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Generation of Heterogeneous Drug Gradients Across Cancer Populations on a Microfluidic Evolution Accelerator for Real-Time Observation
Published on: September 19, 2019
A gravity-driven tissue chip to study the efficacy and toxicity of cancer therapeutics
Pouria Rafsanjani Nejad1, Astha Lamichhane1, Prasiddha Guragain1
1Department of Biomedical Engineering, University of Akron, Akron, OH, USA. tavana@uakron.edu.
Abstract:
Tissue chip and organs-on-chip technologies have emerged as promising tools in preclinical studies. In oncology, this is driven by the high failure rates of candidate drugs in clinical trials mainly due to inadequate efficacy or intolerable toxicity and the need for better predictive preclinical models than those traditionally used. However, the intricate design, fabrication, operation, and limited compatibility with automation limit the utility of tissue chips. To tackle these issues, we designed a novel 32-unit tissue chip in the format of standard 96-well plates to streamline automation, fabricated it using 3D printing, and leveraged gravity-driven flow to bypass the need for external flow devices. Each unit includes three interconnected tissue compartments that model liver, tumor, and bone marrow stroma. The focus on liver and bone marrow stroma was due to their respective roles in drug metabolism and disturbances to the bone marrow niche from off-target toxicity of chemotherapies. We analyzed flow patterns, mixing, and oxygen transport among and within the compartments through finite element simulations and demonstrated the utility of the tissue chip to study the efficacy of commonly-used cytotoxic cancer drugs against tumor cells and their toxicity toward liver and bone marrow cells. The ability to simultaneously study drug efficacy and toxicity in high throughput can help select promising therapeutics in early stages of drug discovery in preclinical studies.
Insights
This study introduces a novel 3D-printed 32-unit tissue chip for high-throughput preclinical drug screening. This innovative organs-on-chip model efficiently assesses cancer drug efficacy and toxicity in liver and bone marrow models.
Area of Science:
- Biomedical Engineering
- Oncology
- Pharmacology
Background:
- High failure rates of cancer drugs in clinical trials necessitate improved preclinical models.
- Traditional preclinical models often lack the predictive power for drug efficacy and toxicity.
- Existing tissue chip technologies face limitations in automation and scalability.
Purpose of the Study:
- To develop a novel, automatable organs-on-chip platform for enhanced preclinical cancer drug evaluation.
- To create a multi-organoid system modeling tumor, liver, and bone marrow interactions.
- To enable simultaneous assessment of drug efficacy and toxicity in a high-throughput format.
Main Methods:
- Designed and fabricated a 32-unit tissue chip in a 96-well plate format using 3D printing.
- Incorporated gravity-driven flow to eliminate the need for external pumps.
- Utilized finite element simulations to analyze fluid dynamics and oxygen transport.
- Validated the platform using common cytotoxic cancer drugs against tumor, liver, and bone marrow cells.
Main Results:
- Demonstrated successful integration of liver, tumor, and bone marrow stroma compartments within each tissue chip unit.
- Confirmed efficient flow, mixing, and oxygen transport essential for maintaining tissue viability.
- Successfully evaluated the efficacy of cytotoxic drugs against cancer cells and their toxicity to off-target tissues.
- Showcased the platform's capability for high-throughput drug screening.
Conclusions:
- The novel 3D-printed tissue chip offers a scalable and automatable solution for preclinical cancer drug discovery.
- This organs-on-chip model provides a more predictive platform for evaluating drug efficacy and toxicity.
- The technology has the potential to significantly improve the selection of promising therapeutics in early drug development stages.
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