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Platelet rich plasma Injection grafts for musculoskeletal injuries：a review（1）.

Steven Sampson,1 Michael Gerhardt,2 and Bert Mandelbaum2

1The Orthobiologic Institute (TOBI), Santa Monica, CA USA

2Santa Monica Orthopaedic Group, Santa Monica, CA USA

Steven Sampson, Email: drsampson@orthohealing.com.

Corresponding author.

Curr Rev Musculoskelet Med. 2008 December; 1(3-4): 165–174.

Published online 2008 July 16.

doi : 10.1007/s12178-008-9032-5

PMCID : PMC2682411

（http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682411/）

Abstract

In Europe and the United States, there is an increasing prevalence of the use of autologous blood products to facilitate healing in a variety of applications. Recently, we have learned more about specific growth factors, which play a crucial role in the healing process. With that knowledge there is abundant enthusiasm in the application of concentrated platelets, which release a supra-maximal quantity of these growth factors to stimulate recovery in non-healing injuries. For 20 years, the application of autologous PRP has been safely used and documented in many fields including; orthopedics, sports medicine, dentistry, ENT, neurosurgery, ophthalmology, urology, wound healing, cosmetic, cardiothoracic, and maxillofacial surgery. This article introduces the reader to PRP therapy and reviews the current literature on this emerging treatment modality. In summary, PRP provides a promising alternative to surgery by promoting safe and natural healing. However, there are few controlled trials, and mostly anecdotal or case reports. Additionally the sample sizes are frequently small, limiting the generalization of the findings. Recently, there is emerging literature on the beneficial effects of PRP for chronic non-healing tendon injuries including Lateral epicondylitis and Plantar fasciitis and Cartilage degeneration (Mishra and Pavelko, The American Journal of Sports Medicine 10(10):1–5, 2006; Barrett and Erredge, Podiatry Today 17:37–42, 2004). However, as clinical use increases, more controlled studies are needed to further understand this treatment.

Keywords : Platelet rich plasma, Injection, Growth factors, Tendon injury, Autologous blood, Musculoskeletal injuries, Chondropenia, Knee osteoarthritis

Introduction

In Europe, and more recently in the United States, an increased trend has emerged in the use of autologous blood products in an effort to facilitate healing in a variety of applications. In recent years, scientific research and technology has provided a new perspective on understanding the wound healing process. Initially platelets were thought to act exclusively with clotting. However, we have learned that platelets also release many bioactive proteins responsible for attracting Macrophages, Mesenchymal stem cells, and Osteoblasts which not only promotes removal of necrotic tissue, but also enhances tissue regeneration and healing.

Based on this principle platelets are introduced to stimulate a Supra-physiologic release of Growth factors in an attempt to Jump start healing in chronic injuries. The current literature reveals a paucity of randomized clinical trials. The existing literature is filled with mostly anecdotal reports or case series, which typically have small sample sizes and few control groups [1, 2]. A large multi-center trial is currently underway providing a more objective understanding of Platelet Rich Plasma (PRP) use in chronic epicondylitis.

According to the World Health Organization (WHO), musculoskeletal injuries are the most common cause of severe long-term pain and physical disability, and affect hundreds of millions of people around the world [3]. In fact, the years 2000–2010 have been termed “the decade of bone and joint” as a global initiative to promote further research on prevention, diagnosis, and treatment [3, 4]. Soft tissue injuries including Tendon and Ligament trauma represent 45% of all musculoskeletal injuries in the USA [4, 5]. The continued popularity of sporting activities has brought with it an epidemic of musculoskeletal disorders focusing attention on tendons. Additionally, modern imaging techniques including magnetic resonance imaging and musculoskeletal ultrasound have provided clinicians with further knowledge of these injuries.

Blood components

Blood contains plasma, red blood cells (RBC), white blood cells (WBC), and Platelets. Plasma is the liquid component of blood, made mostly of water and acts as a transporter for cells. Plasma also contains Fibrinogen, a protein that acts like a Net and Catches platelets at a wound site to form a clot. RBC helps pick up Oxygen from the lungs and delivers it to other body cells, while removing carbon dioxide. WBC fights infection, kills germs, and carries off dead blood cells. Platelets are responsible for Hemostasis, Construction of new connective tissue, and Revascularization. Typically a blood specimen contains 93% RBC, 6% Platelets, and 1% WBC [6]. The rationale for PRP benefit lies in reversing the blood ratio by decreasing RBC to 5%, which are less useful in the healing process, and increasing Platelets to 94% to stimulate recovery.

