Innate immunity and wound repair: The platelet-rich fibrin advantage

Abstract

In this editorial, we comment on the article by Sá-Oliveira et al. We focus specifically on the role of platelet-rich fibrin (PRF) in modulating innate immunity to enhance wound repair. The process of wound healing is complex and involves a coordinated series of biological events, including inflammation, cell proliferation, and tissue remodeling. The innate immune system is important in the early stages of wound repair, with inflammation being a crucial initial phase in tissue regeneration. However, the inflammatory response should be regulated, as excessive or dysregulated inflammation can impair healing. Platelet concentrates, specifically PRF, have originated as promising tools to optimize the tissue repair process. PRF is a second-generation platelet concentrate, and the release of growth factors (GFs) plays a determining role in several aspects of wound healing, including promoting cell proliferation, stimulating angiogenesis, and modulating inflammation. PRF forms a fibrin matrix that entraps platelets and GFs. This structure allows for their sustained release over time, which is believed to provide a more favorable microenvironment for tissue repair. Recent research by Sá-Oliveira et al has provided valuable evidence supporting the efficacy of PRF in promoting wound healing. Their study, conducted on an animal model, demonstrated that PRF-based dressings were more effective in accelerating wound closure in the early stages of the healing process, enhancing tissue repair, and modulating the inflammatory response. We explore how PRF's unique properties contribute to a more controlled and effective healing process. By examining these findings, we aim to highlight PRF's potential as a promising therapeutic strategy for improved wound management.

Key Words: Platelet-rich fibrin; Wound healing; Innate immunity; Inflammation; Tissue regeneration

Core Tip: Platelet-rich fibrin (PRF) is a promising autologous blood product for enhanced wound healing. PRF modulates the inflammatory response and promotes tissue regeneration. Recent research highlights PRF's ability to accelerate wound closure, enhance tissue repair, and modulate the inflammatory response in an animal model.

INTRODUCTION

Effective wound healing is fundamental to maintaining the integrity of the human body and is essential for recovery following injury or surgery[1]. Skin wounds, ranging from minor cuts to chronic ulcers, present a substantial burden, affecting individuals' quality of life and placing a considerable strain on healthcare systems worldwide[2]. The process of wound healing is complex and involves a coordinated series of biological events[3], including inflammation, cell proliferation, and tissue remodeling. Successful healing requires a delicate balance of these processes, while disruptions can result in delayed healing or chronic wounds[3,4].

The innate immune system is important in the early stages of wound repair[5]. Inflammation, a key component of the immune response, is essential for initiating the healing cascade. It involves the recruitment of immune cells to the wound site, the release of signaling molecules, and the clearance of debris and pathogens[6]. However, the inflammatory response must be tightly regulated[7]. Excessive or prolonged inflammation can delay the subsequent phases of tissue repair, leading to complications such as fibrosis and impaired tissue regeneration[8]. Therefore, modulating the innate immune response is a critical target for therapeutic interventions aimed at enhancing wound healing.

Platelet concentrates have been introduced as promising tools to optimize the tissue repair process[9]. Platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) are autologous blood products that contain a high concentration of platelets, growth factors (GFs), and other bioactive molecules[10]. These factors are crucial in various aspects of wound healing, including promoting cell proliferation, stimulating angiogenesis, and modulating inflammation[11]. Unlike PRP, PRF forms a fibrin matrix that entraps platelets and GFs, allowing for their sustained release over time. This sustained release is believed to provide a more favorable microenvironment for tissue repair[12]. Moreover, PRF has demonstrated effectiveness in reducing inflammation and enhancing tissue regeneration in various preclinical and clinical studies[13].

In this editorial, we will discuss the advantages of PRF in modulating innate immunity to enhance wound repair. We will explore how PRF's unique properties contribute to a more controlled and effective healing process, drawing upon evidence from recent research by Sá-Oliveira et al[14].

