Introduction Platelets are known for their function in promoting blood clotting. In 1978, in the course of exploring the pathogenesis of atherosclerosis, researchers found that 10% serum significantly promoted the proliferation of smooth muscle cells in in vitro experiments and that this pro-proliferative effect disappeared after switching to platelet-poor serum [1]. Witte first discovered platelet-derived growth factor (PDGF) in platelet alpha particles. In the following 20 years, platelets were found to contain insulinlike growth factors (IGFs), transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Since the 1990s, with the rise of translational medicine worldwide, platelet-rich plasma (PRP) has been used in clinical practice. In 1998, Dr. Marx was the first to use PRP in the clinical setting for mandibular defect repair and found that PRP significantly shortened the osteogenic repair process [2]. Since then, PRP has been gradually used in orthopedic surgery to promote bone fusion, facilitate fracture repair, and accelerate soft tissue repair in acute and chronic tendon injuries [3; 4]. Recently PRP has started to be used in the field of foot and ankle surgery. Definition and preparation of PRP PRP is a platelet-containing plasma derived from autologous blood, which contains a high concentration of platelets, leukocytes and fibrin. Platelets are produced from bone marrow and do not have a nucleus, but contain structures such as mitochondria, microtubules, and granules. There are two types of secretory granules in platelets: dense granules and alpha granules. The dense granules contain adenosine diphosphate, adenosine triphosphate, 5-hydroxytryptamine and calcium ions; the alpha granules contain many of the aforementioned growth factors, which promote coagulation, migration of inflammatory cells, proliferation and differentiation of bone marrow mesenchymal cells, vascular regeneration and extracellular matrix formation. In general, the platelet concentration in PRP can be 3-17 times higher than that in normal blood [5]. Graziani believes that the optimal platelet concentration in PRP should be 2.5 times the normal baseline value. PRP also contains high concentrations of a variety of leukocytes, including lymphocytes, monocytes/macrophages and neutrophils [5]. The fibrin in PRP provides a three-dimensional scaffold for repair cells and facilitates the attachment and aggregation of various growth factors and stem cells. Thrombin, calcium chloride and collagen exposure after vascular endothelial injury can activate platelets, leading to rapid release of growth factors after platelet degranulation and binding to fibrin scaffolds to form a meshwork structure, rapidly forming a gelatinous protective film at the injury site, which will theoretically further accelerate tissue healing. However, premature platelet activation needs to be avoided because of the short half-life of most growth factors. Commercially available PRP preparation kits generally do not pre-activate platelets. Sodium citrate is usually added to maintain platelets in PRP in a biologically relatively stable state by binding to calcium ions while anticoagulating. Once the PRP is applied to the tissue wound, the exposed collagen will naturally activate platelets, releasing growth factors and producing an inflammatory response lasting about 3 days [6]. Mesenchymal stem cells and fibroblasts accumulate at the site of injury and participate in the tissue proliferation repair process lasting about several weeks before entering the structural remodeling process lasting about 6 months [7]. The preparation of PRP is not yet standardized, and in general, two centrifugations are used to selectively separate the different components of autologous blood. Depending on the settling rate during blood centrifugation, the first centrifugation separates platelet-containing plasma from red blood cells; the second centrifugation separates platelets from platelet-poor plasma. At present, dozens of foreign companies have platelet separation preparation systems on the market, and there are already professional companies in China that have mastered mature technology to produce PRP preparation kits, which are relatively inexpensive and have better platelet concentration meter activity in PRP [8]. Clinical application PRP treatment technology has been widely used in the field of orthopedic surgery abroad, but is still an emerging technology in China. Although many clinical and basic studies have reported that PRP promotes healing of bones and soft tissues, its clinical efficacy in this field is still controversial due to the limited data on its clinical application in foot and ankle surgery. According to Ranly’s study, the main effect of PRP is to promote osteogenesis, but not osteoconduction [9].Gandhi first applied PRP to nine patients with osteointegration after foot and ankle fracture surgery. All of these patients received their first surgical treatment within 20 days after fracture and were diagnosed with osteonecrosis within 4 to 10 months after surgery. In the second revision surgery, the authors combined PRP with autologous bone grafting at the site of the nonunion and