Biologically Active Analogues of the Extracellular Matrix: Artificial Skin and Nerves

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Abstract
Animal development starts as a single cell which proliferates into several new cells; these differentiate into highly specialized tissues, organs, and limbs; and the small but functioning organism eventually grows into its full scale. Throughout development the extracellular matrices, which are complex macromolecular networks, also undergo dramatic changes. Matrix transformations occasionally control the much more well‐studied changes in number and type of differentiating cells. Extracellular matrix (ECM) networks are typically broken down enzymatically to oligopeptides and are then resynthesized (remodeled) to form insoluble and nondiffusible macromolecular structures which confer stability of shape to multicellular systems. Mature ECM, such as skin, tendon, cartilage, and blood vessels, provides stiffness and strength to tissues and organs. Remodeling of ECM also occurs in adult organisms, during wound healing. An understanding of the role that ECM plays during development or wound healing can be obtained by use of synthetic ECM analogues. Several simple chemical ECM analogues have been synthesized and a few have been found to possess remarkable biological activity. One of these analogues has induced the partial regeneration of skin in an adult guinea pig wound model as well as in man. Peripheral nerve has been regenerated in another animal model by use of a similar ECM analogue. In all these mammalian lesions it is well‐known that regeneration does not occur spontaneously. These analogues are graft copolymers of collagen and chondroitin 6‐sulfate (a glycosaminoglycan) in the state of highly hydrated and covalently cross‐linked gels. Procedures are summarized for synthesis of copolymers with adjusted physicochemical properties, such as the rate at which they degrade enzymatically when implanted, the elements of their pore structure, and the degree of collagen crystallinity. ECM analogues have provided a novel window into the complexities of morphogenesis and regeneration and they have pointed towards entirely new directions in the medical treatment of serious organ dysfunction and organ loss. An ECM analogue has already become the basis of a new clinical treatment for massively burned patients. An interpretation of the results leads to a hypothesis about the nature of ECM during development. Since biological activity appears only when the physicochemical parameters fall within very narrow limits, it is intriguing to speculate that these experiments describe a single insoluble growth factor which is specific for skin synthesis. Such an insoluble growth factor appears to be just as essential to skin development as are the much more well‐known soluble growth factors. A different ECM analogue appears to induce nerve regeneration, possibly because each tissue requires its own developmentally active ECM.

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