**2. Reasons to use PRPs as repair process enhancers in orthopaedic surgery: the scientific rationale behind it**

The physicochemical features of PRP liquid formulation, once activated, make it appropriate to reach wide areas of soft and hard tissues such as the tendons, muscles, ligaments, menisci, cartilage and bone. Platelet growth factors and fibrin, together with plasmatic growth factors (HGF, IGF-1) present within PRP, stimulate in a pleiotropic manner cell proliferation and migration, angiogenesis, synthesis and deposition of ECM components and tissue remodelling in the musculoskeletal tissues [6–8]. The surgical site is opened in the normal manner, and in the following 2: 4 minutes, the liquid-activated formulation must be injected as a solution into soft tissues. Because of its local and gradual activation and homogeneous distribution and interaction with the ECM of different tissues, it is converted into a matrix-like malleable transient structure [2]. There is a direct interplay between components of a tissue's ECM (collagens, glycosaminoglycans and adhesive proteins) and the adhesive proteins and growth factors released gradually from the degrading fibrin clot which will influence cellular growth, differentiation and morphogenesis [9]. Therefore, the injection of PRP in its liquid formulation delivers growth factors locally and simultaneously mimics and amplifies the spontaneous healing response in injured areas and in special cell niches, which would otherwise be inaccessible. This in situ generated and moulded plastic nano-scaffold of fibrin interacts with ECM proteins and cells, binding to fibronectin [10], generating a transient three-dimensional scaffold, which will gradually release growth factors and maintain their concentration at the site of the scaffold formation (**Figure 2**)

The fibrin molecules, together with growth factors, influence and govern the repair mechanisms to reconstruct structures and restore function, both by harnessing local or resident cells and by stimulating cell migration and proliferation, thereby regulating angiogenesis, modulating inflammation, chemoattracting circulating progenitor cells and guiding tissue remodelling [11, 12]. PRP in situ generated nano-scaffold of fibrin offers a biologically active cell-matrix landscape where adhesive proteins, namely, fibrinogen, fibronectin, vitronectin and thrombospondin (TSP-1), facilitate cell adhesion, migration, proliferation and differentiation. Furthermore, by the release of stromal cell-derived factor 1 (SDF-1) which has been entrapped in the fibrin network, the nano-scaffold mediates the chemotaxis of CD34 progenitor cells and mesenchymal stem cells (MSCs) [7, 13, 14]. Once recruited, MSCs or pericytes [15] adhere to a fibrin network and may exert several functions such as tissue organisation, regulating the fate of other circulating and resident progenitor cells [16] and serving as

progenitor cells that replace the damaged tissue, prevent scar-forming cells from entering the

PRP Injections in Orthopaedic Surgery: Why, When and How to Use PRP Dynamic Liquid Scaffold…

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Although it is not within the scope of this chapter to address the wide range of therapeutic strategies in the management of injuries in the field of orthopaedics and sports medicine, only a holistic approach will fulfil the objective of surgeons, namely, to stop the progression of disease and to improve function in the shortest period of time. In this respect, and as a clinical application of cell mechanotransduction, a rehabilitation programme, which included the employment of PRP in a synergistic manner would play a crucial role in both promoting the repair or remodelling of injured tissue and avoiding the degradation and atrophy of structures such as the bone, periarticular muscles, tendons and ligaments with the goal of full

There is increasing evidence showing that tendon and ligament adaptation, injury and repair processes share several intracellular pathways, and although it is difficult to draw the line between the cellular and molecular responses that lead to either tissue adaptation or tissue damage, inflammatory processes appear to be at the interface of tendon adaptation and damage [18–20]. Repetitive mechanical loading, as is the case in early stages of tendinopathy, and tendon overuse induce the activation of NF-κB in stromal fibroblasts and thereby the synthesis of matrix metalloproteinases (MMPs), two isoforms of cyclooxygenase (COX)-1 and COX-2 and PGE2 by inflammatory tenocytes and stromal fibroblasts, mast cells and other immunocompetent cells [18, 21–23]. PGE2 is a major systemic and local inflammatory mediator that decreases the production of collagen and causes aberrant differentiation of TDSCs into adipogenic and osteogenic lineages [23], which might partially account for the presence of fibrocartilage, calcifications and adipose tissue in injured and chronic degenerative tendons

An excellent series of in vitro and in vivo studies demonstrated that blood-derived BDDT induced tenocyte proliferation, stimulated the synthesis of type I collagen and neovascularization [9] and promoted differentiation of TDSCs into active tenocytes, but, significantly, the addition of leukocytes into the releseate increased the synthesis of PGE2 and the gene expression of MMP-1, MMP-13 and IL-1β and decreased the expression of alfa-SMA as a marker of active tenocytes. Among the myriad mediators conveyed by blood-derived BDDT, HGF and lipoxin A4 (LX4) have been shown to exert an anti-inflammatory and pro-resolution of

In the case of tendons such as the Achilles, patellar or quadricipital, the volume of blood extracted is approximately 60–70 mL (six to nine tubes). Blood is taken a few minutes prior to surgery, before any fluid or drugs are administered to the patient, in the operating theatre

**3. The use of PRP infiltrations in orthopaedics: surgical applications**

damaged area and exerting immunomodulation activities [7, 14].

recovery of function [17].

[18, 23, 24].

**3.1. PRP infiltrations in tendon surgery**

inflammation effect on injured tendons [21–23].

*3.1.1. Surgical treatment of acute ruptures of tendons*

**Figure 2.** PRP niche therapy approach: injectable dynamic scaffold for molecular intervention.

progenitor cells that replace the damaged tissue, prevent scar-forming cells from entering the damaged area and exerting immunomodulation activities [7, 14].
