Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 2-3 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary 2D monolayer cultures fail to recapitulate the totality of the tumor microenvironments. More complex cancer in vitro models have been developed, but they still lack organ-level structures, fluid flows, and mechanobiological cues that cells experience in vivo. Therefore, physiologically and clinically relevant reproducible models that mimic tissue and tumor microenvironments are urgently needed to improve preclinical radiobiological research. Such model systems could impact several areas, such as the ability to predict efficacy and toxicities of drug-radiation combinations, to determine the relative biological effectiveness of proton therapy, etc. These models are also applicable in other areas of cancer research. Generally, they will reduce the cost of research by improving the preclinical research quality and potentially reducing animal use in research. Microfluidics (materials and techniques) have potential applications in radiobiology, and commonly used siliconebased compounds, such as polydimethylsiloxane (PDMS), have already been tested and found resistant to radiation-induced brittleness and aging and have demonstrated required stability and water equivalency. Lab-on-chip (LOC) microfluidic and “tissue mimetic” technologies have evolved into advanced Organ-on-Chips (OoC). OoC systems containing perfused hollow microchannels populated with living cells have the ability of multiplexed drug testing and may be applied to many radiobiological studies. OoC technologies are already at a higher technological level of maturity. Further development and validation of OoC guided by its intended context of use for translational radiobiological studies are necessary. This SBIR contract mechanism accelerates further development and integration of advanced OoCs into cancer treatment development and translational pipelines in radiobiology and drug radiation combination studies.