Wound healing is an important function of skin; however, after significant skin injury (burns) or in certain dermatological pathologies (chronic wounds), this important process can be deregulated or lost, resulting in severe complications. To avoid these, studies have focused on developing tissue-engineered skin substitutes (TESSs), which attempt to replace and regenerate the damaged skin. Autologous cultured epithelial substitutes (CESs) constituted of keratinocytes, allogeneic cultured dermal substitutes (CDSs) composed of biomaterials and fibroblasts and autologous composite skin substitutes (CSSs) comprised of biomaterials, keratinocytes and fibroblasts, have been the most studied clinical TESSs, reporting positive results for different pathological conditions. However, researchers' purpose is to develop TESSs that resemble in a better way the human skin and its wound healing process. For this reason, they have also evaluated at preclinical level the incorporation of other human cell types such as melanocytes, Merkel and Langerhans cells, skin stem cells (SSCs), induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs). Among these, MSCs have been also reported in clinical studies with hopeful results. Future perspectives in the field of human-TESSs are focused on improving in vivo animal models, incorporating immune cells, designing specific niches inside the biomaterials to increase stem cell potential and developing three-dimensional bioprinting strategies, with the final purpose of increasing patient's health care. In this review we summarize the use of different human cell populations for preclinical and clinical TESSs under research, remarking their strengths and limitations and discuss the future perspectives, which could be useful for wound healing purposes.

/pdf/cellular-human-tissue-engineered-skin-substitutes-r1x878s850.pdf

Cellular human tissue-engineered skin substitutes investigated for deep and difficult to heal injuries.

The skin graft was born in 1869 and since then, surgeons have been using split skin grafts for wound repair. Nevertheless, this asset fails the big burn patient, who deserves an elastic, mobile and robust outcome but who receives the poorest possible outcome based on donor site paucity. Negating the need for the skin graft requires an autologous composite cultured skin and a material capable of temporising the burn wound for four weeks until the composite is produced. A novel, biodegradable polyurethane chemistry has been used to create two such products. This paper describes the design, production, optimisation and evaluation of several iterations of these products. The evaluation has occurred in a variety of models, both in vitro and in vivo, employing Hunterian scientific principles, and embracing Hunter's love and appreciation of comparative anatomy. The process has culminated in significant human experience in complex wounds and extensive burn injury. Used serially, the products offer robust and elastic healing in deep burns of any size within 6 weeks of injury.

https://publishing.rcseng.ac.uk/doi/pdf/10.1308/rcsann.2017.0110

The evolution of acute burn care – retiring the split skin graft

We have developed a biodegradable temporizing matrix (BTM) capable of supporting secondary split-skin graft-take in animal studies. We report its first long-term implantation and use as a dermal scaffold in humans. This preliminary study assesses its ability to integrate, its ease of delamination, its ability to sustain split-skin graft in complex wounds, the degree of wound contraction, and ultimately the quality of the scar at 1 year postimplantation. Ten patients were recruited, each requiring elective free flap reconstruction. Free flap donor sites created were anterolateral thigh flaps, fibular osseocutaneous flaps, or radial/ulnar forearm (RF/UF) flaps. The BTM was implanted when the flap was detached from its donor site. Dressing changes were performed twice weekly. The time elapsed between implantation and delamination depended on the type of flap and thus the wound bed left. Once integrated, the BTMs were delaminated in theatre, and the surface of the "neodermis" was refreshed by dermabrasion, prior to application of a split-skin graft. The BTM integration occurred in all patients (100% in 6 patients, with 90%, 84%, 76%, and 60% integration in the remainder). Integrated BTM sustained successful graft-take in all patients. Complete take was marred in 2 patients, over areas of BTM that had not integrated and graft application was performed too early. The BTM can be applied into wounds in humans and can integrate, persist in the presence of infection, and sustain split-skin overgrafting, despite the trial group presenting with significant comorbidities.

A biodegradable polyurethane dermal matrix in reconstruction of free flap donor sites: a pilot study.

