3-D ‘All-Human’ in vitro modelling for chemo sensitivity testing, therapeutic delivery and tumour metastasis studies in Neuro-oncology

Abstract: Since the early days of the development of in vitro approaches to cells of the central nervous system (early twentieth century) and the subsequent propagation of intra cranial tumours as mono-layer cultures (1930s), such approaches have become increasingly sophisticated and more representative of the organs and tumours involved. In addition, the use of human cells rather than those of non-human species origin, as well as the use of human serum rather than foetal calf serum as a growth modulator, have rendered these in vitro systems better reflective of the in situ environment. Moreover, 3D culture as well as concomitant culture of multiple cell populations has also increased the power of such models with which to study issues including drug delivery and therapeutic sensitivity. We have recently engineered an all-human 3D model of the blood-brain barrier (BBB) (1, 2) which we have used for modulation of BBB opening, drug delivery and cancer cell metastasis to the brain (3, 4). Here, we were also able to incorporate shear stress (flow rate) studies to investigate the influence of different diameter blood vessels on drug delivery and cancer cell metastasis. Moreover, we are engineering complex 3D models incorporating neoplastic cells alongside a variety of normal brain stromal cellular components in the context of therapeutic screening of novel, repurposed and reformulated drugs. It is our expectation that such human relevant scientific approaches will lead to more rapid translation of novel and repurposed therapeutics to clinic without the perceiveed necessity to progress via expensive and generally non-appropriate in vivo animal testing.