Biocompatible polymer interactions with biological structures

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We recently described a universal glue' for cells based on our surprising observation that hyperbranched or linear polymers decorated with zwitterionic choline-phosphate (CP) groups bound strongly to cell membranes containing PC groups, which are ubiquitous in nature. This discovery should lead to numerous biomedical applications, for instance in blood arrest and tissue sealing (hemostasis) during surgery, but the field is evolving slowly because of low efficiencies in synthesizing CP groups. Our long term goal is to develop a new category of hemostatic materials based on this or related types of bioadhesion that would attach to tissue margins and induce plugging by aggregating blood cells. In the near term we will synthesize a family of hyperbranched polyglycerols (HPGs) carrying related betaines, known in all but the CP case to be repulsive to proteins and cells, with and without added polycations to provide adhesive energy for cell binding. The goal here is (a) to better understand the anomaly of CP binding to cells but rejecting proteins, and (b) to develop new bioadhesives based on betaine protection against normally damaging polycation-induced binding. We have recently studied such a polymer system in blood and have found complex coagulation responses, for instance, with the polymers binding to red cells and platelets causing activation and aggregation while inhibiting parts of the coagulation cascade and clot formation. We plan to greatly expand such studies in the next funding period to be able to better tailor the biological response to polymers bearing these groups.****Our second near term interests focus on the compatibility of the above and related HPGs mixing with other polymers and with complex biofluids such as blood plasma, as little is known about the thermodynamic behavior of any hyperbranched polymer in any but a single solvent. While HPGs, for instance, provide an excellent biocompatible platform for chemical modification, very little is known about their subsequent thermodynamic behavior in mixtures, the effects on compatibility of binding or rejection of proteins in plasma or compatibility with linear polymers useful in fibre formation, for instance for hemostatic material development. We will therefore undertake a systematic investigation of phase diagrams of solutions and mixtures containing simple or derivatized HPGs as these depend on the mixing free energy of the species. Linear polymers such as PEG are known to precipitate proteins but HPGs are much denser than linear polymers so their interactions with proteins, which share a high density, should be more benign. The ability of proteins to exist in cell cytoplasm at very high concentrations without obvious phase separation (which can occur when solution conditions change slightly, as with the lens proteins in the eye) is the result of eons of evolution so adding “synthetic proteins” to a mixture could have dramatic effects.****