showed that all nonunions healed after the revision surgery, with a mean healing time of 60 days. The authors also compared the growth factor concentrations in the hematoma at the fracture site in patients with nonunion and healed bone and found that PDGF and TGF-β concentrations in the nonunion hematoma were significantly lower than in fresh fractures. This study suggests that the application of PRP at the site of bone nonunion, as well as the release of growth factors after platelet activation, may play a key role in promoting bone healing [10]. In the clinical prospective study conducted by Bibbo, 62 patients with elective foot and ankle surgery with high-risk factors for bone discontinuity were followed up for 6 months after treatment with PRP. These patients underwent surgery on different parts of the foot and ankle. Some of these patients received both PRP and autologous bone grafting, depending on their condition. Postoperative radiographs were taken every two weeks to assess the efficacy of PRP, and 94% of the patients were found to have achieved bone healing at an average of about 41 days postoperatively. The mean time to bone healing was 40 days for patients treated with PRP alone and 45 days for those treated with the combination [11]. The authors concluded that PRP has an important role in treating patients at high risk for bone discontinuity, however, the study is limited by the fact that these patients had different foot and ankle disorders and surgical procedures. Secondly, the study lacked a control group that was not treated with PRP. Coetzee compared the effect of PRP treatment with or without PRP on the fusion rate of the inferior tibiofibular joint at the time of ankle replacement [12]. After intraoperative osteotomy of the distal tibia and talus, PRP was sprayed at the lower tibiofibular joint, on the tibiofibular osteotomy surface and on the surface of the joint prosthesis. PRP and autogenous bone graft were applied at the joint of the lower tibiofibular joint. Postoperative radiographs were reviewed regularly. The results showed that in the PRP group, compared with the previous 112 patients in the control group who did not receive PRP, the rate of improvement in fusion of the inferior tibiofibular joint was 61.4% and 73.6% at 8 and 12 weeks postoperatively, respectively; in the combined PRP and autologous bone graft group, the rate of improvement in fusion was 76% and 93.9%, respectively, compared with the control group. PRP also significantly reduced the incidence of poor healing or osseous nonunion at the fusion site at 6 months postoperatively. Cartilage lesions The foot and ankle is one of the most vulnerable areas for cartilage damage and osteoarthritis during upright weight-bearing walking. As there are no blood vessels or nerves in the articular cartilage, it lacks the ability to repair itself after injury [13]. TGF-β and PDGF contained in PRP have been shown in basic studies to inhibit the activity of interleukin 1β and tumor necrosis factor α, which are involved in the inflammatory response to cartilage destruction, thereby suppressing the inflammatory response in cartilage injury [14-16]. In addition, PRP promotes the synthesis of proteoglycans and collagen in chondrocytes, which can directly promote chondrocyte growth and directed differentiation of chondrogenic cells to chondrocytes and promote cartilage injury repair [17; 18]. In a prospective study, Mei-Dan compared the clinical effects of intra-articular injection of hyaluronic acid and PRP into the ankle joint for the treatment of talar cartilage injury, respectively [19]. The authors divided the patients into two groups and injected hyaluronic acid or PRP once a week, respectively, for three consecutive weeks, and then followed up the patients in both groups over a period of 28 weeks to assess the improvement in ankle pain, stiffness, and motor function, respectively. The results of the study found that ankle pain and functional recovery were significantly better in the PRP-treated group than in the hyaluronic acid group. Giannini and his colleagues investigated the value of intraoperative application of PRP in the treatment of talar cartilage injuries [20]. In that study, they described an innovative technique: 60 ml of bone marrow cells were aspirated from the patient’s posterior iliac crest by puncture with a conventional bone puncture needle, and these were further centrifuged to obtain 6 ml of concentrated mesenchymal rechargeable stem cells (MSC). After revealing the talar cartilage lesion with ankle arthroscopy, a hyaluronic acid membrane of the same size as the cartilage wound was first used as a scaffold over the wound, and then 2 ml of concentrated MSC were mixed with 1 ml of PRP gel and applied to the surface of the hyaluronic acid scaffold. Eighty-one patients were included in the study, and 25 received this PRP+MSC+hyaluronic acid scaffold treatment; 46 received arthroscopic chondrocyte transplantation; and 10 received open surgical chondrocyte transplantation. Postoperative follow-up was up to 3 years. Clinical evaluation included American Foot and Ankle Surgery Society (AOFAS) scores and imaging analysis. The results