Scientific Bases of PRP Therapy

Abstract

Platelet-rich plasma (PRP) is a minimally invasive treatment modality that harnesses the body’s own regenerative potential and focuses it on an area of need to essentially “force” the body to repair what it failed to naturally. As it pertains to the field of pain management, PRP has shown a great deal of promise with musculoskeletal injuries (i.e., tendonitis, tendon/ligament tears, etc.) that traditionally fail to heal due to poor blood supply. The appeal of PRP as an alternative treatment option for those patients who had previously exhausted conservative medical management has grown in recent years despite a complete lack of insurance coverage. In this chapter, the evidence-based rationale for using PRP to treat musculoskeletal chronic pain will be discussed.

Introduction

In the simplest of terms, platelet-rich plasma (PRP) is defined as a volume of plasma containing a concentrate of platelets above the baseline of typical/healthy blood levels. While PRP therapy has received significant attention as of late from professional athletes, it has been utilized by physicians for over 30 years in dental and orthopedic surgeries to assist in healing. Its growing popularity with the general public stems from its ability to aid in the repair of soft tissue injuries that are reluctant to heal on their own (i.e., tendon, ligament, and muscle). Moreover, there is no fear of immunogenicity as the whole blood from which PRP is derived is autologous. Given the ever-growing applications and versatility of PRP therapy to facilitate healing in chronically inflamed tissues, it is important to understand and establish the role(s) of platelets as well as the mechanisms involved in normal repair and regeneration.

Microanatomy

Platelets (aka thrombocytes) range from 1 to 4 μm in diameter and are derived from the fragmentation of megakaryocyte lineage in the bone marrow. Platelets contain the following compounds contributing to the different phases of healing (Fig. 87.1).

Fig. 87.1

Figure illustrating the different compounds contained within a platelet

Platelet Function and Tissue Healing

Regardless of the tissue type, the normal healing process relies on a combination of two main processes:

• 1. Regeneration – the replacement of damaged tissues by the surrounding healthy living tissues

• 2. Repair – scar tissue formation through granulation tissue maturation to substitute the diseased tissues

In order to ensure the PRP technology is applied safely and logically, it is important to understand the fundamentals of platelet function and normal tissue healing stages: hemostasis, inflammation, proliferation, and remodeling.

Immediately following trauma, the locally damaged blood vessels release blood plasma and other cell mediators into the surrounding areas to induce platelet aggregation to form a fibrin clot. This clot plug is the product of the collagen receptor glycoprotein (GPIb/IX/V) binding to the damaged endothelial wall to act as a base for additional aggregation factor, such as platelet integrin 𝛼IIbβ3, to adhere themselves to the area. Once the platelets aggregate, they become activated to chemotactically mobilize monocytes, neutrophils, and lymphocytes toward the clot. More importantly, platelet activation and degranulation release seven important growth factors:

• Platelet-derived growth factor (PDGF)

• Insulin growth factor one and two (IGF-1, IGF-2)

• Transforming growth factor-β1 (TGF-β1)

• Vascular endothelial growth factor (VEGF)

• Fibroblast growth factor (FGF)

• Keratinocyte growth factor (KGF)

• Connective tissue growth factor (CTGF)

• Epithelial growth factor (EGF)

Over 95% of the abovementioned growth factors are released within the first hour of injury and will continue to release growth factors for the next 7–10 days. Fibroblast stimulation promotes collagen production to replace the fibrin clot during the proliferative phase. Endothelial cells enhance angiogenesis to increase local cellular metabolism. In addition to the growth factors, PRP also contains other bioactive molecules that promote healing. Interleukin 8 (IL-8) promotes angiogenesis. Fibrin, fibronectin, and vitronectin are known cell adhesion molecules for osteoconduction, bone matrix, connective tissue, and epithelial migration during tissue repair.

It is obvious that adequate blood supply is crucial to proper tissue healing. Tendons, ligaments, joints, and certain segments of the muscle all have poor blood supply and are therefore prone to chronic inflammation following initial injury. Chronic inflammation results when acute inflammatory responses are inadequate to restore the prior physiological state. Due to poor blood supply and insufficient endogenous platelet activation/aggregation, macrophages, lymphocytes, fibroblasts, and plasma cells continue to linger at a low concentration without proper healing. Chronic inflammation causes persistent pain, tissue damage, neo-neurovascularization, tissue necrosis, and fibrosis. The exact mechanisms causing incomplete acute inflammation are unknown; however, overuse and repetitive microtrauma to a structure have been implicated.

The success and appropriateness of PRP therapy rely on meeting the following conditions:

• 1. Deliver the high concentration of growth factors to “jumpstart” tissue healing in areas with suboptimal blood supply.

• 2. The target tissue must have the ability to undergo sufficient angiogenesis and accommodate vascularization – thus allowing the body to finish the job.

The rationale is that the high concentration of growth factors merely acts as a beacon to attract and activate endogenous healing molecules that govern protein transcription, cellular division/proliferation, extracellular matrix synthesis, and collagen formation to the injury site. Continued proliferation of epithelial cells, fibroblastic cells, osteoblastic cells, and mesenchymal stem cells must be sustained by sufficient blood circulation to allow healing to reach completion.

Background and Historical Perspective

By definition, any volume of plasma that contains supraphysiologic platelet count is considered “platelet rich.” The characterization of PRP, historically, depended on the platelet concentration alone. However, the concentration and composition of PRP can range widely – this can be due to a number of variables including the physiological state of the patient from which the PRP is derived as well as the method of preparation. This focus on platelet concentration leads to every PRP kit manufacturer claiming their particular product yields the highest platelet counts and/or growth factor concentration. It is important to note that PRP is exempt from the traditional regulatory pathway (human and animal clinical trials) set forth by the Food and Drug Administration (FDA); therefore, any claims by the manufacturers are unverified. Additionally, the ideal platelet concentration is likely to differ depending on tissue type and disease state.

