In recent years, with the development of social economy, the number of patients with trauma caused by traffic injuries and work-related injuries in China has been increasing year by year, among which the injuries to the extremities are especially serious, because the wounds of the extremities are easier to be infected and have longer healing time compared with other parts of the body, which directly leads to the increase of delayed healing and non-healing of wounds in clinical practice. In addition, as China gradually enters an aging society, the elderly population increases, and the number of difficult-to-heal wounds is further increased due to the slow healing of wounds in the elderly, as well as diabetes and bed sores, which are common diseases among the elderly. Therefore, how to promote the repair of difficult-to-heal wounds has become a hot topic of current research. 1. Mechanism and treatment of difficult-to-heal wounds Difficult-to-heal wounds, also known as ulcers. The main causes are trauma or trauma combined with infection, diabetic ulcers, long-term local pressure, excessive radiation exposure, and neurogenic and venous ulcers. The pathogenesis is complex and the duration of the disease is long. In addition to systemic factors, the main mechanisms of difficult wound healing are as follows: first, the presence of wound infection or necrotic tissue; second, poor blood supply and microcirculation in the wound; third, reduced number and activity of local growth factors or uncontrolled regulation of the network between multiple factors; fourth, changes in the scaffolding and excessive apoptosis of repair cells and changes in the structure of receptors on the cell membrane, resulting in the loss of coupling between growth factors and receptors [1 ]. Difficult-to-heal wounds in China are mainly caused by trauma infection, accounting for 67.15% of hospitalized patients with difficult-to-heal wounds [2 ]. Therefore, in addition to the treatment of the primary disease, prevention of wound infection and removal of necrotic tissue are the first and most important steps in the treatment of refractory wounds. Other factors such as burns, electric shocks and high-dose radiation local irradiation are closely related to the local blood supply in the formation of hard-to-heal wounds. Liu Jianzhong et al [3 ] found that the local tissue repair cells (fibroblasts, vascular endothelial cells and epidermal cells) in such wounds were inhibited in their proliferation, the expression of related growth factors was reduced, and vascular lesions (often proliferative endarteritis and other lesions) occurred, which affected wound blood circulation. Inadequate local blood supply directly leads to wound hypoxia, which increases red blood cells, concentrates blood, increases viscosity, and increases platelet adhesion and thrombosis, thus aggravating the circulatory disorder[4] . Cooper et al [5 ] studied chronic wounds with chronic pressure and acute wounds after trauma and found lower growth factor levels in chronic wounds than in acute wounds. Greenhalgh [6 ] also found reduced levels of growth factors in venous ulcers and diabetic ulcers and suggested that this was due to the capillaries being encapsulated by inflammatory exudate fibrin, which prevented blood growth factors from penetrating the vessel walls and reaching the wound. On the other hand, the metabolism of growth factors in chronic wounds was accelerated, which Robson [7 ] suggested might be due to the increase of protein hydrolases due to the long-term inflammatory response, which promoted the metabolism of local growth factors. Sun Tongzhu et al[8 ] used different doses of recombinant platelet derived growth factor-BB (PDGF-BB) to repair diabetic rat wounds, and the experimental results showed that a medium dose of rrPDGF-BB (7 ugPcm2 ) had a significant effect on wound repair. In contrast, no promotion effect was observed between the low dose of rrPDGF-BB (315 μgPcm2 ) and the high dose of rrPDGF-BB (14 μgPcm2 ). He suggested that the mechanism was that the low concentration of growth factors did not reach the effective dose on the trauma surface to initiate the promotion of repair cell growth, and the high concentration disrupted the balance between local growth factors on the trauma surface, inhibited the activity of other growth factors, and caused the deregulation of multiple growth factors on the trauma surface, which was also detrimental to the growth of repair cells. In addition, since wound healing is a complex regulatory process involving multiple growth factors, it is often difficult to achieve good repair results with the application of a single growth factor [9 ]. There are many literature reports on the comparative study of multiple growth factors and single growth factors for wound repair [10-13 ], and it was found that the repair effect of multiple growth factors is often better than that of single growth factors, which may be related to the joint promotion effect between multiple factors, which can act on multiple stages of wound healing process. The difficulty of wound healing is also closely related to the change of scaffolding and excessive apoptosis of repair cells, and the change of receptor structure on the cell membrane. In a study by Xiaobing Fu et al [14 ], it was found that the expression level of fibronectin (Fn) gene in ulcerated wounds was usually reduced by 1P3-1P2 compared to normal skin and scar tissue, and Fn gene expression was also downregulated, which led to the destruction of tissue repair cells and mobile scaffolds and delayed wound healing. It was also found that the expression of the apoptosis-inhibiting gene Bc1-2 in chronic hard-to-heal wounds was decreased by about 60% compared to normal controls [15 ], which demonstrated that excessive apoptosis of tissue cells is an important cytological basis for the delayed or difficult healing of wounds. In addition, it is believed that the reason