Do the Fibrin Architecture and Leukocyte Content Influence the Growth Factor Release of Platelet Concentrates？An Evidence-based Answer Comparing a Pure Platelet-Rich Plasma（P-PRP）Gel and a Leukocyte- and Platelet-Rich Fibrin（L-PRF）（3）
3. A SIMPLE DEMONSTRATION WITH LARGE PERSPECTIVES.
The release patterns of the 6 tested molecules demonstrate the very significant differences between 2 families of products, P-PRP and L-PRF, and this is therefore an important step for the definitive validation of the current classification of platelet concentrate technologies. Even if both products are platelet concentrates, their intrinsic structure, biology and molecular kinetics are completely opposite. The growth factor release was much more intense in the L-PRF than in the PRGF, but it is not possible to claim that one technique would be better than the other : both families of products can have a potential positive impact during healing, and the 2 technologies have simply different indications since P-PRP are injectable liquid platelet suspensions, while L-PRF only exists as a solid dense fibrin biomaterial.
However, our results suggest that when a fibrin gel biomaterial is needed, L-PRF clots or membranes should be preferred to the PRGF gel : indeed, the L-PRF releases much more Growth factors and key Adhesion proteins during a longer time period and presents a much stronger Fibrin architecture than the PRGF gel. Moreover, the L-PRF technique is very simple and inexpensive, while the PRGF production and clotting technique requires many handling steps and is very time-consuming in order to produce a usable fibrin membrane (clotting during 1 hour at 37deg. Celsius). This conclusion contradicts the published opinion [71] of the PRGF team of the BTI company who claimed that the PRGF technology could be used in many different forms: in the gel form, PRGF is probably not the most adequate platelet concentrate to use, particularly in some applications that require a strong fibrin matrix and simple production procedures of many membranes, such as in oral and maxillofacial surgery.
Logically, this conclusion is true for all P-PRP gels, and not only the PRGF, even if there may be substantial differences in the platelet content between the various P-PRP techniques.
This demonstration of the impact of fibrin architecture and leukocyte content on the biological signature of these products is a first step that opens many perspectives. First, since the various families of product seem to use different intrinsic biological mechanisms, it could be very interesting to investigate properly the effects of these different mechanisms on the proliferation and differentiation of various cell lineages in vitro: the current literature on this topic is often confusing and contradictory because of the lack of proper characterization of the products and associated methodological bias [15]. The following step would be to compare the clinical impact of these 2 families of products. These kinds of comparative studies could increase our knowledge about these products, but remain difficult tasks. Second, our demonstration militates for the refoundation of the current confusing literature about platelet concentrates, by following the simple principles of the classification system [3]. Products should be completely characterized before testing. Fibrin architecture and leukocyte content can not more be neglected in this field.
The perspectives of research are however not only related to platelet concentrates for surgical use. Indeed, blood is a low-cohesion circulating tissue, and it truly gets a full solid tissue cohesion only when it assembles itself in a dense fibrin network during the coagulation process: investigating the mechanisms of L-PRF and P-PRP is therefore not only a way to understand the platelet concentrates technologies, but also a way to understand the blood biology.
Several in vitro articles already demonstrated that the dense Fibrin architecture of a L-PRF membrane allowed a Long slow release of many molecules [14, 68, 72, 73], while the membrane itself was still almost intact after 7 days in the culture medium, even in contact with various cell types in culture [15, 69, 70]: the L-PRF membrane behaves like a true fibrin tissue. L-PRF is often considered as an optimized blood clot [49], and it is indeed a very good illustration of the solid form of the circulating tissue. This slow release was not expected for the products from the PRP families: indeed, these products are brutally activated using bovine thrombin, calcium chloride or other clotting agents, and it was not expected that the platelet growth factors could be trapped intrinsically in this artificial light fibrin network [14, 24, 26, 72]. Our data therefore confirmed the current knowledge about the fibrin clotting [18, 21], and that platelet concentrates may be very interesting models for a better understanding of coagulation and healing mechanisms.
As a conclusion, the key issue in Platelet concentrate technologies is Not the Quantity of platelets, but How Platelet, Leukocytes, Fibrin and Growth factors are interlinked in the final product. A strict quantitative approach does not allow to define the biological signature and mechanisms of a family of platelet concentrates. The approach must be qualitative. PRPs and PRFs are not pharmaceutical preparations with a simple and clear composition, they are living tissues which properties are dependent on the combination of cells, factors and matrix within the final preparation. This demonstration highlights the different mechanisms between 2 families of platelet concentrates, and the significance of the current classification system in order to clarify the literature on the topic and to define adequate research strategies.
DISCLOSURE OF INTEREST
The authors declare no competing financial interests.
ACKNOWLEDGEMENTS
This work was supported by the LoB5 Foundation for Research, Paris, France.
AUTHORS
David M. Dohan Ehrenfest,*, Tomasz Bielecki, Allan Mishra, Piero Borzini, Francesco Inchingolo, Gilberto Sammartino, Lars Rasmusson and Peter A. Everts
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