Key Insights On Platelet-Rich Plasma For Soft Tissue Repair

Sean Grambart, DPM, FACFAS

While platelet-rich plasma (PRP) has emerged as a potential adjunctive modality for some lower extremity injuries, there is a lack of conclusive evidence in this regard. Accordingly, this author reviews the available literature and offers insights from his experience in using PRP for Achilles tendinosis and chronic plantar fascial pain.

While oral maxillofacial surgeons have been utilizing platelet rich plasma (PRP) for over a decade, PRP has become an increasingly hot topic in the realm of musculoskeletal pathology in recent years.1

   Technicians would obtain PRP by obtaining a small amount of blood via IV puncture and separating the whole blood components from the platelets typically through the use of a centrifuge. The PRP contains numerous growth factors, including insulin-like growth factors (ILGF) 1 and 2, transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), fibroblast growth factor and hepatocyte growth factor, to name a few. The type and amount of growth factor are patient dependent.

   The basic science behind PRP is fairly simple. Platelet rich plasma is simply defined as a sample of autologous blood with concentrations of platelets that are typically five times greater than baseline levels. The science of PRP basically involves the alpha-granules found within the platelets. Alpha-granules contain growth factors that affect all aspects of the healing cascade to facilitate healing of all types of tissue. The growth factors are proteins that are secreted and bind to a receptor on a membrane to exert a response from the cell, which leads to the healing response. Examples of these target cells are osteoblasts, fibroblasts, endothelial cells, epidermal cells and mesenchymal stem cells (MSCs). There is a high amount of interest in the use of PRP for soft tissue injuries but high quality literature is lacking.

   There are several companies that have the capability of producing the PRP. The concentration typically consists of a separation of red blood cells, platelet concentration and platelet-poor plasma. The amount of blood that is needed to produce the PRP differs among the companies. Activation may occur with or without adding an activating agent. One may add thrombin and/or calcium chloride to begin platelet activation, formation of the clot and release of the growth factors. Some studies have shown the use of thrombin can inhibit bone formation with the use of demineralized bone matrix.2

   The other option is not to use the activating agent. Reports by Mishra, Fufa and their respective colleagues have shown that the exposure of PRP to tendon derived collagen factor alone can cause a slow and sustained activation.3,4

   Tendon and ligament injuries are both subdivided into acute and chronic injuries. Acute injuries involve tearing of collagen fibers; hematoma formation and subsequent healing through inflammation; cellular proliferation, regeneration and repair; and remodeling processes.5 On the other hand, chronic injuries are often associated with overuse and lead to a degenerative process. Tendinopathy involves collagen fiber disruption, mucoid degeneration, neovascularization and the absence of inflammation.6

What The Literature Reveals About Treating Acute Injuries With PRP

Animal studies by Batten and co-workers have shown that specific growth factors such as PDGF improve healing and mechanical strength in early ligament healing with the greatest response occurring within the first 24 hours.7 In another animal study, Murray and colleagues found the application of PRP facilitated early improvement in load to failure, maximum load and stiffness of porcine anterior cruciate ligament (ACL) suture repairs. However, they noted no improvement in laxity, maximum tensile load or linear stiffness with longer follow-up.8

   While basic science does show early enhanced healing in acute injuries with PRP application, randomized controlled studies involving humans have failed to show an improvement over conventional methods.

   In my experience, I have used PRP to treat acute tibiofibular ligament high ankle sprains in college level athletes and performed the injection within 48 hours after the injury. These athletes were able to return to competition seven to 10 days after the injury using a protective ankle support.

   Animal studies by Kajikawa and colleagues show that macrophages and fibroblasts are present in the early stages in tendon healing but decrease over time.9 Platelet-rich plasma enhanced the number of fibroblasts in tendon and the amount of collagen synthesis in the initial stage after tendon injury, according to another study by Kajikawa and co-workers.10

   Research has shown that single PRP injections increase tendon strength to failure, stiffness and ultimately the amount of stress that the tendon can withstand in the early stages of healing.11-13

   Aspenberg and Virchenko transected the Achilles tendon in rats and removed a 3 mm segment of tendon.11 The percutaneous injection of a platelet concentrate into the hematoma increased tendon callus strength and stiffness by about 30 percent after one week, an effect the authors say persisted for as long as three weeks after the injection.

   In a study of 48 rabbits, Lyras and colleagues noted the presence of significantly more angiogenesis in those injected with PRP in comparison to the control group during the first two weeks of the healing process.12 In another study of rabbits, Lyras and colleagues showed that PRP may affect the tendon healing process by altering the expression of TGF-b 1.13

   Sanchez and colleagues performed a case-control study looking at the use of a preparation rich in growth factors (PRGF) in the repair of acute Achilles tendon ruptures.14 Six athletes who had a complete Achilles tendon tear had open suture repair and also received PRGF injections in comparison to six athletes who received surgical treatment without PRGF. The adjunctive PRGF group demonstrated an earlier return to range of motion, an earlier return to gentle running and earlier resumption of sports training activities. The study’s main disadvantage is a low number of patients.

