Role of Platelet Derivatives and Their Therapeutic Potential in Wound Healing

1  Introduction

Platelets are anucleate, disc-shaped cellular fragments derived from megakaryocytes. Their production is regulated by thrombopoietin synthesized mainly in the liver. These fragments play a fundamental role in hemostasis and blood coagulation. After vascular injury, exposed collagen and von Willebrand factor (vWF) bind to glycoprotein VI (GPVI) and glycoprotein Ib (GPIb) receptors on platelets. This interaction initiates platelet activation and adhesion to the damaged vessel wall. This process induces shape change, granule secretion, and recruitment of additional platelets. It triggers vasoconstriction and formation of a platelet plug through GPIIb/IIIa fibrinogen binding, forming the primary hemostatic response. As this phase depends heavily on platelet function, dysfunction may result in bleeding disorders [1]. Platelets also release factors, such as thromboplastin, which activate plasma coagulation factors. The generated thrombin converts fibrinogen into fibrin, stabilizing the platelet plug and completing secondary hemostasis [2].

In addition to their roles in hemostasis and thrombosis, platelets contribute to wound healing, immune responses, and tumor metastasis. Activated platelets secrete molecules, such as P-selectin, CD40L, and interleukin-1β (IL-1β). These mediators recruit and activate leukocytes, thereby promoting inflammation and clearance of debris and pathogens at the injury site [3]. Platelet α-granules store and release growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and insulin-like growth factor 1 (IGF-1). These growth factors stimulate proliferation, migration, and angiogenesis in wound tissues. Although they promote tissue repair, they may also promote tumor growth and metastasis under pathological conditions [3–5]. Thus, platelets play multifaceted roles in human physiology, and their functional components can be harnessed for therapeutic applications.

Given the aforementioned roles, platelets have been widely applied in regenerative medicine, most commonly as platelet-rich plasma (PRP). Recently, depending on clinical purpose (e.g., orthopedic, dermatologic, dental, plastic surgery, and chronic wound healing), application method (solid or liquid forms), and duration (short- or long-term), various platelet derivatives, including PRP, platelet-rich fibrin (PRF), platelet lysate (PL), platelet exosomes, lyophilized platelets, and platelet gels, have emerged. These derivatives are often combined with scaffolds such as collagen, gelatin, fibrin, hyaluronic acid, poly lactic-co-glycolic acid, chitosan, or silk to enhance therapeutic efficacy [6–9]. In this study, we describe in detail the mechanisms through which platelets promote wound healing and introduce various platelet derivatives developed based on these mechanisms. In addition to wound healing potential, we discuss the broader biological effects of these derivatives to provide clinical and research guidelines for their application.

2  Mechanism of Wound Healing Effect Using Platelets

Wound healing is a complex physiological process that restores the structure and function of damaged tissue. It is typically divided into four sequential but overlapping stages, namely, hemostasis, inflammation, proliferation, and remodeling. The hemostasis phase minimizes blood loss and temporarily seals the wound, and the inflammatory phase clears pathogens and cellular debris. The proliferative phase involves the formation of new tissue, and the remodeling phase gradually restores the structural and functional integrity of the tissue. Platelets play either a direct or indirect role in these phases. To elucidate their contribution in wound healing, we initially explore the mechanisms of action in each phase (Fig. 1).

Figure 1: Platelet roles in each phase of wound healing. Platelets act in all stages of wound healing, including hemostasis, inflammation, and proliferation. During hemostasis, platelets promote platelet plug formation, fibrin clot formation, and vasoconstriction; during inflammation, they mediate leukocyte recruitment and antimicrobiosis; during proliferation, they support the proliferation of endothelial cells, fibroblasts, and keratinocytes to drive wound repair. Abbreviation: vWF, von Willebrand factor; TxA2, thromboxane A2; CXCLs, C-X-C motif chemokine ligand; CCL, C-C chemokine ligand; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factor; EGF, epidermal growth factor

2.1 Hemostatic Effect

Hemostasis, the first stage of wound healing, includes more than the initial cessation of bleeding. It establishes a foundation for the subsequent tissue repair. Under physiological conditions, platelets circulate in an inactive state. Following vascular injury, immediate vasoconstriction reduces blood loss; primary and secondary hemostasis then form a stable clot.

