Enhancement of wound healing efficiency mediated by artificial dermis functionalized with EGF or NRG1

Abstract

The use of artificial dermis as a skin substitute is a field of active study, as acellular dermal matrices from cadavers are susceptible to infection owing to their human origin. One such alternative dermal replacement scaffold, INSUREGRAF, is derived primarily from extracellular matrix proteins such as collagen and elastin and has been clinically used to treat severe skin wounds such as burns. This scaffold has proven to be useful to minimize wound contraction and scar formation owing to its biocompatibility, interconnected pore structure, sufficient biodegradability, and suitable mechanical properties. However, INSUREGRAF does not provide scar-free wound healing in cases of severe skin damage such as full-thickness (FT) excision. Considering that the efficient recruitment of fibroblasts and keratinocytes into a wound site represents a critical step in the regeneration of damaged skin, we attempted to enhance the efficiency for wound healing by fabricating growth factor-functionalized INSUREGRAF. In particular, we utilized epidermal growth factor (EGF) and an EGF family member, neuregulin-1 (NRG1), not previously studied in the context of wound healing, whose cellular role is to promote proliferation and migration in fibroblasts and keratinocytes. Both artificial dermis-growth factor combinations led to efficient recruitment of fibroblasts and keratinocytes into a wound site during the early steps of skin regeneration. Notably, EGF- or NRG1-functionalized INSUREGRAF induced rapid proliferation of skin cells in an ERK pathway-dependent manner and exhibited efficient wound healing in a Sprague-Dawley rat FT excision and grafting model. These results provide the foundation for expanding the use of growth factor-functionalized INSUREGRAF to clinical application in cases of severe skin injury.

Epithelial differentiation of human adipose-derived stem cells (hASCs) undergoing three-dimensional (3D) cultivation with collagen sponge scaffold (CSS) via an indirect co-culture strategy

“…Otherwise, differentiation of stem cells depends on the "niche," including diffusible paracrine effects, ECM, and cellular and mechanical factors [21,26,27,56], and most studies are based solely on 2D induction culture missing the biophysical microenvironments of the ECM. In contrast, 3D system using scaffolds (with interconnected pores) which mimic the structure and function of ECM proteins not only promotes cell adhesion, cell-biomaterial interactions, and cell proliferation [10,38,39], but also facilitates differentiation in skin regeneration [10,57,58].…”

“…Skin re-epithelialization is a crucial step in the proliferation phase [10,11], of which keratinocytes, the main components of the epidermis of the skin, play an important role in promoting re-epithelialization [4,11]. Under favorable conditions, the keratinocytes from the edges of the wound begin to migrate towards the center within hours after injury and proliferate continuously until the epithelial surface is intact [12].…”

“…With the development of tissue engineering technology, many skin scaffolds (termed as skin substitutes or artificial dermis) have been conceived as skin wound dressings [6] and applied clinically for eventual scar-free wound healing, including Pelnac® (Japan) [10], Integra® (USA) [10], and Lando® (China) [35] [36,37]. Currently, artificial dermis commercially available mainly consists of collagen sponge scaffolds (CSSs) with multiple desirable characteristics (such as biocompatibility, an interconnected pore structure, and sufficient biodegradability) [10,38,39], which are utilized as templates to promote fibroblasts and endothelial cells to proliferate [40], migrate and mature into scaffolds, and promote dermal regeneration and neovascularization, significantly reducing contracture and scar formation [41][42][43].…”

Light control of RTK activity: from technology development to translational research

“…53 Modern dermal replacement scaffolds derived primarily from extracellular matrix proteins, such as collagen and elastin, are used to treat severe skin wounds and burns. 54 It has been demonstrated that EGF and another EGF family member, neuregulin-1 (NRG1), are able to promote proliferation and migration of broblasts and keratinocytes towards such articial scaffolds. 54 In these cases, opto-RTKs, such as opto-EGFR could be delivered to broblasts and keratinocytes in the wound site using AAV particles.…”

Borrowing From Nature: Biopolymers and Biocomposites as Smart Wound Care Materials

“…Thanks to a facile chemical functionalization of the protein structure, various dressing architectures have been exploited. Collagen-based wound dressings, either in forms of hydrogels, electrospun fibers, or nanocrystal-containing scaffolds, have been applied to cover burn wounds, treat ulcers (Ghica et al, 2017 ; Guo et al, 2017 ; Bhowmick et al, 2018 ; Yoon et al, 2018 ), reduce tissue contraction and scarring, and increase epithelialization rate (Powell et al, 2008 ). Collagen sponges and fibrous membranes were found particularly promising, due to their wet-strength that allows suturing to soft tissues and provides a template for new tissue growth.…”