Characterisation of a phenol-derived polymeric bone glue

背景：对于骨折有几种不同的固定技术，这些技术正在不断改进。在骨折愈合和软组织损伤方面，生物相容性变得越来越重要。尤其是复杂的多段骨折和关节内骨折仍然是外科重建和固定的挑战。因此，开发一种体内适用的骨胶将是骨合成技术的重大进步。已报道的绝大多数生物黏附分子与生物聚合物的偶联反应都是通过直接的酰胺化反应进行的。在体内开发有效的骨胶的一个主要问题是需要准确的pH控制，在生物聚合物上添加过量的反应物和副产物的存在。我们的目的是使用含有苯酚衍生生物黏附分子的聚合物组合物来检测一种新型的骨黏附分子。有证据表明，这种连接反应比目前的方法更有效地将胺连接到生物聚合物上，并且不需要精确的pH控制或反应过程中的pH变化就能有效。材料和方法：首先，必须建立一种强有力的酰胺化技术，在明胶等生物多聚物上合成生物黏附分子。合成的生物偶联物的表征将通过1H核磁共振、分光光度、流变学和层析进行。通常，将收集接枝效率、产率、生物聚合物分子量守恒、溶液粘弹性性质的变化。将评估hTERT-BJ1成纤维细胞与结合物和交联物提取物接触后的细胞毒性。第一步完成后，将分析制备的制剂的生物粘附性以及制备的制剂的止血性能。目的：本项目的主要目的是在临床前表征一种新型生物粘合剂，包括对湿润表面的粘附性、无毒性、制备和灭菌的可行性、足够的强度在所需的时间内稳定骨-骨界面以及不干扰骨修复。我们推测，已经用作止血的明胶，经生物粘附性苯酚衍生功能修饰后，可以应用于孟加拉玫瑰的溶液中，利用可见光粘合骨片。由于止血作用，该制剂可以在体内凝固，同时在可见光激活时与周围组织黏附。临床意义：开发一种有效的、生物相容性的骨胶将意味着最新骨合成技术的关键进步。前景看好的应用领域将是复杂的多段骨折以及婴儿骨折的治疗。

Background: There are several different fixation techniques for bone fractures that are continually refined. Bio-compatibility, in terms of fracture healing and soft tissue damage, becomes more and more important. Especially complex multi-fragment fractures and intraarticular fractures remain a challange for surgical reconstruction and fixation. Therefore, the development of an in-vivo applicable bone glue would be a substantial advancement in osteosynthesis techniques. The vast majority of the reported conjugation reactions of bio-adhesive molecules to biopolymers are performed by direct amidation reaction. A major problem in the develoment of an effective bone glue in vivo is the need of accurate pH control, addition of excess of reactant to graft on the biopolymer and the presence of by-products. Our aim is to examine a novel bone adhesive using polymeric composition containing phenol derived bio-adhesive molecules. There is evidence that this conjugation reaction is more efficient than current methods for ligation of amines to biopolymers and does not require accurate pH control or pH shift during the reaction to be effective. Material and Methods: First, synthesis of bio-adhesive molecules onto biopolymes such as gelatin by a robust amidation technique has to be established. The characterisation of the synthesised bioconjugates will be done via 1H NMR, spectrophotometry, rheology and chromatography. Typically, grafting efficiency, yield, conservation of biopolymers molecular weight, changes in viscoelastic properties of the solutions will be collected. Cytotoxicity will be evaluated assessing the viability of hTERT-BJ1 fibroblasts after contact with conjugates and extracts from the crosslinked conjugates. After this first step is done, the bioadhesion property of prepared formulations will be analysed as well as hemostatic property of prepared formulations.Objective: Primary aim of this project is the preclinical characterisation of a novel bio-adhesive in terms of adhesion to moist surfaces, non toxicicty, preparation and sterilisation feasibility, sufficient strength to stabilise the bone-bone interface for the required time and no interference with the bone repair. We hypothesised that gelatin, already used as an hemostatic, modified with bio-adhesive phenol derived functionalities could be applied in solution with Rose Bengal to glue bone pieces using visible light. The formulation could set in vivo due to the hemostatic effect and simultaneously adhere to the surrounding tissue upon visible light activation.Clinical relevance: The development of an effective and bio-compatative bone glue would mean a crucial advancement in up to date osteosynthesis techniques. Promising areas of application would be complex multi-fragment fractures as well as treatment of infantile fractures.