Vasoconstriction, the initial hemostatic response, is primarily mediated by vasoconstrictors such as endothelin released from damaged endothelial cells and catecholamines (epinephrine, norepinephrine) and prostaglandins released from injured tissue. During primary hemostasis, platelets adhere to exposed collagen and vWF at the site of injury, become activated, and initiate granule secretion. Activated platelets synthesize thromboxane A2 (TxA2) from membrane phospholipids and release serotonin from dense granules (Fig. 2). TxA2 binds to TP receptors on vascular smooth muscle cells and activates Gq-protein-coupled phospholipase C (PLC), which generates inositol trisphosphate (IP3) and diacylglycerol (DAG) [10]. IP3 induces calcium release from the sarcoplasmic reticulum, increasing intracellular calcium levels and activating myosin light chain kinase (MLCK). MLCK phosphorylates MLC and induces smooth muscle contraction. Concurrently, DAG inhibits myosin light chain phosphatase (MLCP), enhancing contraction [11]. TP receptors also activate the Rho/Rho kinase pathway via G12/13 proteins, further inhibiting MLCP and sustaining contraction [12]. Serotonin acts in a similar manner through the 5-HT2B receptor, which couples with Gq and G12/13 to induce vasoconstriction [13].

Figure 2: Platelet roles in hemostasis during wound healing. Upon vascular injury, exposed collagen and von Willebrand factor (vWF) bind platelet receptors to trigger activation and adhesion. Activated platelets release serotonin and generate thromboxane A2 (TxA2), which stimulates vascular smooth muscle cells and myofibroblasts to induce vasoconstriction. Platelet shape change and aggregation form the primary hemostatic plug. Platelets also accelerate the coagulation cascade, and the fibrin stabilizes the thrombus to form the secondary hemostatic plug. Abbreviation: vWF, von Willebrand factor; GPVI, glycoprotein VI; GPIb-IX-V, glycoprotein Ib–IX–V complex; TF, tissue factor; PLCγ, phospholipase C γ; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; TxA2, thromboxane A2; MLCP, myosin light chain phosphatase; MLCK, myosin light chain kinase; FVII, factor VII; FXII, factor XII; FX, factor X; FV, factor V.2.2 Immunologic effect

Following vasoconstriction, primary hemostasis proceeds with platelet adhesion and aggregation. Platelet GPVI and GPIb-IX-V receptors bind to collagen and vWF, respectively, anchoring platelets to the injury site. Collagen binding to GPVI leads to phosphorylation of the immunoreceptor tyrosine-based activation motif on the associated Fcγ receptor (FcRγ) chain by Src family kinases (SFKs) such as Lyn and Fyn. This event facilitates recruitment of Syk kinase and formation of a LAT signaling complex, ultimately activating phospholipase C γ2 (PLCγ2). PLCγ2 increases IP3-mediated calcium release and DAG-mediated PKC activation [14,15]. Meanwhile, vWF binding to GPIb similarly activates SFKs and downstream PI3K/PLCγ2 signaling [16]. These pathways stimulate granule secretion, cytoskeletal rearrangement (shape change), integrin activation, and fibrinogen binding, resulting in the formation of a platelet plug [17–19].

The temporary plug becomes stabilized during secondary hemostasis, during which the coagulation cascade produces a fibrin mesh that reinforces the platelet aggregates. The cascade comprises extrinsic, intrinsic, and common pathways. In the extrinsic pathway, tissue factor (TF) exposed at the injury site forms a complex with factor VII, which activates factor X to initiate coagulation [20]. The intrinsic pathway begins when collagen exposure activates factor XII, which sequentially activates factors XI, IX, and X, amplifying the coagulation response [21]. In the common pathway, activated factor X (Xa) and factor V form a prothrombinase complex, converting prothrombin into thrombin. Thrombin subsequently converts fibrinogen into fibrin, forming a mesh that stabilizes the platelet plug [22]. Thrombin also activates factor XIII, which crosslinks fibrin fibers to further reinforce the clot. In addition, thrombin enhances platelet activation and induces the externalization of phosphatidylserine on the platelet surface, providing a catalytic platform for coagulation factor complexes [23]. Activated platelets release thromboplastin, which mimics TF and accelerates the extrinsic pathway [22]. Fibrin binds to platelet integrins, strengthening thrombus stability. α-Granules from activated platelets release fibrinogen, factor V, and vWF, directly supporting clot formation [24]. Through these events, hemorrhage ceases, and the vascular injury is securely sealed. Beyond mechanical stabilization, the fibrin clot functions as a provisional matrix that protects the wound from pathogens, minimizes injury size, and facilitates healing. This matrix provides a scaffold for the migration, proliferation, and differentiation of fibroblasts, epithelial cells, and endothelial cells. It also facilitates oxygen and nutrient delivery, establishing the foundation for tissue regeneration and repair [25,26].