Skin tissue bioengineering is an emerging field that brings together interdisciplinary teams to promote successful translation to clinical care. Extensive deep tissue injuries, such as large burns and other major skin loss conditions, are medical indications where bioengineered skin substitutes (that restore both dermal and epidermal tissues) are being studied as alternatives. These may not only reduce mortality but also lessen morbidity to improve quality of life and functional outcome compared with the current standards of care. A common objective of dermal-epidermal therapies is to reduce the time required to accomplish stable closure of wounds with minimal scar in patients with insufficient donor sites for autologous split-thickness skin grafts. However, no commercially-available product has yet fully satisfied this objective. Tissue engineered skin may include cells, biopolymer scaffolds and drugs, and requires regulatory review to demonstrate safety and efficacy. They must be scalable for manufacturing and distribution. The advancement of technology and the introduction of bioreactors and bio-printing for skin tissue engineering may facilitate clinical products' availability. This mini-review elucidates the reasons for the few available commercial skin substitutes. In addition, it provides insights into the challenges faced by surgeons and scientists to develop new therapies and deliver the results of translational research to improve patient care.

/pdf/advances-in-skin-tissue-bioengineering-and-the-challenges-of-4t8s12gnys.pdf

Advances in Skin Tissue Bioengineering and the Challenges of Clinical Translation.

The aims were to (1) describe the in vivo studies leading to an optimized model of the biodegradable temporizing matrix (BTM), (2) describe our efforts in effecting closure over this optimized matrix after integration with a cultured composite skin (CCS), and (3) reexamine the ability of the CCS to definitively close fresh wounds (without BTM). Foam scaffolds of biodegradable polyurethane were created to allow in vivo tissue ingrowth or in vitro co-culture. Using the porcine surgical model, multiple BTM optimization studies took place before the BTM-CCS main study was conducted. For the CCS study, optimized sealed 2 mm matrices were implanted into 6-mm deep, 8 × 8 cm wounds (three per pig) and allowed to integrate for 21 days, whereas collected blood and harvested skin tissue were used to prepare autologous composite skins in similar (unsealed) 1 mm matrices. These were then applied at day 21 either over the integrated BTMs or into a freshly created fourth wound. All of the optimized matrices integrated fully, without loss, and were found to resist wound contraction effectively until the composites were ready for application at day 21. The composites demonstrated the ability to generate a bilayer repair with robust epidermis anchored by a basement membrane visible from day 7 after application. The final optimized sealed BTM delaminates easily to produce a clean, temporized wound bed and will be used in the upcoming burn clinical trial. Although the CCS is a magnitude away from human trials, it is still capable of generating a bilayer repair in both BTM-integrated and fresh wounds (onto fat), and with further refinement and optimization of foam structure, seeding densities, and timing, consistent success should be possible.

Optimization of a polyurethane dermal matrix and experience with a polymer-based cultured composite skin.

This study aimed to investigate the ability of an autologous cultured composite skin (CCS) to close similar biodegradable temporizing matrix (BTM)-integrated wounds, and its effectiveness in healing fresh full-thickness wounds after the failure of cultured epithelial autograft in its two forms (sheets and suspensions) to epithelialize over an integrated polymer BTM. Using a porcine model, autologous split-skin grafts were harvested three of four dorsal 8 × 8 cm treatment sites. These three sites were subsequently converted to full-thickness wounds and BTMs were implanted. The grafts were used to produce autologous CCSs for each pig. These consisted of a 1 mm thick biodegradable polymer foam scaffold into which fibroblasts and keratinocytes harvested from the grafts were cocultured. At Day 28, on each animal, the autologous CCSs were applied to two of the integrated BTMs, an autologous split-skin graft was applied to the third integrated BTM, and one CCS was applied immediately into a fresh, "naked" (no BTM applied) wound. The CCSs were capable of generating a bilayer repair over the naked wound's fat base and BTM-integrated wounds, which consisted of dermal elements and a keratinized stratified squamous epidermis anchored with a basement membrane by day 7. The CCSs behaved in different ways: either as a delivery vehicle allowing similar development of a bilayer repair while the polymer foam was shed from the wound, or generating a bilayer repair with the foam scaffold being retained (composite "take"). These results conclude our porcine program and provide proof of concept that the integrated BTM can be closed with an autologous CCS. Once fully optimized, this may provide robust repair without resorting to the split-skin graft, important in those cases where unburned donor site is unavailable.

"Take" of a polymer-based autologous cultured composite "skin" on an integrated temporizing dermal matrix: proof of concept.

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"Take" of a polymer-based autologous cultured composite "skin" on an integrated temporizing dermal matrix: proof of concept.