   In contrast to this study, another randomized controlled trial by Schepull and colleagues compared 30 patients who had repair of an acute Achilles rupture.15 Sixteen patients received an injection with PRP prior to skin closure and 14 patients received no injection. The Achilles Tendon Total Rupture Score showed no significant difference at one-year follow-up in the heel raise index between the groups. In fact, the Achilles Tendon Total Rupture Score was significantly lower in the PRP group.

   There is a lack of high quality studies that prove or disprove the use of PRP in the treatment of acute tendon injuries.

   I have used PRP with repair of acute Achilles tendon ruptures or tears successfully over the last three years. The preferred method is the use of a platelet-rich fibrin clot in order to suture the clot directly into the substance of the tendon.

Exploring The Potential Of PRP For Chronic Tendinopathy

Chronic tendinopathy typically has a histological appearance of collagen fiber disruption, mucoid degeneration, neovascularization and a lack of inflammation.6 Researchers have suggested the use of PRP for chronic tendinopathy improves angiogenesis and collagen synthesis.16,17

   Achilles tendinosis or chronic tendinopathy is one of the most studied tendon injuries in regard to the use of PRP. A randomized control trial by de Vos and colleagues evaluated the effectiveness of injecting 4 mL of PRP into degenerated areas in the Achilles tendon using Doppler ultrasound guidance in comparison to a placebo saline injection.18 The authors found that both groups had similar improvement based on the Victorian Institute of Sports Assessment-Achilles (VISA-A) score and a similar rate of return to sports. However, the authors elected to inject both groups prior to the start of physical therapy.

   Conservative treatment with physical therapy, especially eccentric exercises, is known to treat chronic Achilles tendinopathy effectively.19 So one might argue that the effect of PRP or the placebo would have been masked because most patients will likely respond favorably with the use of eccentric therapy.

   Gaweda and co-workers evaluated the effectiveness of PRP on non-insertional Achilles tendinopathy.20 Fourteen patients (total of 15 tendons) had a 3 mL PRP injection under the guidance of ultrasound into the degenerated portion of the Achilles tendon. The study authors emphasized protected weightbearing for six weeks. Six patients received a repeat injection.

   Patients were allowed to begin normal daily activities between six and 12 weeks after the injection, although sporting activities were discouraged at this time. Researchers evaluated patients with the American Orthopedic Foot and Ankle Society (AOFAS) scoring scale and the VISA-A scale. Both the AOFAS and the VISA-A scores improved significantly from 24 to 96 and from 55 to 96 at 18 months respectively. The authors also noted a decrease in fusiform thickening, peritendinous thickening, hypoechoic foci and intrasubstance tears.

A Closer Look At The Author’s Experience With PRP

I have treated 25 patients with Achilles tendinosis with PRP injections. All patients failed conservative treatment including immobilization and physical therapy. The PRP injection was an attempt to avoid formal surgical debridement of the Achilles tendon.

   The patients received a 5- to 7-mL PRP injection in addition to undergoing a gastrocnemius recession. I performed the procedure with patients under a general anesthetic as a same-day operative procedure. I injected both within the tendon and between the tendon and paratenon.

   The postoperative protocol involved two weeks of weightbearing in a protective cast boot as tolerated. Patients wore the boot for 24 hours per day during the first two weeks. At the two-week follow-up, the patients advanced into shoes as tolerated and continued to sleep in a night splint for the next four weeks. At six weeks post-op, I re-evaluated the patients.

   The patients subjectively rated their improvement as 75 percent (16 of 25 patients), 50 percent (six patients) or 25 percent improvement (three patients). Patients who noted 75 percent improvement were allowed to advance activities as tolerated. For patients who noted 50 percent improvement, I performed another PRP injection. For those who had 25 percent improvement, I considered PRP unsuccessful and gave these patients the option of open Achilles debridement.

   Sixteen of the 25 patients had 75 percent improvement or better, and returned to normal activities. Three patients had less than 25 percent improvement with PRP and all three went on to formal debridement. The remaining six patients had 50 percent improvement.

   All patients with 50 percent improvement received a second PRP injection six to nine weeks after the initial surgery. I performed the second injection as an outpatient procedure with the patients under sedation. The patients wore a walking boot for seven days and were allowed to advance into shoes at that point.

   Four of the six patients improved and have not required further surgery. One of the remaining two felt that the improvement was enough to continue with normal activities and has not proceeded with other treatment. The other patient had open debridement.

   Obviously, the major limitation with this study is that all patients had a gastrocnemius recession, which alone could have led to the improvement. The longest follow-up is three years.