While the hemostatic function of platelets is important during the early stages of wound healing, their immunological mechanisms also serve as key modulators of the healing process (Fig. 3). Numerous studies have shown that platelets directly interact with a wide range of microbes and pathogens. In this context, platelets function as the “first responders” in host defense [27,28]. To fulfill this immunological role, platelets use diverse receptors, including Toll-like receptors (TLRs), FcRs, and G-protein-coupled receptors (GPCRs). Platelets express several TLRs, such as TLR1, TLR2, TLR3, TLR4, TLR7, and TLR9, which belong to a conserved family of pattern recognition receptors that detect pathogen-associated molecular patterns [29,30]. Upon ligand binding, TLRs recruit the adaptor molecule myeloid differentiation primary response 88 (MyD88), which activates IL-1 receptor-associated kinases (IRAKs), particularly IRAK1 and IRAK4. These kinases interact with TNF receptor-associated factor 6 (TRAF6), leading to the activation of NF-κB and MAPK signaling pathways and promoting the release of platelet granule contents [31]. Platelet α-granules store various proinflammatory mediators, including C-X-C motif chemokine ligand 4 (CXCL4), C-C chemokine ligand 5 (CCL5), CD40L, PDGF, and TGF-β, which recruit immune cells and further activate platelets [32]. TLR1/2 activation on platelets also stimulates the PI3K/Akt pathway, enhancing integrin activation and P-selectin expression, which facilitates platelet–leukocyte interactions [31]. By contrast, TLR3 and TLR4 signaling through a MyD88-independent signaling pathway via the adaptor molecule TRIF (TIR-domain-containing adaptor-inducing interferon-β), which activates interferon regulatory factor 3 (IRF3) and IRF7 and promotes the granule secretion [33–35]. Upon activation, platelets also release platelet-derived microparticles. The microparticles contain antimicrobial proteins and peptides such as thrombocidins, CXCL4, platelet basic protein, CCL5, β-defensins, and fibrinopeptides [36,37]. These molecules directly bind to bacterial membranes, increasing membrane permeability, disrupting cellular integrity, and inhibiting bacterial protein synthesis.

Figure 3: Platelet roles in inflammation and immune responses during wound healing. Platelets are activated by pathogen-associated molecular patterns (PAMPs) and exert direct antimicrobial activity. They then promote leukocyte recruitment and activation, facilitating pathogen clearance. Abbreviations: PAMPs, pathogen-associated molecular patterns; MyD88, myeloid differentiation primary response protein 88; TRIF, TIR-domain-containing adapter-inducing interferon-β; IRAK, interleukin-1 receptor–associated kinase; IRF, interferon regulatory factor; TRAF, tumor necrosis factor receptor–associated factor; MAPK, mitogen-activated protein kinase; sCD40L, soluble CD40 ligand; CXCL, C-X-C motif chemokine ligand; CCL, C-C motif chemokine ligand; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; PLCβ, phospholipase C beta; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; NET, neutrophil extracellular trap

Activated platelets release chemokines that recruit leukocytes to wound sites. CXCLs (CXCL1, CXCL4, CXCL5, CXCL7, CXCL8, CXCL12) and CCLs (CCL3, CCL5) within α-granules actively recruit neutrophils and monocytes. Although dense granule components such as ADP and serotonin do not directly recruit immune cells, they enhance chemokine receptor expression and leukocyte activation [32,38]. These chemokines bind to GPCRs (CXCRs and CCRs), activating the PI3K/Akt and MAPK pathways through Gαi signaling, and initiating PLCβ activation through Gβγ signaling, which promotes chemotaxis and leukocyte migration. Platelets also express CD40L (a TNF superfamily ligand) on their surface or release it in a soluble form (sCD40L). Binding of sCD40L to CD40 on leukocytes recruits TRAF proteins to the CD40 cytoplasmic domain, leading to the activation of NF-κB, MAPK, and PI3K/Akt signaling pathways and inducing the production of proinflammatory cytokines, including IL-1β, IL-6, TNF-α, CXCL8, and CCL2 [32,39]. P-selectin, which is upregulated on activated platelets, functions synergistically with CD40L to enhance leukocyte adhesion and recruitment [40]. sCD40L also binds to CD40 on endothelial cells, promoting leukocyte adhesion and transendothelial migration [41]. Recruited neutrophils form neutrophil extracellular traps, which immobilize and kill pathogens. In addition, platelet-mediated inflammation promotes macrophage M1 polarization, enhances antigen presentation by dendritic cells, and stimulates antibody production by B cells [42]. Through these mechanisms, platelets and the inflammatory cells they recruit contribute to pathogen clearance and facilitate the transition of wounds from the inflammatory to the proliferative phase.

