Skin graft healing can be divided into three phases: plasma absorption phase, contact phase, and revascularization phase (30). The plasma absorption phase is when the transplanted tissue absorbs the tissue fluid secreted by the wound. The contact period is when anastomosis occurs between the blood vessels of the donor skin and the recipient site in the dermis (31). The keratinocyte activation phase, on the other hand, appeared only in epidermal transplantation, possibly due to the marked expression of Ki67 (a marker of cell proliferation) and the β1 integrin subunit (a putative marker of keratinocyte stem cells) (32). The revascularization stage is the stage of vascular proliferation, and vascular endothelial growth factor (VEGF) is one of the regulatory factors. The increase of capillary permeability leads to the increase of extravascular tissue fluid. VEGF-mediated neovascularization (29). The exact mechanism is still unclear. However, blood vessels are not involved in epidermal transplantation, so this stage is skipped in epidermal transplantation and epithelization is directly carried out to achieve the purpose of repair (33–35).

Skin grafting is when skin tissue is detached from one site and transplanted to another site, with the transferred skin merging into the recipient site (36, 37). Skin grafting is the most critical part of treatment. If large-scale skin defects are not treated effectively, infection and a series of complications due to prolonged bed rest will occur. In addition to the treatment of avulsion injuries, skin grafts can also be used for skin cancer surgery, leg ulcers caused by diabetes, etc. (38, 39). Skin grafts for repairing nasal injuries were first described by Indian surgeons in 2,500 BC (40). In 1872, Ollier de Lyon described the first STSG technique (39). The STSG technique depends on the depth of graft acquisition in the donor site, so three types of instruments have been designed, including skin grafting knives, drum dermatomes, and electric dermatomes, to speed up the application of STSG (41–43). In 1964, J.C. Tanner et al. developed mesh skin grafts based on STSG (44). FTSG was first described in 1875 by Wolfe et al. (45). FSTG is more prone to necrosis than STSG, but since FTSG is composed of intact dermis and epidermis, scar shrinkage is less (46).

The epidermal blister technique was first described in 1964 by Kiistala et al. (47). Their technique proposes to harvest the epidermal layer of the skin by forming water-absorbing vesicles, providing autologous keratinocytes for transplantation. FTSG and STSG usually require hospitalization, and epidermal grafting can be done as a day surgery. And since there is no damage to the dermis of the donor site, the donor site will not leave scars (12). In 1981, since John Burke et al. invented the artificial skin dermis called Integra consisting of silicon epidermis and porous collagen-chondroitin (48). Various types of skin substitutes have been put into use, epidermal substitutes such as Cultured epidermal autograft (CEA), Epicel, Cell Spray, dermal substitutes such as Matriderm, Biobrane, Pelnac, composite skin substitutes such as Apligraft, StrataGraft, OrCel etc. These become alternatives in the field of reconstructive surgery (10, 49–52). Among the many advantages of all types of skin substitutes, the most prominent are simplicity, immediacy, and plentiful availability (53, 54). However, its use in large skin defects is limited due to its high cost and need for secondary surgery (Table 1).

FTSGs contains full-thickness dermis, and most surgeons use it for facial reconstruction, joint mobility, and part of the lower extremity skin defect. FTSG is less recommended for infection-type wounds, and smoking and bleeding disorders are relative contraindications to FTSG (55, 56). In facial plastic reconstruction surgery, the requirements for appearance are very high, so grafts with less actinic damage are usually selected. Such as the area behind the ear, the skin of the upper eyelid, or the inside of the arm (57). In lower extremity skin defects, full-thickness grafts are an effective reconstruction method for some defects that are difficult to close after primary closure (58). Defects larger than 1 cm in diameter require sufficient granulation tissue to form on the surface so that FTSG is not prone to necrosis (59, 60). To match the texture, color, thickness, and actinic damage of the skin at the recipient site, adjacent skin is ideal. However, when there is a large defect, it is not possible to obtain enough full-thickness grafts, and skin from other parts needs to be selected as the donor. Therefore, the selection of FTSG donor sites is very difficult. In addition, complications such as infection, hematoma/seroma, venous thrombosis, and graft necrosis may occur in lower extremity FTSG (61). Because the skin tissue obtained from the donor site includes deep dermal structures such as hair follicles and sweat glands, it can cause permanent scarring at the donor site. Scar tissue shrinks with age, leading to deformities (62). Notably, Herskovitz et al. found that a full-thickness skin column was collected using a custom-made device that could be applied directly to the wound. The donor site heals with little scarring. However, the pig model was used, and its clinical application needs further research (62). At present, there is no good solution to the damage caused to the donor site.