showed significant clinical outcomes for all three different treatments, with no significant differences between groups. x-rays did not reveal postoperative osteoarthritis, and MRI suggested a high rate of filling of the talar cartilage lesion area and the appearance of new cartilage in the surrounding tissue. Their study suggests that the application of PRP may promote the targeted differentiation of MSC to chondrocytes, which has an important role in repairing cartilage damage. Achilles tendon lesions The Achilles tendon is one of the most vulnerable areas of the body to sports injuries, and the clinical use of PRP in Achilles tendon lesions has been the most widespread in recent years.PRP has been used to treat acute Achilles tendon ruptures and chronic Achilles tendonitis.In 2007, Sanchez first reported the application of PRP to treat athletes with complete Achilles tendon ruptures [21]. In this case-control study, six patients underwent incisional repair of the Achilles tendon rupture. Prior to suturing the paratendinous tissue, 4 ml of activated PRP was injected into the tendon rupture repair site, followed by placement of a fibrin scaffold on the surface of the repair site. He set up a control group of six other patients of similar age, sex, and mechanism of injury with complete rupture of the Achilles tendon who had previously undergone surgery alone. Postoperative follow-up evaluated the time to full return to ankle activity, the time to return to low-intensity running, and the time to return to normal exercise training. The study found that patients who received intraoperative PRP injections had no wound complications, regained normal range of motion of the ankle early in the postoperative period, and took significantly less time to return to low-intensity running and normal exercise training than the retrospective control group. However, a randomized controlled clinical study conducted by Schepull came to the opposite conclusion regarding PRP for Achilles tendon rupture [22]. In his study, he randomized 30 patients with Achilles tendon rupture between the ages of 18 and 60 years into two groups: one group underwent Achilles tendon repair alone, and the other group received 10 ml of PRP injected into the Achilles tendon repair site during the 52-week postoperative follow-up period. The clinical function was assessed by the heel raise index and Achilles Tendon Rupture Score (ATRS). No significant differences were found between the PRP-treated group and the surgical control group in terms of postoperative biomechanical and clinical functional parameters. The study findings do not support the clinical use of PRP for Achilles tendon rupture. In a double-blind randomized controlled clinical study, de Vos evaluated the value of PRP in the treatment of chronic Achilles tendinopathy [23; 24]. Fifty-four patients, ranging in age from 18 to 70 years (mean age 49.5 years), were included in this study. The diagnosis was established based on thickening of the Achilles tendon and pain after activity for more than 2 months. The Achilles tendon lesion was located 2 to 7 cm above the heel stop. Exclusion criteria included concomitant other skeletal muscle injuries (tendon rupture, stopping point disorders), use of medications (quinolones) that could cause Achilles tendinopathy, previous PRP treatment and previous high-intensity exercise. Patients were randomized to the treatment and control groups. Patients in the treatment group received ultrasound-guided injection of 4 ml of PRP at three puncture sites near the Achilles tendon lesion; patients in the control group received the corresponding saline injection. After 1 week of injection, all patients underwent 1 week of Achilles tendon stretching and 12 weeks of eccentric exercise. The results were evaluated at weeks 6, 12 and 24 after treatment and published in two journals. In the first report, the primary measure chosen by the authors was the Victorian Institute of Sports Assessment-Achilles (VISA-A), which quantifies pain and activity levels; other measures included patient subjective satisfaction, return to exercise, and adherence to exercise. This report showed VISA-A scores of 21.7 and 20.5 at 24 weeks in the treatment and control groups, respectively; return-to-exercise rates were 78% and 67%, respectively, but the results were not statistically different [23]. In the second report, the authors found no statistically significant differences between the two groups 1 year after injection in terms of clinical indicators and return to motion rates, and ultrasonographic assessment revealed a decrease in Achilles tendon thickness, a decrease in the number of neovascularization in the Achilles tendon and an improvement in tendon tissue structure in both groups. There were no significant differences between the two groups [24]. Gaweda conducted a prospective study of the application of PRP for the treatment of chronic non-stop Achilles tendinitis [25]. Fourteen patients with non-stop Achilles tendinitis were included in the study. These patients were treated with ultrasound-guided 3 ml PRP injections at the lesion site. Passive ankle exercises were performed for two weeks