Gene-modified tissue-engineered skin: the next generation of skin substitutes

Tissue engineering combines the principles of cell biology, engineering and materials science to develop three-dimensional tissues to replace or restore tissue function. Tissue engineered skin is one of most advanced tissue constructs, yet it lacks several important functions including those provided by hair follicles, sebaceous glands, sweat glands and dendritic cells. Although the complexity of skin may be difficult to recapitulate entirely, new or improved functions can be provided by genetic modification of the cells that make up the tissues. Gene therapy can also be used in wound healing to promote tissue regeneration or prevent healing abnormalities such as formation of scars and keloids. Finally, gene-enhanced skin substitutes have great potential as cell-based devices to deliver therapeutics locally or systemically. Although significant progress has been made in the development of gene transfer technologies, several challenges have to be met before clinical application of genetically modified skin tissue. Engineering challenges include methods for improved efficiency and targeted gene delivery; efficient gene transfer to the stem cells that constantly regenerate the dynamic epidermal tissue; and development of novel biomaterials for controlled gene delivery. In addition, advances in regulatable vectors to achieve spatially and temporally controlled gene expression by physiological or exogenous signals may facilitate pharmacological administration of therapeutics through genetically engineered skin. Gene modified skin substitutes are also employed as biological models to understand tissue development or disease progression in a realistic three-dimensional context. In summary, gene therapy has the potential to generate the next generation of skin substitutes with enhanced capacity for treatment of burns, chronic wounds and even systemic diseases.