Surgical intervention, by its very nature, results in tissue damage that triggers the formation of fibrotic scar tissue as part of the normal wound healing response. Although inflammation and production of extracellular matrix components is necessary for normal wound healing, adhesions may also occur which can lead to significant clinical complications. Simple bioresorbable barriers made from hyaluronic acid, regenerated cellulose, or collagen have been shown to have some efficacy in preventing inter-tissue adhesions, but there are still a significant number of adhesions that occur using this strategy. Another strategy to eliminate post-surgical adhesions is to provide an absorbable barrier between tissue planes which releases an agent which inhibits collagen production, the main protein component of scar tissue. For example, cis-4-hydroxyproline (cHyp) has been shown to be a potent inhibitor of synthesis of collagen, and thus has been considered as a potential antifibrotic agent. However, free cHyp is too toxic to be used as a clinical agent, primarily due to its effects on non-collagen proteins. To reduce the toxicity of this agent, cHyp was attached to a water soluble polymer consisting of low molecular weight polyethylene glycol (PEG) and the amino acid lysine (Lys). The lysine component has a free carboxylic acid pendent group at each monomeric repeat unit which can be used to couple active agents such as cHyp. A series of preliminary in vitro and in vivo studies has established the use of this polymer for the delivery of cHyp, showing that collagen production can be effectively inhibited without other cytotoxic effects. The scientific objectives of this Phase I proposal is to establish a formulation of the PEG-Lys-cHyp polymer which can be used in conjunction with a bioresorbable delivery system to combat post-surgical adhesion formation. A well-described animal model which reliably produces adhesions will be utilized to develop an effective formulation.