Pain recovery from full-thickness skin grafts in the recipient area It has long been thought that the regenerative fibers of the grafted skin grow into the graft independently of the existing Schwann sheath. That is, a healthy wound bed and a satisfactory graft, the final feeling is close to that of the surrounding skin. Napier JR observed that most FTSG were normally reinnervated around the periphery, while in the central region, the grafts were less sensitive. And Napier showed through a series of experiments that the original nerve plexus of the transplanted skin determines the scope and quality of reinnervation (63). It is generally accepted that full-thickness skin grafts have the smallest shrinkage of all autografts. Compared with STSG, the ability to resist contraction is stronger (64, 65). But A.J. Stephenson et al., the first objective measurement in humans, found that the graft shrunk by a third in the absence of infection in the wound; when infection did occur, the wound shrunk by a factor of two. This means that considering the amount of FTSG shrinkage in advance during reconstruction can reduce the effect of late grafts on function to a certain extent (66). Contractures of the graft at the joints of the lower extremities (knee, ankle and toes) can result in limited joint function and walking deformities. Transplantation in adolescents requires predicting graft growth and stretching variables. FTSG has the least shrinkage and is the most suitable type of graft for this type of site. Physical therapy and splints are also used to avoid contractures. Manju D et al. studied the contracture rate of different grafts in 174 children with finger burns and showed that the use of full-thickness skin grafts resulted in a lower rate of contracture and reoperation, especially when the palm and extended into the fingers. Graft contracture rates at lower extremity joints may be similar (46).

Immobilization is required after FTSG to improve the success rate of transplantation due to increased hydrostatic pressure during lower extremity activity and walking (58). However, numerous studies have shown that STSG of the lower extremity usually does not require immobilization (67, 68). Methods of fixation include sutures and physical compression therapy. Two suture methods are commonly used in FTSG, through suture and quilted graft. S. Struk et al. described that penetration sutures with short-term immobilization of lower extremity grafts using plaster casts or compression bandages can achieve graft completion rates as high as 93% (58). Gagik oganesyan et al. fixed the graft with penetrating suture, and the FTSG was superior to the STSG in terms of graft survival and aesthetics (69). The grafting technique using quilting has been applied in many settings, with Patterson for the hand and face, Liew S for nipple reconstruction, and Mc Gregor IA for the oral cavity (70–72). Isaac Harvey et al. used quilted full-thickness grafts for the first time to cover lower extremity defects. The risk of postoperative infection, hematoma, and seroma is greatly reduced (61).

STSGs consists of the epidermis and a part of the dermis. The scope of application of STSG is wider than that of FTSG. STSG can not only cover thick skin grafts of different depths. It can also be used for traumatic or previously infected wounds, such as avulsion wounds, chronic leg ulcers, etc., due to the rapid osmotic transfer of nutrients from the underlying wound bed (13). However, it is not very suitable for joints, and the shear force generated by joint movement can lead to graft failure (36). Mesh grafts are full-thickness or thick-thickness skin grafts cut into staggered slits arranged in parallel. STSG is meshed and can be stretched into any shape to the greatest extent to meet the needs of irregular wounds (Figure 1). And each additional mesh incision multiplies the skin border, speeding up the healing time. It can also drain the accumulated blood in time to avoid infection. However, permanent, unsightly “fishing net” pattern scars are also caused on the grafted skin (62, 73). Avulsion injuries of lower extremities often require large-scale skin grafting, but patients often have numerous concurrent injuries, poor skin nutritional status, and it is difficult to choose a donor site. There is also the risk of pain, scarring and infection at the donor site, which is more troubling to the patient than the primary wound. STSGs are usually translucent and smooth, so it is impossible to achieve tissue texture matching (36).

STSG is more prone to wound contraction, hypoesthesia, hypopigmentation, or hyperpigmentation. There are two contractions of STSG, because the content of elastin fibers is low, and the contraction is relatively small in the first contraction, but in the second contraction, the contraction strength decreases with the thickness of the graft, so the area of STSG contraction is larger (74–76). And the thickness of STSG is proportional to the shrinking area (75). Due to the growth and development of adolescents, wound shrinkage will seriously affect the movement of the lower limbs, resulting in joint deformities. Contractions are currently mainly treated by physical methods, including functional exercises and splinting, and surgical release. Functional exercises are used by all surgeons, and splints are mostly used for contractions caused by burns, so appropriate physical therapy can reshape scar tissue to some extent (77). The acquisition of STSG requires the use of corresponding equipment, and the type of equipment depends on the size and thickness of the STSG. Before using a device that acquires STSGs, the number of STSGs needs to be determined in advance. STSGs in a small size range can be obtained directly using blades or scissors. STSGs with a slightly larger size range require a dermatome system. Among them, electric dermatome is the most common, including Brown dermatome, Zimmer dermatome, DavolSimon dermatome and Weck dermatome and other types of dermatome equipment, which can collect larger and more uniform STSG (39). A dial on the side of the dermatome can be turned to adjust the thickness of the graft (Figure 2). STSG can be divided into thin layers (0.005–0.012 in), medium layers (0.012–0.018 in), and thick layers (0.018–0.028 in). After obtaining the STSG, immerse it in sterile saline solution, and then manually divide the mesh according to the shape of the wound to adequately cover the wound.

