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但潜在的高回报挑战，需要多个科学学科的专业知识。这种粘合剂应该能够被注射到受损部位，但随后迅速凝固，以提供具有高强度和与骨相当的柔韧性的材料。如果粘合剂可以扩散到组织中，则固化反应将提供粘合（微机械），从而为周围骨提供早期支撑。然而，这种材料随后会降解，提供可以被细胞转化为新骨的成分。这种降解还可以提供药物的缓慢释放，从而增强修复或预防感染。目前的聚（甲基丙烯酸甲酯）（PMMA）骨水泥可以快速凝固，但不可降解。目前用作可降解骨螺钉和各种其它医疗应用的常规长链聚（酯）缺乏可注射性，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且提供骨的无机组分所需的元素，但是它们的固化特性难以控制，特别是在水性环境中，并且它们的机械性能远不理想。因此，该项目的一个目的是将联合收割机酯和甲基丙烯酸酯结构化学结合以产生聚合物分子，该聚合物分子足够短以成为流体，但可以在曝光的几秒钟内通过甲基丙烯酸酯基团交联，从而提供像PMMA的高强度粘合剂。其中一个挑战将是准确评估如何改变材料的化学性质，以确保材料在设定骨骼改革的速度后能够降解。这种降解将通过聚（酯）链段发生，导致可以容易地被身体去除的组分。为了提供骨修复所需的元素，流体可以填充有高百分比（> 70重量%）的微米尺寸磷酸钙颗粒。在这项拟议的研究中采用的一种独特的方法，改善了这些颗粒在聚合物中的分散，包括使用磷酸钙，磷酸钙通过与传统磷酸钙水泥相同的过程与水反应。有趣的是，我们可以通过聚合物从周围环境中吸收的水来催化这个反应。吸收的水溶解磷酸钙，使它们能够反应，但随后在聚合物内作为非常细的不太可溶的结晶形式再沉淀。我们还发现，该第二反应导致聚合物和磷酸钙之间更大的相互作用，从而显著增加材料刚性。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有据可查的问题。磷酸钙的添加也为我们提供了一种控制降解速率的替代方法，但我们预计它们将额外改善细胞反应。存在大量可能的可注射聚（酯），但为了减少需要研究以优化新制剂的样品数量，我们之前使用了实验（析因）设计，这些设计使我们了解哪些可变因素最影响聚合物交联的速率和最终水平、刚性和降解以及药物释放速率。在这项新的研究中，我们将扩展这些方法来解释这些性能是如何通过反应性填料的添加而改变的，同时也确定了机械强度。然而，我们新研究的关键将是提高我们对什么化学变化非法增强细胞反应的理解。我们的最终目标是找到最佳配方，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.