Interaction mechanisms of medical agents with calcium phosphate cements for the application as pharmacologically active bone substitutes

磷酸钙骨水泥（CPC）因其良好的生物相容性而被广泛应用于骨缺损的修复。通过添加药剂可以实现进一步的治疗效果。抗生素有助于控制细菌感染。在活检切除肿瘤组织后，加入细胞抑制剂可以降低癌症复发的风险。抗骨质疏松剂，如双膦酸盐，在骨折的情况下会损害进一步的骨吸收。通过将这些试剂直接添加到水泥中，它们可以在需要的地方有效。此外，可以减少全身性不良反应。由于监管原因，将此类复合材料批准为医疗器械实际上是不可能的，因此临床申请人应有机会单独组合联合收割机和医疗试剂。医疗试剂可以对水泥的应用相关性能产生影响，如水合性能、流变性能和凝固后达到的硬度。相反，骨水泥可以影响药物的功效，例如通过它们的pH值。因此，为了成功应用这种制剂，必须详细了解相互作用。因此，在拟定的研究中，将通过添加选定的抗生素、抗肿瘤药和细胞抑制剂来表征类似于临床可用CPC的不同模型骨水泥。该试剂对水泥水化作用的影响的第一次评估将通过等温量热法进行。将通过原位X射线衍射分析改性水泥中定量相组成的发展。为此，将应用外标法，该外标法除了定量结晶相外，还允许定量非晶部分。初始和最终凝固时间将通过配备Gillmore针装置的Imeter测定。此外，水泥浆体的流变性能和可注射性将进行研究。将采用细菌培养物进行试验，以检查选定骨水泥系统中抗生素的有效性，同时将通过适当的细胞培养物评估抗生素和细胞抑制剂的有效性。将定量测量试剂的释放动力学。由于预计释放动力学与孔隙率相关，因此还将进行孔隙率测量。此外，还将研究凝固水泥的力学性能。在研究结束时，应根据骨水泥成分和计划应用的药物种类，向医疗申请人提供关于作为局部给药系统的适用性和有效性的可靠信息。

Due to their excellent biocompatibility, calcium phosphate cements (CPCs) are applied for the repair of bone defects. Further therapeutic effects can be achieved by the addition of medical agents. Antibiotics are helpful to contain bacterial infections. After biopsies to remove tumour tissue, the addition of cytostatics can reduce the risk of cancerrecurrence. Antiosteoporotic agents like bisphosphonates can impair further bone resorption in case of bone fracture. By direct addition of those agents to the cements, they can be efficient at the place there are needed. Furthermore, systemic adverse effects can be reduced. Since the approval of such composites as a medical device is practically impossible for regulatory reasons, clinical applicants should be given the opportunity to individually combine approved CPCs and medical agents. Medical agents can have an influence on applicationrelevant properties of the cements, like the hydration performance, rheological properties and the achieved hardness after setting. Conversely, the cements can affect the efficacy of the medical agents,for example via their pH. Hence, for a successful application of such formulations it is essential to understand the interactions in detail. Therefore, in the proposed study different model cements resembling clinically available CPCs will be characterized with the addition of selected antibiotics, antiosteoporotics and cytostatics. The first evaluation of the agent´s influence on cement hydration will be performed by isothermal calorimetry. The development of the quantitative phase composition in the modified cements will be analysed by in-situ X-ray diffraction. For this purpose, an external standard method will be applied, which besides the quantification of crystalline phases also allows quantification of the amorphous fraction. Initial and final setting times will be determined by an Imeter equipped with Gillmore Needle apparatus. Furthermore, rheological properties and injectability of the cement pastes will be investigated. Assays with bacterial cultures will be applied to check the efficacy of antibiotics in the selected cement systems, while the efficacy of antiosteoporotics and cytostatics will be assessed via appropriate cell cultures. The release kinetics of the agents will be quantitatively measured. Since release kinetics is expected to correlate with porosity, porosity measurements will also be performed. Additionally, mechanical properties of set cements will be investigated. At the end of the study, medical applicants should be provided reliable information about the suitability and efficacy as local drug delivery system, based on the cement composition and the kind of medical agent planned for application.