   I have also used PRP to treat chronic plantar fascial pain. While the patients’ usual presentation is typical of plantar fasciitis, they no longer have signs of inflammation consistent with plantar fasciitis. These patients with chronic plantar fascial pain failed conservative treatment with orthotics, steroid injections, nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy.

   Surgical intervention consists of a gastrocnemius recession and a PRP injection into the medial and central band of the plantar fascia origin. The post-op protocol is the same as I mentioned above for Achilles tendinosis.

   I have followed 54 patients over the last three years. Preliminary results have shown a 90 percent success rate. Forty-seven percent of patients needed another PRP injection while five patients have gone on to receive an open plantar fasciotomy. Once again, the major limitation of assessing these results is that patients underwent a gastrocnemius recession.

In Conclusion

The biochemistry behind using PRP for the treatment of soft tissue pathology seems to be clear although there is a lack of well designed studies with high-level evidence to determine the clinical significance.

   At this point, I have had good success with the use of PRP for chronic injuries of ligaments and tendons. One may employ PRP in an attempt to avoid a more invasive surgical procedure.

   Dr. Grambart is the foot and ankle surgeon for Carle Clinic Association, Division of Orthopedics in Champaign, Ill. He is a Clinical Instructor at the University of Illinois School of Medicine. Dr. Grambart is a Fellow and member of the Board of Directors of the American College of Foot and Ankle Surgeons.

1. Marx RE, Carlson ER, et al. Platelet-rich plasma: Growth factor enhancement for bone grafts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998; 85(6):638-646.
2. Han B, Woodell-May J, et al. The effect of thrombin activation of platelet-rich plasma on demineralized bone matrix osteoinductivity. JBJS Am. 2009; 91(6):1459-70.
3. Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006; 34(11):1774-1778.
4. Fufa D, Shealy B, et al. Activation of platelet-rich plasma using soluble type I collagen. J Oral Maxillofac Surg. 2008; 66(4):684-690.
5. Murray MM, Spindler KP, et al. Enhanced histologic repair in a central wound in the anterior cruciate ligament with a collagen-platelet-rich plasma scaffold. J Orthop Res. 2007; 25(8):1007-1017.
6. Khan KM, Cook JL, et al. Histopathology of common tendinopathies. Update and implications for clinical management. Sports Med. 1999; 27(6):393-408.
7. Batten ML, Hansen JC, et al. Influence of dosage and timing of application of platelet-derived growth factor on early healing of the rat medial collateral ligament. J Orthop Res. 1996; 14(5):736-741.
8. Murray MM, Palmer M, et al. Platelet-rich plasma alone is not sufficient to enhance suture repair of the ACL in skeletally immature animals: an in vivo study. J Orthop Res. 2009; 27(5):639-645.
9. Kajikawa Y, Morihara T, et al. GFP chimeric models exhibited a biphasic pattern of mesenchymal cell invasion in tendon healing. J Cell Physiol. 2007; 210(3):684-691.
10. Kajikawa Y, Morihara T, et al. Platelet-rich plasma enhances the initial mobilization of circulation-derived cells for tendon healing. J Cell Physiol. 2007; 215(3):837-845.
11. Aspenberg P, Virchenko O. Platelet concentrate injection improves Achilles tendon repair in rats. Acta Orthop Scand. 2004; 75(1):93-99.
12. Lyras DN, Kazakos K, et al. The influence of platelet-rich plasma on angiogenesis during the early phase of tendon healing. Foot Ankle Int. 2009; 30(11):1101-1106.
13. Lyras DN, Kazakos K, et al. Temporal and spatial expression of TGF-beta1 in an Achilles tendon section model after application of platelet-rich plasma. Foot Ankle Surg. 2010; 16(3):137-141.
14. Sanchez M, Anitua E, et al. Comparison of surgically repaired Achilles tendon tears using platelet-rich fibrin matrices. Am J Sports Med. 2007; 35(2):245-251.
15. Schepull T, Kvist J, et al. Autologous platelets have no effect on the healing of human achilles tendon ruptures: a randomized single-blind study. Am J Sports Med. 2011; 39(1):38-47.
16. Mehta N, Uchino K, et al. Platelet C4d is associated with acute ischemic stroke and stroke severity. Stroke. 2008; 39(12):3236-3241.
17. Mehta S, Watson JT. Platelet rich concentrate: basic science and current clinical applications. J Orthop Trauma. 2008; 22(6):432-438.
18. De Vos RJ, Weir A, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010; 303(2):144-149.
19. Gärdin A, Movin T, Svensson L, Shalabi A. The long-term clinical and MRI results following eccentric calf muscle training in chronic Achilles tendinosis. Skeletal Radiol. 2010 May;39(5):435-42.
20. Gaweda K, Tarczynska M, et al. Treatment of Achilles tendinopathy with platelet-rich plasma. Int J Sports Med. 2010; 31(8):577-583.

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