THE IMPORTANCE OF INNATE IMMUNITY IN WOUND HEALING

Inflammation is an essential and finely developed phase that represents the crucial initiation of tissue regeneration following injury[15]. Upon breach of the skin's barrier, a complex cascade of biological events is triggered, aimed at restoring tissue integrity[16]. This initial inflammatory response is a critical component of the innate immune system's involvement in wound repair. It serves several vital functions, including the elimination of pathogens, the clearance of damaged cells and debris, and the recruitment of essential cellular mediators to the site of injury[17]. The rapid activation of the innate immune system sets the stage for the subsequent phases of healing, including proliferation and remodeling, which ultimately lead to the restoration of functional tissue[18]. However, the inflammatory process, while essential, must be balanced and precisely regulated. Uncontrolled, excessive, or prolonged inflammation can disrupt the sequence of events necessary for effective wound healing. When the inflammatory response persists beyond its necessary duration or becomes overly intense, it can lead to a range of detrimental consequences[19]. These include damage to surrounding healthy tissues, the formation of chronic wounds, and the development of excessive scar tissue or fibrosis[20]. In pathological conditions, such as chronic non-healing ulcers, the inflammatory phase is often dysregulated, contributing to the persistent nature of these wounds[21].

The wound microenvironment is a dynamic and complex milieu where a diverse array of immune cells and signaling molecules interact to modulate the repair process[22]. Innate immune cells, including neutrophils and macrophages, are among the first responders to injury. Neutrophils migrate rapidly to the wound site to eliminate bacteria and debris through phagocytosis and the release of antimicrobial substances[23]. Macrophages play multidimensional roles, contributing to the clearance of apoptotic cells, secreting GFs and cytokines, and modulating the adaptive immune response[24]. These immune cells communicate with each other and with other cells involved in tissue repair, such as fibroblasts and keratinocytes, through the release of a variety of signaling molecules[25].

Cytokines and chemokines are crucial signaling molecules that regulate the inflammatory response and coordinate the movement of cells within the wound microenvironment[26]. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1, initiate and amplify the inflammatory response, attracting immune cells to the injury site. Chemokines, such as C-C motif chemokine ligand 2, guide the migration of leukocytes to the wound. GFs, including platelet-derived GF and transforming GF-beta, stimulate cellular proliferation, differentiation, and extracellular matrix deposition[27]. The interrelation between these signaling molecules creates a complex network that controls the progression of wound healing[28].

PRF: A NOVEL APPROACH TO MODULATING INNATE IMMUNITY

PRF represents a significant advancement in the field of regenerative medicine, offering a novel approach to modulating innate immunity and enhancing wound healing. One of the key distinctions of PRF lies in its specific structure and composition[29]. PRF is a second-generation platelet concentrate characterized by a dense fibrin matrix. This fibrin network is not merely a passive scaffold; it actively participates in the healing process. The architecture of PRF allows it to capture and concentrate GFs and other signaling molecules released by activated platelets[30]. By retaining these crucial factors at the site of injury, PRF facilitates the establishment of a microenvironment that is highly conducive to tissue regeneration. This localized concentration of GFs supports cellular proliferation, differentiation, and migration, all of which are essential for effective wound healing[31].

Different variations of PRF have been developed, each with slightly altered processing techniques and resulting in distinct characteristics. Advanced PRF is produced with lower centrifugation speeds, leading to a higher concentration of GFs and white blood cells within the fibrin matrix[32]. Injectable PRF is a liquid form obtained by reducing the centrifugation time, allowing it to be easily injected into various tissues. This form is particularly useful for applications requiring deeper penetration or integration with soft tissues[33]. Concentrated GF is another variant produced with higher centrifugation speeds, resulting in a denser fibrin matrix and a higher concentration of GFs[34]. Finally, titanium-prepared PRF utilizes titanium tubes during centrifugation, which can further enhance the release of GFs and improve the mechanical properties of the fibrin matrix[35].