Platelets

Platelets are small discoid blood cells made in bone marrow with a lifespan of 7–10 days. Inside the platelets are many intracellular structures containing glycogen, lysosomes, and two types of granules. The alpha granules contain the Clotting and Growth factors that are eventually released in the healing process. Normally at the resting state, platelets require a trigger to activate and become a participant in wound healing and hemostasis [7]. Upon activation by Thrombin, the platelets morph into different shapes and develop branches, called Pseudo-pods that spread over injured tissue. This process is termed Aggregation. Eventually the granules contained within platelets release the Growth factors, which stimulate the Inflammatory cascade and Healing [7].

PRP

Platelet Rich Plasma is defined as a volume of the plasma fraction of autologous blood having a platelet concentration above baseline [8, 9]. Normal platelet concentration is 200,000 Platelets/ul. Studies have shown that clinical efficacy can be expected with a minimum increase of 4× this baseline (1million Platelets/ul) [6]. Slight variability exists in the ability to concentrate platelets, largely depending on the manufacturer’s equipment. However, it has not been studied if too great an increased platelet concentration would have paradoxical effects.

The use of autologous PRP was first used in 1987 by Ferrari et al. [10] following an open heart surgery, to avoid excessive transfusion of homologous blood products. Since that time, the application of autologous PRP has been safely used and documented in many fields including; orthopedics, sports medicine, dentistry, ENT, neurosurgery, ophthalmology, urology, and wound healing; as well as cosmetic, cardiothoracic, and maxillofacial surgery. Studies suggest that PRP can affect Inflammation, Post-operative blood loss, Infection, narcotic requirements, Osteogenesis, Wound, and Soft tissue healing.

In addition to Local hemostasis at sites of vascular injury, platelets contain an abundance of Growth factors and Cytokines that are pivotal in Soft tissue healing and Bone mineralization [4]. An increased awareness of platelets and their role in the healing process has lead to the concept of therapeutic applications.

Tendons

PRP is increasingly used in treatment of Chronic non-healing Tendon injuries including the elbow, patella, and the achilles among others. As a result of mechanical factors, tendons are vulnerable to injury and stubborn to heal. Tendons are made of specialized cells including Tenocytes, water, and fibrous Collagen proteins. Millions of these collagen proteins weave together to form a durable strand of flexible tissue to make up a tendon. They naturally anchor to the bone and form a resilient Mineralized connection. Tendons also bear the responsibility of transferring a great deal of force, and as a result are susceptible to injury when they are overwhelmed. With Repetitive overuse, Collagen fibers in the tendon may form Micro tears, leading to what is called Tendonitis; or more appropriately Tendinosis or Tendinopathy. The injured tendons heal by Scarring which adversely affects function and increases risk of re-injury. Furthermore, tendons heal at a Slow rate compared with other connective tissues, secondary to Poor vascularization [11–13]. Histologic samples from chronic cases indicate that there is Not an inflammatory response, But rather a limitation of the normal tendon repair system with a fibroblastic and a vascular response called, Angiofibroblastic degeneration [1, 14, 15]. Given the inherent nature of the tendon, new treatment options including Dry needling, Prolotherapy, and Extracorporeal shockwave therapy are aimed at embracing Inflammation rather than suppressing it.

Traditional therapies to treat these conditions do not alter the tendon’s inherent poor healing properties and involve long-term palliative care [16, 17]. A recent meta-analysis of 23 randomized controlled studies on physical therapy treatment for epicondylitis, concluded that there is insufficient supportive evidence of improved outcomes [1, 18]. Corticosteroids are commonly injected, however studies suggest Adverse side effects including atrophy and permanent adverse structural changes in the tendon [14]. Medications including NSAIDs, while commonly used for tendinopathies, carry significant long-term risks including bleeding ulcers and kidney damage. Thus, organically based strategies to promote healing while facilitating the release of one’s own natural growth factors is attracting interest.

Growth factors

It is widely accepted that Growth factors play a central role in the Healing process and tissue Regeneration [4, 19]. This conclusion has lead to significant research efforts examining varying growth factors and their role in repair of tissues [4, 20]. However, there are conflicting reports in the literature regarding potential benefits. Although some authors have reported improved bone formation and tissue healing with PRP, others have had less success [4, 21, 22]. These varying results are likely attributed to the need for additional Standardized PRP protocols, preparations, and techniques. There are a variety of commercially FDA approved kits available with variable platelet concentrations, clot activators, and leukocyte counts which could theoretically affect the data.

Alpha granules are storage units within platelets, which contain pre-packaged Growth factors in an inactive form (Fig. 1). The main growth factors contained in these granules are transforming growth

factor beta (TGFbeta), vascular endothelial growth factor (VEGF) platelet-derived growth factor (PDGF), and epithelial growth factor (EGF) (Table 1). The granules also contain Vitronectin, a cell adhesion molecule which helps with osseointegration and osseoconduction.

Fig. 1

Inactive platelets

Table 1

Growth factor chart [Printed with permission from: Eppley BL, Woodell JE, Higgins J. Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing. Plast Reconstr Surg. 2004 November;114(6):1502–8]