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Clinical Applications of PEF in Musculoskeletal Conditions: History
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Contributor: Ragunanthan Narayanaswamy , Bishnu Prasad Patro , Naveen Jeyaraman , Prakash Gangadaran , Ramya Lakshmi Rajendran , Arulkumar Nallakumarasamy , Madhan Jeyaraman , Prasanna Ramani , Byeong-Cheol Ahn

The newer generation products, including leukocyte-platelet-rich fibrin (L-PRF) and advanced platelet-rich fibrin (A-PRF), have shown superior biological properties in musculoskeletal regeneration than the first-generation concentrates, such as platelet-rich plasma (PRP) and plasma rich in growth factors. These newer platelet concentrates have a complete matrix of physiological fibrin that acts as a scaffold with a three-dimensional (3D) architecture. Further, it facilitates intercellular signaling and migration, thereby promoting angiogenic, chondrogenic, and osteogenic activities. A-PRF with higher leukocyte inclusion possesses antimicrobial activity than the first generations. both L-PRF and A-PRF are used in the management of musculoskeletal conditions, such as chondral injuries, tendinopathies, tissue regeneration, and other sports-related injuries. 

  • platelet-rich fibrin
  • cytokines
  • intercellular signaling

1. Cartilage Regeneration

With an inferior intrinsic potential of cartilage regeneration, the augmentation of regenerative medicine products, such as PRP, PRF, MSCs, and MSC-derived EVs, plays a significant role in the management of cartilage disorders [1]. Chien et al. reported the amalgamation of PRF within a biodegradable fibrin scaffold for enhancing the proliferation and differentiation of chondrocytes, enhanced cell growth rate significantly, and upregulated mRNA expression of type-II collagen and GAG synthesis [2]. El Raouf et al. compared iPRF and PRP from rabbit blood and reported that iPRF was found to be superior in regulating chondrogenesis genes and counteracting IL-1β effects in osteoarthritis (OA)-like environment [3]. In full-thickness critical-sized osteochondral defects of rabbits, iPRF filled the defects with osteochondral regeneration. Histological examination revealed hyaline cartilage within 4 weeks postoperatively, which is because iPRF promotes chondrocyte proliferation and mRNA levels of SOX-9, collagen type-2, and aggrecan when compared with PRP or control groups. iPRF, with the low-speed centrifugation concept, poses an improved cartilage regeneration compared with PRP [3]. Wong et al. demonstrated a single-stage culture-free method for repairing articular chondral defects by combining PRF and autologous cartilage transplantation. PRF facilitates the proliferation, migration, and differentiation of chondrocytes [4]. Souza et al. demonstrated the proliferation and differentiation of adipose tissue-derived stem cells when combined with PRF membrane [5].
In a rat osteochondral defect model, Metineren et al. demonstrated the regenerative potential of cartilage with PRF [6]. Histologically, the osteochondral regenerated tissue demonstrated the presence of hyaline cartilage at the end of 1-year follow-up [6]. Wang et al. demonstrated superior results with the combination of PRP and PRF gels along with microfracture through an arthroscope on knee cartilage defects in 28 cases [7]. Kazemi et al. reported both macroscopic and histological significant differences between PRF-treated and PRF-nontreated experimentally induced knee cartilage defects in animal models [8]. Wu et al. demonstrated the histological evidence of hyaline cartilage formation with intra-articular injection of PRF combined with bone-marrow-derived MSCs for surgically induced chondral defects in rabbit femoral condyle [9]. With the latest cutting-edge technologies, researchers have regenerated cartilage with PRF techniques.

