very useful,” Fu said. “But it also has the potential to be abused … I am not against it, but we really need to sort it out.”

According to Mishra, even a decade of experience with PRP is still not quite enough right now to grasp the ideal uses and formulations. “I have been at it for 10 years, and I am still trying to understand how best to use it and what the best formulation is for specific indications,” he said. “I have dedicated a decade of my life to this, and I understand it somewhat but still have a lot more to learn.”

“I do believe your body has an incredible ability to heal itself, and PRP is a relatively simple way of taking advantage of that autologous healing potential,” he added. “It is certainly less expensive or potentially harmful than stem cell therapies or genetic engineering.”

Arnoczky noted that being optimistic about PRP’s potential is natural – but it should be tempered with caution.

“With all new therapies, you want to be optimistic and say this may provide something new – but we have to understand the mechanisms and indications,” he said. “More importantly, we have to understand the contraindications.”

“I think once we understand the precise mechanisms by which PRP can enhance healing in various applications and, most importantly, are able to assure the contents and potency of the product, PRP will be a useful tool in the armamentarium of the orthopedic surgeon,” he added. – By Robert Press

References:

• De Vos RJ, Weir A, van Schie H TM, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy. JAMA. 2010;303(2):144-149.
• Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006; 34:1774-1778.
• Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: Platelet-rich plasma versus corticosteroid injection with a 1-year follow-up. Am J Sports Med. 2010;38(2):255-262.

Steven P. Arnoczky, DVM, director of the Laboratory for Comparative Orthopedic Research, can be reached at the College of Veterinary Medicine, Michigan State University, G-387 Veterinary Medical Center, East Lansing, MI 48824; 517-353-8929; e-mail: arnoczky@cvm.msu.edu.

Freddie H. Fu, MD,DSc, DPs. (Hon) Distinguished Service Professor, David Silver Professor and Chairman of the Department of Orthopaedic Surgery, University of Pittsburgh, 3471 Fifth Avenue, Kaufman Building suite 1011, Pittsburgh, PA 15213 ; 412-605-3265; e-mail: ffu@upmc.edu.

Allan Mishra, MD, can be reached at Stanford University Medical Center/Menlo Medical Clinic,1300 Crane St., Menlo Park, CA 94025; 650-498-6645; e-mail: am@totaltendon.com. He is a consultant to Biomet Biologics.

Nicholas A. Sgaglione, MD, chairman of the Department of Orthopedic Surgery, North Shore Long Island Jewish Medical Center, can be reached at 600 Northern Blvd., Great Neck, New York, 11021; 516-627–7047; e-mail: nas@optonline.net.

Is PRP a valuable orthopedic option?

Raymond Rocco Monto

From a basic science perspective, platelet rich plasma (PRP) is fairly well understood. High concentrations of a multitude of soft tissue growth factors including PDGF, TGF-beta, IGF, and EGF are present in PRP. While the levels and array of these matrix-inducing cytokines and chemo-attractants may vary from patient to patient and are preparation-dependent, there is little doubt that they are biologically active. These platelet nests become rally points for cellular-based healing zones. Clinical data documenting the efficacy of PRP in the treatment in severe chronic tendinopathy refractory to more traditional treatment and muscle injuries is mounting and its use these applications appears to be safe.

At this time, I believe there is enough well-documented clinical research to support orthopedic surgeons using PRP to treat severe cases of lateral epicondylitis, Achilles tendinosis, plantar fasciitis, and patellar tendinosis that have not responded to standard treatment protocols. It is in these clinical challenging scenarios that PRP offers real utility to the surgeon. There is also enough data to support the adjunctive use of PRP to enhance early healing with tendon repair. New data also suggests that the use of un-activated PRP (applied without thrombin) enhances osteo-induction in demineralized bone graft.

One of the attractions of PRP is that while the science is complex, its application and use is relatively safe and easy for both patient and physician. Additionally, there has been much discussion of PRP in the media and popular demand has until recently outpaced clinical research. This presents a unique problem for clinicians in that they must be restrained when approaching the use of PRP and disciplined when reviewing research in this field. Clearly, it is not applicable for many orthopedic problems. Although research is rapidly progressing and appears promising, there is insufficient data at this time to support the use of PRP as a primary treatment for osteoarthritis, chondral injury, or neurologic damage. The use of PRP in rotator cuff surgery has also shown mixed results in clinical trials and an effective vector of delivery for PRP in these cases remains elusive.

