Mechanisms of Wound Healing:
Studies with the Bilayered Cellular Matrix, OrCel®
By Melvin Silberklang, Ph.D.
I-Horus Inc. has developed a new tissue-engineered wound healing product, a bilayered cellular matrix produced from allogeneic living skin cells, trademarked OrCel®. This product contains cultured donor neonatal human keratinocytes and fibroblasts in separate compartments of a bilayered collagen sponge. OrCel®ís first FDA approvals were obtained last year for treatment of acute surgical excisions, such as contracture release sites and donor sites in Epidermolysis Bullosa patients undergoing hand reconstruction surgery and donor sites in burn victims undergoing excision and autografting. Since the cells used to produce Orcel® are extensively expanded in vitro, they cease to express significant levels of HLA-II antigens and, upon application to a wound bed, are apparently not immediately recognized by the recipientís immune system as foreign.
This has been confirmed in both clinical trial and commercial experience, as no clinical observations of signs of tissue rejection have ever been reported. In addition, in a recent pilot study with the experimental cryopreserved OrCel® product, no HLA-cytolytic antibody response to alloantigens in the product was detected in a cohort of 13 patients after four sequential weekly product applications. Resorption appears to take place gradually, with no remnants of the donor cells or matrix being detectable by two weeks post-treatment. Our working hypothesis is that extracellular secretion of cytokines and growth factors by the living cells in OrCel® is a major contributing factor to the productís ability to accelerate wound healing.
Under in vitro culture conditions, the close keratinocyte-fibroblast proximity afforded by the matrix enhances the ability of each cell type to exert a paracrine effect on the other through extracellular diffusible factors it expresses. The composite cytokine and growth factor expression profile of a keratinocyte-fibroblast co-culture exhibits synergistic features that significantly exceed the individual contribution of either cell type when grown alone. Studies conducted by Forticell also reveal differences between growth factor expression by OrCel® and competitive products. Interestingly, the net composite expression by OrCel® in vitro has also been found to closely resemble the net profile of secreted endogenous growth factors measured in normal clinical volunteers in vivo in acute skin wound fluid from experimental donor sites. Thus, when placed into contact with a wound bed, the product appears to be capable of supplementing the endogenous wound fluid with an exogenous supply of normally balanced growth factors characteristic of a healthy, healing acute wound.
Our clinical results with the treatment of donor sites demonstrate an acceleration of time to 100% healing. In the case of chronic wounds, we hypothesize that OrCel®ís balanced mixture of exogenous growth factors contributes to the activation of the patientís own local cells to resume a healing profile. Finally, a very practical feature of OrCel® is its ability to be cryopreserved and to recover full potency upon thawing. Cryopreserved OrCel® can provide a sophisticated off-the-shelf wound treatment, available on demand at point of use.