Biomimetic approaches to protein and gene delivery for tissue regeneration.

Novel therapeutic strategies that promote wound healing seek to mimic the response of the body to wounding, to regenerate rather than repair injured tissues. Many synthetic or natural biomaterials have been developed for this purpose and are used to deliver wound therapeutics in a controlled manner that prevents unwanted and potentially harmful side-effects. Here, we review the natural and synthetic biomaterials that have been developed for protein and gene delivery to enhance tissue regeneration.

Biomimetic delivery of keratinocyte growth factor upon cellular demand for accelerated wound healing in vitro and in vivo.

Exogenous keratinocyte growth factor (KGF) significantly enhances wound healing, but its use is hampered by a short biological half-life and lack of tissue selectivity. We used a biomimetic approach to achieve cell-controlled delivery of KGF by covalently attaching a fluorescent matrix-binding peptide that contained two domains: one recognized by factor XIII and the other by plasmin. Modified KGF was incorporated into the fibrin matrix at high concentration in a factor XIII-dependent manner.

In vivo model of wound healing based on transplanted tissue-engineered skin.

Advances in understanding the complex process of wound healing and development of novel growth factor and gene therapies would benefit from models that mimic closely the physiology of human wounds. To this end, we developed a hybrid wound-healing model based on human tissue-engineered skin transplanted onto athymic mice. Grafted tissues were infiltrated with mouse mesenchymal cells as native and foreign dermal regions fused together.

A novel role of fibrin in epidermal healing: plasminogen-mediated migration and selective detachment of differentiated keratinocytes.

Recent studies have shown that fibrin promotes epidermal regeneration in vitro and maintains the stem cell population after transplantation of keratinocytes in vivo. As epidermal keratinocytes do not express integrin alpha(v)beta3, the receptor for fibrin and fibrinogen, the mechanism through which fibrin affects epidermal cells remains elusive. To investigate the role of fibrin in epidermal wound healing, we developed an in vitro model in which fibrin was added to the top of wounded keratinocyte monolayers grown on collagen.

Fibrin promotes migration in a three-dimensional in vitro model of wound regeneration.

We developed an in vitro model of wound reepithelialization based on engineered composite skin equivalents of human keratinocytes. Such organotypic cultures are unique in that regulatory mechanisms of cell growth and differentiation can be investigated under conditions mimicking those in vivo. We employed this model system to evaluate fibrin as a substrate for keratinocyte growth and migration after incisional wounding.