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Multi-compartmental Organ-on-a-Chip

Periodic Reporting for period 1 - MOOAC (Multi-compartmental Organ-on-a-Chip)

Reporting period: 2018-04-01 to 2020-03-31

Drug development is stuck in an innovation gap, in which it incurs staggering expenses and takes many, ten to fifteen, years to get a drug to market, furthermore, during the process many animals are sacrificed in preclinical work, and in the end many times the results from the animal studies does not accurately predict what will happen in humans, resulting in failures, delays, and recalled drugs. Organ-on-chip technologies have the potential of closing this gap and have the potential of curtailing the high experimental costs and complexities associated with in vivo studies. Eventually these tools could evolve into next generation tools for therapeutic validation and development.

The project proposal initially proposed that by using a multi-compartment microfluidic platform, while integrating synthetic biointeractive hydrogels into and between the compartments, to produce a multi-organ-on-a-chip which recapitulates organ-like functions in each compartment and a vascular similar conduit system between compartments to produce an early stage human on-a-chip for future therapeutic assessment and development applications. Successful production of this platform will improve the therapeutic and pharmaceutical development pipeline, while also minimizing our reliance on animal testing in accordance with the needs and guidelines within the EU. The long-term implications of this work would result in increasing the throughput of therapeutics, directly minimizing the cost of drug development and increasing the efficiency. This would lead to lowered economic burden to produce drugs, as well as quicker turn around, having large implications on improving the quality of life in globally.

This project shifted over the period of research, with a focus on developing a microfluidic system that incorporated a newly developed, proprietary elastomeric thermoplastic as the housing chamber for the organ-on-chip device. This shift focused on moving away from the more traditionally used polydimethylsiloxane (PDMS). PDMS while very useful as a versatile prototyping material, is not as well suited for scaled up manufacturing and has some limitations in terms of drug absorption and has been implicated in impacting some characteristics of biological samples. This new direction of research focused on evaluating a new material to increase the manufacturability of organ-on-chip devices and moving away from the more traditionally used PDMS material. Effectively the goal was to have a technology that once validated, would have greater potential for scaled up manufacturing, and effectively increasing the potential dissemination of the technology to other research and corporate lab settings.

The development of a more robust, manufacturable OOC technology platform, will have positive implications on improving the therapeutic pipeline to generate, novel therapeutics while minimizing the failure and inherent cost of these failures in developing these therapeutics by creating a commercially viable toolset for therapeutic development.
The work focused on building various Organ-On-Chip (OOC) modules out of FlexDym and other more manufacturable thermoplastics. FlexDym is a newly developed, proprietary elastomeric thermoplastic developed by a collaborating European startup. Benefits of this material both in fabrication as well as integration with OOC research and work extend the potential of scalable production. Furthermore, this material maintains a reasonable biocompatibility and a reduction of absorbed molecules, which hinders the potential application of OOC devices in therapeutic discovery and work with cell-permeable molecules, such as small molecule therapeutics and cell-permeable hormones.

Microfluidic devices for OOC systems were successfully generated from FlexDym™. While a reduced biological evaluation was accomplished, due to the early termination of the award, the development of the devices was established and characterized. Primarily the work demonstrated the mechanical validation of the system, and that the device could sustain cellular culture in different formats. This included a three-layer barrier device produced from FlexDym™ and Polycarbonate membranes. The work is currently being finalized and submitted to an international scientific journal and is expected to be published in 2020. Additionally, the work was presented in various international and European conferences.

Key results demonstrated the mechanical characteristics of bonding FlexDym™ and polycarbonate, cellular attachment and viability on FlexDym™ and within the devices.
Elastomeric thermoplastics, such as FlexDym™ enable the ability to work at the academic/research lab scale, but also scale up the production of these devices. This work began the early stage characterization of this material for the potential of building OOC technologies.
While this work was limited in terms of finalizing the project goals, due to the early departure of the fellow, the development of a thermoplastic based microfluidic device for OOC technologies was established. This work incorporated an elastomeric thermoplastic with the potential for scaled up manufacturing of OOC microfluidic devices. The benefit of this work is in the ability to incorporate a material that enables rapid, low-cost, accessible prototyping that can then be easily transferrable to larger-scale fabrication methods, being applied to a burgeoning research tool, OOCs.
This project has found a way to integrate these materials into successfully producing OOC systems and demonstrated cellular viability and maintained culturing in the devices. While the biological validation of the system was not completed by recapturing specific organ functions, the potential viability of these materials was established, and provides an enabling platform to continue developing these devices.
One of the key developments was the low energy, scalable assembling of the devices defined by the ability to assemble and bond the devices in a low cost, low equipment environment. Unlike traditional methods of making OOC devices with materials such as PDMS, the speed of manually making the FlexDym™ based devices, was less than 30 minutes, increasing a low-throughput scalability of the system, and highlighting the potential of a rapid turnaround with the appropriate manufacturing equipment.
The development of an OOC device that is more capable of increased manufacturability was established and provides a pathway to developing increasingly viable commercial products.
Flexdym Barrier Organ-On-Chip Device
Cellularized Device - Cultured cells in the System
Schematic of Flexdym Based Fabrication