2.2 Proliferative Effect

During wound healing, the proliferative phase begins once the initial inflammatory response subsides, marking the onset of active tissue regeneration. This phase is characterized by angiogenesis, fibroblast proliferation, granulation tissue formation, epithelialization, and wound contraction. Endothelial cells, fibroblasts, and keratinocytes are the major cell types involved. Platelets significantly contribute by releasing growth factors and cytokines that stimulate cell proliferation, thereby accelerating tissue regeneration (Fig. 4).

Figure 4: Platelet roles in cell proliferation during wound healing. Platelet growth factors activate multiple signaling pathways in endothelial cells, myofibroblasts, keratinocytes, and fibroblasts, thereby promoting proliferation, anti-apoptosis, and migration. Abbreviations: VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; EGF, epidermal growth factor; IGF, insulin-like growth factor; VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; TβR, transforming growth factor-β receptor; EGFR, epidermal growth factor receptor; IGFR, insulin-like growth factor receptor; PLCγ, phospholipase C gamma; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; FAK, focal adhesion kinase

Angiogenesis, driven by endothelial cell proliferation, supplies oxygen and nutrients to the wound site, replaces damaged vessels from the inflammatory phase, and delivers necessary factors for repair. Among platelet-derived factors, VEGF plays the most significant role in endothelial proliferation and neovascularization. VEGF release is further promoted under hypoxic conditions through HIF-1α and is abundantly secreted from platelet α-granules [43]. The binding of VEGF to VEGFR-2 endothelial cells activates the PI3K/Akt signaling pathway, which promotes cell cycle progression via mTOR and upregulates cyclin D1 expression, facilitating endothelial proliferation. In addition, this signaling inhibits apoptosis by enhancing Bcl-2 expression and suppressing pro-apoptotic proteins such as Bad and caspase-3 [44–47]. Activation of the PLCγ-PKC pathway increases intracellular calcium levels, promoting actin polymerization and endothelial migration. This activation also disrupts VE-cadherin and increases vascular permeability, facilitating the influx of plasma proteins and cells, thereby creating a pro-healing environment [48]. PKC activation stimulates the MAPK/ERK cascade through Ras/Raf/MEK/ERK signaling, which induces proliferation-related genes, such as c-Myc and cyclin D1, by activating transcription factors c-Fos and c-Jun [49–51]. Both the PI3K/Akt and PLCγ/PKC/MAPK pathways also activate NF-κB, enhancing the expression of E-selectin and intercellular adhesion molecule 1 (ICAM-1) [52]. E-selectin interacts with PSGL-1 on endothelial progenitor cells (EPCs), mediating rolling, whereas ICAM-1 binds to β2 integrin on EPCs, facilitating firm adhesion and recruitment of EPCs to the injury site for angiogenesis [53]. Src activation promotes cytoskeletal rearrangement and enhances cell motility, while focal adhesion kinase (FAK) facilitates endothelial migration via integrin interactions [54,55]. VEGF regulates stalk cell differentiation via Dll4/Notch1 signaling and supports vascular lumen formation through interactions with αvβ3 integrin [56,57]. VEGF also activates eNOS to produce nitric oxide, promoting endothelial survival and vasodilation, and interacts with CXCR4 to recruit EPCs and initiate new vessel formation [58,59]. FGF binds to FGFR-1/2 (particularly FGFR-1), and PDGF, particularly PDGF-BB, binds to PDGFR-α/β, strongly inducing the PLCγ/PKC/MAPK, PI3K/Akt, and Src pathways to stimulate endothelial proliferation [60,61]. PDGF-BB also promotes pericyte and smooth muscle cell proliferation via PDGFR-β, enhancing vascular stabilization and maturation through cyclin D1 expression and cell survival via the PI3K/Akt/mTOR pathway [62]. The JAK/STAT pathway supports cell differentiation and maturation, whereas FAK/Src signaling promotes pericyte and smooth muscle cell migration [63,64]. TGF-β influences endothelial cells via both Smad-dependent and Smad-independent mechanisms. The Smad-independent pathway, triggered by TβR-I/II, activates PLCγ/PKC/MAPK and PI3K/Akt/mTOR signaling, promoting endothelial proliferation [65]. RhoA-ROCK activation enhances junctional protein stability, such as VE-cadherin, reducing permeability and promoting mature vascular structure formation [66]. In the Smad-dependent pathway, low TGF-β levels during the early phase recruit ALK1, leading to Smad1/5/8 phosphorylation and Id1-mediated proliferation [67]. At later stages, higher TGF-β levels activate ALK5, inducing Smad2/3 phosphorylation, and through PAI-1, p21, and p27, suppressing proliferation while promoting vessel stabilization [65,68,69]. SDF-1 binding to CXCR4/CXCR7 also activates PLCγ/PKC/MAPK and PI3K/Akt/mTOR pathways, enhancing endothelial proliferation [70]. Moreover, PKCζ increases HO-1 expression, leading to CO production that activates the CO/PKG/VASP pathway, thereby promoting endothelial actin polymerization and tube formation [71].