The use of PRP was first introduced in the 1980s in the field of cardiothoracic surgery as a method to conserve intraoperative use of the whole blood. In the 1990s, PRP showed promising results in promoting wound healing in extremity chronic ulcers. Since then, many surgical subspecialties such as maxillofacial, orthopedics, plastics, and podiatry had success of using PRP to achieve excellent outcomes.

The therapeutic effects of PRP rely on complex interactions of platelet-derived proteins, growth factors, cytokines, hormones, and white blood cells (WBC) to create an ideal microenvironment for cellular repair and regeneration at the site of injury. Similar to platelet concentration, WBC quantification has also been studied and used to categorize PRP into:

• 1. Pure PRP (low WBC, anti-coagulated)

• 2. Leukocyte-rich PRP (high WBC, anti-coagulated)

• 3. Pure platelet-rich fibrin (PRF) (low WBC, coagulated)

• 4. Leukocyte-rich PRF (high WBC, coagulated)

The inclusion of WBC-rich buffy coat has been debated as excessive WBC may cause pain and unwanted scarring. Different cell types cultured in the same PRP yielded different tissue responses. It has also been found that extreme platelet concentrations produced inferior bone regrowth, while moderate concentrations were more effective. Similarly, rotator cuff fibroblasts responded favorably to low and moderate concentrations compared to high concentration. Future research is needed to better define the ideal PRP compositions and concentrations that are disease specific.

Uses and Indications

With the biotechnological advancement in improving the precision and ease of PRP preparation, PRP therapy can be conveniently and safely administered in the office settings. While there are many potential indications and uses for PRP therapy, the most important step begins with patient selection. Physicians should carefully obtain a thorough history including history of injury, location, chronicity, intensity of pain, aggravating and alleviating factors, and prior treatments. Clinical presentation must be supported by imaging to confirm that underlying tissue damage is indeed the symptom/pain generator. After the diagnosis has been established, the standard treatment(s) should be tried first. Similar to rationales that govern regenerative medicine as a whole, PRP therapy candidates typically fall into one of the three groups:

• 1. Asymptomatic patients with high degeneration risks.

• 2. Symptomatic patients in the beginning phase of degeneration process.

• 3. Symptomatic patients in the late phase of degeneration process.

The therapeutic effects of PRP therapy are reduced in older individuals with obesity and advanced stages of degeneration. In contrast, younger patients with lower body indices and early stages of disease demonstrated a more favorable outcome with PRP treatment. Therefore, it is important to present the advantages and disadvantages to all patients considering pursuing PRP therapy:

Advantages:

• 1. Blood sample is easily and safely obtained from peripheral venipuncture.

• 2. PRP therapy can be performed in an office setting.

• 3. It is relatively inexpensive compared to other tissue regenerative options.

• 4. Since the blood sample is obtained directly from the patient, there is low risk of allergic reaction and infection.

Disadvantages:

• 1. Injection could be very painful as PRP creates an acute inflammatory reaction.

• 2. The patient is required to avoid NSAIDS days before and several weeks after PRP administration.

Tendinous and ligamentous injuries are the earliest and common conditions that PRP was used to treat and showed good outcomes. PRP is particularly effective in treating injured body parts with tenuous blood supply. As hemostasis of the inflammatory cascade is vascular dependent, poor blood supply impedes optimal delivery of endogenous platelets and growth factors to initiate the tissue healing process. Injections of PRP to these areas can essentially mitigate a decrease in vascular perfusion and “jump start” the healing cascade. The common musculoskeletal pathologies encountered by pain management physicians can be grouped into the following:

• 1. Tendon/Ligamentous Injury

  • Medial/lateral epicondylopathy/epicondylitis

  • Medial/lateral collateral ligament injury

  • Anterior cruciate ligament injury

  • Patellar tendinopathy

  • Rotator cuff tendinopathy

  • Achilles tendinopathy

• 2. Cartilage Degeneration

  • Acetabular labral tear

  • Glenoid labral tear

  • Osteoarthritis (OA)

• 3. Muscle Injury

• 4. Degenerative Disc Disease

Contraindications, relative and absolute, for the use of PRP are listed in Table 87.1.

Table 87.1 Relative and absolute contraindications for PRP

Evidence for Efficacy

The evidence of PRP therapy is rapidly expanding. At the time of this chapter preparation, PRP search on Pumed.gov alone yielded nearly 4000 publications. The evidence supporting the use of PRP in treating musculoskeletal pathology will undoubtedly continue to grow. The highest level of available evidence with the corresponding musculoskeletal pathologies is tabulated in the order of empirical evidence strength (Table 87.2).

Table 87.2 PRP evidence table

Pearls and Pitfalls

• PRP is safe and effective to induce or accelerate healing and pain relief.

• Despite a lack of coverage by the current insurance system, there is good and growing evidence to support the use of PRP.

• Pain physicians should be familiar with the absolute and relative contraindications to ensure patient safety.

• NSAIDs should be held for at least 7 days and 10 days for steroid before initiating PRP therapy. Following PRP treatment, NSAIDS should not begin within 30 days.

• Multiple repeated PRP injections in the same location may be necessary in order to achieve an optimal clinical outcome.

• Future standardized studies are needed to delineate different tissue disease-specific PRP concentration and composition.