Platelet-rich plasma promises pain relief and healing, but remains controversial

The use of platelet-rich plasma remains controversial as treatment regimens and formula concentrations are not standardized, high-level studies proving efficacy are few and many health care systems worldwide hesitate to adopt the treatment due to lack of reimbursement.

Elizaveta Kon, MD, of Rizzoli Orthopaedic Institute, in Bologna, Italy, told Orthopaedics Today Europe some specific patient groups have already been identified in which platelet-rich plasma (PRP) is highly effective.

“We found out that PRP is more effective than hyaluronic acid (HA), especially in young patients and patients with low degrees of degeneration” of knee cartilage, Kon said. “When you have old patients with advanced degrees of osteoarthritis, PRP has been demonstrated, in our hands, equal in [its] results respective to HA.”

In addition to their efforts to find the right patients and indications for PRP treatment, European sources told Orthopaedics Today Europe they have garnered support from their hospitals or health care systems to use PRP through experimental clinical studies. Kon and others said it was necessary for them to restrict the PRP injections only to study participants. Otherwise, the patients would have to pay out of pocket for them, Kon said.

Image: Rapp SM; Orthopaedics Today Europe

These are a few of the many challenges related to PRP use that clinicians and researchers worldwide now face.

Proteins of importance

“There is tremendous variability within PRP formulations,” Scott A. Rodeo, MD, of Hospital for Special Surgery, in New York City, told Orthopaedics Today Europe. “It is a compelling concept to isolate autologous cytokines and factors from blood, but we are still at the tip of the iceberg. It is in its infancy. We need to become more refined in the understanding of what we want to give to the patient.”

The numerous brands, concentrations, doses and uses of PRP also pose a challenge in determining the best formulations for patients, according to Rodeo. The mechanisms for healing of PRP solutions vary and are dependent upon platelet numbers and captures, the efficiency of those captures from given blood samples, activation techniques, leukocyte counts and specific growth factors or proteins.

“We say all these growth factors are good,” Rodeo said. “That is a blanket statement. We need to know which of the hundreds of growth factors or proteins are important. That is going to vary for the tissue, situation or injury. The non-standardization and the variability is one of the biggest challenges in interpreting the data that exist in this area.”

While many studies have shown significant pain relief in patients who receive PRP, Rodeo said researchers hope PRP will regenerate tissue and reduce the need for surgery.

“The biggest benefit would be as a nonoperative modality for conditions that are difficult to treat,” he said.

Patients with tissue conditions involving poor cellularity, such as chronic tendonitis, arthritis or cartilage injuries, would benefit the most from these formulations, Rodeo said. “The hope would be for PRP to give more sustained benefit and regenerate tissue,” he said.

Confounding variables

According to Nicola Maffulli, MD, MS, PhD, FRCS(Orth), “well-conducted, properly powered” studies with standard outcome measures to prove the benefits of PRP are lacking.

“Animal studies have, at least in part, been performed, but the clinical studies lag behind,” Maffulli, of The London Independent Hospital, in the United Kingdom, told Orthopaedics Today Europe. “The translational aspect of PRP use has not been well studied,” he said.

Maffulli cited potentially biased studies in which researchers have financial conflicts of interest related to PRP manufacturers as another thorny issue surrounding these treatments. Such studies have shown positive results, Maffulli said, while non-sponsored studies have shown poorer outcomes.

“The meta-analyses and the systematic reviews consistently show that the studies that claim the best results are the ones that are scientifically less skewed,” he said.

Rodeo added, “They are all proprietary, and you do not have great information as to compare studies. There is a commercial and financial marketing part of it that makes it difficult to interpret data. Company-derived data have to be viewed with a bit of skepticism.”

Taco Gosens, MD, PhD, of St. Elisabeth Hospital Tilburg, in Tilburg, The Netherlands, suggested many studies have too few patients to be well-powered.

“You need lots of patients to say whether PRP ‘X’ is better than PRP ‘Y,’” Gosens told Orthopaedics Today Europe.

However, Gosens and Maffulli noted that an ideal PRP formulation does not exist given the autologous nature of PRP and the changing composition of markers in blood through the day.

“Blood composition is not constant,” Maffulli said. “There has been no attempt to standardize this simple variable.”

Different formulations abound

The jury is still out on the optimal product and delivery mode of PRP, according to F. Alan Barber, MD, of Plano, Texas, USA, as it can be spritzed on wounds or injected into joints in a liquid form or placed as a solid in a matrix or membrane construction. In addition, PRP formulations can be leukocyte-rich or poor, activated with thrombin or with excess calcium chloride.

There are eight manufactured brands of PRP, each with different formulations and their own centrifugation processes, according to Rodeo.

