PRP-related biomaterials enhance bone and nerve repair

Abstract

Bone and nerve injuries are the most common problems in orthopedic trauma, so orthopedic researchers are committed to studying efficient and economical strategies for repairing bone defects and nerve injuries. Platelet-rich plasma (PRP) is a self-derived blood derivative rich in growth factors and bioactive components, which plays a key role in promoting bone defect repair and nerve regeneration, and can effectively cope with the clinical problem of marginal bone defect with nerve injury. However, the explosive release of growth factors in PRP affects its practical use, and the controllable release of growth factors on demand can effectively enhance its efficiency in bone and nerve repair. In this paper, the application and mechanism of PRP reinforced biomaterials in bone and nerve regeneration are systematically reviewed. In the process of bone regeneration, PRP can promote the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), induce type H angiogenesis, and promote the regeneration of vascularized bone. In the field of nerve repair, PRP can promote the regeneration of peripheral and central nerve injury sites, stimulate the synthesis of new connective tissue and vascular reconstruction, down-regulate pro-inflammatory factors to build anti-inflammatory microenvironment and reduce nerve cell damage.To sum up, this study deeply discussed the mechanism of PRP in bone and nerve repair, and elaborated various advanced multifunctional biomaterials to solve the explosive release problem of PRP in use, providing theoretical basis for the standardized application and clinical transformation of PRP.

Graphical abstract

1. Introduction

Large-area bone defects caused by trauma and tumor resection are common in orthopedics, and these defects cannot achieve ideal repair effect by themselves [1,2]. It is important to note that bone defects are frequently accompanied by varying degrees of nerve damage. The normal development and regeneration of bone tissue are closely associated with neural innervation. Nerve injury can further impede the bone repair process by compromising local blood circulation, osteoblast function, and the secretion of relevant cytokines, thereby presenting greater challenges in clinical treatment [3]. Severe peripheral and central nerve injury is a great clinical challenge at the same time and usually leads to permanent functional deficits, chronic pain, and decreased quality of life [4]. At present, autologous bone transplantation is the “gold standard” for orthopedic treatment of bone defects, because autologous bone has good osteogenic induction and no immunogenicity [5]. However, the application of autogenous bone is limited by the lack of bone mass and the infection of donor site, so it is necessary to find a new alternative strategy for bone transplantation [6,7]. At present, titanium, polyetheretherketone(PEEK) and tantalum are the most commonly used materials in orthopedic treatment of bone defects, but these materials have poor biological activity and cannot induce bone formation [8,9]. Unlike bone tissue, which exhibits high regenerative capacity, nerve repair is a more complex process that requires robust axonal regeneration, remyelination by Schwann cells, revascularization to ensure adequate nutrient supply, and precisely coordinated immune responses, along with the removal of debris without inducing secondary damage. These demanding biological requirements present significant challenges for the design and performance of biomaterials [10]. Therefore, it is not sufficiently effective in promoting nerve repair and regeneration when concurrent with nerve injury. Therefore, there is a need to explore more effective strategies, such as the development of novel biomaterials that exhibit both favorable osteogenic activity and neuroinductive properties, in order to achieve synergistic regeneration of both bone and nerve tissues [11].

In recent years, with the development of bone tissue engineering, more and more substitute materials provide new possibilities [12]. Platelet-rich plasma (PRP) is an autologous derivative obtained by multiple centrifugation of whole blood, and it is necessary to resuspend the obtained concentrated plasma to obtain an appropriate concentration when using it [13,14]. It contains a variety of highly concentrated growth factors that promote proliferation and differentiation, including platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF), transforming growth factor -β(TGF-β) and vascular endothelial growth factor (VEGF) [15,16].Initially used for clinical improvement of hemostasis [17].In recent years, it has been found that PRP plays an important role in regenerative medicine, especially in bone and nerve repair [18,19] (Fig. 1).In 2002, Dugrillon and others used PRP for the first time to treat local bone defects and achieved positive results [20].In 2007, Farrag research team found that PRP has a positive effect on peripheral nerve regeneration [21].With the deepening of research in recent years, it is found that PRP also plays an active role in bone tissue regeneration, cartilage repair, spinal fusion and nerve repair [22,23].However, the application strategies of PRP in bone defect, cartilage repair and nerve regeneration are similar, and its specific application strategies still need further study and standardization [24].

Fig. 1.

Schematic diagram of PRP regeneration mechanism. This summarizes the current main preparation methods of PRP and mechanisms and its application in the field of bone and nerve repair.

Based on the concept of translational medicine, we need to apply the results of experimental research to clinic, which will strengthen the connection between scientific research and clinic [25]. In fact, the application of PRP in the medical field is extensive. In addition to its well-established roles in bone and nerve repair, PRP demonstrates significant utility across a diverse range of other clinical disciplines. Therefore, we analyzed the cases of using PRP in clinic, and the most common one is that PRP is used to heal skin wounds, burns and ulcers [26].In addition, PRP can also be used to treat alveolar atrophy [27], treatment of acute toxic arthritis by injecting PRP into knee joint [28], and has positive effects on repairing articular cartilage and removing inflammatory factors in the treatment of rheumatoid arthritis [29].It shows that PRP has a good clinical reference prospect. Previous studies have found that the explosive release of growth factors in the early stage of PRP restricts its use and reduces its effect in the later stage of repair [30]. Therefore, if the controllable release of growth factors in PRP can be realized, the clinical transformation of PRP will reach a new level.

To sum up, in order to master the research progress of PRP in orthopedic treatment of bone defects and nerve regeneration. In this paper, PRP, bone repair and nerve repair are used as keywords to search in Web of Science and PubMed databases, and the articles are filtered. Finally, 234 papers were screened out according to the inclusion criteria. This paper introduces the preparation and standardized use of PRP in detail, focusing on the role and specific use strategy of PRP in bone tissue formation, blood vessel formation in bone defect, nerve regeneration and cartilage repair. At the same time, the current restrictions on the use of PRP are summarized and the improvement methods are put forward.

2. Preparation and standardization of PRP

The preparation of PRP shows different methods in different articles, but it is generally obtained by centrifugation for more than two times [31]. Leng et al. used apical blood sampling method to obtain arterial blood, and centrifuged the blood twice at 20 °C with 209g, after 16min each time, the bottom red blood cells were removed, and then centrifuged at 20 °C with 1500g for 12min, which was the bottom quarter of PRP [32].Yu et al. collected the blood from the central ear artery, centrifuged at 800 rpm for 15min at 20 °C, and then extracted the plasma separated from the bottom blood cells, and centrifuged at 2000 rpm for 15min at 20 °C to obtain PRP [33].Murphy et al. obtained a platelet concentration of 109/ml by taking apical blood, centrifuging at 300g for 15min, and then centrifuging the supernatant at 1600g for 10min [34].Xie et al. measured PRP platelet concentration, and the enrichment coefficient (PRP platelet concentration/whole blood platelet concentration) was more than 4 [35].The enrichment coefficient of PRP prepared by Niemeyer et al. also reached 4–5 [36].In the process of PRP preparation, the centrifugal parameters are inconsistent, but the standard for testing PRP preparation is the enrichment coefficient, which needs to reach more than 4 to meet the standard [37].Because platelet activation requires calcium channel mobilization [38]. Therefore, 10 %CaCl2 is generally used to activate PRP [39].When PRP is used, bovine thrombin is generally used to make it gel [40].In addition, it is necessary to determine the concentration of growth factors in PRP by enzyme-linked immunosorbent assay (Elisa), which is very important for the subsequent determination of factor release [41].In addition, factors are inactivated when PRP is stored, and freeze-drying PRP is one of the effective strategies to maintain its biological activity for a long time [42].To sum up, at present, the preparation and use strategies of PRP are inconsistent, and there is no unified standard and specification. This may be a big problem in the standardized treatment of PRP in the future.

3. The role of PRP in bone repair

In the past, it was found that PRP contains a lot of growth factors needed in the process of bone formation, so it is widely used in the field of bone tissue engineering [43,44]. Among them, different growth factors play different roles, among which PDGF is the most abundant. PDGF can be used as an inducer to promote mitosis of BMSCs [45], PDGF is an angiogenic factor secreted by osteoclast precursor cells, which can induce the formation of H-type blood vessels and stimulate bone repair [46].IGF plays an important role in cell proliferation and differentiation [47].Studies have shown that IGF can combine with insulin-like growth factor receptors of osteoblasts and endothelial cells to induce osteogenesis and angiogenesis [48].TGF-β regulates bone development by activating serine/serine kinase receptors [49], it plays an important role in bone development, cartilage formation and differentiation and bone homeostasis [50]. FGF is one of the protagonists in the repair of callus fracture [26], the effect of promoting the formation of bone and blood vessels can be achieved by adjusting the administration time, dosage and mode [51].VEGF is the main inducer of angiogenesis during bone repair [52]. Bone formation is indirectly induced by regulating related osteogenic growth factors and activating paracrine signals [53]. PRP is rich in various growth factors, so it has a positive effect on angiogenesis, cartilage repair and bone formation.