for this is that, firstly, the expression of C-fos and C-jun, the early and immediate genes, is significantly increased in inflammatory cells, which leads to the release of a large number of proteases by activated neutrophils, resulting in extracellular matrix lysis and non-healing of the wound [16]; secondly, the structure and function of the target cells of growth factors, which are closely related to the regulation of wound healing, are altered, making it difficult for growth factors to bind properly to their corresponding receptors and resulting in uncontrolled signaling [17]. The second is that the structure and function of the growth factor target cells, which are closely related to the regulation of wound healing, are altered, making it difficult for growth factors to bind properly to their corresponding receptors and uncontrolled signaling occurs [14]. Autologous platelet-rich plasma (APRP) is a plasma containing a high concentration of platelets isolated from whole blood by centrifugation. Because platelets are activated to release a large number of growth factors, such as PDGF, transforming growth factor-β1 (TGF-β1) and TGF-β2, insulin-like growth factor (IGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) [17-19]. All these growth factors have been shown to promote soft tissue and skin healing, and there are good synergistic effects between them [20-24 ]. Depending on the method of preparation, the concentration of these growth factors in PRP can be several times or even hundreds of times higher than normal [25-28 ]. The use of APRP for the repair of difficult-to-heal wounds is a recent development, and in experimental and clinical studies, APRP has shown good effects in promoting the repair of difficult-to-heal wounds.Crovetti et al[29 ] used APRP for the treatment of skin ulcers and found that APRP was better at forming granulation tissue at the wound site and promoting complete regeneration of wound epithelial tissue compared to the control group. He concluded that APRP released several growth factors locally that together promoted wound repair, such as the chemotactic effect of TGF-β1 on neutrophils and monocytes that mediated the inflammatory response of the wound, PDGF that stimulated the proliferation and differentiation of fibroblasts and promoted tissue remodeling, and VEGF that accelerated vascular regeneration. It is interesting to note that patients in the APRP treatment group also experienced less pain at the wound site than the control group. This is consistent with the experimental results of Marx [21 ]. However, the exact mechanism has not been elucidated. It may be related to the fact that the repair rate of skin tissue is faster than the growth rate of the nerves, and it may also be related to the decrease in the number of days for wound healing and the time for pain detection. In this study, it was found that APRP had a beneficial effect on wound healing. In addition, it was also found that the wound scar was less in the APRP group, which he believed might be due to the high content of leukocytes and monocytes in APRP, which inhibited the inflammatory response in the wound and resulted in less scarring. In the field of wound repair, there is also a lot of literature, such as the use of APRP after wrinkle excision, which was found to reduce wound edema, accelerate healing and reduce complications [30 ]. The use of APRP in surgical procedures has been shown to reduce wound bleeding and prevent wound infection [31 ]. APRP has unique advantages for wound repair. As an autologous platelet concentrate, the ratio of various growth factors in APRP is similar to the normal physiological concentration. The optimal synergistic effect among growth factors is an important factor for APRP to promote tissue repair more rapidly [21 ]. ②APRP contains a large amount of fibrin, which provides a good scaffold for repair cells and can also shrink the wound surface[32 ]. ③APRP can be coagulated into a gel by thrombin and applied to the wound, which not only provides a moist environment, but also facilitates the growth of wound healing. It also allows the growth factor to be confined to the wound for a long time, avoiding the disadvantage of liquid recombinant growth factor reagents which are widely used in clinical practice and are easily lost and evaporated in the wound. ④APRP is autologous, which fundamentally avoids the concerns of immune rejection caused by exogenous growth factors, disease transmission, and possible alteration of human genetic structure by heterologous recombinant gene products. (5) Because the sedimentation coefficients of leukocytes and monocytes are similar to those of platelets in blood, APRP made by centrifugation also contains a large number of leukocytes and monocytes, which can better prevent infection. (6) APRP is simple to produce, and only requires blood from a patient’s vein (mostly from the jugular or elbow vein), which is less invasive to the patient and can be done in about 20-30 minutes. Moreover, the cost is very low, which can reduce medical expenses. (7) So far, no adverse reactions and toxic side effects of APRP have been found in the body. APRP has shown good results in the repair of difficult-to-heal wounds, and it provides a new idea of using growth factors to promote wound healing. In clinical practice, it can reduce postoperative bleeding, relieve pain, reduce postoperative complications, heal wounds faster, and reduce the number of hospital days [31 ], which has a broad application prospect. However, there are still many problems to be elucidated. Wound repair is a complex biological process, and since the lifespan of growth factors in APRP is only about 5 d, it is unlikely to affect the whole process of wound repair. As for how the various growth factors in APRP are metabolized in the wound, the mutual regulation of each growth factor, and the optimal time and dose of APRP for wound repair, further studies are needed.