Fibroblast proliferation is critical for granulation tissue formation, extracellular matrix (ECM) production, and structural support at wound sites. PDGF plays the most prominent role in early fibroblast proliferation. Platelets contain PDGF-BB, -AB, and some PDGF-AA, which activate PDGFR-α/β on fibroblasts, inducing PI3K/Akt/mTOR-mediated cyclin E expression and promoting cell survival via Bcl-2 upregulation and Bad suppression. ECM synthesis is enhanced by SREBP activation [72–75]. PLCr/PKC/MAPK signaling increases c-Fos and c-Jun expression to promote transcription and proliferation [76,77]. These pathways also upregulate tissue inhibitor of metalloproteinases-1 (TIMP1) and TIMP2, which inhibit MMP activity and maintain ECM stability [78,79]. Fibroblast motility is enhanced through RhoA/ROCK-mediated actin-myosin interaction and LIMK1/2 phosphorylation, which inactivates cofilin and promotes lamellipodia formation [80–83]. FAK and Src phosphorylation induce MMP-2/9 expression, facilitate fibroblast invasion, and enhance ECM adhesion through phosphorylation of focal adhesion proteins such as paxillin, vinculin, and talin [84–88]. FGF binds to FGFR1/2, and SDF-1 binds to CXCR4/CXCR7. TGF-β activates fibroblasts via PI3K/Akt/mTOR, PLCγ/PKC/MAPK, RhoA/ROCK, and FAK/Src signaling [65,89].

Keratinocyte proliferation restores the epidermal barrier and prevents infection. EGF is the primary platelet-derived factor responsible for keratinocyte proliferation. Binding of EGF to EGFR activates the PI3K/Akt/mTOR pathway, which inhibits apoptosis by suppressing Bad and caspase-9 phosphorylation and upregulating Bcl-2/Bcl-xL. This pathway also promotes proliferation through cyclin D/E stabilization [90]. Activation of PLCγ/PKC and MAPK via Ras enhances keratinocyte proliferation, whereas RhoA/ROCK and FAK/Src signaling promote migration [90,91]. PKCα/δ regulates keratinization by inducing keratin and involucrin expression [55]. Additional growth factors such as PDGF, TGF-β, FGF-2, and IGF-1 contribute to keratinocyte proliferation and migration through similar mechanisms [92]. Altogether, platelet-mediated proliferation of endothelial cells, fibroblasts, and keratinocytes mutually reinforces the function of each cell type, accelerating re-epithelialization, granulation tissue formation, and ultimately scar formation, which restores the structural and physiological integrity of wounded tissue.

3  Characteristics and Application of Platelet Derivatives

3.1 Platelet-Rich Plasma

PRP refers to plasma containing a high concentration of platelets extracted from blood, typically 2–5 times higher than that of whole blood. The most common preparation method involves centrifugation, in which the plasma layer is selectively isolated and concentrated. In many applications, platelets are activated approximately one hour before use by adding calcium chloride or thrombin, promoting the release of growth factors and cytokines essential for wound healing. Current clinical uses of PRP extend beyond acute wounds to include chronic wounds, surgical wounds, radiation-induced injuries, skin grafts, burns, dental implants, aesthetic dermatology, and hair loss treatments [68,93–95]. PRP is also applied in musculoskeletal tissues (muscles, tendons, joints, bones, and cartilage), the eye (cornea, conjunctiva, retina), and the nervous system for the treatment and regeneration of inflammatory, degenerative, traumatic, and ruptured lesions, highlighting its wide-range role in regenerative medicine [96–98]. Recent applications of PRP in skin wounds and various regenerative medicines are summarized in Tables 1 and 2.