3.1. Effect of PRP on bone formation and its application

The role of PRP in the formation of bone tissue is mainly reflected in the formation of osteogenesis and chondrogenesis [54]. Currently, the influence of PRP can be observed in numerous bone regeneration biomaterials (Table 1). Shi et al. improved the osteogenic activity of PEEK material by coating PRP on the frosted PEEK surface, which provided a new idea for the treatment of bone defects with PRP [55].Wei et al. printed a hybrid scaffold based on silk fibroin by bio-printing technology, and coated PRP on the surface of the scaffold. It was found that coating PRP promoted the osteogenic differentiation of stem cells [56], which is consistent with the conclusion of Qin et al. that PRP increased the ratio of osteoprotegerin (OPG)/nuclear factor κ B ligand receptor activator (Rankl) and promoted the differentiation of BMSCs into osteoblasts [57]. Studies by Fernadndes et al. showed that PRP increased the activity of alkaline phosphatase in a dose-dependent manner with the increase of concentration in the dosage of 2.5 %–10 %, and then significantly promoted bone regeneration [58]. Jiang et al. prepared PRP- gelatin methacryloyl (GelMA) hydrogel scaffolds with different concentrations. It was found that 20 % PRP-GelMA could induce more macrophages to polarize to M2 compared with 50 % group, which indicated that too high dose of PRP might affect the osteogenic effect of PRP [59] (Fig. 2). Although PRP plays an important role in orthopedic treatment of bone defects, there are still some problems, such as explosive release of growth factors and limitation of use methods [60].Qiao et al. treated osteoporosis rabbits by coating PRP prepared by traditional method and freeze-drying method on 3D printed titanium alloy scaffold, and found that PRP prepared by freeze-drying method showed better osteogenic advantages and cell activity [61].By encapsulating freeze-dried PRP into Collagen Type I (COL-1) hydrogel, Chen et al. not only utilized the osteogenic activity of PRP, but also improved the mechanical properties of hydrogel, providing a new form for orthopedics to treat bone defects with PRP [62].Van Eps uses PRP, Mg, hydroxyapatite and COL-1 scaffolds for spinal fusion, which significantly improves the spinal fusion rate and achieves better bone regeneration effect, providing a new method for orthopedics to treat bone defects with PRP [63].In addition, Huang et al. found that platelet lysate (PL) obtained by freezing and thawing at ultra-low temperature has a potential role in the treatment of glucocorticoid-induced femoral head necrosis, which provides a new idea for orthopedics to preserve PRP and treat related diseases [64]. From another perspective, insufficient blood supply in bone defect healing will lead to the obstacle of bone defect repair, so enhancing vascular regeneration in bone defect is also the key to treatment [65,66].Recent studies have shown that PRP can effectively improve angiogenesis and wound healing [67]. For example, Bretschneider et al. found that PRP co-cultured with BMSCs and human umbilical vein endothelial cells detected the expression of various angiogenic proteins, which indicated the angiogenic potential of PRP [68]; Chun Liu et al. developed a novel polycaprolactone/β-tricalcium phosphate/platelet-rich plasma/gelatin composite scaffold and demonstrated that the incorporation of platelet-rich plasma enhanced the viability, proliferation, migration, and osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells, and at the same time PRP guaranteed the sustained release effect for more than 3 weeks, thereby promoting vascularized bone regeneration and facilitating the repair of large bone defects [69]. Similarly, Junyan An et al. developed a hyaluronic acid hydrogel coating loaded with PRP and NGF on the surface of PEEK material. The results demonstrated that the coating enabled sustained release of multiple growth factors, including NGF, thereby effectively enhancing implant osseointegration as well as neovascularization and new bone formation [70].Lian et al. used GelMA to load PRP, and found that it can improve cell migration and angiogenesis in vitro, forming vascularized bone regeneration and accelerating bone repair efficiency, and they evaluated the release of growth factors. It was found that the release of growth factors lasted for 35 days, which solved the problem of explosive release of growth factors [71] (Fig. 3).

Table 1.

PRP-containing biomaterials for bone repair.

Material	Chemical compound/Phase	Form	Functions	Ref
Polymer scaffold	PEEK, PRP	Coating	Promote cell proliferation and differentiation, and promote bone defect repair.	[55]
Polymer scaffold	Silk fibroin, Gelatin, Hyaluronic acid, PRP	Coating	Promote the growth and proliferation of stem cells, as well as the late gene expression after osteogenic differentiation.	[56]
Hydrogel	Gelatin methacryloyl, PRP	Loaded drugs	Promote bone tissue regeneration by promoting the proliferation and differentiation of mesenchymal stem cells, and effectively create a repair environment for osteochondral regeneration by regulating the polarization of macrophages to M2 direction.	[59]
Alloy scaffold	Ti6Al4V, PRP	Coating	The introduction of PRP promoted the attachment, proliferation, survival, migration and osteogenic differentiation of bone marrow mesenchymal stem cells in osteoporotic state which is beneficial for bone regeneration.	[61]
Hydrogel	Col I, Freeze-dried PRP	Loaded drugs	PRP effectively alleviates the in vitro contraction of collagen hydrogels, promotes the adhesion, proliferation, osteogenic differentiation of rBMSCs, and the expression of early and late osteogenesis-related proteins.	[62]
Nano-structured scaffold	Magnesium, Hydroxyapatite, Col I, PRP	One of the components	Enhances the expression of key osteogenic genes, including RUNX2, SPARC, and SPP1, thereby demonstrating strong osteoinductive potential.	[63]
Polymer scaffold	Gelatin microspheres, Polycaprolactone, PRP, β-tricalcium phosphate	Loaded drugs	Achieve the long-term release of PRP-related cell growth factors and promote vascularized bone regeneration.	[69]
Polymer scaffold	PEEK, Hyaluronic acid hydrogel, PRP	Coating	Promote the osseointegration of the implant and the integration of new bone and new blood vessels to achieve vascularization and osteogenesis	[70]
Hydrogel	Gelatin methacrylate, PRP	Loaded drugs	Significantly improved cell migration and angiogenesis and promoted vascularized bone regeneration.	[71]

Fig. 2.

Scheme of osteochondral regeneration through M2 macrophage polarization in a rabbit model. (A–D) SEM images of BMSCs with different proportions of PRP-Gel gel. (E–H) Alizarin red staining to judge osteogenic differentiation. (I–L) Alcian Blue staining was used to judge cartilage differentiation. (m–p) mRNA expression levels of RUX2, OCN, COL2A1 and SOX9 in BMSCs (A-L scale: 200 μm). (Q–S) Arg1 immunofluorescence staining of Raw264.7 cells cultured in different hydrogels. CD206 immunofluorescence staining of (T–V) Raw264.7 cells. (w) q-PCR results of M2 gene expression in raw 264.7 cells (x) q-PCR results of M1 gene expression in raw 264.7 cells (Q-V scale: 50 μm). (∗P < 0.05) [59].

Fig. 3.

(A)Isolation and preparation of PRP and preparation and treatment of large segmental bone defect model. (B)Function of GM@PRP hydrogel in bone repair. (C) The pore size of different hydrogels. (D)Release curve of growth factors PDGF, EGF and TGF-β in GM@PRP immersed in PBS. (E)Live/dead cell staining of human umbilical vein endothelial cells (HUVECs), MC3T3-E1 and rBMSCs on Day1 and Day5, scale: 600 μm. (F)24h image of scratch repair experiment, scale: 500 μm. (G)12-h migration experiment of HUVECs in vitro, scale: 600 μm. (H)In vitro tubule formation experiment of HUVECs in 6 h, scale: 500 μm. (I)Digital picture of tibial defect. (J)Digital pictures of GM @ PRP treating tibia defect (Week4 and Week8). (K)CT images of bone defects after treatment [71]. (∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001).

3.2. Effect of PRP on cartilage repair and its application

Cartilage injury is a common disease in joint surgery. Because of its limited ability to repair cartilage tissue, it is generally treated by joint replacement [72,73]. At present, tissue engineering research has found that PRP can be used as an alternative therapy for cartilage repair, but its standardized use in cartilage repair needs to be standardized [74,75] (Table 2). In 2012, Xie et al. found that PRP can release endogenous growth factors to induce BMSCs to differentiate into chondrocytes, which proved that it is suitable for cell-based cartilage repair [76]. Giannetti et al. studied the differentiation of bone marrow-derived stem cells (AFSCs) cultured in vitro into cartilage or osteoblasts by PRP, and found that cartilage formation markers showed higher expression, which provided a new research direction and idea for regenerative medicine to treat osteochondrosis [77]. PRP is a self-derived therapeutic adjuvant for cartilage injury. Although it provides growth factors needed for tissue regeneration, there are still some problems in the clinical treatment of PRP, which need to be improved [78].Jiang et al. prepared PRP- GelMA hydrogel scaffolds with different concentrations, and it was found that 20 % PRP-GelMA showed better cartilage and subchondral bone regeneration [59] (Fig. 2). Lin et al. further integrated fat pad-derived mesenchymal stem cells with PRP and demonstrated that PRP can effectively promote chondrogenic differentiation of stem cells and enhance hyaline cartilage regeneration [79]. Irmak et al. used 3D printing technology to build an osteochondral scaffold with PRP, stem cells, extracellular matrix and GelMA as bio-ink. The strength of hydrogel was improved by photo-crosslinking, and osteochondral formation was promoted in vitro. Among them, PRP induced cells to differentiate into cartilage, and high-strength hydrogel achieved cartilage regeneration through high-intensity physical stimulation [80]. Similarly, regarding the possible burst release issue of PRP, Liu et al. realized the controllable release of growth factors by adding hyaluronic acid into PRP gel, and its cartilage repair effect provided a new method for the transformation and application of PRP because of the PRP gel activated by thrombin [81]. Furthermore, the latest research indicates that PRP-associated exosomes (PRP-Exos) have become a current research hotspot due to their targeted delivery and more precise mechanism of action. For example, Chen et al. found that exosomes derived from PRP can promote angiogenesis in diabetic mice by delivering sphingosine-1-phosphate (S1P), thereby enhancing wound repair [82]. Similarly, PRP-Exos has also been applied to cartilage. Xuchang Liu et al. developed a β-TCP scaffold functionalized with PRP-Exos in combination with a cyclic peptide, demonstrating that the incorporation of PRP-Exos significantly enhanced cartilage repair in rabbit models of knee cartilage defects. The study further investigated the involvement of the PI3K/AKT signaling pathway through a series of complementary in vitro and in vivo experiments [83]. To sum up, there are many studies on the application of PRP in cartilage repair, but there is no standardized specification that can be implemented, which will be the key to the treatment of cartilage injury and transformation by PRP in the future.

