An Innovative Approach to Platelet-Rich Plasma Application in Military Medicine; a Review Article

Military people and athlete are encountered with variety of casualties and injuries during their physical activity in playing ground or in combat situation. Platelet-rich plasma (PRP) is being introduced in skin lesion treatment, facial rejuvenation, and dentistry and recently, its advantages are being employed to other branches of medical science such as orthopedic practices and dermatology. PRP medical application in sport medicine is recognized as a promising method to improve the bone injuries and pain control (1).

Similarity in sport injuries and war casualties makes PRP a potential treatment for military medical implications. Plasma exists in blood and forms 55% of blood volume and water constitutes 93% of plasma. Plasma carries red blood cells (RBCs), platelets, white blood cells (WBCs), ions, proteins, minerals, carbon dioxide, and glucose. In fact, PRP refers to a part of the blood left when the RBCs and WBCs are removed and therefore, plasma remains with a high proportion of growth factors, stem cells, and platelets (2). PRP could be defined also as autologous blood with platelets concentration of 94% while normal platelets concentration is only 6%. Platelets half-life is said to be seven days within the body and the normal count in the blood is 150 × 10⁹/L to 350 × 10⁹/L (3). In fact, PRP is the serum embodying thrombocytes; platelets have no nucleus, and are comprised of many elements including 1000 proteins acting as pulses and located inside or outside of the membrane. They contain small granules known as alpha, delta, and lambda and particularly 50 to 80 alpha granules per platelet. In those granules almost 30 types of proteins, called growth factors, are present and growth factors are mostly involved in homeostasis and healing process (4). Growth factors are released from platelets through a physiologic activation by human thrombin after the injury, and then are renewed through a cascade process on a regular basis. PRP secretes various growth factors including vascular endothelial growth factor, platelet-derived growth factor (agitate angiogenesis), insulin-like growth factor, and fibroblast growth factor. Platelets gained attention as a promising tool for regenerative medicine following by extensive experiments in oral and maxillofacial surgery (5). Addition of calcium chloride and thrombin to the platelets concentration leads to the active secretion of growth factors from alpha granules.

Some studies indicate that platelets have anti-inflammatory and analgesic effects and secrete antimicrobial peptides and therefore, have antibiotic effects (6). Grows factors secreted in this matrix affect various cell types such as chondrocytes (7), osteoblasts (8), fibroblasts (9), endothelial cells mesenchymal stem cells from different origins (10), myocytes, and tendon cells (11), which make a broad range of surgical and clinical applications and treatments possible (12). Platelets were first described by German anatomist Max Schultz in the mid-1800s. PRP has been an interesting topic in regenerative medicine since the beginning of 1970s (13). PRP was initially used in 1987 in an open heart surgery procedure (14). In the early 1990s, multiple experiments in maxillofacial surgery, skin grafting, and dentistry showed improvement in healing quality with PRP. Since then physicians have applied PRP to boost bone healing after spinal injury and soft tissue recovery caused by plastic surgery (15, 16). In fact, history of PRP started much earlier with the research works about the fibrin glues used to improve skin wound healing in a rat model in 1970 (17, 18).

Plastic surgeons and oral surgeons were among the first group of experts who applied the PRP in their surgical operations and then observed improved recovery level (19). In an animal model in 1982, a rabbit cornea model was investigated and showed that platelets along with fibrin trigger a process compulsory for tissue lesion to repair including collagen synthesis, cell migration, angiogenesis, and fibroplasias (4). At the time, PRP therapy was an expensive technique, but various scientists began to implement it on joints injuries, then it was tried by the professional athletes to cure their injuries. In the early years of 2000s, the PRP was use in orthopedics to boost healing in fractures and bone grafts and then sports medicine widely used PRP for soft tissue repair (20). In 2006 Mishra and Pavelko, published the first human study of the use of PRP for chronic tendon problems (21).

The search for potentially relevant studies was performed in PubMed, Science Direct, and Wiley for all publications up to January 15, 2015. The primary search of the literature was done by one investigator (Farzad N) under administration of the principal investigator (Farshad N), who is a PRP therapy expert. After controlling the title and abstract of papers non-relevant trials were excluded and appraisal of eligibility assessment for the remaining studies was performed carefully. The subsequent medical MeSH terms were used: “PRP” and “musculoskeletal injuries”. No limitations on publication status or date were made. Several language publications were found, but only papers written in English language were included. In addition, reference lists of relevant trials were searched for other potentially appropriate publications. In order to assess the perspective of PRP application in military medicine, relevant studies with regenerative medicine approach were retrieved, which they were mainly in the field of wound healing, tendon injury, and bone grafting. Twenty-six papers were retrieved from PubMed Library and 33 papers from Science Direct and Wiley online. The similar and unrelated papers were deleted from the study and 55 papers were remained. Based on eligibility criteria by authors, 49 papers were approved for the study. In this review, inclusion criteria were based on the outcomes such as success in PRP therapy, and the preferred studies were based on evidence-based medicine, which were experimented on the animals and humans (Figure 1).

