Year: 2015
Type: article
Abstract: In this issue of experimental dermatology, Wong et al. 1 reviewed the anatomy and patterning of skin, discussed the factors that may affect it and hypothesized its importance. The application of these concepts to the development of clinically useful biologic products and devices for wound repair has recently largely been overlooked. Conceptual ideas expressed by Wong et al. may in fact be critical to the success of engineered skin products for the treatment of refractory chronic wounds. Chronic wounds are common, are associated with significant morbidity and mortality and are often refractory (S1). As an example, in the United States over six million Americans suffer from chronic wounds, and these chronic wounds are associated with greater mortality than cancer 2. In the best hands, only two-thirds heal, and the cost to the US healthcare system, even with conservative estimates, exceeds $25 billion (S2). Cell- and tissue-based products (CTBP) have been developed as adjuvants to standard care. While over 60 products fit into this category, far fewer have been studied in a randomized fashion and only two are currently approved by the US Food and Drug Administration (S3). Within this category, both cellular and acellular products exist, and while the majority is biological in origin, synthetic and biosynthetic matrices also are used. While evidence suggests cellular constructs might be superior, controversy exists (S4). Best studied are the FDA-approved cellular therapies, a human dermal equivalent (Dermgraft, Organogenesis, Canton, MA, USA) and the bilayered cellular construct (Apligraf, Organogenesis, Canton, MA, USA). The exact mechanism of action (MOA) of both of these products is not clearly understood, but the persistence of cell and matrix does not appear to be long-lived 3. Rather, it is generally thought the short-lived presence of the matrix provides a scaffold for cellular ingrowth or a way station for cell signalling and/or the applied cells, while present, provide cytokines while living or apoptotic signals Unfortunately, even the best results using CTBP in substantial numbers of patients suggest not all patients respond. Wong et al. work sheds light on possibility of other (physical as opposed to biologic) targets for MOA for these products. It also adds perspective to a recently published successful result of a large trial using a biologic scaffold (collagen and chondroitin sulphate) (Integra Life Sciences, New Jersey) for the treatment of diabetic foot ulcers 4. In this study of over 300 patients with plantar diabetic neuropathic foot ulcers, use of the construct leads to better and faster healing. It is possible the mechanical properties of this construct, developed for burn wounds to simulate human dermis, is the critical part of this product's MOA, even in the hostile environment of chronic wounds. The mechanical properties of skin (providing and resisting stretch and elasticity) arise primarily from the composition and organization of the extracellular matrix (ECM) in the dermis [derived primarily from the collagen fibres and their morphology, organization and cross-link density (S5)] 5. ECM including elastic fibres and proteoglycans influences activity and function of fibroblasts as they adapt to the stiffness of their cytoskeleton to that of their substrate 6, 7, (S6–S7). The ECM also influences cell proliferation, differentiation, migration and gene expression 8, 9, (S8). These properties vary with anatomical site, age and genetic background of the individual (S9). Wounded skin is subjected to tensile stress. Tensile stress is mainly anisotropic (unequal physical properties along different axes), due to multilayered, non-homogenous and nonlinear viscoelastic properties of the skin 10. Collagen fibres rotate, align and straighten in the direction of stretch when the tissue acquires a strain-stiffening behaviour. These properties may be critical to cell signalling. The direction and degree of anisotropy and material properties vary by location (S10–S11). The skin can adjust its elastic modulus (coefficients of elasticity of a body, expressing the ratio between a stress or force per unit area that acts to deform the body and the corresponding fractional deformation caused by the stress) 11. The tensile stress on skin during healing creates cellular mechanisms at the wound site by which stress is sensed and transduced to a physiological response. (Fig. 1) Connective tissue of the wound bed, either through natural processes or potentially through placement of engineered products mediates the mechanism of transducing the cellular reaction to tensile stress into a physiological response creating tension leading to healing 12. Therefore, one might reason physical properties of a construct and its response to tension during healing affect fibroblasts proliferation, apoptosis and activity of signalling pathways 10, 13, (S12). It is not yet clear whether the topography of the basement membrane can affect the epithelium intrinsic cells in humans, dictating their behaviour driving stem cell development into the cell of 'interest' in the correspondent environment 10. Some studies suggest that stem cells are organized in varying patterns in different locations in the skin 10. The behaviour of the skin cells can also be affected by the stiffness of the ECM. Research suggests the stiffer the substrate, the greater the spread of cells. Several studies 14, (S13, S14) found that wound stiffness increases during wound healing indicating that the tautness of the wound bed acts as mechanism to ensure wound coverage. With next-generation products, ideal mechanical culture conditions should take into account the measurement of tissue stiffness at the cell perception level (S15). A knowledge gap exists regarding balancing degradation of the collagen scaffold and synthesis of extracellular matrix during the remodelling process and its impact on repaired skin's organization and functional properties, such as tissue stability and range of motion (S16). Some work has been carried out; for example, Sander et al. mechanically tested an engineered skin substitute (ESS) containing human cells at 2 weeks of incubation in vitro and at 6 weeks after grafting to a full-thickness wound in athymic mice. Mechanical tests were conducted on collagen–glycosaminoglycan scaffold (CGS), dermal skin substitute (DSS), ESS, grafted ESS, autografts and native mouse skin 5. Several factors found to contribute to ESS mechanical strength included synthesis of new ECM and degradation of scaffold, cellular replication, differentiation and tissue morphogenesis. While the above study focused on dermal aspects of a construct, epidermal response is also likely critical to the development of an optimal skin construct. As an example, correlation between ESS tensile strength and the properties of the engineered epidermis have been found (S17, S18). Complex beyond the confines of this commentary, many factors are operating on variables in skin engineering. Considerable room for research in tissue engineering to develop more physiological alternatives for wound healing and to restore the essential mechanical and biological properties is needed. (S19, S20) These include further studies evaluating the impact of stiffness, topography and dimensions of the ECM to which cells attach would affect wound healing and the development of new skin substitutes. Wong et al. work provides an impetus for such studies. Ingrid Herskovitz performed the research, acquisition, analysis and interpretation of data, drafted and edited the paper, performed the final submission. Robert Kirsner designed, wrote and edited the research study. Flor Macquhae performed research, contributed with essential tools and conceived the drawing. Joshua Fox performed data research Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Source: Experimental Dermatology
DOI: 10.1111/exd.12916
Institution: University of Miami
Language: English
Topic: Wound Healing and Treatments
Subfield: Rehabilitation
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2284116123