PRP can be classified into leukocyte-rich PRP (LR-PRP) and leukocyte-poor PRP (LP-PRP) based on leukocyte content. LR-PRP can be obtained by low-speed centrifugation or by actively collecting the buffy coat layer, which contains abundant leukocytes. LR-PRP generally has a higher leukocyte content than whole blood, and its platelet recovery rate is typically higher than that of LP-PRP, thus containing higher concentrations of growth factors [139]. Monocytes in LR-PRP secrete anti-inflammatory cytokines such as IL-10, IL-4, and TGF-β. These cytokines suppress inflammation; promote M2 macrophage polarization, thereby facilitating tissue repair; and release growth factors such as VEGF to promote angiogenesis [140]. Moreover, the phagocytic activity of monocytes removes dead cells, pathogens, and tissue debris from the wound site, resolving the inflammatory environment and preparing for the proliferative phase of wound healing [141]. Lymphocytes also contribute by secreting anti-inflammatory cytokines (IL-10, IL-4, IL-13, and TGF-β), promoting M2 macrophage polarization, and supporting tissue regeneration [142,143]. However, excessive neutrophils in LR-PRP secrete pro-inflammatory cytokines, including IL-1β, TNF-α, IL-6, and IL-8, and recruit additional neutrophils, further amplifying inflammation [144]. They generate large amounts of reactive oxygen species (ROS), which help eliminate pathogens but may also cause oxidative damage to healthy tissues. In addition, excessive secretion of MMP-8, MMP-9, and elastase can degrade the ECM, leading to structural tissue damage [145]. Because neutrophils in LR-PRP often appear earlier and act more aggressively during the initial wound healing phase, the risk of excessive inflammation and oxidative stress remains significant [146]. When using LR-PRP, strategies to suppress the rapid surge of inflammatory cytokines should therefore be considered. Potential approaches include structural modifications that enable sustained release (e.g., gelation into platelet gels or PRF, or application with scaffolds) or increasing the monocyte/lymphocyte ratio to reduce inflammation-related side effects [147].

Although many formulations are available for various purposes in regenerative medicine, PRP offers several distinct advantages compared with other options. Because PRP is derived from autologous material, it carries no risk of immune reactions such as allergy or inflammation-induced tissue damage. Even in allogeneic or xenogeneic applications, PRP exhibits low immunogenicity, which minimizes the risk of toxicity or immune responses commonly associated with synthetic materials [148,149]. Allogeneic and even xenogeneic PRP is prepared from stringently screened donors, resulting in a lower risk of pathogen transmission than autologous PRP [150,151]. Moreover, platelets, unlike leukocytes, express HLA class I but essentially lack class II, and when PRP is formulated as leukocyte-poor PRP (LP-PRP), antigen presentation is limited [152]. In addition, PRP is most often administered locally by injection or topical application, and once activated, its constituents diffuse gradually within the tissue [153]. As a result, there is minimal spillover into the systemic circulation and few opportunities for immune activation. In patients with chronic wounds or diabetic foot ulcers treated with allogeneic PRP, no abnormalities were observed in vital signs, serum biochemistry, hematology, or urinalysis [154]. Additionally, there was no evidence of anti-platelet antibody formation, no change in bacterial burden, and no wound maceration [154]. Furthermore, the therapeutic mechanism of platelets closely reflects the natural physiological healing process of the body, in which growth factors promote cell proliferation, angiogenesis, and collagen synthesis. Therefore, PRP accelerates tissue repair while causing few adverse effects [155]. Among platelet-based formulations, PRP is one of the easiest to prepare, making it cost-effective. Because production requires only a simple blood draw, the procedure is minimally invasive [156,157].

In contemporary wound care, the clinical focus has shifted from acute, superficial wounds, which heal relatively easily, to chronic deep wounds, which are more difficult and time-consuming to treat. Therefore, PRP is particularly effective for treating chronic, deep wounds. Although PRP can support acute injuries, such as burns or surgical wounds, its effects in these cases remain relatively limited because adequate blood flow generally supports natural healing [158]. By contrast, in intractable wounds, such as chronic ulcers in patients with diabetes, radiation-induced tissue damage, or infections, healing is delayed owing to impaired perfusion, leading to stagnation in the repair process. In such situations, supplementation with growth factors and cytokines can profoundly improve outcomes by overcoming the healing barrier [159]. Because PRP is a liquid formulation, it can be applied topically in combination with dressings. For deep wounds, PRP can be injected directly into the wound margins, making it particularly suitable for chronic wound management [160]. Moreover, PRP retains several advantages even when compared with recently developed advanced wound care therapies. In contrast to stem cell–based approaches, which represent an advanced form of regenerative medicine, PRP carries a much lower risk of tumor formation and is more cost-effective [6,161]. In addition, although many bioengineered skin substitutes provide excellent structural coverage and mechanical protection of wounds, they contain much lesser intrinsic growth factors or cytokines, and thus their actual regenerative efficacy is relatively limited compared with PRP [162]. They are also associated with a risk of immune rejection and face challenges in large-scale production [163].

