Biomimetic radiation-crosslinked collagen and gelatin as in vitro model to study the physics of tumor progression and medication.

癌症是世界范围内导致死亡和疾病的主要原因之一，开发有效的治疗方法被认为是人类面临的最大挑战之一。然而，尽管在过去的几十年中取得了很大的进展，但对促进肿瘤进展和转移形成的潜在物理过程的了解还远未完成，更有效的治疗方法的概念是非常可取的。本项目从物理学的角度解决癌症研究的这两个挑战，同时专注于胶原及其衍生物的交联性这一非常特殊的问题。事实上，虽然几十年来肿瘤学家们已经证实，触诊可以检测到乳腺癌等肿瘤，但交联剂诱导的细胞外基质(ECM)硬化与肿瘤发展，特别是侵袭性肿瘤行为的关系，直到最近才被认识到。在这种背景下，I型胶原作为细胞外基质的主要成分之一，在肿瘤(实际上是癌症)周围起着至关重要的作用。在跨学科的方法中，电子辐照提供了一种工具来系统地解决这些问题，因为它具有无试剂交联胶原蛋白和建立体外仿生基质的能力。此外，它将使我们能够开发出一种新型的三维肿瘤模型，它具有真实的可调的力学性能，基于可变硬度的多孔胶原蛋白作为ECM模型，其中将结合不同侵袭性的恶性细胞的球体。它不仅可以识别肿瘤扩散的参数，而且实际上也可以作为体外化疗的模型。后者将是该项目第二个挑战的焦点，该挑战侧重于开发一种可编程的、可生物降解的、基于明胶的化疗控释系统。从胶原蛋白中提取的明胶可以通过电子辐射进行类似的交联化，从而在生理条件下产生高度可调的释放速率和寿命。用新开发的三维肿瘤模型评估这一新型控释系统对化疗药物输送特性的影响，将完成这一项目，并为更好地理解机械特性和细胞动力学如何影响肿瘤进展以及临时化疗药物扩散如何导致细胞死亡提供新的视角。

Cancer constitutes one of the leading causes of death and illness worldwide, and development of effective therapies can be considered among the largest challenges that mankind faces. Despite much progress during the past decades, however, understanding of the underlying physical processes that foster tumor progression and the formation of metastasis are far from complete, and concepts for even more effective therapeutic approaches are highly desirable. The present project addresses both of these challenges of cancer research from a physics perspective, while focusing on the very particular question of crosslinking of collagen and its derivatives. In fact, while it has been established for decades among oncologists that tumors such as mamma carcinomas can be detected by palpation, the relation of crosslinkinginduced extracellular matrix (ECM) stiffening to tumor development, in particular invasive tumor behavior, has only been appreciated recently. In this context collagen I as one of the major components of the ECM in the surrounding of the tumor (in fact, carcinomas) plays a crucial role. Within an interdisciplinary approach, electron irradiation provides us with a tool to systematically address these questions by its capabilities to reagent-free crosslink collagen and build up a biomimetic in vitro matrix. Beyond that, it will enable us to develop a novel type of three dimensional tumor model with realistic 'tunable' mechanical properties based on porous collagen of variable stiffness as ECM model, in which spheroids of malignant cells of different aggressiveness will be incorporated. It will not only allow for identification of parameters for tumor spreading, but, in fact, also serve as in vitro model for chemotherapy. The latter will be in the focus of the second challenge of this project, which focuses on development on a programmable biodegradable gelatin-based con¬trolled release system for chemotherapy. Derived from collagen, gelatin can be similarly crosslinked using electron irradiation, resulting in highly tunable release rates and lifetimes under physiological condition. Assessing this novel controlled release system with the newly developed three dimensional tumor model in terms of delivery characteristics for chemotherapeutics, will complete this project and offer new perspectives to a better understanding how mechanical properties and cellular dynamics influence tumor progression and how temporal chemotherapeutics spreading causes cell death.