Treatment with leukocyte-rich or poor PRP depends on surgeon preference. However, Maffulli said leukocyte-rich PRP may cause unwanted inflammatory tissue reactions and subsequent pain.

“If there are too many leukocytes, it can be accompanied by an inflammatory flare, which is normal given the presence of leukocytes,” he said. “But this inflammatory flare may not be a good thing because it can cause pain and you may alienate patients because they go to you to get better and they get pain,” Maffulli said.

Leukocyte-rich PRP caused success in 73% of cases vs. 38% with steroid after 2 years, according to Gosens. The resulting inflammatory response is painful in the beginning, but dissipates at 6 weeks, he said.

Solid or liquid PRP

The solid formulations include two scaffold constructions, a platelet-rich fibrin matrix (PRF-matrix) and a platelet-rich fibrin membrane (PRF-membrane), according to Barber.

He noted Musculoskeletal Transplant Foundation ConMed Linvatec (Edison, N.J., USA) manufactures the Cascade Autologous Platelet System, which includes the older generation Cascade Platelet-rich Fibrin Matrix and the newer Cascade Platelet-rich Fibrin Membrane products. The solids allow surgeons to suture the product into the surgical site. Solids elute their product for up to 5 days to 7 days compared to 8 hours to 12 hours for liquid PRP, according to Barber.

He highlighted work by L.C. Visser and colleagues, which showed “more effective release of products that are good from the membrane” in canine tendon cells. The solids are spun down two times as opposed to one time for liquids. PRF-matrix and PRF-membrane centrifuge faster compared to liquids (5 minutes to 10 minutes vs. 30 minutes), Barber said.

PRF-matrix and PRF-membrane are more useful for arthroscopic or open surgery, such as ligament reconstruction or rotator cuff repair, because they can be sewn into the surgical site, according to Gregory F. Fanelli, MD, of Geisinger Medical Center, in Danville, Pa., USA.

“The gels and fibrin patches are easier to work with because you can retain them in a particular place,” he told Orthopaedics Today Europe.

Fanelli cited a study by Barber and colleagues that showed improved healing in patients with rotator cuff tears treated with two 9-mm aliquots of PRF-matrix.

In his own study presented at the Arthroscopy Association of North America Annual Meeting in 2010, Fanelli and colleagues found decreased osteolysis and tunnel expansion when PRF-matrix was applied to patients’ ACLs. He also saw increased wound healing when PRF-matrix was sewn into collateral ligaments. “There is much less swelling,” Fanelli said. “[Patients] seem to heal at a calmer and faster rate than without it.”

PRF-membrane is superior to PRF-matrix, Barber said, because it uses twice the volume of blood (18 mL). It has a more robust fibrin structure that captures the intact platelets without using thrombin or excess calcium “by coming into contact with factors in the surrounding environment and slowly releasing these factors over a prolonged time,” he said.

“It is not a liquid and more robust than a gel,” Barber told Orthopaedics Today Europe. “It is leukocyte poor. It is more durable and more easily handled than the older generation matrix.”

Liquid PRP for wounds, injection

Researchers have also found increased pain relief using liquid PRP, Fanelli said, noting its applicability for use on wounds or percutaneous applications.

“For tennis elbow, a liquid form would be preferable because you are doing it in an awake patient percutaneously,” Fanelli said.

Kon prefers a leukocyte-poor high concentration liquid PRP for intra-articular injection. She and colleagues have seen promising results in patients with knee cartilage degeneration and early osteoarthritis when treated with an intra-articular injection of liquid PRP created at their institute.

Gosens and colleagues conducted a randomized controlled trial of 100 patients with tennis elbow who received either liquid leukocyte-enriched PRP injections (GPS Gravitational Platelet Separation System; Biomet, Warsaw, Ind., USA) or corticosteroid injections. They found patients who received leukocyte-enriched PRP injections had better results than those who received corticosteroid injections, which are the gold standard in Europe, according to Gosens.

“The PRP patients were getting better and better by 3, 6, 12 and 24 months whereas the steroid patients were getting back to their baseline level,” he said.

High cost and hospital cooperation

Hospitals and health care systems in Europe and North America are reluctant to allow PRP use because insurance companies do not cover its steep cost, according to sources for this article.

The cost of PRP could start at $15 US for a single vial, according to Maffulli.

However, according to Rodeo, factoring in the costs for centrifugation, disposable materials, physician and injection fees, or ultrasound guidance, if needed, can inflate the cost up to $2,000 US.

“Many hospitals are making a financial decision to restrict the use of PRP, even though there are certain applications — such as pain relief — that show it is advantageous, simply because they are not getting reimbursed,” Barber said.

In the United States, some hospitals and organizations allow the use of PRP once surgeons have demonstrated its clinical and cost-effectiveness, he said.

Fanelli’s organization permits PRP use as long as it is deemed “beneficial.”

