Engineering an in vitro model of the central nervous system leukaemic niche to improve treatments for childhood leukaemia.

癌症是1-14岁儿童的主要死因。急性淋巴细胞性白血病(ALL)是最常见的儿童癌症。所有患者存活率的最大进步来自于认识到它经常扩散到中枢神经系统(CNS)，因此所有患者都需要中枢神经系统指导的治疗才能实现长期治愈。这涉及到需要强化治疗的儿童，包括直接向脑脊液注射有毒化疗，以实现长期治愈和防止脑/中枢神经系统内的所有复发。这种治疗虽然成功，但也会产生严重的副作用，特别是在智商、学习和记忆力方面，这会影响20-40%接受ALL治疗的幸存者。因此，迫切需要开发更有效、毒性更低的中枢神经系统白血病治疗方法。为了发现治疗中枢神经系统白血病的新药，准确地模拟中枢神经系统利基的独特细胞和环境成分是至关重要的。目前缺乏体外模型是这一领域取得进展的主要障碍。该项目将利用组织工程学开发一种与生理相关的中枢神经系统利基模型，将其纳入适用于药物发现的微流控设备中。细胞(白血病细胞和脑膜基质细胞)将在工程膜上培养，并具有可控的特性(硬度、厚度、孔隙度)，这将在中枢神经系统利基环境和正常血浆条件之间提供接口。它还将包括中枢神经系统利基环境的关键组成部分，包括低营养环境(低脂、低糖)，并使重要的细胞间相互作用得以模拟，因为这些已知会导致对当前化疗的抗药性。该系统将能够研究白血病细胞从血液转移到中枢神经系统时的行为变化，并提供一个独特的模型来研究所有人的药物反应。该项目将在生物材料、组织生物工程、复杂流体和流变学方面提供培训和发展专业知识。它将涉及设计先进的生物界面，包括生长因子、细胞外基质和癌细胞/基质细胞的相互作用，以及使用微流控方法和设计适合于药物发现的系统。开发临床前管道以识别毒性较低的中枢神经系统活性药物是一项尚未满足的主要临床需求。

Cancer is the leading cause of death for children aged 1-14 years. Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer. The largest advance in survival rates for ALL came with the recognition that it often spreads to involve the central nervous system (CNS) and therefore all patients require CNS-directed treatment to achieve long-term cure. This involves children requiring intensive treatment, including direct injection of toxic chemotherapy into the cerebrospinal fluid to achieve long-term cure and to prevent ALL recurrence within the brain/CNS. Although successful, this treatment causes significant side-effects, especially with IQ, learning and memory, which affects 20-40% of survivors treated for ALL. There is therefore an urgent need to develop more effective, and less-toxic, treatments for CNS-leukaemia. In order to discover novel drugs for CNS leukaemia, it is essential to accurately model the unique cellular and environmental components of the CNS-niche. The current lack of in vitro models is a major barrier to progress in this field. This project will use tissue engineering to develop a physiologically relevant model of the CNS niche incorporated into a microfluidic device suitable for drug discovery. Cells (leukaemia cells and meningeal stromal cells), will be cultured on an engineered membrane, with controlled properties (stiffness, thickness, porosity), which will provide an interface between the CNS niche and normal blood plasma conditions. It will also incorporate key components of the CNS niche including a low nutrient environment (low lipid, low glucose) and enable important cell-to-cell interactions to be modelled as these are known to confer resistance to current chemotherapy treatment. This system will enable investigations into how leukaemia cell behaviour changes when they transit from the blood to the CNS and provide a unique model to investigate drug responses in ALL. This project will provide training and develop expertise in biomaterials, tissue bioengineering, complex fluids and rheology. It will involve the design of advanced bio-interfaces, incorporating growth factors, extracellular matrix and cancer cell/stromal cell interactions, as well as the use of microfluidic approaches and design of systems suitable for drug discovery. Developing preclinical pipelines to identify less-toxic CNS-active agents is a major unmet clinical need.