Table 2.

PRP-containing biomaterials for cartilage repair.

Material	Chemical compound/Phase	Form	Functions	Ref
Hydrogel	Gelatin methacryloyl, PRP	Loaded drugs	Regulate the polarization of macrophages towards M2 effectively creates a repair environment for osteochondral regeneration and directly promotes the chondrogenic differentiation of mesenchymal stem cells.	[59]
Hydrogel	PRP, Infrapatellar fat pad-derived mesenchymal stem cell Thermoresponsive chitosan-graft-poly(N-isopropylacrylamide)	Loaded drugs	PRP provides an appropriate environment for AdMSCs to differentiate into osteochondral tissue and enhances the expression of bone and cartilage specific genes.	[79]
Hydrogel	PRP, Adipose tissue-derived mesenchymal stem cells, Extracellular matrix, Methacrylated gelatin	Loaded drugs	PRP contributes to enhanced cartilage and osteogenic gene expression, cartilage and bone-specific extracellular matrix production, hyaline cartilage regeneration, and mineralized bone tissue formation.	[80]
Hydrogel	Hyaluronic acid, PRP	Loaded drugs	The addition of PRP can promote the proliferation and migration of chondrocytes and bone marrow stem cells, and achieve the overall hyaline cartilage regeneration.	[81]
Scaffold	PRP, β-tricalcium phosphate	Exosomes	Promote cartilage repair through the PI3K/AKT signaling pathway.	[83]

To sum up, the application of PRP in the field of bone repair cartilage repair has been very common, and many solutions have been found to limit the explosive release, preservation and use of growth factors in PRP, which provides a theoretical basis for orthopedic treatment of bone defects.

4. The role of PRP in nerve repair

In fact, within the complex clinical contexts of bone injuries, concurrent nerve damage is frequently observed. For example, in cases of accidental cuts caused by sharp objects, the sharp blade that results in a fracture may simultaneously sever or bruise the surrounding nerve tissue. Similarly, in severe traffic accidents, the intense impact force can cause bone fractures with displacement, thereby compressing, stretching, or even tearing adjacent nerves. Furthermore, bone fragments resulting from violent fracture may directly inflict lacerative damage upon nearby nerves [[84], [85], [86]]. Collectively, these scenarios indicate a strong association between bone injury and nerve damage.

There are several treatment options available for nerve injuries, such as neurolysis, nerve grafting, and tendon transfer [87]. The emergence of PRP is not only of great significance in the process of bone repair but also holds remarkable potential in the repair of nerve tissue. PRP can initiate the hemostatic cascade by releasing a variety of bioactive factors, promote the synthesis of new connective tissue and revascularization, thereby aiding in the recovery of damaged tissues [88]. Further studies have shown that PRP, as an autologous source of bioactive factors, plays a synergistic role in neuronal survival, Schwann cell function and microenvironment regulation, which is beneficial for neuroprotection, treatment of neurogenic diseases and regulation of neuroinflammation [89]. Additionally, it has demonstrated excellent neuroregenerative and analgesic capabilities in both in vitro and in vivo experiments [90,91].

4.1. The mechanism of PRP promoting nerve repair

Researches have shown that the mechanism by which PRP promotes nerve tissue repair may involve various endogenous and exogenous activating substances that stimulate platelet activation following biological tissue injury. This activation triggers degranulation of α-granules within platelets, releasing a large number of bioactive substances such as growth factors, fibrinogen, cathepsins, and hydrolases. The released growth factors then bind to the outer surface of target cell membranes via transmembrane receptors, inducing the activation of endogenous signaling protein pathways including PI3K/Akt and p38MAPK, while inhibiting the activation of inflammatory pathways such as NF-κB. This process further promotes various intracellular gene expressions, cell proliferation, matrix formation, and collagen synthesis, thereby achieving the repair and regeneration of nerve tissue [92,93].

Zheng, CB et al. pointed out that the core function of PRP stems from its secretome, such as platelet-derived wound healing factor (PDWHF) activated by PRP [94]. It contains angiogenic factors like VEGF-A and PDGF-BB, which can not only promote the formation of endoneurial vessels to provide necessary nutrients for the repair process, but also increase the secretion of neurotrophic factors such as NGF (Nerve Growth Factor) and GDNF (Growth Differentiation Factor), providing biological signals required for nerve repair and further improving the regenerative microenvironment for nerve repair [95,96]. By binding to its high-affinity receptor, tropomyosin receptor kinase A (TrkA), NGF not only promotes the survival of sensory and sympathetic neurons but also functions as a potent chemoattractant, guiding axonal growth cones toward their target destinations. Similarly, brain-derived neurotrophic factor (BDNF) signaling through the tropomyosin-associated kinase B (TrkB) receptor is critical for the survival and maintenance of motor neurons and a subset of sensory neurons, and plays a significant role in modulating synaptic plasticity and consolidating functional neural circuits during recovery [97]. Meanwhile, growth factors in PRP including TGF-β and IGF-1 exert a catalytic effect on accelerating the regeneration of nerve fibers [98]. IGF-1, on the other hand, exerts positive effects on nerve repair in multiple aspects. It can not only stabilize the extracellular matrix and promote the production of collagen and other extracellular matrix proteins, providing support and a structural framework for regenerating nerve fibers [99], but also activate the PI3K/Akt pathway to promote plasmalemmal expansion at the neuronal growth cone, leading to the recruitment and insertion of new membrane components at the growing tip, which is the fundamental driving force behind axon elongation [100]. Furthermore, studies have shown that IGF-1 reduces the excitotoxicity induced by glutamate on neurons through the ERK1/2 and PI3K/Akt signaling pathways and inhibits neuronal apoptosis, thereby improving the survival rate of neurons [101].

After nerve injury, Schwann cells (SCs) undergo a significant phenotypic transformation, differentiating from the myelin state to a phenotype that promotes repair, which is essential for successful regeneration. Throughout the entire regeneration process, PRP plays a multi-faceted role in activating and maintaining these SCs that support repair. In the early phase after injury, the rapid proliferation and migration of SCs are critical to form the so-called “Büngner bands”—cellular cords that physically guide regenerating axons across the injury gap. PRP components are potent drivers of this response. PDGF-BB, IGF-1 and GDNF present in PRP act as powerful mitogens and chemoattractants for SCs, promoting Schwann cell proliferation by activating the PI3K/Akt/mTOR signaling pathway, which is conducive to ensuring that a sufficient number of SCs are recruited to the injured site to form scaffolds that are beneficial for regeneration [102]. In addition, a critical step in functional nerve repair is myelination of regenerating axons. In this process, TGF-β in PRP plays a decisive role. TGF-β signaling promotes redifferentiation of repaired SCS into a myelin phenotype. It does so by regulating the expression of key transcription factors and myelin-related genes, ultimately driving the synthesis and encapsulation of myelin sheathe around newly formed axons [103].

In the process of nerve repair, precise regulation of the inflammatory response is crucial for promoting nerve regeneration. Excessive or persistent inflammatory responses can exacerbate neuronal damage, inhibit axonal growth, and impede myelin formation, thereby limiting the recovery of nerve function. Conversely, a moderate inflammatory response helps clear necrotic tissue debris, promote angiogenesis, and recruit reparative cells to the injury site, creating a favorable microenvironment for nerve regeneration [104]. A defining and therapeutically crucial feature of PRP is its ability to exert precise spatiotemporal immunomodulation, actively resolving detrimental inflammation and steering the immune microenvironment toward a pro-regenerative state [105]. Studies by Yadav, A et al. found that PRP or its derivative, platelet-rich growth factor (PRGF), can downregulate the expression of TNF-α, IL-1β, IL-6, and CD68⁺ M1 macrophages in a rat model of sciatic nerve transection. This shifts the inflammatory microenvironment in nerve tissue from a pro-inflammatory state to an anti-inflammatory state, thereby reducing nerve cell damage and enhancing axonal regeneration potential [106]. Similarly, Anjali Yadav et al. found that PRP could reduce the expression of proinflammatory mRNA such as TNFα, IL-1β and IL-6 in M0 macrophages, and increase the expression of M2 regenerative macrophage markers represented by CD206. Moreover, the regenerated axon protein gene product (PGP9.5), Schwann cells (S100β) and myelin basic protein (MBP) were increased, indicating that the regulation of PRP on the immune microenvironment after injury promotes nerve repair to a certain extent [106].Additionally, studies by Zeng, Y et al. revealed that PRP can activate cellular autophagy to inhibit oxidative stress, which also appears to have excellent regulatory potential for the inflammatory response at nerve injury sites, further demonstrating the positive effects of PRP on inflammatory responses and nerve repair [107,108].

