An ideal adhesive for bone repair : Injectable, rapidly crosslinkable, biodegradable poly(esters) containing reactive calcium phosphate fillers.

开发一种理想的骨修复粘合剂是一项困难的挑战，但可能会带来很高的回报，需要几个科学学科的专业知识。这种粘合剂应该能够注射到受损部位，然后快速固化，以提供高强度和相当于骨骼弹性的材料。如果粘结剂能够扩散到组织中，固化反应将提供粘附性(微机械)，从而早期支持周围的骨骼。然而，这种材料应该会降解，提供可以被细胞转化为新骨的成分。这种降解还可以提供缓慢释放的药物，以加强修复或防止感染。目前的聚甲基丙烯酸甲酯(PMMA)骨水泥可以快速固化，但不能降解。传统的长链聚(酯)酯目前被用于可降解的骨螺钉和各种其他医疗应用，但缺乏注射性，从而缺乏粘附性或用于微创关节镜手术的能力。相反，尽管磷酸钙骨水泥是可注射的，并提供了骨的无机成分所需的元素，但它们的固化特性很难控制，特别是在水环境中，而且它们的机械性能远不理想。因此，该项目的一个目标是将酯和甲基丙烯酸酯结构进行化学结合，以产生足够短的聚合物分子，这些聚合物分子足够短，可以在光照后几秒钟内通过甲基丙烯酸酯基团进行交联，从而提供一种像PMMA一样的高强度粘合剂。其中一个挑战将是准确地评估如何改变材料的化学成分，以确保材料在设定好后能够以骨骼重塑的速度降解。这种降解将通过聚(酯)段发生，导致成分很容易被身体移除。为了提供骨修复所需的元素，可以在液体中填充高百分比(&gt；70wt%)的微米尺寸的磷酸钙颗粒。在这项拟议的研究中，采用了一种独特的方法来改善这些颗粒在聚合物中的分散性，包括使用磷酸钙，通过与传统磷酸钙粘结剂相同的工艺与水反应。耐人寻味的是，我们可以通过SET聚合物从其周围吸收的水来催化这一反应。被吸收的水溶解了磷酸钙，使它们能够发生反应，然后在聚合物中以极细的、不易溶解的结晶形式重新沉淀。我们还发现，这第二个反应导致聚合物和磷酸钙之间的相互作用更大，大大增加了材料的刚性。再沉淀磷酸盐的另一个优点是，它可以中和聚酯的酸性降解产物，防止潜在的不良炎症反应，这是用这些聚合物生产的医疗器械的一个众所周知的问题。磷酸钙的加入也为我们提供了另一种控制降解率的方法，但我们预计它们将额外改善细胞的反应。有大量可能的可注射聚(酯)，但为了减少需要研究以优化新配方的样品数量，我们以前使用了实验(析因)设计，使我们了解哪些变量因素对聚合物交联率和最终水平、刚性和降解性以及药物释放速率影响最大。在这项新的研究中，我们将扩展这些方法，以解释这些特性是如何通过添加活性填料而改变的，同时还可以确定机械强度。然而，我们新研究的关键将是提高我们对哪些化学物质会非法改变细胞反应的理解。我们的最终目标将是找到一种最佳配方，然后在体内进行评估。

Developing an ideal adhesive for bone repair is a difficult but potentially highly rewarding challenge requiring expertise from several scientific disciplines. Such an adhesive should be able to be injected into a damaged site but then set rapidly to give a material of high strength and comparable flexibility to bone. Provided the adhesive can spread into the tissue the setting reaction would provide adhesion (micromechanical) and thereby early support for the surrounding bone. The material should then, however, degrade providing components that can be converted by cells to new bone. This degradation could additionally provide slow release of drugs that enhance repair or prevent infections. Current poly(methylmethacrylate) (PMMA) bone cements can be rapidly set but are non degradable. Conventional long chain poly(esters), presently used as degradable bone screws and various other medical applications, lack injectability and thereby adhesion or the ability to be used in minimally invasive arthroscopic procedures. Conversely, although calcium phosphate cements are injectable and provide the elements required for the inorganic component of bone their setting characteristics are difficult to control particularly in an aqueous environment and their mechanical properties are far from ideal. One aim of this project is therefore to chemically combine ester and methacrylate structures to produce polymer molecules that are sufficiently short to be fluid but that can crosslink through the methacrylate groups within seconds of light exposure providing a high strength adhesive like PMMA. One challenge will be assessing exactly how to vary the chemistry of the materials to ensure the material can degrade after set at the rate at which bone could reform. This degradation will occur through the poly(ester) segments leading to components that can readily be removed by the body. To provide the elements required for bone repair, the fluids can be filled with high percentages (>70wt%) of micron dimension calcium phosphate particles. A unique method employed in this proposed study that improves the dispersion of these particles within the polymer involves using calcium phosphates that react with water via the same process that sets conventional calcium phosphate cements. What is intriguing is that we can get this reaction to be catalysed by water that the set polymer absorbs from its surroundings. The absorbed water dissolves the calcium phosphates, enables them to react but then reprecipitate as a very fine less soluble crystalline form within the polymer. We have also discovered that this second reaction leads to greater interaction between the polymer and calcium phosphate substantially increasing the material rigidity. A further advantage of the re - precipitated phosphate is that it can neutralise the acidic degradation products of poly(esters) preventing potential adverse inflammatory reactions which are a well documented problem with medical devices produced with these polymers. The calcium phosphate addition also provides us with an alternative means to control degradation rate but we anticipate they will additionally improve cellular responses. There is a massive range of possible injectable poly(esters) but to reduce the number of samples that need to be studied to optimise new formulations we have previously used experimental (factorial) designs that provide us with understanding as to which variable factors most affect rate and final level of polymer crosslinking, rigidity and degradation and drug release rates. In this new study we will extend these methods to interpret how these properties are altered through reactive filler addition but also determine mechanical strength. Key in our new investigations however, will be improving our understanding of what chemical changes illicit enhanced cellular responses. Our ultimate aim will be to find an optimal formulation that will then be assessed in vivo.