Concise review: tissue-engineered skin and nerve regeneration in burn treatment

Abstract

Burns not only destroy the barrier function of the skin but also alter the perceptions of pain, temperature, and touch. Different strategies have been developed over the years to cover deep and extensive burns with the ultimate goal of regenerating the barrier function of the epidermis while recovering an acceptable aesthetic aspect. However, patients often complain about a loss of skin sensation and even cutaneous chronic pain. Cutaneous nerve regeneration can occur from the nerve endings of the wound bed, but it is often compromised by scar formation or anarchic wound healing. Restoration of pain, temperature, and touch perceptions should now be a major challenge to solve in order to improve patients' quality of life. In addition, the cutaneous nerve network has been recently highlighted to play an important role in epidermal homeostasis and may be essential at least in the early phase of wound healing through the induction of neurogenic inflammation. Although the nerve regeneration process was studied largely in the context of nerve transections, very few studies have been aimed at developing strategies to improve it in the context of cutaneous wound healing. In this concise review, we provide a description of the characteristics of and current treatments for extensive burns, including tissue-engineered skin approaches to improve cutaneous nerve regeneration, and describe prospective uses for autologous skin-derived adult stem cells to enhance recovery of the skin's sense of touch.

Keywords: Cell biology; Epidermis; Neuron; Skin grafts; Tissue regeneration; Transplantation.

Figure 1.

Addition of Schwann cells and hair buds to improve nerve regeneration in a tissue-engineered skin. (A, B): Intraepidermal nerve fibers were stained for protein gene product 9.5 in normal human skin (A) (red) and tissue-engineered skin after 21 days of in vitro innervation (B) (red; cell nuclei in blue). The dotted lines represent the dermo-epidermal junction. (C): The addition of Schwann cells (green) in the tissue-engineered skin induced the deposition of laminin in vitro (red). (D): Nerve fibers (green) stuck to the laminin (red) produced by Schwann cells. (E): In reconstructed skin, hair bud-like structures included prior to graft (Keratin 6, in red, below the dotted line delineating the epidermis) attracted nerve fibers (Neurofilament-M, green) from the wound bed 1 month after transplantation on mice. Scale bars = 40 μm (A, B), 30 μm (C), 50 μm (D), and 60 μm (E).

Figure 2.

Schematic representation of different strategies to enhance nerve regeneration in a tissue-engineered skin. All the cellular components should preferentially be isolated from a single uninjured autologous skin biopsy. Dermal papilla cells cultured with ORS keratinocytes from hair follicles and melanocytes (according to the differentiation method of Lindner et al. [67]) can be added to promote hair bud formation and growth, and functional mecanoceptor regeneration. Hairs may also be obtained from skin- or adipose-derived stem cells. This approach would enhance touch, pain, and temperature perceptions. Skin-derived precursor cells or adipose-derived mesenchymal stem cells can be differentiated into Schwann cells prior to being included in the tissue-engineered skin in order to promote nerve regeneration. Laminin can be embedded into a biomaterial subsequently used to prepare the tissue-engineered skin. Both approaches promote pain and temperature perceptions but not recovery of the sense of touch. Any of these possibilities will promote a better nerve regeneration in grafted skin compared with the same tissue made only of fibroblasts and keratinocytes, which will fail to achieve pain and temperature perceptions identical to those of normal skin, and will not promote sense of touch recovery. In contrast, late coverage of wounds without dermal regeneration will induce scar formation and loss of touch, pain, and temperature perceptions, in addition to increased risks of chronic pain and pruritus. Abbreviations: ORS, outer root sheath; TE, tissue-engineered.