The controlled and sustained release of GFs from the PRF matrix contributes to the modulation of immune response. These GFs not only stimulate tissue regeneration but also exert anti-inflammatory effects, helping to dampen excessive inflammation and promote a more balanced healing environment[36]. The fibrin matrix of PRF acts as a reservoir, gradually releasing GFs over an extended period. This prolonged release mimics the natural healing process more closely and provides a more sustained stimulation of tissue repair mechanisms[37]. In contrast, other platelet concentrates may release GFs more rapidly, leading to a shorter duration of action. The sustained release from PRF ensures a more effective clonal expansion and cellular differentiation, ultimately leading to improved tissue regeneration[38]. When comparing PRF with PRP, several key differences highlight the unique advantages of PRF. PRP, while also beneficial for wound healing, lacks the dense fibrin matrix characteristic of PRF. This structural difference results in a more rapid release of GFs from PRP compared to PRF[13]. Moreover, the preparation of PRF typically does not involve the use of anticoagulants, which may be used in PRP preparation. This difference in preparation methods may also contribute to the distinct biological properties of PRF and PRP[29]. Table 1 outlines the mechanisms and factors by which PRF facilitates wound healing. The Table 1 includes key mechanisms such as fibrin matrix formation, sustained release of GFs, modulation of inflammation, enhanced cell migration and proliferation, promotion of collagenization, angiogenesis, and matrix remodeling.

Table 1 Mechanisms and factors by which platelet-rich fibrin facilitates wound healing.

Mechanism/factor	Details	Role in wound healing	Signaling molecules/cytokines/chemokines
Fibrin matrix formation	PRF forms a dense fibrin matrix	Provides a structural scaffold for cell migration and proliferation. Traps and concentrates GFs and signaling molecules at the wound site
Sustained release of GFs	PRF allows for the gradual and sustained release of GFs	Prolonged stimulation of tissue repair mechanisms. Supports cellular proliferation, differentiation, and migration	PDGF, TGF-β, VEGF
Modulation of inflammation	PRF helps regulate the inflammatory response	Prevents excessive or prolonged inflammation, promoting a balanced healing environment	May involve modulation of pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1) and anti-inflammatory mediators
Enhanced cell migration and proliferation	GFs released from PRF stimulate cell migration and proliferation	Accelerates tissue regeneration and wound closure	PDGF, TGF-β, and other GFs stimulate cellular signaling pathways involved in cell migration (e.g., Rho GTPases) and proliferation (mitogen-activated protein kinases/extracellular signal-regulated kinase)
Promotion of collagenization	PRF supports collagen deposition and organization	Contributes to the structural remodeling of the wound matrix and enhances long-term tissue strength	TGF-β plays a key role in stimulating collagen synthesis by fibroblasts
Angiogenesis	PRF promotes the formation of new blood vessels	Improves blood supply to the wound, delivering oxygen and nutrients necessary for healing	VEGF stimulates signaling pathways involved in endothelial cell proliferation and migration (such as VEGF-R signaling)
Matrix remodeling	PRF influences the remodeling of the extracellular matrix	Contributes to the restoration of functional tissue and minimizes scar formation	Involves matrix metalloproteinases and their inhibitors

GF: Growth factor; PDGF: Platelet-derived growth factor; PRF: Platelet-rich fibrin; TGF-β: Transforming growth factor-beta; VEGF: Vascular endothelial growth factor.

In comparison to traditional wound dressings, PRF offers a bioactive approach to tissue repair. Conventional dressings primarily serve to protect the wound and maintain a moist environment. While these are important, PRF actively contributes to the healing process by providing GFs, modulating inflammation, and creating a favorable microenvironment for tissue regeneration[36]. This active involvement in the healing process distinguishes PRF as a more advanced therapeutic option for wound management.

EVIDENCE FROM RECENT RESEARCH

Recent research by Sá-Oliveira et al[14] has provided valuable evidence supporting the efficacy of PRF in promoting wound healing through modulation of innate immunity. Their study, conducted on an animal model, investigated the effects of PRF-based dressings on cutaneous wound healing in Wistar rats, comparing its effects to PRP and a control treatment. The findings of their research highlight PRF's ability to accelerate wound closure, enhance tissue repair, and modulate the inflammatory response[14].

