017 Universal Medium/Blood Mimetic for Use in Integrated Organs-on-Chips
Fast-Track proposals will not be accepted.
Number of anticipated awards: 1-2
Budget (total costs, per award): Phase I: $225,000 for 9 months; Phase II: $1,500,000 for 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning.
The objective of this topic is to develop a universal medium, or blood mimetic, that can be used to perfuse and support multiple tissue constructs or organ types within multiple integrated microphysiological systems (MPS), or organs-on-chips.
Organs-on-chips are bioengineered micro devices that model the function of human organ tissues in vivo. The development of these platforms has provided tools that can be used to investigate the effects of drugs, compounds and therapeutics on human tissues in vitro, providing information on safety and efficacy of promising compounds. They are also used to model a wide variety of disease states and investigate pathophysiology and disease mechanisms in novel ways. However, their full utility can be realized when tissue systems are linked and cellular constructs from multiple organs can interact in a physiologically relevant way, moving towards a "human-on-a-chip". Linking multiple tissue constructs is challenging to achieve as linked organs-on-chips need support in the culture medium for many different tissue construct types, yet the ability to link them is limited because each tissue construct requires specific nutrients and growth factors which may not be optimal for other tissue types. Currently, researchers do not have a fluid that can adequately support multiple human tissues in integrated systems. This means that tissue combinations cannot survive adequately for meaningful studies to be conducted and therefore limits the current utility of integrated organ-on-chip systems.
NCATS has previously issued supplemental funding to investigators funded under the Tissue Chips for Disease Modeling program, and some solutions to the problem have been developed, as in the inclusion of endothelial barriers to create organ-specific niches and the mixing of culture media for linked organ systems by number of systems e.g. 50:50 for two systems; 33:33:33 for three systems. However, these solutions are not tenable for broader adoption of tissue chip technology as they are technically and biologically challenging, cannot fulfil appropriate cellular support, or are not scalable to more than two or three tissue constructs. This SBIR topic will allow experts with experience in extended cell culture to address the issue.
This topic aims to address a pressing need in the field of microphysiological systems (MPS), or organs-on-chips, to develop a universal cell culture medium/blood mimetic that can be used to support multi-cellular tissues from multiple organ systems in linked, integrated organ-on-chip platforms. The goal of this project is to create a universal medium/blood mimetic that can be used with multiple tissue types to maintain cells in a healthy and functional state for extended cell culture (>1 month) and can supply the basic universal requirements of cells e.g. appropriate pH, oxygen and carbon dioxide levels, and certain growth factors.
This task will be achieved by addressing the following aspects:
(1) Culture and maintenance of multiple (at least 3) cellularly heterogeneous and discrete induced pluripotent stem cell (iPSC)-derived tissue constructs by perfusion of tissues with a universal medium/blood mimetic on a single or linked cell culture platform(s) e.g. heart, liver and lung through linked microfluidic channels or across permeable membranes;
(2) Creation of a cell medium that will address all basic universal cellular requirements e.g. pH; oxygenation; nutrients and growth factors of multiple interconnected tissue types;
(3) Creation of a cell medium that can retain cells in a viable and/or functional state for at least one month, according to standard metrics of cell health or functionality assays e.g. cell viability and growth; pH buffering; stable gene transcription; and other functional readouts.
Phase I Activities and Expected Deliverables:
• Creation and maintenance of at least three separate mature iPSC-derived cellularly heterogeneous and discrete tissue constructs (e.g. heart, liver and lung) in independent tissue-specific culture media. o Tissues must remain differentiated and in a stable and mature phenotype (as shown by widely accepted cellular and genetic markers) for at least 28 days.
o Tissues must express appropriate functional markers at the end of the >28-day culture period (e.g. albumin production by hepatocytes; calcium transients by neurons; expression of glucose transporter proteins in kidney tubule cells; appropriate RNA expression profiles).
• Linkage of at least two separate iPSC-derived tissue constructs perfused by a single culture medium that adequately supports all constructs for at least 7 days. o Tissues must remain differentiated and in a stable and mature phenotype at the end of this >7-day period (as shown by widely accepted cellular and genetic markers).
o Tissues must express appropriate functional markers at the end of this >7-day period.
• Monitoring and/or proven absence of cellular distress/death markers or unexpected decreased production of functional markers in tissues in linked systems perfused by single culture medium at the end of the >7-day culture period.
• Provide NCATS with all data resulting and resources from Phase I Activities and Deliverables
Phase II Activities and Expected Deliverables:
• Creation of at least three iPSC-derived tissue constructs containing heterogeneous cellular types e.g. hepatocytes, liver-specific endothelial cells, liver-specific immune cells. o Tissues must remain differentiated and in a stable and mature phenotype (as shown by widely accepted cellular and genetic markers) for at least 28 days.
o Tissues must express appropriate functional markers at the end of the >28-day culture period.
• Linkage of at least three separate cellularly heterogeneous iPSC-derived tissue constructs perfused by a single culture medium that adequately supports all constructs for at least 28 days. o Tissues must remain differentiated and in a stable and mature phenotype at the end of this >28-day period (as shown by widely accepted cellular and genetic markers).
o Tissues must express appropriate functional markers at the end of this >28-day period.
• Proven compatibility with current iterations of microfluidic technology materials and organ-on-chip platforms.
• Development of reliable manufacturing protocols that ensure <5% batch variation of the universal medium.
• Provide NCATS with all data and resources resulting from Phase II Activities and Deliverables.
• In the first year of the Phase II contract, provide the Program and contract officers with (a) letter(s) of commercial interest.
• In the second year of the Phase II contract, provide the Program and contract officers with (a) letter(s) of commercial commitment.
• Present Phase II findings and demonstrate final deliverables to the NCATS Program staff via webinar.