Collagen is the most frequently used protein in the fields of biomaterials and regenerative medicine. Within the skin, collagen type I and III are the most abundant, while collagen type VII is associated with pathologies of the dermal–epidermal junction. The focus of this review is mainly collagens I and III, with a brief overview of collagen VII. Currently, the majority of collagen is extracted from animal sources; however, animal-derived collagen has a number of shortcomings, including immunogenicity, batch-to-batch variation, and pathogenic contamination. Recombinant collagen is a potential solution to the aforementioned issues, although production of correctly post-translationally modified recombinant human collagen has not yet been performed at industrial scale. This review provides an overview of current collagen sources, associated shortcomings, and potential resolutions. Recombinant expression systems are discussed, as well as the issues associated with each method of expression.

The complexity of the dermal layer of skin means that damage to this section can result in permanent impairment of function. Partial or total dermal loss is a feature of deep burns and chronic wounds such as pressure sores or diabetic ulcers. The issues posed by traditional skin grafts have led to substantial research being carried out in the fields of tissue engineering and biomaterials science to develop a vast array of alternative skin substitutes. Given the large number of different materials, manufacturing methods, and techniques for implementation described for artificial skin substitutes, many classification systems have been created to simplify their categorization. Some of these systems are oriented towards clinicians while others towards researchers. However, none address the needs of both groups and none are intuitive. The creation of an effective classification system would be particularly helpful in the regulation, distribution, organization and selection of skin substitutes. The aim of this review is to examine existing methods of classification of skin substitutes, and to propose a new system that uses an algorithm that is inspired by factorial design. Our system allows multiple factors to be simultaneously investigated or in this case, described, since all skin substitutes possess multiple characteristics: 1) cellularity (acellular or cellular), 2) layering (single layer or bilayer), 3) replaced region (epidermis, dermis, or both), 4) materials used (natural, synthetic, or both), and 5) permanence (temporary or permanent). The factors and levels are combined into an algorithm where all the possible combinations are shown. The multi-factorial and palindromic structure of our system should enable all users to quickly understand the makeup of a selected skin substitute, or search for a skin substitute depending on their specific requirements. We feel that our proposed classification can be used by clinicians and biomedical researchers alike, which should be an advantage given the multi-disciplinary nature of the tissue engineering field and the science which underpins the development of skin substitutes. We also touch upon some of the state-of-the-art skin substitutes that are commercially available or under development to demonstrate how our new method of classification might work.

Due to great clinical need, research where different biomaterials are tested as 3D scaffolds for skin tissue engineering has increased. In vitro studies use a cell suspension that is simply pipetted onto the material and cultured until the cells migrate and proliferate within the 3D scaffold, which does not mimic the in vivo reality. Our aim was to engineer a novel biomimetic in vitro model that mimics the natural cell infiltration process occurring in wound healing, thus offering a realistic approach when pre-screening and testing new skin substitutes. Our model consists of porous membrane cell culture inserts coated with gelatin and seeded with human dermal fibroblasts, inside which two different commercially available dermal substitutes were placed. Several features relevant to the wound healing process (matrix contraction, cell infiltration and proliferation, integration of the biomaterial with the surrounding tissue, and secretion of exogenous cytokines and growth factors) were evaluated. Our results showed that cells spontaneously infiltrate the materials and that our engineered model is able to induce and detect subtle differences between different biomaterials. The model allows for room for improvements or “adds-on” and miniaturization and can contribute to the development of functional and efficient skin substitutes for burns and chronic wounds.