Hypoxic-Core Spheroids on a Chip

Tumor hypoxia is defined as an oxygen partial pressure [pO2] lower than physiological. Naturally resulting from the unchecked proliferation rate and progressively erratic vasculature of solid tumors, hypoxia triggers in cancer cells a set of metabolic and cellular adaptations mainly designed to survive the acidic and nutrient-scarce hypoxic conditions. Along with intrinsic physico-chemical characteristics of the hypoxic microenvironment, these adaptations contribute to increased tumor invasion and metastasis, resistance to most anti-cancer treatment (e.g., chemotherapy, radiotherapy, immunotherapy), and have therefore been typically associated with worsened patient outcomes. Despite the clinical relevance of hypoxia, there is an apparent lack of user-friendly tools and methodologies to properly emulate the hypoxic microenvironment in either in vitro or in vivo models. Regardless of the in vitro tumor model used (2D monolayer or 3D spheroid), most studies on hypoxia resort to chemical induction or oxygen-controlled environments, failing to adequately mimic the multi-layered three-dimensional structure of solid tumors and the interplay between cells of various oxygenation and phenotypic status. In addition, these experimental setups are impractical and at times incompatible with proper treatment and analysis of hypoxic samples. Although in vivo models do recapitulate the architecture, microenvironment and mechanisms of in vivo tumors, they are not without disadvantages. The hypoxic content of in vivo tumors is poorly predictable and hard to quantify, and experimental requirements for large hypoxic tumors can come into direct conflict with regulatory bodies. Coupled with their expensive and time-consuming nature, this makes animal models ill-suited for pre-clinical study of hypoxia.