However, the therapeutic effect of PRP on nerve tissue repair does not rely on a simple linear relationship. Studies by Takeuchi, M et al. revealed that 5 % and 10 % PRP diluted in horse serum medium can maximize axonal regeneration through mechanisms related to IGF-1 and VEGF, whereas 20 % PRP exhibits a significant inhibitory effect on co-cultured substances from other organs. It was also found that 5 % PRP maximally promotes the proliferation of human adipose-derived stem cells and human dermal fibroblasts, while 20 % PRP fails to show a corresponding proliferative effect [109]. Similarly, Canbin Zheng et al. investigated the impact of PRP concentration on the proliferation, migration, and neurotrophic function of Schwann cells, and found that 20 % PRP is the threshold for these beneficial effects. PRP promotes Schwann cell proliferation and the secretion of neurotrophic molecules such as NGF and GDNF in a dose-dependent manner when its concentration is below 20 %, while high concentration (40 %) PRP exerts adverse effects on Schwann cells [110]. This is consistent with the research by Graziani et al., who found that 16.5 % PRP has the optimal positive effect on the functions of osteoblasts and fibroblasts in vitro [111]. Therefore, we conclude that PRP at concentrations below 20 % exerts excellent therapeutic effects on nerve tissue repair. However, the specific optimal concentration may vary among individuals and be influenced by different PRP preparation methods [112]. “In addition, the duration of PRP treatment represents a critical factor influencing the efficacy of nerve repair. Muhammad Pandunugrahadi et al. demonstrated that administering PRP on days 0, 3, 7, and 14 post-injury resulted in optimal therapeutic outcomes in the 14-day treatment group, suggesting that delayed PRP administration may yield superior results [113]. This observation may be attributed to the body's intrinsic capacity to generate sufficient growth factors immediately following nerve injury. Consequently, exogenous supplementation with growth factors via PRP within the early phase may not confer significant additional benefits. It is therefore proposed that PRP plays a more prominent role in promoting nerve maturation rather than merely stimulating cellular proliferation [114]. Therefore, the mechanism of PRP promoting nerve repair is not limited to the molecular pathway, and its concentration, preparation method, and application time all have important effects on the effect of nerve regeneration, which also suggests that there is still a lot of space to be explored for the application of PRP in the field of nerve repair in the future.”

4.2. Application of PRP in nerve repair

The therapeutic potential of PRP, due to its multifaceted mechanisms, has translated into a wide range of experimental and clinical applications for nerve repair. These applications can be broadly divided into the fields of peripheral nerve regeneration and central nerve repair, as well as exploratory studies of more challenging neurodegenerative pathologies [115,116] (Table 3, Table 4, Table 5).

Table 3.

PRP-containing biomaterials for peripheral nerve repair.

Material	Chemical compound/Phase	Form	Functions	Ref
Vein autograft	Left jugular vein, PRP	Loaded drugs	It promotes the formation of new blood vessels in the early stage of axon regeneration, thereby facilitating axon regeneration in sciatic nerve segmental defects.	[126]
Polymer scaffold	PCL, collagen, PRP	Loaded drugs	It enhances sciatic nerve repair, reduces muscle atrophy, and functional recovery through topical delivery of PRP.	[127]
Hydrogel	Gelatin methacryloyl, Sodium alginate, PRP	Loaded drugs	It regulates the regeneration microenvironment through continuous release of growth factors, which significantly promotes Schwann cell migration and endothelial cell neovascularization, thereby accelerating sciatic nerve repair.	[128]
Fibrin membrane	PRP, PRF	Loaded drugs	It is used for clinical treatment of pressure injury healing in patients with spinal cord injury.	[130]
Polymer composite film	Collagen, Chitosan, PRP	Loaded drugs	It can promote nerve regeneration and functional recovery in rats with sciatic nerve injury.	[131]
Conduits	Polyurethane, Gelatin nanofibers, PRP	Loaded drugs	It can successfully promote the regeneration of injured sciatic nerves.	[132] [133]
Vein autograft	Superficial subcutaneous vein, PRP	Loaded drugs	It can enhance the proliferation and migration of Schwann cells, accelerate axonal regeneration, and facilitate the recovery of tibial nerve defects.	[135]
Platelet-rich plasma-derived exosomes	PRP	Exosomes	Promote the proliferation of Schwann cells and the growth of dorsal root ganglion axons, weaken the senescence of MSCS, and treat peripheral nerve injury.	[140]

Table 4.

PRP-containing biomaterials for central nerve repair.

Material	Chemical compound/Phase	Form	Functions	Ref
Polymer scaffold	Chitosan, PRP	Loaded drugs	It promotes nerve fiber regeneration and angiogenesis, prevents scar tissue formation, and demonstrates significant efficacy in repairing injured spinal cords.	[154]
Hydrogel	PRP, Bioengineered human embryonic stem cells	Loaded drugs	Promote axonal regeneration after dorsal root transection and restore sensory-motor function.	[155]
Hydrogel	Sodium alginate, PRP, Gelatin methacrylate,	Loaded drugs	It promotes neuronal differentiation, inhibits astrocyte differentiation, supports axonal regeneration, and enhances the migration and angiogenic capacity of endogenous neural stem cells, thereby offering an effective therapeutic approach for spinal cord injury.	[156]
Hydrogel	PRP-Exo	Exosomes	Enhance the expression of tight junction proteins helps to reduce the leakage of blood spinal cord barrier and relieve the inflammatory environment in the damaged area, thereby improving the recovery of neurological function	[157]
Exosomes	PRP, Dexamethasone	Exosomes	Reduce the size of the lesion, lymphocyte infiltration, vacuolation, cavity size and tissue disorder at the site of spinal cord injury, and also improves motor recovery.	[158]

Table 5.

Concentrations of PRP that exert different regenerative effects.

	Concentration for osteogenesis	Concentration for angiogenesis	Concentration for nerve regeneration	Concentration for inhibitory effects
PRP	2.5 %–10 %	10 %–20 %	5 %–20 %	>20 %

