Despite recent advances in surgical technique and the development of numerous therapeutic agents, the formation post surgical adhesions (PSA) continues to cause complications for many patients. In this research, we have employed a rational system to develop a novel treatment to address this clinical need. Based on an understanding of the biochemical events that lead to PSA formation, a series of targeted polymeric biomaterials was designed to interrupt the fibrin gel matrix propagation and suppress PSA formation. Using group transfer polymerization, a series of well controlled block copolymers of polyacrylic acid and poly(ethylene glycol-methacrylate) based materials was synthesized. Subsequent functionalization with the pentapeptide Cys-Arg-Glu-Lys-Ala (CREKA) was employed to target the materials to fibrin as a marker of pro-adhesive sites. While preliminary testing of the untargeted materials verified their ability to suppress non-specific protein adsorption to model surfaces, numerous in vitro tests were conducted to study the ability to inhibit fibrin gel propagation. The ability to inhibit both the rate and quantity of fibrinogen deposition to a fibrin coated surface has been demonstrated. In addition, the rate of fibrin gel propagation and the degree of cellular attachment can modulated. Taking advantage of the systematic variation in structure facilitated by the robust synthetic methodology employed, statistical analysis was used to elucidate the structureproperty relationships governing the performance of these materials. The most important factors that lead to enhanced performance in in vitro tests are the length of PEG chain and number of peptide units conjugated to the polymer: increasing PEG chain length and increasing the number of peptides conjugated to the polymer both improve performance in all tests. The synthetic methods that have been developed, in conjunction with the experimental results, will be used to direct future studies, including cytotoxicity and animal studies.

Post surgical adhesions (PSAs) are an inevitable outcome of surgery and their presence leads to pathogeneses and significant economic impact. The studies within this thesis utilised standard and reproducible abrasion models, in rabbits, pigs and rats, to investigate the formation and maturation of PSAs with strict quantitative analyses. These studies have shown that the development of PSAs is a series of complex, multi-factorial processes. PSA development can be classified into two stages: (i) PSA modelling occurring up to/including 16 hours post injury characterised by the inflammatory response and fibrin deposition and maturation; and (ii) PSA remodelling occurring from 16 hours onwards and characterised by tissue repair, collagen deposition and maturation and chemical mediation by TGF-P. Treatment with VivostatTM System Derived (novel) Fibrin Sealant significantly reduced the formation of PSAs with mean PSA reduction of 80% for the rabbit uterine horn abrasion model, from 3 separate studies; 83% for the pig stomach/colon/caecum abrasion model, from 2 separate studies; 80% for the rat caecum abrasion model. This is significantly better than other fibrin sealants investigated in this thesis. PSA prevention with novel fibrin sealant demonstrated a similar pattern to PSA development, with two stages of development evident: (i) tissue generation modelling occurring up to/including 16 hours post injury characterised by the inflammatory response and fibrin deposition and maturation; and (ii) tissue generation remodelling occurring from 16 hours onwards and characterised by tissue repair, collagen deposition and maturation and chemical mediation by TGF-P. However the extent and subsequent time taken for these changes to occur was significantly reduced. The prevention of PSAs and alterations of wound healing by novel fibrin sealant is most probably due to the sealant acting as a haemostat, as well as a physical barrier. Thus preventing fibrinous and subsequent fibrous PSA formation.

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