“Our institution’s practitioners are allowed to use PRP within broad limits if they think it is reasonable for their patients,” Rodeo said. “If we use it intraoperatively, the hospital may get reimbursed by insurance, but to varying degrees. If you are a practitioner and you want to make the case for them to pay for this, it may be hard to do.”

Barber’s institution allows him to use PRP because he does not use expensive and disposable electrocautery devices for every shoulder arthroscopy, which saves them money, and he negotiated with local vendors on PRP kit prices.

Evidence for complications

Few studies have shown complications related to treatment with PRP, Rodeo said. Although leukocyte-rich PRP may cause inflammation and the growth factors in PRP may be linked to arthrofibrosis, Fanelli said strong clinical evidence of these complications is lacking.

“I think long-term complications are unusual,” Rodeo said. “It is safe as an autologous material; it is your own blood. But still, you have to draw the blood, handle it and process it in the centrifugation, so there is some risk of infection.”

He cited a study by Patel and colleagues that showed 22% of patients with early bilateral knee osteoarthritis experienced nausea and dizziness immediately following one PRP injection. The patients with these reactions had significantly higher platelet levels, which may have caused a “non-specific response,” Rodeo said.

Future of PRP

Questions remain about the roles of specific growth factors and proteins in PRP and which are important for healing and re-growing tissue. The interactions between growth factors, proteins and other components of blood are also unknown, Rodeo said.

“The future is more refined formulations that are more tailored to what we think we need for given conditions, different types of tissue and injuries,” he said. The way PRP interacts with different cells is also missing from the equation. Certain cells may “respond” to PRP and attract more cells to grow in an area, Rodeo said.

“Perhaps we will learn certain factors that will attract cells to the site,” Rodeo added. “We do know some tissues seem to have a small subset of intrinsic stem-like cells within adult tissue that, in the right circumstances, become stimulated to support healing.” – by Renee Blisard Buddle

• References:
• Barber FA. Arthroscopy. 2011;doi:10.1016/j.arthro.2011.06.010.
• Castricinni R. Am J Sports Med. 2011;doi:10.1177/0363546510390780.
• Fanelli GC. Course #104. Presented at: Arthroscopy Association of North America Annual Meeting; May 20-23, 2010; Hollywood, Fla., USA.
• Filardo G. BMC Musculoskelet Disord. 2012;doi: 10.1186/1471-2474-13-229.
• Filardo G. Knee Surg Sports Traumatol Arthrosc. 2011;doi:10.1007/s00167-010-1238-6.
• Gosens T. Am J Sports Med. 2011;doi:10.1177/0363546510397173.
• Kon E. Arthroscopy. 2011;doi:10.1016/j.arthro.2011.05.011.
• Kon E. Knee Surg Sports Traumatol Arthrosc. 2010;doi:10.1007/s00167-009-0940-8.
• Kon E. Knee Surg Sports Traumatol Arthrosc. 2011;doi:10.1007/s00167-010-1306-y.
• Patel S. Am J Sports Med. 2013;doi:10.1177/0363546512471299.
• Rodeo SA. Am J Sports Med. 2012;doi:10.1177/0363546512442924.
• Visser LC. Am J Vet Res. 2011;doi:10.2460/ajvr.72.5.699.

• For more information:
• F. Alan Barber, MD, can be reached at Plano Orthopaedic Sports Medicine and Spine Center, 5228 W. Plano Parkway, Plano, TX 75093, USA; email: khalligan@posmc.com.
• Gregory C. Fanelli, MD, can be reached at Sports Injury Clinic, 100 N. Academy Ave., Danville, PA 17822, USA; email: gfanelli@geisinger.edu.
• Taco Gosens, MD, PhD, can be reached at Hilvarenbeekseweg 60, 5022 GC, Tilburg, Netherlands; email: t.gosens@elisabeth.nl.
• Elizaveta Kon, MD, can be at reached III Orthopedic Clinic, Via Di Barbiano 1/10, 40136 Bologna, Italy; email: e.kon@biomec.ior.it.
• Nicola Maffulli, MD, MS, PhD, FRCS(Orth), can be reached at 1 Beaumont Square, Stepney Green, London GBR E1, United Kingdom; email: n.maffulli@gmul.ac.uk.
• Scott A. Rodeo, MD, can be reached at 535 E. 70th St., New York, NY 10021, USA; email: rodeos@hss.edu.

Disclosures: Barber receives royalties from DePuy-Mitek and Linvatec, and research and educational support from Arthrex, ArthroCare, Biomet, DePuy-Mitek, Linvatec, MedShape, Smith & Nephew and Stryker. Gosens had a study sponsored by Biomet. Fanelli, Kon, Maffulli and Rodeo have no relevant financial disclosures.