4.2.1. Application of PRP in peripheral nervous system injury

Peripheral nerve regeneration remains a significant clinical hurdle. While the peripheral nervous system has a greater intrinsic regenerative capacity than the central nervous system, functional recovery is often suboptimal, particularly when facing substantial nerve gaps. In this context, PRP has been widely investigated as a pro-regenerative adjuvant. Its primary application involves incorporation into biomaterial conduits and scaffolds, which serve to bridge anatomical defects while providing sustained release of its bioactive factors to enhance the endogenous healing process [117,118]. The sciatic nerve is the largest and longest nerve in the human body, innervating almost all sensory and motor functions below the knee joint, which is often used as a classic model for studying peripheral nerve regeneration and repair [119]. Factors such as lumbar disc herniation, spinal stenosis, pelvic fractures, and tumors are the main causes of sciatic nerve injury, which can not only cause sensory and motor dysfunction but also lead to vasomotor and nutritional disorders as well as the occurrence of decubitus ulcers [120]. Common sciatic nerve repair methods range from direct suture to autologous nerve transplantation, and now to the use of polymer graft materials with stronger strain capacity and viscoelasticity, such as poly lactic-co-glycolic acid (PLGA). These materials provide good structural support through adjustable degradation rates and appropriate mechanical strength, while loading neurotrophic factors (such as NGF, BDNF) or anti-inflammatory drugs for local sustained release, creating a biocompatible and functionally oriented microenvironment for axonal regeneration, and have become an excellent method for nerve repair at present [121,122]. However, exogenous neurotrophic factors have limitations in the field of nerve repair due to their single-factor release mode, which is difficult to simulate the complex growth factor network in vivo, and systemic application is prone to induce immune responses [123]. It is worth noting that the repair effect of autologous-derived and low-immunogenicity substances on nerve tissue provides a new therapeutic idea for sciatic nerve repair. As early as 2007, Farrag, TY et al. discovered the effective repair effect of PRP combined with suturing on the facial nerve, which also paved the way for the application of PRP in the field of nerve repair [124]. Studies by Ikumi, A et al. found that PRP increased the diameter and number of regenerated axons in the distal part of rats with sciatic nerve defects and accelerated the proliferation of Schwann cells [125]. Therefore, introducing PRP as a bioactive substance into nerve implants can significantly enhance the effect of nerve repair. For example, Minn, Kim, JY et al. used venous grafts containing PRP to bridge 10 mm-long sciatic nerve defects in rats. Compared with simple grafts without PRP, the study found that the addition of PRP resulted in a higher number of myelinated axons, larger axon diameters, and thicker myelin sheaths at the defect site, demonstrating its positive effect on sciatic nerve regeneration [126]. Chen, WF et al. used polycaprolactone (PCL)/collagen scaffolds loaded with PRP and Schwann cells at the site of sciatic nerve injury. Compared with the pure negative control group and the implant group consisting only of polymer (PCL/CCOL), the introduction of PRP significantly enhanced the recovery of sensory and motor functions in the lower limbs of rats [127]. Qi Dong et al. incorporated PRP into GelMA and sodium alginate (SA) hydrogels to fabricate composite nerve conduits. The study found that the introduction of PRP not only improved the mechanical properties of the hydrogel with a more appropriate degradation rate but also could continuously release growth factors to promote the migration of Schwann cells and neovascularization at the injured site, thereby facilitating the repair of injured sciatic nerves in rats (Fig. 4) [128]. In addition, PRP can not only serve as a source of bioactive proteins but also act as a well-suited suturable membrane, which can effectively prevent fibrosis and promote axonal regeneration [129]. For instance, Swarnakar, R et al. developed a platelet-rich fibrin membrane, which showed excellent efficacy in healing neural pressure injuries in patients with spinal cord injury [130]. Yuan, B et al. loaded PRP gel onto the surface of Col/Cs composite membranes, which not only significantly improved the biocompatibility of the membranes but also promoted the proliferation of Schwann cells, showing good nerve repair effects in a rat model of sciatic nerve defect [131]. Further studies have found that more excellent therapeutic effects can be achieved when PRP is used in combination with other active factors. For example, Salehi, M et al. used PRP as a carrier for resveratrol (RVT) and incorporated it into polyurethane (PU)/gelatin nanofiber (GNFS) conduits for the treatment of sciatic nerve injury, achieving better sciatic nerve repair effects [132]. In the same way, they constructed a polyurethane/gelatin nanofiber nerve guide conduit containing PRP and melatonin and used it as a carrier for SCs. The use of PRP to activate the proliferation of exogenous SCs can effectively promote nerve regeneration after peripheral nerve injury and improve the rate of nerve recovery [133]. Additionally, Zavala, A's team compared the therapeutic effects of curcumin and PRP when administered alone and in combination on sciatic nerve injury. The study found that the combined application more significantly enhanced axonal regeneration in acute vertebral nerve injury in rats, with more favorable therapeutic significance [134]. In summary, research on the application of PRP in human sciatic nerve repair may provide new ideas and methods for human nerve injury repair. In fact, the application of PRP in peripheral nerves is not limited to the sciatic nerve; it has equally extensive applications in repairing more types of nerves. For example, Yaqiong Zhu et al. found that using autologous vein grafts filled with PRP and active nerve microtissues is effective in repairing tibial nerve defects in rabbits. The application of PRP significantly improved the recovery of lower limb motor function in the animal model [135]. Studies have shown that PRP can not only enhance the repair effect of chitosan gel on the facial nerve but also, when used alone, promote the recovery of nystagmus, eyelid closure, and electrophysiological function in rats with facial nerve crush injury [136,137]. In addition, Ding, XG et al. found that PRP also has a repair effect on the cavernous nerve. In a rat model of cavernous nerve injury, the use of PRP significantly promoted the formation of more myelinated axons and more nicotinamide adenine dinucleotide phosphate diaphorase-positive nerve fibers, which is conducive to nerve regeneration and the recovery of erectile function [138]. On this basis, Chun-Hou Liao et al. further studied the mechanism by which PRP promotes cavernous nerve repair and the recovery of erectile function. It was found that PRP prevents the degeneration of cavernous nerves after prostatectomy, protects the nerves by significantly increasing neurofilament 1 (NF-1) expression and preserving myelinated axons, and simultaneously prevents autologous smooth muscle atrophy and reduces collagen deposition, thereby promoting cavernous nerve repair and the recovery of erectile function [139]. In addition to the direct application of PRP in biomaterials, recent studies have demonstrated that PRP-derived exosomes are enriched with bioactive molecules capable of mediating intercellular communication and hold promise for integration with stem cell therapy in the treatment of peripheral nerve injuries. For example, Xiaodong Geng et al. found that PRP-Exos enhanced the vitality, survival rate, dryness and neurotrophic paracrine characteristics of MSCS, reduced the apoptosis of MSCS under stress, maintained the dryness of MSCS, and weakened the senescence of MSCS. Furthermore, pExo-MSCs co-culture was found to activate the PI3K/Akt signaling pathway in MSCs to promote the secretion of GDNF-based neurotrophic factors, which mediated Schwann cell proliferation and migration as well as DRG axon outgrowth. Therefore, transplantation of pExo-MSC to the injured site of peripheral nerve can improve the functional recovery of PNI by promoting axon regeneration and myelin regeneration [140,141].

Fig. 4.

PRP promotes sciatic nerve repair in rats. (A) Schematic diagram of the preparation of a composite hydrogel catheter containing PRP and its repair of peripheral nerves by promoting Schwann cell migration and angiogenesis. (B) The expression of VEGF-A signaling pathway genes in HUVECs. (C) Compare the nerve regeneration by G-ratio. (D) The migration of RSC96 cells in the control group, GelMA/SA-3 group and GelMA/SA-3/PRP-20. (E) The histological assessment of regenerated nerves was conducted using HE staining and TB staining. (F) Immunofluorescence analysis of regenerating nerves by using NF200 and S100. (G) Representative images of the regenerated nerves [128]. (∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001).

In conclusion, PRP not only provides essential nutrients for peripheral nerve repair through its rich bioactive substances such as neurotrophic factors and growth factors, but also regulates inflammatory responses, promotes the migration and proliferation of stem cells to the injured site, and facilitates nerve regeneration. Therefore, PRP has a multi-dimensional mechanism for promoting peripheral nerve repair and plays an important therapeutic role in various types of peripheral nerve injuries.

4.2.2. Application of PRP in central nervous system injury

Central nervous system diseases include injuries to the brain or spinal cord, tumors, and degenerative diseases of the central nervous system such as multiple sclerosis (MS), Parkinson's disease (AD), and vascular dementia (VD), among others. These conditions exert a significant negative impact on patients' quality of life [142,143]. Therapeutic approaches for repairing central nervous system injuries include the use of anti-inflammatory drugs and neurotrophic factors, immunotherapy, stem cell therapy, and implantation of biomaterials, etc [[144], [145], [146]]. PRP is often used as a preparation rich in nerve growth factors or added to nerve repair implant materials. It not only has a strong neurotrophic effect but also can promote the migration of stem cells and regulate the immune microenvironment, enhancing the effect of nerve repair in various ways, which is also applicable to the repair and treatment of central nerves [147,148]. Spinal cord injury (SCI) is one of the common forms of central nervous system injury, and it is also the most commonly used disease for PRP [149]. Spinal cord injury is a severe disabling condition that leads to tissue degeneration through neuronal loss and fiber disruption, thereby impairing sensorimotor function [150]. PRP has been proven to promote axonal growth from the cerebral cortex to the spinal cord and reverse or minimize the adverse effects caused by spinal cord injury, which is of great significance for the repair of spinal cord injury [109]. Studies by Zahra Behroozi et al. found that injecting human umbilical cord blood-derived PRP (HUCB-PRP) into the spinal canal of rats with spinal cord injury can exert neuroprotective effects by inhibiting apoptosis and GSK3β enzyme, effectively improving the recovery of motor function in rats [151]. Simple PRP treatment already has excellent nerve repair effects. With the development of biomedicine and clinical medicine, more and more researchers have applied PRP in combination with stem cells to exert their coordinated role in the treatment of spinal cord injury. This not only retains the neurotrophic effect of PRP but also leverages its ability to promote the migration of stem cells to the injured site, secrete neuroprotective growth factors such as BDNF, NGF, and PDGF, and differentiate into cells required for nerve regeneration [150,152]. For example, Hu, ZB et al. compared the effects of PRP and human dental pulp stem cells (hDPSCs) when used alone and in combination in the treatment of spinal cord injury in rats, and found that the combined application of stem cells and PRP indeed achieved better therapeutic effects [153]; Ai, J et al., on the basis of using PRP preparations, used chitosan scaffolds as carriers for stem cell delivery, providing support for axonal regeneration, promoting nerve fiber regeneration and angiogenesis, and preventing the formation of scar tissue during spinal cord injury repair [154]; Root avulsion at the junction where nerve roots connect to the spinal cord is also a common type of spinal cord injury. Mateus Vidigal de Castro et al. used PRP gel combined with bioengineered human embryonic stem cells to promote substantial and significant axonal regeneration after dorsal rhizotomy in mice, successfully restoring spinal reflexes [155]. Zhihe Yun et al. constructed a PRP/Alg/GelMA triple composite network hydrogel, which promotes neurogenesis and angiogenesis after spinal cord injury by enhancing the PI3K/AKT/mTOR signaling pathway, serving as a simple, feasible, and promising therapeutic strategy for nerve regeneration after spinal cord injury (Fig. 5) [156]. Similarly, as a current research hotspot, PRP-Exos has also been applied to the treatment of central nervous system injury, including spinal cord injury. Xinyu Nie et al. encapsulated PRP-Exos into hydrogels and found that PRP-Exos reduced Evans blue dye leakage, enhanced tight junction protein expression, protected the integrity of the blood-spinal cord barrier (BSCB), and alleviated the inflammatory environment in the damaged area through in vivo experiments [157]. On this basis, Naeimeh Akbari-Gharalari et al. prepared PRP-derived exosomes loaded with dexamethasone (Dex), and showed that intravenous injection of PRP-ExoDex significantly reduced the size of the lesion site, lymphocyte infiltration, vacuolization, cavity size and tissue disorder through animal experiments by targeting the Bax/Bcl2 pathway, which also improved motor recovery in mice. It also opens up new ideas for the application of PRP-Exos in the field of spinal cord injury [158]. However, any therapeutic agent has two sides. PRP has been shown to have the potential to induce inflammatory reactions [159,160]. On this basis, Nan-Fu Chen et al. further pointed out that although PRP can induce inflammation in both normal and injured spinal cords, low-dose PRP has vascular protective effects and enhances endogenous angiogenesis, which is beneficial for the recovery of spinal cord injury, and more excellent axonal regeneration ability was observed in animal models [161].

