CART-23-0095_PRP PAPER.pdfIn the United States, autologous platelet rich plasma (PRP) systems are regulated as Class II medical devices1. Commercial PRP systems, commonly referred as “kits”, receive FDA-clearance for commercial use by demonstrating “substantial equivalence” to an existing, FDA-cleared predicate system2, using hematology assay data of healthy-donor blood processed through test- and predicate kits. Commercial PRP kits in the U.S. are defined for the “Preparation of autologous platelet rich plasma from a small sample of peripheral blood for mixing with bone graft to improve handling characteristics”3. However, PRP has emerged as “orthobiologics” and a treatment modality in musculoskeletal conditions including knee osteoarthritis4.
Unlike the approval of drugs, biological agents (“biologics”), and Class III medical devices in the U.S. market, “pivotal clinical data” for PRP kits do not exist. Even if drugs or biologics are in early clinical development, preclinical and early-phase clinical study data are often published in peer-reviewed journals as part of a broader, industry-driven process of disseminating scientific information to key opinion leaders in applicable therapeutic domains. Manufacturers’ PRP kit assay-data submitted to the FDA are not typically (if at all) published for peer-review.
Querying FDA’s “Establishment Registration & Device Listing” using the FDA-defined “ORG” product code3 for PRP kits reveals additional reasons for the “wild west” nature of the PRP industry in the U.S. market: kits may be “manufactured”, “developed”, or “repackaged”/ “relabeled” from existing kits to distribute under new product names. The same PRP kits may be sold under different brand names and different marketing claims from different distributors. Lack of access to original assay data submitted by the manufacturer to the FDA and opaque points of origin of commercial PRP kits leaves healthcare providers and researchers alike to rely on manufacturers’ marketing claims or independent assays of commercial kits by academic researchers that have been published in peer-reviewed journals5.
Seven PRP classification systems currently exist toward a standard nomenclature for interpreting key components of the resultant biological product: MISHRA, PAW, PLRA, DEPA, MARSPILL, ISTH, and Expert Consensus; none has been widely adopted5 beyond academia, in community clinical practice. Calls to standardize “dosage” as a function of the absolute number of platelets and other hematological-derived components administered to an individual6 requires well-designed dose-response clinical studies with a defined therapeutic use (intended “indication”): this proves difficult when controlling for heterogeneity in both the resultant autologous biological products and donor-recipients.
Difficulty in community-based adoption of standard nomenclature may be illustrated by example with established commercial PRP systems. Arthrex ACP, which has a 10- or 15-mL blood-draw yielding 3 to 6.5 mL PRP after a (single) 5-minute centrifugation at 1500 RPM7-10, would be labeled “1-3-1-0”, “2-3-1-0”, “1-3-0-0”, or “2-4-0-0” under N1-4 definitions of the Expert Consensus classification system4. RegenLab’s thixotropic gel-based Regen device, which has a 6- or 8 mL blood-draw yielding 3.1- to 6 mL PRP after a (single) centrifugation8,11-13, would be labeled “2-3-0-0”, “2-4-1-1”, “1-2-0-0”, or “2-0-0-0” under the same classification system.
Commercial marketing for PRP systems relies on concentration factor (“X”), which deserves a valid criticism for “creating an illusion”6 but remains a default method for many clinicians when comparing commercial PRP systems. Assumptions of “more (platelets, growth factors) is better (outcomes)” may be seen in marketing brochures and websites from both manufacturers and clinicians. A missing link in demystifying marketing claims in platelet concentrations and the attendant “X”-factor is normalizing reported platelet yield with blood-draw volume.
Regardless of data origin (academia or industry), normalizing resultant platelet count by total blood volume required pierces the illusion of a magic PRP kit yielding “5X”, “9X”, even “12X” typical of double-spin systems. Table 1 shows a sampling of data for 6 FDA-cleared, commercially available PRP kits published by academic or commercially sponsored sources, normalized to platelet-count per milliliters of drawn blood. Figure 1 shows regardless of single- or double-spin systems, the number of platelets per milliliter of drawn blood ranges from 73 to 180 million (125.5 +/- 53.1), and heterogeneity from the same PRP kit should render moot any claims to “X” concentration. Furthermore, concentration claims from healthy donor blood do not guarantee relevant clinical outcomes using PRP prepared from patients’ blood and do not extrapolate to disease- or condition-specific platelet profiles.
The need for PRP component profiles with associated growth factor levels is underscored by a recent comparison between responders and impaired responders to PRP in 75 knee OA patients receiving a single injection of PRP14. Impaired responders showed significantly higher absolute platelet counts compared to responders, twice the concentration of VEGF, and a third more EGF – growth factors dominant in angiogenesis15. Transforming growth factor-beta1 (TGF-b1) is a potent tissue morphogenesis factor that can either stimulate or inhibit proliferation of fibroblasts16, endothelial cells17, or epithelial cells18 depending on cellular context and cross-signaling with other growth factors including VEGF and EGF19. Autocrine and paracrine activation of VEGF has been shown to affect TGF-b1-mediated cell inhibition and apoptosis20 as part of endothelial angiogenesis, while TGF-b1 has been shown to activate non-canonical signaling pathways21 as well as oppose effects of interleukin-1 (IL-1) in myofibroblast viability critical in wound healing22.
TGF-b growth factor superfamily, VEGF, and EGF are but a few of the myriad growth factors and cytokines available in any autologous human PRP preparation that would interact and counteract, and therefore should be investigated as part of PRP data quality control and collection of “real world evidence”. Given a prospective dose-response may not be feasible in a clinical research setting, instead of relying on platelet count claims, clinicians should prioritize an analysis of “response” versus “sub-optimal” or “non-response” when evaluating any commercial PRP devices.
Acknowledgment
I am grateful to Jérémy Magalon and Cassandra Lee for their advice and perspective.
References
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