Shedding light on biosafety of platelet rich plasma

Dear Editor

The response to our article [2016] expresses concerns about the side effects of platelet rich plasma(PRP) on nerve repair and more specifically, ‘in the case when the nerve injury is due to excision of an invading tumor’. Our paper focused on peripheral nerve repair after nerve damage by traumatic, toxic, and nontraumatic mechanisms such as compression, adhesion, and fibrosis. The work we have done in nerve repair is just the most recent edge of 20 years of PRP application in different medical fields, from orthopedic surgery [2] and sports medicine [3] to dermatology, odontology [4], and ophthalmology [5]. Having honed the optimum preparation of this entirely autologous product, and in light of consistent successful functional recoveries in bone, ligament, tendon, muscle, and injured peripheral nerve, we can claim with confidence that there are no relevant side effects in using PRPs [3,6].

The author/s state that the effect of PRP on human dermal fibroblast proliferation and response is unknown; however, we would like to acquaint them with some helpful references. Platelet-rich plasma exerts several biological effects on human dermal fibroblasts. For example, it has been reported that plasma rich in growth factors (PRGF), one type of autologous platelet-rich plasma, significantly increases fibroblast proliferation, migration, and cell adhesion on type I collagen matrix. In addition, PRGF stimulates the autocrine expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and hyaluronic acid (see published results [7–9]). The myofibroblast phenotype, which is characterized by expressing alpha-smooth muscle actin, was inhibited and reverted by treating cells with PRGF [7]. Furthermore, when PRGF was applied to ultraviolet-irradiated dermal fibroblasts, cell survival was promoted while apoptotic and reactive oxygen species (ROS) levels were noticeably reduced [10].

In addition, the authors express concern about the high growth factor concentrations in PRPs. A clarification about the kinetic release of proteins from PRPs and their in vivo action will help here. The centerpiece of biological activity in PRP is the fibrin matrix, which is formed after the activation of PRP. This element emerges as part of the particular preparation of the blood plasma from the patient, after coagulation cascade is activated. Only by understanding the unbreakable link between growth factros (GFs) and fibrin matrix will we grasp the in situ PRP biologic function of PRP as an autologous multi-growth-factor biodegradable scaffold in which diffusion and fibrinolysis yield a gradual and sustained release of many biologically active agents at once, thereby circumventing most GF-therapy drawbacks such as short half-life, single application, and overdose, as is the case in several of the articles mentioned by authors [11]. As is the case in transforming growth factor B1(TGF-β1), VEGF, and HGF, most of the growth factors and cytokines in PRPs act on a variety of tissues just as they do in any biological system. These proteins exert their regulatory and pleiotropic-biological functions as members of a molecular network linking different modules or systems [12–14].

We believe it is not appropriate to seek single, uni-directional causal agents in biological processes; single specific biological factors do not exist for each function. Platelet-derived growth factors are relatively small polypeptides that act as extracellular signals and bind to cell transmembrane receptors. This binding induces changes in the cytoplasmatic configuration of receptors, thereby initiating a cascade of intracellular events (known as signal transduction) by activating several very well-conserved intracellular signaling pathways mitogen-activated protein kinase(MAPK), nuclear factor kappa B (NFkB), and others) which will end up regulating the expression of several nuclear genes [15].

Therefore, by applying PRP, whose pivotal targets are tissue resident cells, we do not modify any DNA sequence, thus growth factors do not induce any type of mutation. As an example, Reinisch A et al. cultured multipotent mesenchymal stromal cells with the pool of growth factors derived from platelets and observed that proliferation kinetic was not altered compared with optimized culture conditions. Moreover, no chromosomal abnormalities were detected even after many expansion procedures [16].

In a more recent study, Deborde et al. demonstrated that Schwann cells promote cancer invasion only in the presence and direct contact with cancer cells, while paracrine signaling and remodeling of the matrix, as in the mechanisms by which PRP operate, are not sufficient to induce invasion even in the presence of malignant cells [17]. In addition, as clearly expressed by Boilly et al. [18], only the already existing cancer cells and tumors harness the three basic exploratory systems in morphogenesis and regeneration, namely, angiogenesis, neurogenesis, and the immune adaptive system [19] to progress and colonize other tissues.

In this sense, it is true that PRPs, acting locally in an autocrine and paracrine way, stimulate morphogenesis signaling pathways or partially recapitulate embryonic micro-environments as strategy for the regeneration of tissues, and where the resolution of angiogenesis and neurogenesis are mainly regulated by platelet-derived and plasmatic growth factors. However, the fact that cancer and regeneration share similarities does not have to open the door to a statement of affirming the consequence, by which a therapy that promotes regeneration through angiogenesis and neurogenesis, as is the case of PRP, will also promote cancer.

Finally, as the authors of the letter state, while there is no data yet for the use of PRP in patients with nerve injury due to resected malignancy and while this should be carefully studies, our experience and the wealth of data on safe use of PRP over 15 years lead us to anticipate that there is likely little risk for exacerbating or inducing a malignancy.

Declaration of interest

BTI is a company that studies and sells PRGF technology, one type of PRP. E Anitua is the Scientific director of BTI while S Padilla and G Orive scientists at BTI. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are supported by the Laboratory of Regenerative Medicine, Biotechnology Institute BTI, Vitoria, Spain.