3.2 Platelet Derivatives

Although PRP provides many beneficial functions, several derivatives have been developed to enhance its properties. PRF is obtained by immediately centrifuging freshly drawn blood without anticoagulants at a low speed, resulting in a coagulum. Because anticoagulants are not required and preparation requires only simple centrifugation (400–700× g for 8–12 min), PRF is the easiest platelet derivative to produce and can be manufactured most rapidly, making it particularly suitable for clinical use [164,165]. Moreover, PRF forms a sticky, flexible fibrin matrix in gel form, which undergoes natural degradation in vivo and adheres stably to wound or defect sites without external scaffolds, while also filling the site for hemostasis [166,167]. However, PRF contains high concentrations of leukocytes, which can cause inflammatory side effects. In addition, high centrifugation speeds can produce a dense and compact fibrin matrix that results in the rapid burst release of growth factors during the early phase. Shorter centrifugation speeds yield a loose and unstable fibrin matrix that degrades rapidly in vivo, thereby reducing its longevity [168]. To address these limitations, advanced PRF (A-PRF), prepared by centrifugation at a lower speed (200× g) for a longer duration (14 min), forms a loose yet stable fibrin matrix that traps growth factors for longer periods and enables their gradual release, resulting in more favorable long-term regenerative effects [169]. Furthermore, to improve applicability in cases where solid PRF is difficult to use, injectable PRF (i-PRF) is produced by brief centrifugation (3–4 min) before complete fibrin coagulation. This approach allows i-PRF to form a fibrin network immediately after injection, which is particularly effective for deep wounds or anatomically difficult-to-reach areas [170].

Platelet gel is produced by inducing the gelation of PRP using agonists such as CaCl2 and thrombin, forming a gel-like fibrin matrix similar to PRF [171,172]. Compared to PRF, its manufacturing process is more complex, requiring anticoagulants and platelet agonists, and the resulting fibrin matrix is relatively fragile, resulting in shorter persistence [173]. Nevertheless, platelet gel contains fewer leukocytes, which reduces the risk of excessive inflammatory responses and related complications. It also releases growth factors more rapidly and undergoes faster degradation, making it advantageous in situations requiring prompt healing [173].

PL is a liquid preparation obtained by disrupting platelets to release growth factors and cytokines contained within. The process typically begins with PRP preparation to concentrate platelets, followed by disruption through repeated freeze–thaw cycles, ultrasonication at 20 kHz for up to 30 min, or stimulation with agonists such as CaCl2 and thrombin to release intracellular growth factors, followed by centrifugation or filtration to remove cellular debris [174]. Compared with PRP and other platelet derivatives, PL lacks cell membranes, does not trigger immune responses, and represents a cell-free preparation. PL has been shown to be an excellent substitute for fetal bovine serum in promoting the proliferation of various cell types, including mesenchymal stem cells, keratinocytes, endothelial cells, and chondrocytes [175–178]. However, because growth factors are completely released, their effects are highly transient, necessitating multiple applications. Furthermore, additional manufacturing steps increase production time [179].

Lyophilized PRP is produced by freezing PRP at –80°C and then removing ice through sublimation under vacuum (freeze-drying). This process yields PRP in powder or sponge form, which can later be rehydrated with saline prior to application. Lyophilization greatly extends storage duration compared with the conventional short shelf life of fresh PRP, which typically lasts only several days under refrigeration. Growth factor activity can be preserved for years, even at room temperature, enabling pre-manufacturing, bulk storage, and convenient clinical application after simple rehydration with saline [180,181]. The use of protectants, such as trehalose and mannitol, both highly biocompatible and stable, helps mitigate protein aggregation and oxidative stress induced by freeze-drying, thereby protecting platelet membranes and proteins while preserving growth factor activity [182–184]. However, lyophilization requires specialized equipment, and the post-rehydration recovery rate of biological activity (reported to be approximately 70%–90%, verification needed) is lower than that of fresh PRP. Moreover, freeze–thaw processes can cause platelet rupture and immediate growth factor release, reducing sustained effects [185,186]. Despite these limitations, lyophilization is particularly suitable for the long-term storage of PLs, given their cell-free nature. PRF and platelet gel can also be stored long-term via lyophilization, although fibrin matrix damage presents some limitations [187,188]. For platelet gel, an effective approach for long-term preservation is to lyophilize PRP, rehydrate it, and then induce gelation with platelet agonists to maintain a stable fibrin matrix structure [189]. Recent applications of platelet derivatives in skin wounds are summarized in Table 3.