after injection and active exercises including heel lifting were performed after 2 weeks. The AOFAS hindfoot score, VISA-A and ultrasound imaging were used to assess the efficacy at 1.5, 3, 6 and 18 months after treatment. At 18 months after treatment, the AOFAS hindfoot score and VISA-A score showed significant improvement compared to the pre-treatment scores. Follow-up ultrasound imaging also revealed significant improvement in tendon structure after treatment; normalization of peritendinous tissue morphology; and a gradual decrease in Achilles tendon blood flow after a significant increase in the first 3 months after treatment. The authors concluded that PRP treatment significantly improved clinical symptoms in patients with nonstop Achilles tendinitis and facilitated the restoration of normal structure to the Achilles tendon tissue. In another study, Delos investigated the efficacy of PRP application in 32 patients with Achilles tendinitis who had failed after 6 weeks of conservative treatment [26]. During the 1-year follow-up period, 25 patients (78%) had complete resolution of clinical symptoms after PRP treatment; the remaining 7 patients (22%) had no improvement or worsening of symptoms after treatment. Metatarsal tenosynovitis Metatarsal tenosynovitis is the most common cause of achalasia and is usually treated clinically with nonsurgical treatment, including changes in daily activity habits, application of foot pads, stretching exercises, application of nonsteroidal anti-inflammatory drugs and local injection of endosteroids. It is now generally accepted that metatarsal tenosynovitis is a degenerative lesion rather than a purely inflammatory process. The histomorphology of the surgically excised metatarsal tendinopathy is degenerative with a chronic inflammatory response and fibroblast proliferation [27].The multiple growth factors contained in PRP may inhibit the metatarsal tendinopathy degenerative process. In a recent double-blind clinical cohort study, AKsahin compared the efficacy of applying PRP and steroid hormones in the treatment of metatarsal tenosynovitis [28]. He divided 60 patients into two groups: the PRP group received a single 3 ml PRP injection at the lesion site; the hormone group received a single 3 ml corticosteroid injection. After 6 months of follow-up, patients in both groups showed significant improvement in symptoms and function compared to pre-treatment, while there was no significant difference in comparison between the two groups. The authors concluded that PRP has a better therapeutic effect on metatarsal tenosynovitis and should be used as the treatment of choice in clinical practice. Although there was no significant difference in the efficacy of PRP compared with steroid hormones, at least the potential risks of hormone therapy could be avoided. In a recent study, Ragab and Othman treated 25 patients with chronic plantar tenosynovitis with a single injection of 5 ml PRP at the lesion site [29]. Pain and foot function were assessed during a mean follow-up period of 10 months. The results revealed that more than 90% of the patients were highly satisfied with the results of the treatment, had complete recovery of foot function and were able to resume daily activities 2 weeks after the PRP injection. Ultrasound imaging revealed a significant reduction in the thickness of the diseased metatarsal tendon after treatment compared to before treatment. The authors concluded that PRP can promote regenerative repair of the metatarsal tendon membrane and is a safe and effective treatment method. Diabetic foot Diabetic patients with combined foot disorders are often difficult to treat clinically. These patients are prone to osseous discontinuity or failed osteoarticular fusion surgery, complicated by infection and difficult healing of skin ulcers. Basic studies have shown that the concentrations of several key growth factors are significantly reduced at the site of diabetic foot injury and at the surgical site [30; 31]. In recent years, PDGF and VEGF levels were found to be significantly lower in diabetic patients who underwent failed Charcot joint reconstruction surgery compared with normal subjects at the site of osteoarticular fusion [32].PRP contains several growth factors and has been clinically reported as an adjunct to PRP therapy in Charcot joint reconstruction surgery. In a prospective clinical study in 2012, Pinzur applied PRP as an adjunct to foot surgery for the treatment of Charcot arthropathy [33]. A total of 44 high-risk diabetic patients (including 46 feet) who underwent foot osteoarticular fusion surgery participated in this study. The mean age of the patients was 54.9 years and the mean height body mass index (BMI) was 38.0. 