Biocompatible polymer interactions with biological structures

我们最近描述了一种用于细胞的“万能胶”，基于我们令人惊讶的观察，用两性离子胆碱-磷酸（CP）基团装饰的超支化或线性聚合物与含有PC基团的细胞膜强烈结合，PC基团在自然界中无处不在。这一发现将导致许多生物医学应用，例如在手术中的血液停止和组织密封（止血），但由于合成CP基团的效率较低，该领域发展缓慢。我们的长期目标是开发一种基于这种或相关类型的生物粘附的新型止血材料，这种材料可以附着在组织边缘并通过聚集血细胞诱导堵塞。在近期，我们将合成一个家族的超支化聚甘油（HPGs）携带相关甜菜碱，已知在所有的情况下，除了CP的情况下，是排斥蛋白质和细胞，有或没有添加聚合为细胞结合提供粘接能量。这里的目标是(a)更好地理解CP与细胞结合但排斥蛋白质的异常现象，以及(b)开发基于甜菜碱保护的新型生物粘合剂，以防止通常有害的聚阳离子诱导的结合。我们最近研究了血液中的这种聚合物系统，并发现了复杂的凝血反应，例如，聚合物与红细胞和血小板结合引起激活和聚集，同时抑制部分凝血级联和凝块形成。我们计划在下一个资助期内大大扩展这类研究，以便能够更好地定制含有这些基团的聚合物的生物反应。****我们的第二个近期兴趣集中在上述和相关HPGs与其他聚合物以及与复杂生物流体（如血浆）混合的相容性，因为除了单一溶剂外，对任何超支化聚合物的热力学行为知之甚少。例如，虽然HPGs为化学修饰提供了一个极好的生物相容性平台，但对于它们在混合物中的后续热力学行为、对血浆中蛋白质结合或排斥的相容性的影响，或与纤维形成中有用的线性聚合物的相容性（例如用于止血材料的开发），人们知之甚少。因此，我们将对含有简单的或衍生的HPGs的溶液和混合物的相图进行系统的研究，因为这些依赖于物种的混合自由能。众所周知，聚乙二醇等线性聚合物会沉淀蛋白质，但HPGs比线性聚合物密度大得多，因此它们与蛋白质的相互作用（它们具有高密度）应该是良性的。蛋白质能够以非常高的浓度存在于细胞质中，而没有明显的相分离（当溶液条件发生轻微变化时，就会发生这种情况，就像眼睛中的晶状体蛋白质一样），这是亿万年进化的结果，因此在混合物中加入“合成蛋白质”可能会产生戏剧性的效果。****

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.****