Skin regeneration, repair, and reconstruction: present and future

The full-thickness skin graft has proven to be the best choice, both functionally and cosmetically, for covering burned areas on the face, hands, and over large joints in particular, since the strong dermal component prevents excessive scarring with subsequent shrinkage.

The limiting factor for use of full-thickness skin grafts, however, is the fact that the removal sites for full-thickness skin grafts always have to be primarily closed; thus, mostly only smaller grafts are available [2‐4].

In the case of full-layer skin defects in functionally important regions (e.g., hands), combined skin reconstruction using a split-thickness skin graft (often non-meshed) in combination with a dermal matrix is often used. There are currently several matrices available (e.g., Matriderm® [MedSkin Solutions Dr. Suwelack AG, Germany] and Integra® [Integra Life Sciences, Germany], PolyNovo® [Polynovo Limited, Australia]) [5, 6].

With the lattice split-skin graft, a defined mesh-like perforation is produced on a roller in combination with a corresponding template using a special arrangement of parallel knives on a roller, which leads to a relative increase in the area of the transplant. Split-skin grafts are particularly useful where large burned areas can only be covered with a remnant of healthy skin. An expansion ratio of 1:1.5 to 1:3 is preferably selected. With larger expansion ratios, the Meek graft is superior to the mesh graft in terms of healing and expansion [7, 8].

In 1958, Meek described a dermatome with which the split skin obtained can be cut into small square islands of equal size. In the 1990s, this method was modified in connection with an easy-to-use transplantation method, which made it possible, in one step, to not only cut the split skin layer, but also to expand it in ratios of up to 1:9 after applying it to a cork and silk support and to transplant. This method, which is somewhat easier to use, has now become established in many burn centers because of the mathematically favorable use of the enlargement factor and is preferred to the mesh graft for very large burns and other skin defects. This grafting technique has also become established for the coverage of chronic wounds [2, 3, 7‐10].

If there are not enough donor areas available, allogeneic transplants can be used temporarily as a temporary skin replacement. Allogeneic transplants became more widespread when the so-called sandwich technique was used, in which widely meshed autologous transplants are covered with less widely meshed allografts [2, 10‐12].

Since the mid-1950s, especially in China, pigskin has often been used to temporarily cover large wound areas. After transplantation, the xenograft initially finds a nutritive connection to the basal wound bed. The dermis is initially revascularized, but then usually quickly dissolved and replaced by collagen structures. Especially in countries where allogeneic transplants are not used for ethical reasons, temporary wound covering with xenografts is still an important procedure today. These grafts are not only used in the case of severe burns, particularly in situations where donor sites are scare, but have been used for the treatment of other acute and chronic wounds [2, 3, 13].

Transplantation of a cultured epidermal membrane of autologous keratinocytes (cultured epidermal autografts, CEA) was the first successful clinical use of a cultured organ component. Applied cultured epidermis transplants usually consist of three to five cell layers. However, the transplants are very fragile and hard to handle. Another problem is the lack of a dermal component in case of third-degree burns. In order to counteract this problem, the development of dermal analogs of different compositions has been promoted and used clinically with success [2, 23, 24].

In 1895, the first successful transplantation of scraped keratinocytes suspended in autologous wound serum was performed. However, this technique was not initially able to establish itself, because of a lack of suitable carrier substances. The use of allogeneic keratinocyte suspensions aims primarily to utilize the paracrine-secreting activity of the cells. In areas with a burn degree of 2a to 2b, the re-epithelialization of the remaining skin appendages can be stimulated and the time until healing can be shortened. The same technology can be used to treat split-skin donor areas, where this possibility of using allogeneic cells is intended to ensure that the donor areas are available again more quickly [2, 3].

The combination of cultured autologous keratinocytes on alloplastic or mixed synthetic/biological materials as dermal regeneration matrices has been investigated by different groups. In the 1980s, Yannas and Burke produced a skin equivalent by centrifugation of primarily trypsinized keratinocytes and fibroblasts in a collagen–glycosaminoglycan matrix (C-GAG), which healed completely after transplantation in guinea pigs [29‐31]. Today, this and other matrices have been increasingly used for this purpose, also in humans [23, 24].

In spite of the tremendous advances in skin tissue engineering, a “complete” tissue-engineered skin substitutes is not yet available. Current substitutes are mainly composed of keratinocytes and fibroblasts, but still lack some of the functional components such as nerves, adnexal structures, and pigment cells. [22].

Common methods for the production of biomaterials are freeze drying, salt leaching, gas foaming, and electrospinning. Freeze drying (lyophilization) is a gentle technique for drying sensitive valuable materials (such as proteins) and can be used effectively for the production of collagen mats, for example. A porous 3D structure is created that can either be populated with endogenous cells or allow endogenous cells to grow in from the surrounding tissue and ECM. Salt leaching and gas foaming are techniques in which salt crystals or gas (e.g., CO₂) are deliberately introduced into the material mixture and later released. This is how porous 3D membranes are created. With electrospinning, natural (e.g., collagen) or synthetic polymer solutions (e.g., PCL) can be spun into very thin fibers (nanometers to microns) in an electric field. These fibers (e.g., polymer, collagen) can also be processed as bundles as well as mats.

Beside the therapeutic impact, 3D bioprinting has the potential to serve as a platform for studying tissue development and homeostasis and for modeling diseases in pharmaceutical testing [35]. Bioprinting seems to be a technology that could overcome the gap between grafts and skin substitutes.

As very briefly described, 3D bioprinting seems to be very promising, but the next step is already being taken: 4D bioprinting, where the fourth dimension is transformation. It is the 3D printing of smart, stimuli-responsive biomaterials to create constructs that emulate the dynamic processes of biological tissues and organs.

Imagine, for instance, that instead of having to 3D print a skin graft for a burn victim, with all the entailed complexity, you could 4D print a basic skin graft that would, once implanted on the patient, vascularize itself, develop all nerve endings, take on the patient’s complexion, and even grow hair if on the head. In a way, 4D bioprinting is to medicine what artificial intelligence is to computer science (Fig. 6; [35‐38]).