The releasing profiles and dynamics of growth factors during oral wound healing : biological implications of L-PRF, clinical outcomes and perspectives

Abstract

Wound healing processes are regulated by a cluster of immune-inflammatory mediators and growth factors (GFs). Limited knowledge on local releasing profiles of wound healing mediators may preclude the optimal use of biologics clinically. Leucocyte and platelet-rich fibrin (L-PRF) has been increasingly applied as a source of GFs to promote alveolar ridge preservation. However, little is understood regarding their local releasing profiles and dynamics, and the clinical equipoise for the efficacy remains unclear. Currently, there is a lack of understanding on the releasing profiles of GFs and cytokines from L-PRF. This study attempted to i) assess the releasing profiles of GFs and cytokines during early wound healing of coronally advanced flap (CAF, primary intention healing) and post-extraction alveolar sockets (secondary intention healing); ii) identify the effects of L-PRF application on the releasing profiles of GFs and cytokines as well as the healing patterns of soft and hard tissues in post-extraction sockets; and iii) investigate the in vitro and ex vivo release kinetics of GFs and cytokines of L-PRF.

The intraindividual randomized controlled trial (RCT) assessed the biological and clinical effects of L-PRF on post-extraction socket healing in 18 systemically healthy, non-smoking subjects. The natural wound healing either by primary or secondary intention was evaluated, via comparing the levels of GFs, cytokines and matrix-metalloproteinases (MMPs) in wound fluid (WF) of subjects after tooth extraction or CAF surgery. The GFs and mediators in WF and those from culture media released by L-PRF and L-PRF exudate were analyzed using a multiplex assay. The early healing profile of soft tissue was assessed through evaluating the changes in volumes on digital scans. Hard tissue changes were evaluated on CBCT images following 5-month healing period.

Firstly, the RCT showed that L-PRF accounted for higher concentrations of GFs as compared to spontaneous healing, while there was no detectable difference in patterns or peak time. Moreover, there was no significant difference existed between the testing and control sites in early healing parameters, alveolar ridge/bone resorption profiles, and the ability to make treatment plan digitally for the guided placement of dental implants (Chapters III & IV). Secondly, the releasing rates of GFs from L-PRF followed first-order kinetics in vitro and ex vivo. Higher rates of release were found ex vivo, indicating that significant amounts of GFs could be produced in local healing niches (Chapter V). Thirdly, specific patterns were identified between primary and secondary intention healing wounds. Notably, greater amounts of multiple GFs (e.g., PDGF-AB/BB, EGF, FGF-2, VEGF, MMP-1 & 2) while smaller amount of IL-1β were released in primary intention healing wounds, reflecting a milder inflammatory response and faster healing rate in CAF with reference to tooth extraction (Chapter VI).

In conclusions, the healing processes of oral wounds are mediated and characterized by different profiles and specific patterns of GFs and cytokines. L-PRF can increase the local concentrations of GFs in WF without necessarily shifting the healing pattern. Importantly, clinical delivery of L-PRF may not translate into the anticipated effectiveness in soft/hard tissue outcomes.