The fixation of STSG is not as complicated as that of FTSG, and the blood supply between the wound bed and STSG is better than that of FTSG. The periphery of the graft is secured with common sutures or staples (78). There are generally two methods for securing STSG to the wound bed, including the basting suture technique and the helical suture technique (79, 80). Although STSG has a high survival rate, there is still a small chance of necrosis and even graft failure. Clinically, doctors have explored a variety of ways to improve the success rate. There are three main approaches to promoting STSG healing, including wound bed improvement, effective fixation of grafts, and other adjunctive physical therapy (81). Platelet-rich plasma (PRP) can improve wound bed conditions, thereby promoting STSG healing. Two studies in the treatment of complex skin defects and lower extremity ulcers have shown that PRP can promote STSG healing after uniformly receiving a combination of STSG and platelet-rich plasma (82, 83). Phenytoin ointment has a similar effect, and Younes et al. in a study of 16 patients with diabetic foot concluded that topical phenytoin ointment improved STSG survival (84). The secure fixation between the STSG and the wound bed prevents shear forces that interfere with graft healing. Both supportive dressings and Negative pressure wound therapy Negative pressure wound therapy(NPWT) are common means of effective graft fixation. It is worth adding that it is necessary to limit the patient's activities in the short term after STSG, which can reduce the generation of shear force. A short period of bed rest (2 days) reduces the incidence of wound infection, venous thrombosis, and does not affect graft survival (85, 86). Other adjuvant therapy, such as laser therapy, basic fibroblast growth factor (bFGF). It also has a certain promotion effect on the healing of STSG (87, 88).

Epidermal grafting is an emerging technique to overcome scarring at the donor site. Epidermal transplantation (EG) is the transfer of an epidermal layer from the donor area to the wound bed. The epidermis is harvested by applying continuous negative pressure at the donor site to promote blister formation and transferred to the wound (89). Because the dermis is not involved, and the epidermis has a strong ability to regenerate and heal wounds quickly (renew every 4 weeks), the epidermis regenerates completely without scarring (38, 90). And EG, unlike the other two grafts, not only provides wound coverage but also stimulates wound regeneration (89). The pain-sensing nerves of the skin are located in the dermis, so EG is often painless, without the use of anesthesia, and is a day surgery. EG does not require entering the operating room and can be performed in an outpatient setting. Compared to FTSG and STSG, it is less invasive, easier to harvest, and has virtually no donor site morbidity (12, 91).

With the continuous development and improvement of the function and technology of the EG acquisition system, EG has been widely used in the outpatient setting. The first device developed by Kiistala in 1968 was the Dermovac, which consisted of a glass suction cup and a hand pump. Blister formation time is 1–2 h. Because of the long blister formation time and the large size of the device, it is not practical in practical work, so it has not been mass-produced (92, 93). Another common EG collection system is the syringe system. The principle of the device and the parts used are relatively simple. There are two syringes, one large and one small, and a three-way connector. Blister formation takes 1 h but requires surgical excision under anesthesia (94, 95). The newly developed CelluTome epidermis harvesting system consists of an automatic harvester, a vacuum head and a control unit. 30 min can produce EG more than 40cm². Its entire procedure is fully automated, anesthesia-free and painless, and the graft size is consistent. Therefore, the device can easily provide EG in outpatient and community settings (96, 97). A study by Hachach-Haram et al. showed that after epidermal grafting of acute or chronic wounds in an outpatient setting with the device CelluTome, both the wound and the donor site healed well and the skin returned to its original appearance within 2 weeks (98, 99). Oliver J Smith and colleagues studied patient satisfaction with the graft in 20 patients who received FTSG and EG, respectively. Eighty percent of CelluTome patients are completely satisfied with the graft site results, and the cost of using the CelluTome system is much lower than that of patients with FSTG (96).