4  Challenges in PRP Application and Overcoming Strategies

PRP and platelet derivatives have gained considerable attention as promising agents for wound healing and regenerative medicine, supported by a strong theoretical foundation. Although they provide numerous advantages for tissue repair and regeneration, several limitations persist. In patients with hematological disorders (e.g., sepsis, coagulopathies, malignancies, and anemia), blood collection poses a significant challenge, making the application of autologous PRP difficult. Even when blood can be drawn, concerns remain regarding potential adverse effects from PRP prepared from such whole blood [200–202]. Studies have reported that platelet function in patients with liver cirrhosis or disseminated intravascular coagulation is reduced compared with that in healthy individuals, resulting in lower concentrations of growth factors within PRP [203,204]. For patients in whom blood collection is difficult, allogeneic PRP may serve as an alternative. However, rigorous donor screening is essential to minimize the risk associated with harmful PRP preparation. Furthermore, a consensus statement proposed by the International Research Group of Platelet Injections emphasizes that conditions such as diabetes, cancer, or systemic infections may increase the risk of complications. Careful evaluation of the patient’s condition and cautious use of PRP are therefore necessary to ensure safety [205].

By contrast with conventional pharmaceutical products that maintain consistent quality, platelet derivatives vary in composition depending on patient health status, sex, blood composition, and hematologic parameters. These variations alter leukocyte and platelet ratios as well as growth factor concentrations, complicating the delivery of an optimal therapeutic dose [202,206,207]. Furthermore, well-designed randomized controlled trials using PRP have not been adequately conducted. A perfectly standardized and reproducible centrifugation protocol that maximizes platelet recovery and function while minimizing leukocyte-associated adverse effects has yet to be established, further hindering clinical application. Critical variables, such as the final platelet concentration in PRP, the type and concentration of agonists used for activation, activation duration, and the frequency and dosage of PRP administration, remain undefined. Numerous studies have reported that PRP either provides no benefit in wound healing or regenerative medicine or, in some cases, causes adverse effects [208]. These inconsistencies likely result from the aforementioned variability and uncontrolled factors, hindering the movement of platelet-based therapies toward evidence-based clinical adoption. To address these challenges, pooling blood from multiple donors could reduce variability. To reduce variations in study design and to clearly determine the therapeutic efficacy of PRP across different diseases, well-powered, standardized randomized controlled trials with long-term follow-up are required to establish robust evidence before widespread clinical adoption.

5  Conclusion and Future Perspective

A wide range of regenerative biomaterials is attracting considerable attention today, each demonstrating outstanding efficacy in specific indications. PRP has likewise been extensively investigated owing to its low immunogenicity, immediate hemostatic action, and direct regenerative stimulation via multiple growth factors. Nevertheless, the demand for more efficient and standardized regenerative materials continues to grow, and diverse lines of research are underway to meet this need. Furthermore, recent advances in scaffold technologies using collagen, fibrin, alginate, silk, or hydrogels, combined with 3D printing, have enabled the development of diverse structural formats (sponges, hydrogels, films, membranes, nanofibers, etc.), thereby facilitating more efficient and effective PRP delivery [209]. Going forward, PRP and other platelet-derived formulations are expected to be increasingly integrated with advanced regenerative modalities, including stem cell therapies, gene therapy, immunomodulatory biomaterials, and bioengineered skin substitutes [162,210]. Such combinations are anticipated to provide new therapeutic options not only for wound healing but also for chronic diseases, refractory tissue injuries, and age-related conditions. To maximize the efficacy and efficiency of platelet-based products, biomaterials-driven engineering strategies, standardized clinical protocols with commercial kits and regulatory frameworks, large-scale randomized trials, and long-term safety evaluations will be essential research priorities, ultimately enabling more concrete and practical implementation in routine clinical practice.

Acknowledgement: None.

Funding Statement: This research was funded by the National IT Industry Promotion Agency (NIPA, RQT-25-030567), the National Research Foundation of Korea (NRF-2022R1A2C1003638), and the Basic Research Lab Program (2022R1A4A1025557) through the NRF of Korea, funded by the Ministry of Science and ICT.

Author Contributions: The authors confirm contribution to the paper as follows: conceptualization, Soochong Kim and Sanggu Kim; validation, Soochong Kim; investigation, Sanggu Kim and Seongmo Yang; writing―original draft, Sanggu Kim; writing―review and editing, Soochong Kim; supervision, Soochong Kim. All authors reviewed the results and approved the final version of the manuscript.

Availability of Data and Materials: Not applicable.

Ethics Approval: Not applicable.

Conflicts of Interest: The authors declare no conflicts of interest to report regarding the present study.

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