Magnetic field controlled passage of multifunctional hybrid materials through cellular barriers within a continuous flow system

该项目的目的是研究多功能混合材料与生物系统之间的相互作用。一个非常重要的问题是，这些相互作用是否可以通过外部磁场来影响或控制。首先，必须准备好混合材料。这些混合材料由一个磁芯和一个由蛋白质组成的外壳组成。在两者之间有一层不同的材料（如CMD，淀粉，PEI）作为蛋白质的锚定层。为了制备蛋白质涂层，必须测试几种蛋白质来源（例如FCS、牛血清白蛋白、患者血浆和合成蜘蛛网蛋白）。这些混合材料由于其在不同医疗应用中的巨大潜力而获得多功能，例如MRI， MPI，磁性药物靶向和磁热疗。在研究多功能杂化材料与生物系统的相互作用之前，必须对其进行预处理。这意味着开发紫外线辐射灭菌程序以及建立冷冻干燥法以长期储存混合材料。必须确认混合材料具有血液相容性，并且对人体细胞没有毒性作用。为了测试混合材料与不同细胞系的相互作用，必须将这些细胞整合到耶拿大学医院开发的微流控生物芯片中。与现有的静态细胞培养系统相比，流体芯片能够长期研究颗粒-细胞相互作用，而无需任何动物实验，因为细胞培养物可以在芯片上保存数周至数月。特别强调的是在流控芯片上模拟血胎盘屏障，利用该系统建立预定的胎盘灌注研究的实验工作流程。除了杂交材料通过细胞屏障的通道外，另一个主要焦点是通过STED显微镜（MPS和MRX）研究细胞内粒子相互作用的空间和时间分辨率。此外，流控芯片提供了在没有任何动物实验的情况下调查混合材料在生物系统中的生命周期的机会。为此，将对混合材料或细胞内剩余磁芯的分解进行长期研究。这些研究结果为今后利用胎盘灌注模型对制备的杂交材料与人体组织的颗粒-组织相互作用进行离体研究奠定基础。通过将可控磁场梯度耦合到芯片或胎盘灌注模型，可以分析这些相互作用是否可以受到磁场的影响或控制。

Aim of this project is the investigation of the interaction between multifunctional hybrid materials and biological systems. A very important point is the question, if these interactions can be influenced or controlled by means of an external magnetic field. First, the hybrid materials have to be prepared. These hybrid materials consist of a magnetic core and an outer shell made of proteins. In between there is a layer of various materials (e.g. CMD, starch, PEI) serving as an anchor layer for the proteins. For the preparation of the protein coating, several protein sources have to be tested (e.g. FCS, BSA, blood plasma from patients, and synthetic spider web proteins). These hybrid materials obtain a multifunctionality due to their high potential for the use in different medical applications, e.g. MRI, MPI, magnetic drug targeting and magnetic hyperthermia. Prior the investigation of the interaction with biological systems, the multifunctional hybrid materials have to be pre-processed. This means the development of procedures for sterilization by UV-radiation as well as the establishment of lyophilization for long-term storage of the hybrid materials. It has to be confirmed that the hybrid materials have blood compatibility and show no toxic effects on human cells. To test the interaction of the hybrid materials with different cell lines, those cells have to be integrated into a microfluidic biochip which was developed at the Jena University Hospital. In comparison to existing static cell culture systems, the fluidic chip enables the long-term investigation of the particle-cell interactions without any animal experiments because the cell cultures can be maintained on the chip for weeks to months. Particular emphasis is on the emulation of the blood-placenta barrier on the fluidic chip to use this system for establishing the experimental workflow of the scheduled placenta perfusion studies. Beside the passage of the hybrid materials through the cellular barriers, another main focus is the investigation of the spatial and temporal resolution of the particle interaction inside the cells by means of STED microscopy flanked by MPS and MRX. Furthermore, the fluidic chip gives the opportunity to survey the life cycle of the hybrid materials in biological systems without any animal experiments. For this, the disintegration of the hybrid materials or the remaining magnetic cores within the cells will be investigated on a long-term scale. All these findings serve for the planning and implementation of ex-vivo studies of the particle-tissue interactions between the prepared hybrid materials and human tissue by using the placenta perfusion model for final key experiments. By coupling a controllable magnetic field gradient to the chip or the placenta perfusion model it can be analysed, if these interactions can be influenced or controlled by a magnetic field.