Figure 1.

Flowchart of the Search

From 49 papers selected for reviewing, some papers discussed cell-based models, some were about animal models, and some were RCTs in tendon injuries, bone injuries, and skin lesions. Results from evaluated studies were analyzed and reviewed by authors in six subcategories including bone injury, tendon injury, dermatology, alopecia, wound healing, rejuvenation, and hair growth. According to reviewed papers PRP therapy is a relatively simple nonsurgical treatment for many fields including sports medicine, orthopedics, cosmetics, faciomaxillary, and urology, and the aim is to increase the healing properties of the organ by increasing the amount of growth factors. There are promising results about the use of PRP in soft tissue injuries, oral surgery, skin wound healing, spinal surgery, trauma surgery, burns and plastic surgery, gastrointestinal surgeries, heart bypass surgery, and joint injuries and arthritis (29). One of the most interesting applications of PRP is in dermatology especially in skin rejuvenation (30). PRP was acknowledged by the popular media after its extensive use in treating sports injuries in professional athletes (31).

Despite the multiple studies on the PRP, the results are still contradictory and the published data are difficult to sort and interpret; however, because PRP functions as a medium of cytokines and GFs, this blood product is highly practical for application in numerous conditions in reconstructive and plastic surgery. The complicated interaction of various factors and physiologic mechanisms involved in tissue regeneration makes the application of PRP more remarkable than the use of a single recombinant growth factor. In this review, we reported a valuable effect of PRP on wound healing, which caused improved proliferation of vascularization and endothelial cells. In addition, beneficial effects were also observed when PRP was frequently applied to the wound site. When PRP was applied, not only more wounds healed, but also healing time got noticeably shorter leading to a reduction of sickness-related health expenditures. In fact, PRP can be used in wound care process as an adjuvant agent to promote wound healing, along with conventional techniques. Clinical successes of PRP are combined results of the injury state, severity and duration, patient’s age and PRP characteristics. We believe that the type of PRP plays a key role that has strong effect over the clinical outcome. The different methods utilized for PRP production might be a logical explanation for the uncertain results observed in some clinical studies. The results observed in treating multiple tissue lesions in some clinical conditions are strongly impressive and make PRP therapy a potent treatment for future; however, there is a lack in defining and validating methods, products, clinical indications, and quality parameters of PRP products. This review suggests that PRP brings benefits for different indications within the field of reconstructive and cosmetic surgery. Many conclusive studies support the application of PRP to boost healing quality of diabetic lower limb ulcers and to improve bone grafting. Regarding wound healing and fat grafting, there are several medical publications supporting the PRP application. In theory, the combination of PRP with fat grafts may result in an enhanced survival rate. However, strong evidence from well-designed clinical trials to support PRP therapy for hair growth and skin regeneration is still insufficient. It is clear that PRP is currently in a transition period in regenerative medicine. Hence, at this time, PRP requires more investigation with better scientific studies to assess the efficacy of PRP with high quality RCTs using similar assessment tools. Nevertheless, the implementation of PRP as a clinical alternative would become difficult because its therapeutic use has not evolved toward the standardization of the techniques yet. Insufficient description of the adopted procedures reduces the chance of extensive medical recognition of PRP. We strongly believe that due to the absence of high-quality RTCs and lack of standard protocols for the effective platelet concentration and preparation method of PRP, the PRP efficacy could not be recognized scientifically. Therefore, it is required to create standard criteria for obtaining a PRP of high quality, as well as indicate the proper concentration of platelets for the different clinical conditions. It seems that clinical use of PRP produced “promising” but “inconsistent” results in early trials. PRP therapy could not be considered as a “quick fix” solution in dermatology because collagen regeneration takes four to six months and may need multiple injections therefore PRP therapy is expected to promote long-term healing of the injured tissues.

In this review, we have discussed several beneficial effects of PRP and attempted to discuss and clarify the major mechanisms. Although we consider PRP therapy highly potent, in our point of view, military medicine needs more evidence-based trials and concrete and practical solutions instead of hypothetical benefits to utilize PRP in military medical applications in near future.