Platelet-Rich Plasma: New Performance Understandings and Therapeutic Considerations in 2020

Abstract

Emerging autologous cellular therapies that utilize platelet-rich plasma (PRP) applications have the potential to play adjunctive roles in a variety of regenerative medicine treatment plans. There is a global unmet need for tissue repair strategies to treat musculoskeletal (MSK) and spinal disorders, osteoarthritis (OA), and patients with chronic complex and recalcitrant wounds. PRP therapy is based on the fact that platelet growth factors (PGFs) support the three phases of wound healing and repair cascade (inflammation, proliferation, remodeling). Many different PRP formulations have been evaluated, originating from human, in vitro, and animal studies. However, recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, progress has been made in understanding PRP technology and the concepts for bioformulation, and new research directives and new indications have been suggested. In this review, we will discuss recent developments regarding PRP preparation and composition regarding platelet dosing, leukocyte activities concerning innate and adaptive immunomodulation, serotonin (5-HT) effects, and pain killing. Furthermore, we discuss PRP mechanisms related to inflammation and angiogenesis in tissue repair and regenerative processes. Lastly, we will review the effect of certain drugs on PRP activity, and the combination of PRP and rehabilitation protocols.

Keywords: analgesic effects; angiogenesis; immunomodulation; inflammation; lymphocytes; monocytes; neutrophils; platelet dosing; platelet-rich plasma; regenerative medicine; rehabilitation; serotonin.

Figure 1

Cellular density separation of whole blood following a two-spin centrifugation procedure using the PurePRP-SP^® device (EmCyte Corporation, Fort Myers, FL, USA). After the first centrifugation procedure, the whole blood components are separated in two basic layers, the platelet (poor) plasma suspension and the RBC layer. In A, the second centrifugation step has been completed. The factual needed PRP volume can be extracted for patient application. The magnification in B shows at the bottom of the device the organized multicomponent buffy coat layer (indicated by the blue lines), containing high concentrations of platelets, monocytes, lymphocytes, based on density gradients. In this example, a minimal percentage of neutrophils (<0.3%) and RBCs (<0.1%) will be extracted, following a neutrophil poor C-PRP preparation protocol.

Figure 2

Electron microscopic picture of a cluster of platelets from a PRP vial and a extrapolation of a single platelet (original magnification × 10,000) (from volunteer PE), representing the most familiar cellular constituents of α-granules (α), dense granules (DG), and lysosomes (L), including some platelet surface adhesion molecules. Adapted and modified from Everts et al. [61].

Figure 3

Activated platelets, releasing PGF, and adhesion molecules mediate a variety of cellular interactions: chemotaxis, cell adhesion, migration, cell differentiation, and stipulate to immunomodulatory activities [67,68]. These platelet cell-cell interactions contribute to angiogenesis [46,69,70] and inflammatory [71,72] activities, ultimately to stimulate tissue repair processes. Abbreviations: BMA: bone marrow aspirate, EPC: endothelial progenitor cell, EC: endothelial cells, 5-HT: serotonin, RANTES: Regulated upon Activation Normal T Cell Expressed and Presumably Secreted, JAM: junctional adhesion molecules type, CD40L: cluster of differentiation 40 ligand, SDF-1α: stromal cell-derived factor 1 alpha, CXCL: chemokine (C-X-C motif) ligand, PF4: platelet factor 4. Adapted and modified from Everts et al. [9].

Figure 4

Platelet and leukocyte interactions in innate immunity cell interactions. Platelets interact with neutrophils, monocytes, and ultimately as well with MΦs, modulating and increasing their effector functions. These platelet-leukocyte interactions result in inflammatory contributions through different mechanisms, including NETosis [67]. Abbreviations: MPO: myeloperoxidase, ROS: reactive oxygen species, TF: tissue factor, NET: neutrophil extracellular traps, NF-κB: nuclear factor kappa B, MΦ: macrophage.

Figure 5

Illustration of the multifaceted 5-HT responses following inflammatory PRP-platelet activation. After platelet activation, platelets release their granules, including 5-HT from dense granules, inciting a wide range of differential effects on various immune, endothelial, and smooth muscle cells. Abbreviations: SMC: smooth muscle cell, EC: endothelial cell, Treg: regular T lymphocyte, MΦ: macrophage, DC: dendritic cell, IL: interleukin, IFN-γ: interferon gamma. Modified and adapted from Everts et al. and Herr et al. [9,69].

Figure 6

Platelet-derived growth factors and dense granular constituents are expressively involved in BMAC trophic processes, supporting MSC induced tissue repair and regeneration. Abbreviations: MSC: mesenchymal stem cell, HSC: hematopoietic stem cell.