Fig. 5.

PRP is used to treat spinal cord injury in rats. (A) Schematic diagram of PRP/Alg/GelMA triple network hydrogel promoting spinal cord injury. (B) KI67 immunofluorescence was used to detect PRP's effect on NSCs proliferation. (C) The expression of VEGF gene in the spinal cord injury model in different groups. (D) The differentiation of NSCs was observed by immunofluorescence imaging of Tuj-1, GFAP and Tuj-1/GFAP. (E) Representative spinal cord images of Sham, AG and PAG at 8 weeks. (F) Representative MRI images after SCI repair in Sham, AG and PAG. White arrows indicate the lesion area of the SCI. (G) Representative images of H&E and Masson staining show the morphology of the spinal cord in Sham, AG and PAG. Sham: Sham Operation Group. AG: Alg- GelMA hydrogel. PAG: PRP- Alg- GelMA hydrogel [156]. (∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001).

In summary, traditional therapeutic approaches for CNS injury repair mostly rely on a single mechanism and are difficult to balance the regulation of the microenvironment, resulting in limited repair efficiency. However, due to its richness in neurotrophic factors, PRP can not only independently exert the effects of neuroprotection, promotion of axonal regeneration and myelin repair, but also regulate the immune microenvironment, promote the migration and differentiation of stem cells, and form a synergistic effect with stem cells or biomaterials. It has demonstrated therapeutic advantages in multiple dimensions for CNS injury diseases and has already become a developmental direction for future CNS injury repair. Nevertheless, it still carries the risk of inducing inflammatory reactions, thus requiring optimization of dosage and combination strategies to balance efficacy and safety. More clinical studies are needed in the future to verify its long-term effects.

4.2.3. Application of PRP in central neurodegenerative diseases

Central neurodegenerative diseases often have pathological features including protein aggregation, chronic neuroinflammation, and impaired neurotrophic support, which create an unfavorable microenvironment leading to progressive neuronal damage [162]. The multifaceted biological activity of PRP, which simultaneously delivers neurotrophic factors and exerts potent immunomodulatory effects, makes it a compelling therapeutic against these complex pathological cascades. Victoria Linden de Rezende et al. explored the feasibility of PRP in the treatment of neurodegenerative diseases from the perspective of aging [163]. That is, chronic inflammation caused by aging can lead to the damage of the blood-brain barrier, leading to immune cell infiltration and further aggravating neuronal damage [164,165]. The neurotrophic and immunomodulatory effects of PRP are the key to solve this problem. Exposure to young blood circulation, via xenosymbiosis or administration of young plasma or PRP, reverses the cognitive deficits observed with aging, contributes to increased synaptic plasticity and hippocampal gene expression networks related to cognitive function, as well as acting on inflammatory and anti-inflammatory markers and proteins responsible for maintaining the integrity of blood-brain barrier [166,167]. At present, many studies have investigated the application of PRP in the treatment of neurodegenerative diseases. Moon and JH et al. established a rat model of vascular dementia (VaD) by bilateral common carotid artery occlusion and hypovolemia surgery. The study found that intraperitoneal injection of PRP in the postoperative rats could effectively alleviate VAD-related memory impairment, hippocampal neuronal degeneration and neuroinflammation. Further studies found that the effect of PRP was related to the up-regulation of BDNF/TrkB pathway [168]. For Parkinson's disease characterized by high inflammation, intrathecal cytokine changes and α -synuclein deposition, E Scott Sills et al. proposed to design a Phase I clinical study, suggesting that intrathecal concentrated plasma growth factor processed from thrombin activated PRP may successfully alleviate inflammation, correct background fibrosis and inactivated abnormal cells. It restored local tissue function and improved protein deposition by influencing lymphatic drainage [169]. Pláteník, J et al. found that the concentration of BDNF in patients with Alzheimer's disease is reduced, and BDNF and other neurotrophic factors contained in PRP seem to be able to address the dementia caused by low BDNF concentration [170]. Based on this, Anitua, E et al. showed therapeutic potential for Alzheimer's disease by intranasal injection of PRP into mice, whose findings reduced toxic amyloid-β peptide-induced neurotoxicity and neurodegeneration, enhanced hippocampal neurogenesis, and reduced neurodegeneration [171]. The team of Borhani-Haghighi, M found that PRP can reverse the high expression of microglia, astrocytes, infiltrating inflammatory cells, and pro-inflammatory factors, improve the motor and sensory function of mice with experimental autoimmune encephalomyelitis, and promote remyelination and oligodendrocyte generation, making it one of the most promising strategies for the treatment of multiple sclerosis [172]. Farid, MF et al. injected PRP into cats with spinal cord multiple sclerosis (MS) via intrathecal injection. This method increased the immunoreactivity of myelin basic protein and Olig2 (oligodendrocyte transcription factor 2), reduced the immune markers of Bax (Bcl-2 associated X protein) and glial fibrillary acidic protein, thereby promoting myelin regeneration, and proved that intrathecal injection of PRP is an effective, safe, and promising treatment for MS [173].

5. Application of PRP in clinical treatment

As mentioned above, the repair effect of PRP in the fields of bone injury and nerve injury has been introduced, along with detailed elaboration on the specific mechanisms underlying its therapeutic effects and the optimal concentration that may exert different regenerative effects. In fact, with the development of biomedicine and clinical medicine, PRP has not been limited to basic research but has been applied in various clinical departments. Due to its advantages of being autologous-derived, easily accessible, and targeting biological repair, it has exerted effective therapeutic effects on patients with different diseases [174]. Therefore, the application of PRP in multiple clinical disciplines shows broad prospects, and its therapeutic value is being verified and expanded through an increasing number of clinical practices.

5.1. Application of PRP in the clinical treatment of orthopedics

PRP has been most widely applied in orthopedics, and in recent years, a large number of clinical studies on the application of PRP in orthopedic diseases have been reported. Fracture is the most common orthopedic disease and also a typical clinical application of PRP in orthopedics [175]. The application of PRP in orthopedics can be traced back to 1998, when Marx, RE et al. first applied PRP in oral and maxillofacial surgery to promote bone tissue repai [176]. Since then, the application of PRP in orthopedics has witnessed vigorous development. For example, Roop Singh et al. injected PRP into patients during surgery for acute diaphyseal fractures of the femur. Compared with the control group that only received intramedullary nail implantation, the PRP treatment group showed a higher rate of bone integration [177]. Moreover, PRP also has the effect of alleviating pain at the fracture site. Namazi, H et al. applied PRP to the joint area of patients with intra-articular distal radius fractures. The study found that the application of PRP had a significantly positive impact on reducing patients' pain and restoring arm motor function, alleviating postoperative pain and shortening the recovery time [178]. This clinically confirms that PRP can relieve pain caused by inflammation by regulating the inflammatory response, and the growth factors it contains can promote the proliferation, growth, and differentiation of osteocytes and osteoblasts, accelerate the healing process of the injured site, and thus promote the recovery of arm motor function.

In addition to accelerating bone integration in fracture cases, PRP also plays an important role in various other orthopedic-related conditions, including vertebral fusion, osteoarthritis, cartilage injury, post-ligament injury healing, muscle strains, enthesopathy, and various acute and chronic soft tissue injuries. For example, Sato, K's team used artificial bone blocks impregnated with PRP to fill bone grafts in spinal fusion surgeries. Compared with grafts using artificial bone blocks without PRP, this significantly increased the interbody fusion rate one year after surgery [179]. Rafal Kaminski et al. injected PRP into patients with meniscal injuries during percutaneous meniscal trephination. The study found that the combination of percutaneous meniscal trephination and PRP treatment significantly accelerated the healing of chronic meniscal tears and reduced the need for future arthroscopic examinations [180]. Furthermore, Alessandro Mazzotta et al. injected umbilical cord PRP and autologous PRP into patients with hip osteoarthritis and achieved satisfactory therapeutic effects. However, they also pointed out that PRP shows better efficacy in patients with low-grade arthritis. Further studies with larger case series, stronger study designs, longer follow-up periods, and better descriptions of patient and disease characteristics that may affect outcomes are needed to confirm the indications and potential of this biological injection method [181]. Jiajia Qiao et al. confirmed the efficacy of PRP in the treatment of knee osteoarthritis by detecting biochemical indicators in patients with knee osteoarthritis who received PRP injections. They concluded that autologous PRP injection therapy can significantly improve the levels of inflammatory biomarkers such as IL-1β, TNF-α, and hs-CRP in patients with knee osteoarthritis, and effectively enhance knee joint function and motor function [182]. In terms of soft tissue injuries, PRP has been widely used clinically. Koch, M et al. directly injected PRP into the injured ligaments of patients with partial anterior cruciate ligament (ACL) tears. The study found that patients who received PRP injections returned to sports after an average of 5.8 months, with significantly reduced knee joint laxity, and functional performance tests showed no significant differences between the affected and unaffected sides, reducing the need for subsequent ACL reconstruction surgery [183]. Cory A. Kwong et al. compared the efficacy of ultrasound-guided PRP injection versus standard corticosteroid injection in patients with partial-thickness rotator cuff tears or rotator cuff tendinopathy. The study found that patients who received PRP achieved better pain relief and functional improvement in short-term follow-up (3 months) [184]. Building on this, Luciano Andrés Rossi's team conducted a longer follow-up survey and found that during the 12-month follow-up, PRP injection also showed significantly superior and sustained pain relief and functional improvement compared to traditional corticosteroid injection therapy [185].

