DDRugging glioblastoma through the development of smart biomaterials

从一开始，拟议的项目就专门参照EPSRC医疗保健技术主题进行设计。与本主题的第一个“大挑战”目标一致，该项目有望解决一系列工程挑战，以开发一种具有未来临床转化潜力的新疗法。由于脑肿瘤造成的寿命损失比任何其他癌症都要多，我们相信这些研究的临床背景与该主题关注最优先的医疗保健挑战的愿景的“强大特征”非常一致。胶质母细胞瘤是一种最常见、最具侵袭性的脑癌，以前开发的手术治疗方法并未常规用于临床，因为许多物理限制阻碍了它们的疗效，包括：快速、潜在毒性的药物释放；物理特性，包括与人脑不太匹配的硬度，以及；不可降解性所用化合物的永久性、不可降解性需要一个全新的、多学科的工程视角来开发新的生物材料，以完全适应当前未满足的临床需求。因此，拟议的项目将处理一些关键的工程挑战，以提供一种具有改善患者预后潜力的新型复合生物材料。首先，以前的PLGA/PEG糊状物的性质需要进行实质性的修改，以便能够提供许多靶向药物治疗，并提供比以前的研究更能与大脑媲美的硬度。其次，需要开发具有允许电离辐射触发靶向药物和替莫唑胺释放特性的微珠。虽然我们预计这些可能是基于使用聚二（羧基苯氧基）磷腈（PCPP）水凝胶与硒胺交联基质，但将开发许多替代方案，以提供最佳的“开/关”药物释放，同时也考虑到“药物充电”的潜力。第三，作为迭代工程过程的一部分，复合生物材料的两个组成部分都需要改进，以确保它们的组合使用不会对期望的性能产生不利影响，并提供远远超过目前发表的材料的整体药物释放概况和持续时间。这是一项重大挑战，但对于提供患者迫切需要的持久治疗反应至关重要。第四，该项目解决了开发潜力的工程挑战，将药物化合物补充到智能生物材料中。这提供了一个新的问题，要解决这个问题，我们希望学生需要从当前的植入式神经外科设备（如anOmmaya储存器，或巴氯芬泵）中获得灵感，并根据这些设备开发出一种可以与早期研究中开发的智能生物材料结合使用的新设备。在我们的支持下，一个特别有才华的学生可能会进一步推进这一想法——例如，通过开发一种具有传感能力的生物电子设备来监测手术切除腔附近的药物浓度，并在需要补充药物时提醒用户和/或以自动方式给药。最后，研究将结合3D生物链接打印切除腔模型的开发，以测试生物材料对解释的胶质母细胞瘤细胞或组织的功效。这种新型模型的“按比例”或“接近人体规模”的性质将代表我们团队目前正在设计的3D胶质母细胞瘤模型的重要进步，并且可能需要许多创新来保持这种规模的细胞活力，包括3D打印血管/灌注网络原型的集成。

From inception, the proposed project has been designed specifically with reference to the EPSRC HealthcareTechnologies Theme. In line with the first 'grand challenge' aim of this theme, the project is expected to tacklea number of engineering challenges to develop a new therapy, with the potential for future clinical translation.Since brain tumours are responsible for more years of life lost than any other cancer, we believe the clinicalcontext of the studies aligns strongly with the 'strong features' of the Theme's vision to focus on the highestpriority healthcare challenges. Previously developed surgically-delivered therapies for glioblastoma - the mostcommon and aggressive brain cancer - are not routinely used in the clinic due to a number of physical limitationswhich hamper their efficacy including: rapid, potentially toxic drug release profiles; physical properties includingstiffness which are not well matched with the human brain, and; the permanent, non-degradable nature ofcompounds used. A fresh, and multidisciplinary engineering perspective is required to develop new biomaterialsthat are fully attuned to the current unmet clinical need. As such, the proposed project will deal with a number ofcritical engineering challenges to provide a novel, composite biomaterial with the potential to improve patientoutcomes. Firstly, the properties of previous PLGA/PEG pastes will need to be substantially modified to enablethe delivery of a number of targeted drug therapies, and provide a stiffness much more comparable to brain thanin previous studies. Secondly, microbeads with properties that permit the ionizing radiation triggered release ofboth targeted drugs and temozolomide will need to be developed. Although we anticipate these may be based onuse of a poly-di(carboxylatophenoxy)phosphazene (PCPP) hydrogel with a selenocystamine cross-linked matrix, anumber of alternatives will be developed to provide optimal 'on/off' drug release, whilst also considering thepotential for 'drug recharge'. Thirdly, both components of the composite biomaterial will need to be improved aspart of iterative engineering process to ensure their use in combination does not adversely impact desiredproperties and to provide an overall drug release profile and duration which far exceeds materials published todate. This represents a significant challenge, but is critical to provide the durable treatment responses thatpatients desperately require. Fourthly, the project deals with the engineering challenge of developing potentialways to replenish drug compound(s) into the smart biomaterial. This provides a fresh problem, which to resolve,we expect the student will need to take inspiration from current implantable neurosurgical devices (such as anOmmaya reservoir, or a baclofen pump) and adapt these to develop a new device that can be used in conjunctionwith the smart biomaterial developed earlier in the studies. With our support, a particularly talented student maybe able to further advance this idea - for example, by developing a bioelectronic device with sensing capabilitiesto monitor drug concentration adjacent to the surgical resection cavity and alert the user when drugreplenishment is required and/or administer this in an automated manner. Finally, the studies will incorporatedevelopment of a 3D bioink printed resection cavity model to efficacy test the biomaterials against explantedglioblastoma cells or tissue. The 'to-scale' or 'near human scale' nature of this novel model will represent animportant advance in the 3D glioblastoma models our team are currently engineering and is likely to requirenumerous innovations to maintain cell viability at this scale, including integration of a 3D printed prototypevascular/perfusing network.