 

What challenges would you expect in getting hospitals or health care systems to agree to clinical use of PRP?

More clinical evidence needed

Platelet-rich plasma (PRP), a blood derivative with a supraphysiological concentration of platelets, has received increasing scientific attention for its potential in treating musculoskeletal injury. Platelets contain more than 1,100 bioactive proteins, inside their granules and on the cell surface, that promote local angiogenesis, cell homing, migration, proliferation, differentiation and collagen deposition — all key in tissue regeneration.

Although in vitro studies demonstrate the synergetic effect of PRP on various tissues’ healing, clinical evidence is lacking. Two recent reviews concluded that the poor methodological quality of PRP and tendon injury trials mean evidence for its clinical effectiveness is limited. A 2012 systematic review/meta-analysis of PRP for orthopaedic conditions stated the need for adequately powered studies using disease-specific and patient-important outcomes and to investigate the effect of platelet concentration. There is an urgent need to conduct adequately powered studies to translate the therapy potentials from bench to bedside. Without evidence to support the clinical efficacy and cost-effectiveness of PRP, convincing health care service providers to agree to use it would be difficult.

Furthermore, there are currently various PRP products available commercially with varying components and efficacy. This will need to be explored further to determine PRP products’ effectiveness in each specific condition with purposely designed and adequately powered clinical trials, which should also incorporate health economic analyses. In today’s cash-starved health care systems, the use of any therapy without strong evidence of its effectiveness and its cost impact is resisted by the providers. The support of impartial health research funders to conduct cost-effectiveness trials would ensure the quality of PRP research and help shed more light on the benefits in terms of the patient’s recovery and health service costs.

Joseph Alsousou, LMSSA Lon, MD , MRCS Ed, is a Research Fellow in Trauma and Orthopaedic Surgery at Nuffield Department of Orthopaedic Rheumatology and Musculoskeletal Sciences, at the University of Oxford, Oxford, United Kingdom.
Disclosure: Alsousou has no relevant financial disclosures.

New clinical evidence available

Platelet-rich plasma (PRP) utilization, until now, has been driven primarily by elite athletes and weekend warriors in search of nonoperative solutions for challenging problems such as chronic tendinopathy. Lack of reimbursement and a perception the existing data are inconclusive are the primary reasons why most hospitals and health care systems have not widely adopted the use of PRP for orthopaedic injuries and disorders. Papers published within the last 7 years have also used a variety of PRP compositions and protocols further confusing patients, physicians and payers. The data landscape, however, has recently and significantly changed.

At the American Academy of Orthopaedic Surgeons meeting in March, several papers were presented confirming the value of PRP, especially for chronic tennis elbow. One study investigated extensor tendon needling with and without unactivated, leukocyte-enriched PRP in a prospective, randomized, double-blind multicenter fashion. The authors found significantly higher success rates at 6 months in PRP-treated patients. (PRP 84% vs. control 68%; n=119). The PRP success rate, based on pain reduction with resisted wrist extension, is similar to reported rates with surgical intervention. Importantly, there was also less elbow tenderness at 6 months in PRP-treated patients compared to the active control group (PRP 29% vs. control 54%). This study used the same Biomet GPS PRP system (Warsaw, Ind., USA) and protocol as those used in two studies published in the American Journal of Sports Medicine. Together, these three studies represent 350 patients treated in a prospective, controlled fashion. All the studies found significant value for this type of PRP. Importantly, they were conducted over more than a decade and all reported an excellent safety profile for PRP.

In the context of the newly presented and published supporting data, PRP may evolve from a novel therapy into a standard treatment option for patients with chronic elbow tendinopathy. Recent studies confirm PRP is cost-effective at a price of $1,200 US per procedure, especially when compared to the cost of surgical intervention that can be $8,000 US or more.

As health care systems and other payers recognize patients with this condition can forgo surgery and be treated effectively with PRP, they will begin to incorporate it into their list of approved procedures. PRP is one of the few recent biologic innovations that now has multiple level 1 studies supporting success rates similar to surgery with lower costs. This information could convince physicians and hospitals that incorporating PRP into their practices will help them with their mission of delivering excellent patient care in a cost-effective manner.

• References:
• Gosens T. Am J Sports Med. 2011;doi: 10.1177/0363546510397173.
• Mishra A. Am J Sports Med. 2006;doi: 10.1177/0363546506288850.
• Mishra A. Paper #504. Presented at: American Academy of Orthopaedic Surgeons Annual Meeting; March 19-23, 2013; Chicago.

Allan K. Mishra, MD, is an orthopaedic surgeon at Stanford University Medical Center/Menlo Medical Clinic, in Menlo Park, Calif., USA.
Disclosure: Mishra has financial relationships with Biomet, BioParadox and ThermoGenesis.