5.2. Application of PRP in clinical treatment of neurology

Nerve injury, characterized by high disability rates, difficulties in nerve regeneration, diverse etiologies, and surgical complexity, is a clinical problem that urgently needs to be addressed at present [186]. PRP has been proven to possess powerful nerve repair effects and has also been applied in clinical cases related to nerve injury, achieving satisfactory therapeutic efficacy.

Currently, PRP is mainly used clinically to treat peripheral nerve-related lesions and injuries, with the most common application in patients with carpal tunnel syndrome. Carpal tunnel syndrome is the most prevalent peripheral compressive neuropathy, and its traditional treatment is dominated by conservative approaches. However, the main challenges currently lie in the long recovery time and poor recovery outcomes [187]. Wu, YT's team used PRP injection to treat carpal tunnel syndrome, and the study found that PRP effectively alleviated pain and promoted the recovery of wrist motor function in patients with carpal tunnel syndrome by releasing various growth factors and creating an anti-inflammatory environment conducive to nerve repair [188]. On this basis, Yu-Ping Shen et al. conducted a comparative study on the therapeutic effects of perineural PRP and traditional hypertonic glucose injection therapy on carpal tunnel syndrome, and found that PRP injection had a better effect in reducing the cross-sectional area of median nerve injury caused by carpal tunnel syndrome [189]. The team of Senna, MK further demonstrated the advantages of PRP in treating carpal tunnel syndrome. By comparing the efficacy of PRP injection with traditional corticosteroid injection therapy, it was found that PRP was superior to corticosteroids in improving median nerve pain, restoring median nerve motor conduction velocity and distal sensation [190].In addition to its role in median nerve injury in carpal tunnel syndrome, PRP also has a significant therapeutic effect on the radial nerve, which is the most frequently injured nerve in the upper extremity. Unai García de Cortázar et al. performed continuous intraneural infiltration of PRP under ultrasound guidance in patients with radial nerve transection. After 11 months of PRP treatment, the reinnervation of the radial nerve-dependent muscle tissue in the patient was completely restored, achieving satisfactory efficacy [191]. In addition, Jaime Javaloy et al. applied PRP to patients after Laser-Assisted In Situ Keratomileusis (LASIK), which promoted the recovery of corneal sensitivity and the anatomy of the subbasal corneal plexus, also demonstrating the ability of PRP to promote nerve repair and regeneration [192]. Manal Hassanien et al. found that PRP can treat diabetic demyelinating neuropathy by increasing myelin thickness and axon count, effectively relieving neuropathic pain and numbness, and improving the motor conduction velocity of the deep peroneal nerve and posterior tibial nerve [193]. PRP can also effectively treat neurological sensory abnormalities caused by viral invasion. For example, Anjayani, S et al. injected PRP around the posterior tibial nerve and ulnar nerve in leprosy patients, which improved the sensory function of peripheral nerves by promoting axonal regeneration and myelination by Schwann cells [194]. The team of Zenghua Zhou combined PRP injection with computed tomography-guided pulsed radiofrequency modulation of the dorsal root ganglion. Through the growth and nutritional factors rich in PRP, it regulated the activity of immune cells, reduced the release of pro-inflammatory cytokines, alleviated the inflammatory response of perineural tissues, and reduced the stimulation of nerves by inflammation, achieving better relief of neuralgia [195].

5.3. Application of PRP in clinical treatment of other departments

With the deepening understanding of PRP by researchers, its clinical applications have extended beyond bone repair and nerve repair, exerting powerful regenerative medical effects in various clinical fields. El Taieb, MA et al. compared the efficacy of PRP injection and traditional topical minoxidil solution application in the treatment of alopecia areata. Although both achieved similar hair regrowth-promoting effects, patients receiving PRP treatment showed more obvious early hair regrowth, reduced vellus short hair, and improved effects on malnourished hair [196]. Evman, MD applied PRP to patients with post-COVID olfactory dysfunction. In cases where traditional treatment with steroids combined with D-panthenol/vitamin A nasal spray was ineffective, studies found that PRP could induce neuroepithelial regeneration and improve patients' olfactory detection thresholds and baseline odor recognition values [197]. Yilmaz, G et al. used PRP as a key drug in the conservative treatment of patients with chronic anal fissure, which not only relieved patients' pain but also accelerated epithelialization and healing [198]. Similarly, Shetty, VD et al. observed that PRP had better efficacy than traditional corticosteroids in patients with recalcitrant plantar fasciitis [199]. In the field of skin cosmetology, the team of González-Ojeda, A revealed through a self-controlled study that PRP reduced the intensity of melasma patches and improved skin quality in patients with melasma [200]; while the team of Neinaa, YME applied PRP in the cosmetic treatment of keloids, achieving therapeutic effects similar to botulinum toxin with fewer side effects [201]. On this basis, Garcia, PT et al. used light and temperature to trigger and stimulate platelets, generating photothermally biostimulated PRP, and applied it to female volunteers with signs of hand aging, promoting skin rejuvenation and improving patients' sensory function of the skin [202].

In fact, PRP is more commonly used as an adjuvant therapy after clinical surgeries to accelerate the healing of wound sites and the recovery of function in damaged areas [203]. For example, Dinaki, K et al. injected PRP into the submucosa around the sinuses of patients after endoscopic sinus surgery. Compared with traditional treatment, the PRP group had a lower incidence of postoperative mucosal adhesion, infection, bleeding, and granulation, which was beneficial to wound healing [204]. Gaafar, A et al. applied PRP to patients after microlaryngeal surgery, which significantly improved the patients' voice quality [205]. Moreover, PRP can also reduce the occurrence of postoperative complications. The team of Scala, M implanted PRP gel into patients undergoing superficial parotidectomy. Compared with the control group, it reduced the postoperative hospital stay and the occurrence of side effects such as facial nerve defect, Frey syndrome attack, and abnormal facial muscle behavior [206]. Lee, PJ et al. injected PRP into the urethral sphincter of patients after prostatectomy, which significantly reduced the incidence of complications such as stress urinary incontinence [207].

Therefore, research on PRP is no longer confined to basic mechanisms; its potential in the field of regenerative medicine has been translated into practical applications. Currently, PRP has been applied in various clinical disciplines, including neurology, orthopedics, and dermatology, addressing clinical challenges such as fracture repair, osteoarthritis rehabilitation, ligament injury, nerve regeneration, and skin cosmetology. It not only serves as an adjuvant therapy to accelerate the recovery of damaged sites but also provides opportunities for conservative treatment to patients who would otherwise require surgical intervention, achieving satisfactory therapeutic effects in these contexts.

6. Limitations and improvement methods of PRP use

Although a relatively comprehensive system has been established for both basic research and clinical applications of PRP, there remain limitations in its practical use. For instance, Yu-Ping Shen et al. pointed out that in current clinical applications, the process of platelet counting for PRP samples is lacking, thus failing to evaluate the potential correlation between platelet counts and symptom relief, which may lead to resource waste or the occurrence of adverse reactions [189]. The team of Paul Gressenberger conducted a randomized placebo-controlled study on PRP for the treatment of androgenetic alopecia, noting that single PRP therapy did not improve hair growth in men with androgenetic alopecia [208]. Similarly, C. Graf Guimarães et al. compared patients with androgenetic alopecia treated with PRP and those treated with anti-dandruff shampoo, and the results showed no statistical differences between the two groups in terms of erythema, crusting, hair loss, transplanted hair shedding, or transplanted hair sprouting [209]. In response to this, the team of Michael Bigby conducted a systematic review on PRP for androgenetic alopecia, concluding that the therapeutic effect of PRP alone is marginally better than that of placebo [210]. This seems contradictory to the previously mentioned positive efficacy of PRP in patients with androgenetic alopecia [211], which may be related to the limitation that PRP lacks standardized methods for preparation and application [212]. In fact, this issue also exists in the application of PRP in other clinical disciplines. For example, Mirco Lo Presti et al. pointed out that a single PRP injection did not provide overall benefits in terms of pain relief, function, objective parameters, and recovery of motor activity in patients after arthroscopic partial meniscectomy [213], which also contradicts some existing clinical cases [214]. This indicates that although a robust framework has been established for the basic research and clinical application of PRP, certain limitations still exist in its practical implementation. These limitations may be attributed to factors such as the preparation quality and storage conditions of PRP. For example, insufficient platelet concentration in PRP may result in a lower enrichment coefficient, which reflects reduced product quality [215]. Additionally, prolonged storage duration or improper storage methods may lead to a decline or alteration in the activity of key growth factors [216]. Meanwhile, specific protocols such as the treatment cycle and the number of treatments for PRP therapy have not been standardized. These issues collectively may compromise the effectiveness of PRP treatment. Therefore, it is essential to establish a unified protocol for preparation and evaluation based on extensive clinical trial data, in order to identify the most effective PRP treatment strategies for diverse patient populations, continuously refine its preparation and storage methodologies, and fully harness the inherent regenerative potential of PRP.