Orthopedic surgeons should still exhaust standard therapy and treatment when approaching difficult cases of tendon and ligament conditions before considering PRP. However, the selective use of PRP when all else has failed can provide effective and durable clinical results with limited risk. Because of this, PRP should have a place in your orthopedic toolbox.

Raymond Rocco Monto, MD, Monto Orthopedics, Nantucket and Martha’s Vineyard, Mass.

References:

• Foster TE; Puskas BL; Mandelbaum BR; Gerhardt MD; Rodeo SA: Platelet-rich plasma: from basic science to clinical applications. Am J Sports Med 2009 Nov; 37(11): 2259-72.
• Hall MP; Band PA; Meislin RJ: Jazrawi LM; Cardone DA: Platele-rich plasma: current concepts and application in sports medicine. J Am Acad Orthop Surg 2009 Oct; 17(10): 602-8.
• Mishra A; Pavelko T: Treatment of chronic elbow tendonosis with buffered platelet-rich plasma. Am J Sports Med 2006 Nov; 34(11): 1774-8.
• Monto R: Platelet-rich plasma effectively treats chronic Achilles tendonosis. Presented AAOS annual meeting 2010.
• Peerboms JC; Sluimer J; Bruijn DJ; Gosens T: Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: Platelet-rich plasma versus corticosteroid injection with a 1- year follow-up. Am J Sports Med 2010 Feb; 38(2): 255-62.
• Hammond JW; Hinto RY; Curl LA; Muriel JM; Lovering RM: Use of autologous platelet-rich plasma to treat muscle strain injuries. Am J Sports Med 2009 Jun; 37(6): 1135-42.
• Sanchez M; Antitua E; Azofra J; Andia I; Padilla S; Mujika I: Comparison of surgically repaired Achilles tendon tears using platelet-rich fibrin matrices. Am J Sports Med 2007 Feb; 35(2): 245-51.
• Lyras DN; Kazakos K; Verettas D; Botaitis S; Agrogiannis G; Kokka A; Pitiakoudis M; Kotzakaris A: The effect of platelet-rich plasma gel in the early phase of patellar tendon healing. Arch Orthop Trauma Surg 2009 Nov; 129(11): 1577-82.
• de Mos M; van der Windt AE; Jahr H; van Schie HT; Weinans H; Verhaar JA; van Osch GJ: Can platelet-rich plasma enhance tendon repair? A cell culture study. Am J Sports Med 2008 Jun; 36(6): 1171-8.
• Loez-Vidriero E; Goulding KA; Simon DA; Sanchez M; Johnson DH: The use of platelet-rich plasma in arthroscopy and sports medicine: optimizing the healing environment. Arthroscopy 2010 Feb; 26(2): 269-78.
• Han B; Woodell-May J; Ponticello M; Yang Z; Nimni M: The effect of thrombin activation of platelet-rich plasma on demineralized bone matrix osteoinductivity. J Bone Joint Surg Am 2009 Jun; 91(6): 1459-70.
• Butcher A; Milner R; Ellis K; Watson JT; Horner A. Interaction of platelet-rich concentrate with bone graft materials: an in vitro study. J Orthop Trauma 2009 Mar; 23(3): 195-200; discussion 201-2.
• Kon E; Buda R; Filardo G; Di Martino A; Timoncini A; Cenacchi A; Fornasari PM; Giannini S; Marcacci M: Platelt-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc 2010 Apr; 18(4): 472-9.

Douglas W. Jackson

I have asked patients who have received PRP injections what their understanding of the treatments was. I received varying responses that included the patient understanding of being told that PRP makes the area where it is applied “pro-repair” or “better able to heal.” Some said they were told that their cells would react to the growth factors within the platelets and lead to a healing response they would not ordinarily have. Other benefits of PRP being extolled: it has healing powers taken from your own blood; improves the healing environment and the platelets contain growth factors that help to ramp up healing.

In the case of PRP, many, many scientific questions need to be answered regarding these treatments on an avascular tissue (biological deserts) before its wide spread use? Where is the documentation that a relatively more concentrated platelet-plasma solution will benefit a patient’s avascular degenerative articular surfaces and/or tendons? What concentration of platelets is needed and how does an extrinsic “minute” one-time dose (that is potentially diluted by synovial fluid) have on stimulating the cascading of healing and/ or repair process that is proposed? What is delivery mechanism carrying these factors into the target tissue? As in any area of medicine, the proponents of a new treatment have an obligation to demonstrate its effectiveness with meaningful scientific data and outcomes?

Douglas W. Jackson, MD, is Chief Medical Editor of Orthopedics Today.