In terms of wound closure and contraction, the study demonstrated that PRF-based dressings were more effective in accelerating wound closure in the early stages of the healing process[39]. Specifically, on days 3 and 7 post-wounding, animals treated with PRF showed a significantly greater reduction in wound area compared to the control group and the PRP-treated group[14]. This early acceleration of wound closure suggests that PRF promotes the initial phases of tissue repair, facilitating a more rapid return to tissue integrity. PRF also demonstrated positive effects on collagenization and tissue repair. Histopathological analysis revealed that the PRF group exhibited significant collagenization at the later stages of the repair process, specifically on days 14 and 21[40]. This increased collagen deposition indicates that PRF supports the structural remodeling of the wound matrix, contributing to the long-term strength and stability of the healed tissue[14].

Furthermore, the study provided information into PRF's role in modulating the inflammatory response. The inflammatory infiltrate in the wound area was significantly lower in the PRF group compared to the PRF + CaCl₂ group on days 3 and 7, indicating that PRF was effective in reducing the inflammatory response in the early phase of wound healing[14]. While some level of inflammation is necessary for initiating the healing process, PRF appears to prevent excessive inflammation that could impair tissue regeneration, in accordance to previous findings[41].

These findings demonstrate PRF's ability to modulate innate immunity and promote effective wound repair. By accelerating wound closure in the early stages, enhancing collagenization in the later stages, and modulating the inflammatory response throughout the healing process, PRF optimizes the conditions for tissue regeneration[42]. The study's results support the notion that PRF's unique properties, including its fibrin matrix structure and sustained release of GFs, contribute to its therapeutic efficacy in wound healing[43]. Figure 1 illustrates the process and advantages of using PRF dressings for wound healing.

Figure 1 The process and advantages of using platelet-rich fibrin dressings for wound healing and controlled immune response. The dressing promotes wound healing through various mechanisms, including accelerated wound closure, enhanced tissue repair and collagenization, modulation of the inflammatory response, stimulation of cell migration and proliferation, and support for angiogenesis. These advantages contribute to the therapeutic efficacy of platelet-rich fibrin in wound management. CCL2: C-C motif chemokine ligand 2; IL-1: Interleukin-1; PDGF: Platelet-derived growth factor; TNF-α: Tumor necrosis factor-alpha; PRF: Platelet-rich fibrin.

The findings from Sá-Oliveira et al[14] have several potential clinical applications in wound management. Given PRF's ability to enhance early wound closure, modulate inflammation, and promote tissue repair, PRF-based therapies could be particularly beneficial in treating acute wounds, surgical wounds, and potentially chronic wounds where delayed healing is a concern[14]. The translational potential of these research findings to human patients is significant. While the study was conducted in an animal model, the biological processes involved in wound healing are largely conserved across species. PRF is derived from autologous blood, which minimizes the risk of adverse immune reactions, making it a safe and potentially effective therapeutic option for a wide range of patients. However, further research is needed to fully elucidate the mechanisms of PRF and optimize its use in clinical settings and more focus on optimizing PRF preparation and application techniques to enhance its therapeutic efficacy.

CONCLUSION

In this editorial, we have discussed the advantages of PRF in modulating innate immunity and promoting wound repair. PRF has demonstrated effectiveness in accelerating wound closure, particularly in the early stages of healing. PRF enhances tissue repair by promoting collagenization and improving the structural remodeling of the wound matrix. PRF plays a crucial role in modulating the inflammatory response, preventing excessive inflammation that can impair tissue regeneration. These properties contribute to PRF's ability to create a microenvironment conducive to tissue repair. The findings from recent research by Sá-Oliveira et al[14] provide convincing evidence for PRF's therapeutic potential. PRF represents a promising therapeutic approach for enhanced wound healing. Its capacity to modulate innate immunity and promote effective tissue regeneration makes it a valuable tool in clinical settings. As research continues to elucidate the mechanisms of PRF and optimize its applications, it holds the potential to significantly improve patient outcomes and reduce the burden associated with wound management.