Collagen hydrogels strengthened by biodegradable meshes are a basis for dermo-epidermal skin grafts intended to reconstitute human skin in a one-step surgical intervention

Abstract

Extensive full-thickness skin loss, associated with deep burns or other traumata, represents a major clinical problem that is far from being solved. A promising approach to treat large skin defects is the use of tissue-engineered full-thickness skin analogues with nearly normal anatomy and function. In addition to excellent biological properties, such skin substitutes should exhibit optimal structural and mechanical features. This study aimed to test novel dermo-epidermal skin substitutes based on collagen type I hydrogels, physically strengthened by two types of polymeric net-like meshes. One mesh has already been used in clinical trials for treating inguinal hernia; the second one is new but consists of a FDA-approved polymer. Both meshes were integrated into collagen type I hydrogels and dermo-epidermal skin substitutes were generated. Skin substitutes were transplanted onto immuno-incompetent rats and analyzed after distinct time periods. The skin substitutes homogeneously developed into a well-stratified epidermis over the entire surface of the grafts. The epidermis deposited a continuous basement membrane and dermo-epidermal junction, displayed a well-defined basal cell layer, about 10 suprabasal strata and a stratum corneum. Additionally, the dermal component of the grafts was well vascularized.

Introduction to cell–hydrogel mechanosensing

“…The compression technique can be manipulated to allow fluid flow out of the hydrogels in a particular direction resulting in a more aligned fibre arrangement [147,148]. Plastic compression has several applications including the development of hydrogels with incremental increases in stiffness to study the effect of stiffness on cell migration and proliferation [92,145] and it has been under examination for cornea regeneration [146,149] and dermal tissue engineering and repair [23,24]. To date, this technique has primarily been used on collagen hydrogels, because most other hydrogels are incompressible under high strains, in part, owing to their hydrophilic nature.…”

“…These types of hydrogel are particularly useful in examining cellular behaviour owing to their biocompatibility, biodegradability and biofunctionality [68]. cornea agarose-fibrin [29] alginate-gelatin nanofibre [163] collagen [146,149,150] collagen-PLGLA nanofibre [160] alginate [34] cellulose [35] heparin [36] alginate-hyaluronic acid [33] collagen [190] collagen-chitosan [32] dextran [30,31] hyaluronic acid [44] alginate [27] collagen [23,24] dextran [25] gelatin [26] collagen [17,97] fibrin [37] agarose [51,175,179,196] alginate [126] chitosan [20,50] fibrin [42,51] gellan gum [22,51] hyaluronic acid [110] PEG [60] A key factor when examining cell-material mechano-interactions is the mechanisms of cell adhesion to the hydrogel. Cell surface receptors such as integrins bind to ligands within the hydrogel if such adhesion sites exist.…”

“…This remodelling behaviour is influenced by several factors, in particular, the type of hydrogel, the type of cell and the absence or presence of biochemical and mechanical stimuli. To date, cell-seeded hydrogels have been under investigation to repair or replace several tissue types, including cartilage [20][21][22], skin [23][24][25][26][27], cornea [28,29] and vascular tissues [30][31][32][33] among other tissues [34][35][36][37] (figure 1). As this field has grown, it has become evident that a greater understanding of the cell-material interactions in hydrogel systems is required to properly explain the mechanical mechanism that cells use to remodel their surroundings and to exploit this behaviour to develop functional tissues and tissue repair strategies.…”

The Influence of Stromal Cells on the Pigmentation of Tissue-Engineered Dermo-Epidermal Skin Grafts

“…Since several years, we are investigating diverse characteristics and properties of dermo-epidermal skin substitutes (DESS) for future clinical application to full-thickness skin defects. [11][12][13][14][15] The importance of site-specific cellular epidermal and dermal components has been shown in the context of reproducing the original donor skin color in our pigmented skin substitutes. 16 Moreover, the applied preclinical model enables us to analyze the influence of different fibroblast populations in an in vivo setting.…”

About ATMPs, SOPs and GMP: The Hurdles to Produce Novel Skin Grafts for Clinical Use

“…These skin grafts have successfully been tested in pre-clinical studies [12,13,14]. Since 2013, the developed skin grafts are produced in the facilities of the Wyss Translational Center Zurich, Switzerland, under good manufacturing practice (GMP) conditions for clinical trials.…”