Biocompatible polymer interactions with biological structures

我们最近描述了一种用于细胞的“通用胶”，这是基于我们令人惊讶的观察结果，即用两性离子胆碱磷酸盐（CP）基团修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基团在自然界中普遍存在。这一发现将导致许多生物医学应用，例如在手术期间的止血和组织密封（止血），但由于合成CP基团的效率低，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，其将附着于组织边缘并通过聚集血细胞诱导堵塞。在短期内，我们将合成一个家庭的超支化聚甘油（HPGs）携带相关的甜菜碱，已知在所有但CP的情况下，是排斥蛋白质和细胞，有和没有添加聚阳离子，以提供细胞结合的粘附能。 这里的目标是（a）更好地理解CP结合细胞但排斥蛋白质的异常，以及（B）开发基于甜菜碱保护的新的生物粘合剂以抵抗通常破坏性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，与红细胞和血小板结合的聚合物引起活化和聚集，同时抑制部分凝血级联反应和凝块形成。 我们计划在下一个资助期内大大扩展此类研究，以便能够更好地定制对带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与其他聚合物和复杂的生物流体，如血浆混合的上述和相关的HPGs的相容性，因为很少有人知道任何超支化聚合物在任何但单一溶剂中的热力学行为。虽然HPG例如为化学改性提供了优异的生物相容性平台，但关于它们在混合物中的后续热力学行为、对血浆中蛋白质的结合或排斥的相容性的影响或与用于纤维形成（例如用于止血材料开发）的线性聚合物的相容性知之甚少。 因此，我们将进行系统的调查相图的解决方案和混合物含有简单的或衍生的HPGs，因为这些取决于混合自由能的物种。已知线性聚合物如PEG沉淀蛋白质，但HPG比线性聚合物密度大得多，因此它们与共享高密度的蛋白质的相互作用应该更良性。 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（当溶液条件稍微改变时会发生相分离，就像眼睛中的透镜蛋白质一样），这是进化的结果，因此向混合物中加入“合成蛋白质”可能会产生巨大的影响。

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.****