To further improve the success rate of EG, the wound environment can be improved, such as the formation of sufficiently fresh granulation tissue and infection control. It is also possible to sterilize the donor site with alcohol before heating or wetting it during the operation of EG, which can accelerate the formation of blisters. When transferring the graft, try to keep all the epidermis on top of the clear film dressing. Finally, the success rate of EG is improved by ensuring that the graft is in close contact with the wound (91). The specific mechanism of EG healing is currently unclear, but the following three mechanisms may play a role: keratinocyte activation, growth factor secretion, and re-epithelialization of the wound edge (33). Activated keratinocytes are so proliferative that small areas of EG can cover more than 30% of their total body surface area in burn patients (100, 101). And cytokines and extracellular matrix products secreted by keratinocytes play a key role in wound re-epithelialization (102). There are many types of growth factors, and one study found that EG contains vascular endothelial growth factor, TGF-α, platelet-derived growth factor AA, platelet-derived growth factor AB/BB, hepatocyte growth factor, and granulocyte colony-stimulating factor (100). Growth factors are known to accelerate wound healing and to stimulate the wound healing process (33). The re-epithelialization of the wound edge may be due to the graft-secreted growth factors at concentrations sufficient to modulate the gap junction proteins at the wound edge, thereby stimulating re-epithelialization at the wound edge (103). EG is mostly used for small, shallow wounds. Lower extremity avulsion injuries are often large-area, full-thickness skin defects, and epidermal transplantation alone is not effective. However, the combination of FTSG and STSG meshing treatments with epidermal grafts resulted in faster wound healing and increased wound coverage (104).

The skin substitutes we mentioned here are composed of biomaterials. Others, such as xenografts, are not discussed here. The purpose of biomaterial skin substitutes is to provide extracellular matrix to accelerate wound healing (105). The primary role of the skin substitute is the same as the purpose of the graft, which is to prevent wound infection, keep the wound moist, and cover the defect. An absorbent dressing made of cotton wool was first developed in 1880 by Joseph Gamgee. Its advantages are also significant, such as being resistant to infection, durable, mass-produced, non-antigenic, and widely applicable (106). However, skin substitutes also have limitations, such as reduced vascularization, scarring, high price, and temporary wound coverage, ultimately requiring a secondary autologous skin graft (107, 108). The market for skin substitutes is huge, and countless researchers are devoted to the research and development of skin substitutes. There are many types of skin substitutes on the market. Artificial dermis has good biocompatibility, good adhesion, and easy access, avoiding the dilemma of insufficient autologous skin (38, 109). Moreover, it can also form a fresh wound on the exposed tendon, providing conditions for a second epidermal skin graft (53, 54).

The representative product of the double-dermis replacement, Integra has become one of the most popular double-dermis replacements since it was developed. It consists of a matrix of bovine tendon collagen type 1, shark chondroitin-6-sulfate, and silica gel (110). It enables long-term wound coverage, protects the wound from infection, and allows vascular invasion of the wound bed to degrade (111). For children with lower extremity avulsion injuries and multiple injuries throughout the body, the advantages of artificial dermis are significant. An example is the Integra Dermal Regeneration Template (IDRT), which has two layers. The outer layer is made of a silicone membrane and the inner layer consists of a matrix of cross-linked fibers. It can regenerate the functional dermis (112). Pelnac is also a two-layer dermal substitute consisting of a collagen matrix layer as the bottom layer and a semipermeable silicone layer as the outer layer. ZhenmuLv reported a case of a 48-year-old patient with a degloving injury of the upper extremity who was covered with Pelnac after initial surgical skin necrosis with satisfactory functional and aesthetic appearance. This is the first report of Pelnac addressing this complex skin defect (113). Lv et al. studied 16 patients with large skin defects of the lower extremities using the Pelnac dermal regeneration template and the recovery after secondary epidermal skin grafting, and 93.7% (15/16) of the patients achieved satisfactory functional outcomes. All patients were satisfied with the appearance. Attia and Tarek Elmenoufy treated 4 patients with extensive lower extremity avulsion injury using a combination of a NPWT and a dermal regeneration template (IDRT), and all 4 were healed with satisfactory results. The appearance of the reconstructed skin is near normal (15).

There are also emerging wound dressings that can also play a role in wound healing, such as Amnion is the thin translucent tissue in the innermost layer of the fetal membrane and is mainly used for canthus burns. It can be used as a temporary dressing over full-thickness or superficial burn wounds (114). Acticoat is a silver antibacterial dressing containing nanocrystalline silver that reduces healing time and reduces pain (115). It is suitable for full-thickness and partial-thickness wounds (116). Such as cell-laden hydrogels and hydrogel nanofiber mixtures, 3D printed skin substitutes, prevascularized skin equivalents, and even silk biomaterials as wound dressings use (Table 2). These emerging skin substitutes will have a huge impact in plastic surgery in the near future. However, the realization of these products still requires detailed and rigorous clinical studies to verify (117, 118).