24 were male and 20 were female. Twenty-eight of them had combined open wounds and osteomyelitis of the foot. All were fixed with a circular external fixation frame after orthopedic surgery. At the time of wound closure, all patients received autologous PRP and bone marrow aspirate injection. Postoperatively, 42 feet showed bone healing at a mean of 26.2 months. Two patients had their feet amputated due to persistent foot infection. The authors concluded that PRP combined with the application of a small amount of bone marrow aspirate for the adjunctive treatment of Charcot arthropathy in high-risk diabetic patients is comparable in efficacy to autologous bone grafting in osteoarticular fusion procedures. In a multicenter prospective clinical randomized controlled study, Driver et al. applied autologous PRP gel for the treatment of diabetic foot ulcers. A total of 40 eligible patients were enrolled in the study. They were randomized into two groups: the treatment group (19) received topical treatment with PRP gel; the control group (21) received saline gel. Ulcer healing was assessed every 2 weeks for a total of 12 weeks. Kaplan-Meier healing time analysis also showed that the PRP treatment group was significantly better than the control group. no serious side effects were observed during PRP treatment. The study concluded that the use of PRP in diabetic foot ulcers is highly effective. The use of PRP in the field of foot and ankle surgery is emerging and has been used to treat a variety of foot and ankle surgical disorders including fractures, osteoarticular fusion, osteoarthritis, Achilles tendinopathy, chronic plantar tendinitis, and diabetic foot, and its clinical indications are expanding. However, we must be aware that the absolute indications for PRP treatment have not been clearly established at this stage. Whether it should be used as a conservative treatment or as an adjunct to foot and ankle surgery has not yet been determined. Regarding the method of PRP preparation, including the method of blood separation and related parameters, there is a lack of uniformity in the commercial kits for PRP preparation provided by various companies both domestically and internationally. The optimal concentration of platelets in separated PRP has yet to be determined. It has been shown that the concentration of platelets and the growth factors contained in them may not have a linear relationship with their pro-repair effect on the diseased tissue. The receptor sites on the cell surface at the site of injury may be “saturated” with growth factors. Once the amount of growth factors exceeds the number of corresponding receptors on the cell surface, the excess free growth factors in the tissue may even inhibit cellular activity, thus affecting the clinical efficacy of PRP [34]. In addition, previous studies have shown that in normal individuals possessing similar platelet concentrations, growth factor concentrations vary from one person to another. Such differences may affect the clinical efficacy of PRP for a specific disorder and may consequently affect the accuracy of data analysis during the study. Leukocytes and monocytes may be present in the isolated PRP. Their role in the early stages of the inflammatory response is well known. Some researchers have suggested that leukocytes in PRP can remove local necrotic tissue and pathogenic microorganisms, but others have suggested that leukocyte-mediated production of proteases and oxygen radicals may be detrimental to tissue repair when PRP is applied in an inflammatory response [35]; in injured tissues, the expression of some genes involved in tissue catabolism is significantly enhanced as leukocyte concentrations increase [36]; based on the current stage of studies, it is still unclear whether leukocytes are included in the isolation of PRP. There is still a lack of generally agreed treatment guidelines for the clinical application of PRP in foot and ankle surgery, both nationally and internationally. In particular, when used for the non-surgical treatment of a specific disease, there is no uniform requirement for the dose of PRP per injection, the total number of injections required and the interval between each injection. PRP in foot and ankle surgery should be avoided in patients with co-morbidities such as thrombocytopenia, hemodynamic instability, sepsis, and infection in the bone graft area. The application of PRP when drawing blood from these patients may aggravate bleeding; aggravate shock and lead to the spread of infection. Caution should also be exercised when applying PRP to patients with combined bone tumors, as there is a risk that the various growth factors contained in PRP may promote the growth of tumor appreciation. In addition, intra-articular injection of PRP at high concentrations may cause joint pain and transient joint dysfunction, and full communication with the patient is required to gain his complete trust and cooperation before applying PRP. The use of PRP in foot and ankle surgery has just started at home and abroad, and has shown exciting clinical prospects. Most patients are satisfied with the results of PRP treatment. However, the number of published clinical studies is still very limited, and a significant portion of these publications are empirical retrospective reports. In the future, there is a need to conduct well-designed, high-quality randomized controlled studies with large samples to further confirm the value of PRP application, and to develop targeted clinical application guidelines for PRP autologous blood isolation and foot and ankle surgery in China in order to better serve patients.