In addition, there are still many side effects associated with clinical treatments using PRP. For example, Olivera Stojadinovic et al. reported side effects of PRP in the treatment of alopecia, including scalp pruritus, telogen effluvium, and lymphadenopathy [217]. Krishnapriya Alyam et al. reported a case of acute vision loss in the right eye after PRP injection into the glabellar region for skin rejuvenation to repair wrinkles [218]. Moreover, the use of PRP in clinical orthopedic treatments is not entirely ideal. For instance, Kaux, JF et al. injected PRP into patients with tendinopathy, which induced a severe inflammatory response [219]. In addition, Didem Dincer et al. also found side effects of PRP treatment; injecting PRP into patients with gastrocnemius muscle injury caused leg infection and ulceration [220]. The underlying reason may be that the actual therapeutic effect of PRP is affected by the concentration, proportion, and preparation methods of various growth factors and active components. If growth factors are overactivated, they may induce excessive local inflammatory reactions, leading to tissue damage and ulceration.

In fact, with the widespread clinical application of PRP, an increasing number of studies have pointed out that the therapeutic effects of PRP are not as ideally regenerative as suggested by current basic research mechanisms. For example, PRP can enhance soft tissue repair, particularly in tendons, but may inhibit bone formation and potentially lead to the formation of fibrous connective tissue and scars [221]. The composition of PRP used in treatment varies among patients and may also differ based on the equipment used for its preparation, storage time and methods before use, and whether it interacts with other biological agents or materials. All PRP-based treatments should be patient-driven. Therefore, current research on PRP needs to be more closely aligned with clinical practice, establishing standardized paradigms and more precise control over indications. To this end, many researchers have proposed different improvement methods. Firstly, combining PRP with other drugs can enhance its therapeutic effect and reduce the occurrence of adverse reactions. For instance, Anitua, E et al. suggested that using PRP in combination with other hair loss-related products may enhance the final therapeutic effect [222]. The team of Wafaa Mohammad Ramadan retained the original minoxidil treatment while using PRP for hair loss patients, and the study found that the addition of PRP improved the efficacy of minoxidil and shortened the time required for optimal improvement [223]. In addition, in clinical orthopedics, the combination of PRP with other drugs has also reduced adverse reactions and improved efficacy. For example, Kemmochi, M et al. found that the combined application of platelet-rich fibrin (PRF) and PRP in patients after meniscal repair surgery resulted in more favorable functional recovery and meniscal repair outcomes [224]. Moreover, some researchers have improved the treatment method of PRP, replacing traditional injection therapy with PRP-containing microneedles, which has also achieved superior efficacy [225]. On this basis, Gentile, P et al. combined microneedle technology, low-level laser therapy, and PRP in the treatment of patients with androgenetic alopecia. Compared with the use of PRP alone, this combination achieved more favorable results in improving hair count and hair density [226].

In summary, with the widespread clinical application of PRP, an increasing number of researchers have found that PRP therapy has not met the fully ideal expectations for regeneration and repair. This is not only due to the diversity in the composition, proportion, and even preparation methods of PRP itself, but also the uncontrollable nature of side effects in clinical practice. To further improve therapeutic efficacy and achieve efficient and low-risk utilization of PRP, it is necessary to establish standardized paradigms for PRP preparation and precisely control its indications. More importantly, PRP is not an isolated therapeutic agent; instead, it should be combined with other drugs to enhance efficacy and reduce adverse reactions. Similarly, with the development of medical technology, modifying traditional treatment approaches also serves as a key entry point to improve therapeutic outcomes, as it can minimize side effects while maximizing the synergistic effects of various treatment modalities.

7. Deficiencies and prospects

As a promising autologous derivative, PRP has demonstrated multifaceted therapeutic effects in various fields such as bone repair and nerve regeneration. In bone repair, accumulating evidence has confirmed its basic medical mechanisms, including that PRP stimulates the proliferation and differentiation of osteoblasts to promote osteogenesis by activating active factors such as PDGF and BMP; promotes vascularized bone regeneration by enhancing the expression of vascular growth factor VEGF; and can also promote chondrocyte regeneration by inhibiting MMP activity and facilitating the synthesis of type II collagen, thus treating osteoarthritis and so on. Clinically, PRP has been successfully applied in the treatment of various orthopedic diseases, including accelerating the healing of long bone fractures and alleviating pain in patients with osteoarthritis, among others. In nerve regeneration, PRP provides essential nutrients for nerve repair through its rich neurotrophic factors and growth factors such as NGF and BDNF; it can also create an anti-inflammatory microenvironment conducive to nerve repair by downregulating the expression of pro-inflammatory factors like TNF-α and IL-1β. Additionally, PRP can promote the migration and proliferation of stem cells, including Schwann cells and mesenchymal stem cells, to the injured site, thereby facilitating axonal regeneration and myelination for nerve regeneration, showing favorable effects in repairing various types of nerve injuries such as sciatic nerve and central nerve injuries. Its clinical applications have expanded to the repair of peripheral nerve injuries such as carpal tunnel syndrome and radial nerve injury, as well as the treatment of central nervous system disorders including spinal cord injury. Beyond these fields, PRP has also shown positive therapeutic potential in dermatology, otolaryngology, and other clinical disciplines, such as in the treatment of acne scars, keloids, alopecia, and postoperative wound healing, demonstrating extensive applicability.

However, the current research and clinical application of PRP still face severe challenges. Firstly, the lack of standardized protocols for PRP preparation and administration remains a primary issue. The current PRP preparation techniques exhibit high heterogeneity; the variability in centrifugation parameters, platelet concentration, and activation methods not only affects the comparability of research results but also increases the uncertainty regarding therapeutic efficacy and safety. Secondly, although PRP generally has good safety, some studies have identified and emphasized the occurrence of adverse reactions during PRP treatment, such as local inflammatory responses, alopecia, and infections. In addition, there are many ambiguous areas in defining the efficacy boundaries of PRP. In some cases, the therapeutic effects in treatment scenarios such as androgenetic alopecia and recovery after arthroscopic meniscectomy remain controversial. Further research is needed to clarify its exact indications and optimal administration strategies, and large-sample, long-term follow-up randomized controlled trials are required to accurately define the efficacy range of PRP.

Future research on PRP will advance in several directions. Standardization should be prioritized through multicenter collaborative studies to establish consensus-based guidelines for PRP preparation, including platelet concentration thresholds, quantification of growth factors, and administration regimens tailored to specific pathologies. This will enhance the reproducibility of results and facilitate evidence-based clinical decision-making. Another promising avenue is synergistic therapy that combines PRP with other modalities to enhance efficacy and mitigate adverse reactions. For instance, the integration of PRP with stem cells, biomaterials, or pharmaceuticals can augment regenerative outcomes in bone and nerve repair by precisely regulating the cascade of physiological recovery [227,228]. Meanwhile, technological advancements driven by interdisciplinary integration will bring revolutionary breakthroughs in PRP delivery and regulation. For example, PRP-loaded microneedle arrays, with their minimally invasive properties, can penetrate the epidermis to reach the dermis, improving local retention of PRP, enabling targeted delivery, enhancing patient compliance, and reducing systemic exposure [229]. In addition, high-quality clinical trials with larger sample sizes, long-term follow-ups, and standardized outcome measures are essential. Leveraging artificial intelligence and machine learning algorithms to analyze complex datasets can deepen understanding of patient-specific responses, thereby enabling personalized PRP therapy [230]. Meanwhile, advancements in PRP extraction equipment and the development of more sophisticated storage methodologies have emerged as critical strategies to address standardization challenges. Such advancements will not only refine our comprehension of PRP's therapeutic mechanisms but also strengthen the evidentiary basis for its broader clinical application.

In conclusion, PRP holds significant promise in revolutionizing the field of regenerative medicine by offering tangible therapeutic benefits to patients suffering from a wide range of diseases, as research advances and technological innovations continue to evolve. To fully unlock its clinical potential, it is essential to address existing challenges through the implementation of standardized protocols, interdisciplinary collaboration, and evidence-based research methodologies. This strategic approach will ultimately position PRP as a foundational component of contemporary regenerative therapies.

8. Conclusion

PRP, with its autologous safety profile and multi-target regenerative capacity, holds promise as a core tool in the fields of regenerative medicine. By systematically addressing existing challenges through standardized preparation processes and larger-scale clinical trials, and integrating with advanced technologies such as tissue engineering and biomaterials engineering, its clinical translation value will be further unleashed, providing novel therapeutic regimens for various degenerative and traumatic diseases.

CRediT authorship contribution statement

Han Zhang: Writing – review & editing, Writing – original draft. Yunnong Luo: Writing – review & editing, Writing – original draft. Yunmeng Wang: Writing – original draft, Resources, Investigation. Mengmeng Sun: Writing – review & editing, Writing – original draft, Investigation.

Declaration of competing interest

The authors declare no conflicts of interest.

Data availability

No data was used for the research described in the article.