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NIH/NCI 462 – Organ-on-Chip for Preclinical and Translational Radiobiological Studies

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 silicone-based 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.

Project Goals

This contract topic’s goal is to further develop and validate OoCs devices for research and preclinical applications for studies with radiation and drug radiation combinations. Successful completion of the deliverables and the data obtained from experiments performed under controlled conditions using OoCs from this contract solicitation will ultimately improve the predictability of clinical outcomes in preclinical radiobiological assays that currently suffer from reproducibility and outcome predictability issues. OoC devices developed with this contract solicitation may also have potential cross-utilities in other areas of cancer research. 

Some examples of potential OoC commercial applications for preclinical research include but are not limited to an evaluation of the effects of therapeutic radiation, radiation-effect modulators, and drug-radiation combinations; monitoring of tumor response, progression, and recurrence after treatment; quantitative measurement of immune infiltrates into tumors after treatment; smart dosimetry technologies traceable to the national standard to improve the quantitation of radiotherapy dose at the biological level (e.g., determining relative biological effects); measurement of defined gradients of oxygen tensions across the OoC to study hypoxia-mediated responses; any other relevant preclinical radiobiology and/or drug radiation combination studies.

Phase I Activities and Deliverables:

  • Design, review, improvise, integrate, and/or fabricate advanced OoC devices for the specific intended use that is compatible with any one or more of the following areas of study:
    • Evaluation of the effects of radiation, radiation-effect modulators, and/or drug radiation combinations.
    • Monitoring of tumor response and progression after treatment.
    • Quantifying immune infiltrate dynamics into tumor microenvironments and normal tissues after treatment.
    • Smart dosimetry technologies traceable to the national standard to improve quantitation of radiation dose at the biological level (e.g., determining relative biological effects).
    • Study the impact of defined gradients of oxygen tensions across the OoC to study hypoxic-mediated responses. 
    • Any other relevant preclinical radiobiology and/or drug radiation combination studies.
    • Provide defined metrics for measurement of success. 
  • Demonstrate maintenance of sterility, temperature, nutritional, physiological, oxygen status, and other conditions in the OoC for the intended use.
  • Stability of the materials and compatibility of advanced OoC used against one or more radiation sources, routinely used in laboratories designed for irradiating cell cultures, small animals, or external beam radiotherapy sources used in the clinic. 
  • Demonstrate tissue functional equivalency necessary for radiobiological studies.

The Phase I contract technical proposal should include the following information:

  • The intended setting (context of use), its preclinical utility, technology development, and validation plan. 
  • An assessment of the technology maturity level of the system or component subsystems of the planned advanced OoC at present and upon completion of the proposal.
  • Design concept, material selection, and fabrication procedures, approach for sterilization, selection of biological elements and supporting cell types, life-supporting materials, and methods, such as culture medium, incubation, perfusion circuits, etc., and monitoring of tissue microenvironment in OoC, including but not limited to microbial contamination, adhesion status, etc.
  • Detailed plans for:
    • Designing and fabrication of advanced OoC devices by integrating the 3D scaffolds with microfluidics for co-culturing of at least two or more relevant cell types and/or excised tumor samples from orthotopic xenograft animal models, as needed for intended use.
    • Demonstrate stability and shelf-life of the OoC system and system components.
    • Irradiation with dosimetry traceable to the national standard and demonstration of compatibilities with radiation and drug radiation combination experiments.
    • Online (integrated), offline, and/or in situ endpoint analysis (e.g., clonogenic survival, analysis of circulating immune and/or tumor cells from the sampled medium from the OoC, microscopy, cell proliferation, and death, gene expression analysis, imaging, etc.).
    • Demonstrating technical validity with scientific rigor and reproducibility.
    • Demonstrating analytical validity with scientific rigor and reproducibility.
    • The developmental pathway for regulatory approval and commercialization. An early discussion with FDA is encouraged if necessary and applicable. In such meetings with the FDA, the offeror is expected to invite NCI’s experts in preclinical radiobiology and translation.

Phase II Activities and Deliverables:

Offerors must propose activities leading to the manufacturing and regulatory approval of the device, including but not limited to: 

  • Successfully demonstrate the ability to grow co-cultures of at least two or more cell types or excised biospecimen from one or more animal orthotopic xenograft tumor models in OoCs that are routinely treated with radiation or drug radiation combinations. 
  • Perform online (integrated), offline, and/or in situ endpoint analysis (e.g., analysis of circulating cells such as immune and circulating tumor cells from the sampled aliquots from the OoC, microscopy, cell proliferation, and death, gene expression analysis, imaging, etc.).
  • Demonstrate technical validity with scientific rigor and reproducibility.
  • Demonstrate analytical validity with scientific rigor and reproducibility.
  • Demonstrating the superiority of the technology over 2D cell culture models to predict outcomes in suitable orthotopic xenograft animal models by comparison for the selected endpoints under controlled conditions.
  • Demonstrate preclinical utility in radiobiology and drug radiation combination studies and enhancement of relevance to clinical studies by comparison of OoC technologies with outcomes in animal models as relevant and needed for the intended use.
  • Demonstrate the ability to study one or more radiobiologically relevant issues as below with scientific rigor and reproducibility:
    • Evaluation of the effects of radiation, radiation-effect modulators, and drug radiation combinations.
    • Monitoring of tumor response and progression after treatment.
    • Quantifying immune infiltrate dynamics into tumors and normal tissues after treatment.
    • Smart dosimetry technologies traceable to the national standard to improve quantitation of radiation dose at the biological level (e.g., determining relative biological effects).
    • Any other relevant preclinical radiobiology and/or drug radiation combination studies.

Phase II contract proposals should include a description of:

  • Logical path to commercialization. 
  • Description of the advanced OoC device and the assay. 
  • Proposed schedule for meetings with the FDA regulators regarding approval if needed.
     

Receipt date: November 14, 2023, 5:00 p.m. Eastern Standard Time

Apply for this topic on the Contract Proposal Submission (eCPS) website.

View the full PHS2024-1 Contract Solicitation.

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