Organs Made to Order for Testing New Countermeasures

Courtesy Photo | Stock image for JSTO in the News.  

FORT BELVOIR, VA, UNITED STATES

03.06.2017

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

A milestone in medical science, the first laboratory-grown organ was implanted into a patient in 1999 by Dr. Anthony Atala of the Wake Forest Institute for Regenerative Medicine (WFIRM). The bladder was not synthetic or simulated tissue, but engineered to be biologically similar to the patient’s original bladder cells. For the past 18 years, the WFIRM team has continued their innovative approach to organ replacement and are now exploring bioprinting technologies for the development of warfighter countermeasures.

In a joint effort between the Defense Threat Reduction Agency’s Joint Science and Technology Office and WFIRM, Atala and his team are utilizing the technology to develop interconnected human organoids for pre-clinical testing. Researchers will use these organoids to evaluate the safety and pharmacological effects of new drug candidates and their metabolites. The project, eX vivo Capacity for Evaluation and Licensure -Focused Innovative Technologies, or XCEL FIT, utilizes both bioprinting and bioinks to test drug-to-drug or organ-to-organ interactions under various drug exposures.

This project allows WFIRM researchers to test Department of Defense threat agents, which cannot be tested in humans due to their high toxicity. The organoids will bridge a gap between animal testing and Phase I clinical trials that are normally conducted in human volunteers. Although using the organoids will add another layer to the drug development process, the enhanced process will save lives and reduce drug development costs. Composed of human cells, WFIRM’s interlinked organoid models may also offer enhanced capabilities for predictive toxicology, which the FDA is receptive to.

Potential drug candidates get their initial biological testing in cell cultures, known as in vitro testing, that initiates the process of determining drug toxicity levels or which organs may be most susceptible. The next phase, called in vivo testing, utilizes animal models (rodents to non-human primates) to evaluate the biological half-life, exposure levels and toxicities for the candidate drug and its metabolites. These assessments are required by the FDA to conduct clinical trials to prove efficacy, but are expensive and can pose safety risks to humans.

However, many compounds that enter the clinical phase fail due to some degree of toxicity in human subjects. In fact, candidate drugs fail so often during this phase that this key transition is referred to as the “Valley of Death” for drug research and development. There are numerous examples of drug candidates
displaying significant adverse events during human safety evaluations that had not been previously indicated.

Atala’s organoids may change that. Grown on chips and interconnected with sustained viability and function capable of mimicking human toxic potential, the organoids are the Holy Grail of “Predictive Human Toxicology.” The WFIRM team engineers the organoids from biocompatible hydrogels and human organotypic cells obtained from like-hepatocyte (liver) and cardiomyocyte (heart) stem cells. These 3D bioprinted organoids are intended to evaluate direct or indirect toxicity to the most sensitive and vital human organs by mimicking structural architecture and functionalities, bridging the gap between tissue culture and animal testing.

Using this technology, real-time analysis can determine the direct effects of a drug on the organoids, from cytotoxicity to up- or down-regulation of key enzymes and proteins that could be key predictors of adverse findings or pathology in humans. The same testing can be performed for the primary metabolites of a drug.

The organoids are 3D bioprinted into multi-well plates that permit many replicates to be tested simultaneously, increasing accuracy, efficiency and the number of different compounds and concentrations that can be assessed, offering a high-throughput screening capacity. The multi-organoid constructs also appear to perform metabolic activities that can convert prodrugs to active forms or drugs to metabolites, representing a step change in the assessment of human drug responses in simplified, less costly ex vivo systems. Utilizing XCEL FIT, drug candidates that show promise in vitro and demonstrate sufficient in vivo safety and efficacy can be exposed to human “organs” with zero risk.

The XCEL FIT technology may play an instrumental role in reducing costs and time for developing medical countermeasures for the warfighter and new medications for public use by reducing expensive pre-clinical and clinical testing and determining long-term effects of a drug on vital organs.

Atala, the principal investigator on the XCEL program, was recently named the “2016 Innovator of the Year” by R&D Magazine for his additional work in 3D bioprinting. For this work, Atala uses supportive biocompatible hydrogels along with human donor cells to create complex 3D functional living organs.

POC: Dr. Gary Qiao; [e-mail]

• Date Taken: 03.06.2017
• Date Posted: 03.06.2017 10:10
• Story ID: 225810
• Location: FORT BELVOIR, VA, US