2. Tendon Repair, Augmentation, and Regeneration

Autologous PRF improves the cellular and biomechanical response in tendon injury and enhances the quality of the repair. Dietrich et al. proved the superior healing effects of Achilles tendon in rat model tendinopathy with autologous PRF than PRP. The PRF-treated group showed a delayed release of growth factors over 14 days when compared with the PRP group. H and E staining analysis showed that the PRF-treated group demonstrated enhanced healing rates at both assessment timelines than the PRP and control groups [10]. Anitua et al. reported that the presence of platelets within fibrin matrices enhances the proliferation of tendon cells significantly in sheep Achilles tendon and exhibits higher synthesis of COL1 and growth factors, such as VEGF and HGF [11]. Visser et al. reported a higher concentration of TGD-β1 elution and enhanced tendon cell proliferation through PRF constructs than whole blood clots in a canine tendon cell in vitro [12].
Beitzel et al. studied the cellular response of MSCs to scaffolds (fresh–frozen rotator cuff tendon allograft, human highly cross-linked collagen membrane, and porcine noncross-linked collagen membrane) in comparison with PRF- and fibrin-matrix-based PRP. They observed a significant number of MSCs adhered to both the noncross-linked porcine collagen scaffold and PRF than the fresh–frozen rotator cuff tendon allograft [13]. Zumstein et al. reported the long-term elution of growth factors from L-PRF in rotator cuff repair. They emphasized (a) the highest concentration of platelets and leucocytes were observed with 400× g, (b) sustained release of growth factors, such as TGF-β1, VEGF, and MPO, in the first 7 days of L-PRF clot cultured in the medium, and (c) enhanced growth factor release (CXCL4, IGF-1, PDGF-AB, and VEGF) in the gelatinous group when compared with the dry group, and concluded that the gelatinous type of L-PRF delivers growth factors for up to 28 days and helps in augmenting rotator cuff repair [14].
Castricini et al. reported that PRF augmentation might be beneficial in small, medium, large, and massive rotator cuff tears, given the heterogenUR eity of PRF preparation protocols available in the market [15]. PRF does not improve the retear rates and postoperative functional outcome scores in cases of full-thickness rotator cuff tears operated arthroscopically. No difference in tendon thickness or size of the tendon footprint thickness was observed with rotator cuff tears [16][17][18][19]. Alviti et al. reported that Achilles tendon repair, along with PRF augmentation, displays a significant functional improvement in motion efficacy than Achilles tendon repair alone [20]. The augmentation of PRF in gluteus medius tendon repair help in improving the subjective outcomes of hip-specific physical functioning than in terms of pain or clinical evidence of tendon retear rates [21]. With the available in vitro, preclinical, and clinical evidence, the role of PRF in tendon augmentation and repair has to be explored in a controlled randomized trial for clinical translation as a therapeutic modality.

3. Sports and Over-Use Related Injuries

With the increased popularity in the usage of platelet products in sports injuries, it is hypothesized that platelet products accelerate tendon ligamentization, leading to early return to daily activities. Theoretically, PRF possesses graft maturation and hemostatic effects along with analgesic effects in the postoperative period. Beyzadeoglu et al. reported superior graft integration and maturation in the proximal third of PRF-treated autologous hamstring ACL reconstruction when compared with non-PRF-treated grafts in complete ACL tear cases [22]. PRF-treated autologous hamstring grafts display lower MRI signal intensity and less fluid in the graft tunnel interface when compared with controls for the entire graft length [22]. Matsunaga et al. observed 78% of the ultimate failure load of PRF repair tissue at 20 weeks in a bilateral central half-resected patellar tendon in a rabbit model and hence proved that PRF tissue enhances ligament healing [23].

4. Meniscal Injuries

Meniscal injuries pose a greater challenge in management, as they pose a temporal association between partial or total meniscectomy and the development of OA [24][25]. The need for biological modality for meniscal repair warrants (a) a scaffold for adherence with meniscal tissue, (b) intercellular signals for cellular proliferation and ECM synthesis, and (c) an appropriate number of cells to promote tissue healing. Scanning electron microscopic analysis of PRF demonstrates a honeycomb appearance with plugging-in of platelets along with a fibrin skeleton [26]. PRF scaffolds provide anabolic cytokines to enrich the cells. PRF promotes neoangiogenesis as it possesses low thrombin levels for the migration of fibroblasts and endothelial cells, which could help in meniscal healing [27]. Narayanaswamy et al. reported the usage of iPRF in meniscal repair and augmentation [28]. iPRF application holds better and produces significant functional outcomes in partial meniscectomy. Such iPRF elutes growth factors over 4 weeks, which matches with the healing phase of meniscal tears [28]. Wong et al. demonstrated that rabbit’s PRF augments meniscal repair by facilitating the proliferation and migration of meniscocytes and enhancing ECM synthesis. PRF enhanced the synthesis and deposition of ECM by cultured meniscocytes, which were evaluated both morphologically and histologically [29]. Kurnaz et al. concluded that PRP and PRF matrix augmentation on vertical meniscal tears in a rabbit model resulted in early recovery and enhanced repair of meniscus tissue [30]. The role of PRF in terms of healing and regeneration of meniscus tissue needs to be explored.

This entry is adapted from the peer-reviewed paper 10.3390/bioengineering10010058

References

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