Regeneration of the dermis does not occur spontaneously in the adult mammal. The epidermis is regenerated spontaneously provided there is a dermal substrate over which it can migrate. Certain highly porous, crosslinked collagen-glycosaminoglycan copolymers have induced partial morphogenesis of skin when seeded with dermal and epidermal cells and then grafted on standard, full-thickness skin wounds in the adult guinea pig. A mature epidermis and a nearly physiological dermis, which lacked hair follicles but was demonstrably different from scar, were regenerated over areas as large as 16 cm2. These chemical analogs of extracellular matrices were morphogenetically active provided that the average pore diameter ranged between 20 and 125 lsm, the resistance to degradation by collagenase exceeded a critical limit, and the density of autologous dermal and epidermal cells inoculated therein was >5 X 104 cells per cm2 of wound area. Unseeded copolymers with physical structures that were within these limits delayed the onset of wound contraction by about 10 days but did not eventually prevent it. Seeded copolymers not only delayed contraction but eventually arrested and reversed it while new skin was being regenerated. The data identify a model extracellular matrix that acts as if it were an insoluble growth factor with narrowly specified physicochemical structure, functioning as a transient basal lamina during'morphogenesis of skin.Throughout development, extracellular matrices (ECMs) are continuously being remodeled-i.e., synthesized, degraded, and resynthesized (1)(2)(3)(4)(5). Healing of a deep skin wound also requires remodeling of an ECM-the basal lamina (basement membrane) between the epidermis and the dermis (2). ECMs are largely insoluble and nondiffusible, and they confer stiffness and strength to multicellular systems (1, 2). During remodeling, the ECM necessarily suffers degradation of macromolecular chains, a process that dramatically reduces the insolubility of the ECM and impairs its role as mechanical reinforcement of a multicellular system undergoing development. It is not clear just how the resistance of the ECM to degradation affects its role during morphogenesis.In physical terms, ECMs can be described as macromolecular networks that are covalently crosslinked and are highly swollen in extracellular fluid. Accordingly, the physical structure of an ECM can be characterized initially by specifying the volume fraction 'of macromolecular components (swelling ratio), the average diameter of pores in the highly swollen network, the density ofcrosslinks tying chains to each other, and the degree of crystallinity present. This model leads to questions such as the following ones. Is it necessary for a developmentally active ECM to persist as an undegraded, crosslinked macromolecular network (and, therefore, remain insoluble and nondiffusible) over a critical time scale? Is it necessary for such an ECM to contain pores of a critical size? We have answered these questions in a preliminary way by use of we...

Prompt and long-term closure of full-thickness skin wounds is guinea pigs and humans is achieved by applying a bilayer polymeric membrane. The membrane comprises a top layer of a silicone elastomer and a bottom layer of a porous cross-linked network of collagen and glycosaminoglycan. The bottom layer can be seeded with a small number of autologous basal cells before grafting. No immunosuppression is used and infection, exudation, and rejection are absent. Host tissue utilizes the sterile membrane as a culture medium to synthesize neoepidermal and neodermal tissue. A functional extension of skin over the entire wound area is formed in about 4 weeks.

Clearance of hylan fluid and hylan gel, components of the hyaluronan (HA)-derived viscosupplement hylan G-F 20, following intra-articular injection into normal, healthy rabbits was evaluated. Radiolabeled hylan G-F 20 was injected at a volume of 0.3 mL into both knee joints of 12 rabbits. At sacrifice, synovial fluid, joint tissues, blood, popliteal lymph nodes, liver, spleen, kidney, and lung were analyzed for radioactivity. The half-life of the fluid component, a high-molecular weight hylan, was 1.5 ± 0.2 days while the half-life of the hylan gel component, a crosslinked hylan, was 8.8 ± 0.9 days. There was no radioactivity detected in the blood or the major internal organs following intra-articular injection. A rat model was used to evaluate the clearance of a large intravenous bolus of solubilized hylan gel. No accumulation of hylan gel degradation products was observed in any major organs and the half-life of hylan elimination from the blood was within normal ranges for HA elimination. The dosing used in the nonclinical rabbit intra-articular study was equivalent (v/w) to a single 6 mL dose in humans. These results are consistent with the current clinical data that demonstrates safety and effectiveness of an increased volume of hylan G-F 20 injected into the osteoarthritis knee.

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