ARPA-H-SOL-26-165_COSMOS_ISO.docx

ARPA-H-SOL-26-165, COSMOS

INNOVATIVE SOLUTIONS OPENING

FOR

COMPREHENSIVE ORGAN SYSTEM MODELING IN OUTER SPACE

COSMOS

HEALTH SCIENCE FUTURES (HSF)

ARPA-H-SOL-26-165

16 September 2026

Table of Contents

ATTACHMENTS

ATTACHMENT A: Proposal Model Documents (3 total) ATT A.1: Volume 1 Model (Technical and Management Proposal) ATT A.2: Task Description Document Model [MS Word] (component of Volume 1) ATT A.3: Milestone and Payment Table ATTACHMENT B: COSMOS Eligibility and Conformance Certification Sheet ATTACHMENT C: COSMOS Schedule ATTACHMENT D: COSMOS Cost Proposal Template ATTACHMENT E: COSMOS Administrative and National Policy Requirements

Solicitation Summary Information FEDERAL AGENCY: Advanced Research Projects Agency for Health (ARPA-H) TITLE: Comprehensive Organ System Modeling in Outer Space (COSMOS) ANNOUNCEMENT TYPE: Innovative Solutions Opening (ISO)

ISO SOLICITATION NUMBER: ARPA-H-SOL-26-165

ISO CONTACT: COSMOS@ARPA-H.GOV

ANTICIPATED AWARDS: Multiple Other Transaction (OTs) Agreements DATES: (All times listed are Eastern Time) Questions & Answers (Q&A) due date: October 1, 2026, 5pm ET Full Proposals due date: October 7, 2026, 2pm ET ISO closing date: October 7, 2026, 2pm ET

WHERE TO SUBMIT:

Proposals: https://solutions.arpa-h.gov/Submit-Proposal/ Questions: https://solutions.arpa-h.gov/Ask-A-Question/

Registration is required to submit documents via the ARPA-H Solution Submission Portal, which may take several business days. Plan to register well in advance of the submission deadline; late submissions resulting solely from delays with registration may not be considered.

ISO PURPOSE:

ARPA-H seeks proposals from all eligible entities (see Section 8, Eligibility Information) to accomplish the COSMOS goals as described in this solicitation package. Ultimately, ARPA-H intends to negotiate multiple OT Agreements with Proposers whose proposals are most advantageous to the government.

INTRODUCTION TO COSMOS

Background Executive Summary Regenerative therapeutics, those that return healthy function to damaged or otherwise compromised tissues, are an aspirational goal at present. Currently, there are no targeted therapeutics to mitigate or reverse diseases of age in the heart, brain, uterus or kidney. Current approaches frequently require 10 to 15 years to move from discovery to approved therapy. This is in part because existing preclinical models do not adequately capture the biology of human aging- the central driver of many of these diseases.

Cellular senescence, where cells no longer divide but maintain most other processes, combined with direct damage may represent important components of aging. Microgravity in low Earth orbit (LEO) is believed to accelerate aging (or potentially senescence) over weeks rather than years, offering a unique research opportunity to investigate aging. However, that acceleration of aging has never been substantiated or experimentally validated. To meaningfully perform biotechnology and biomedical R&D in LEO, it is essential that we first understand whether accelerated aging takes place in LEO to justify the investment. Moreover, above a certain aging rate threshold, biomedical R&D in LEO may in fact be cheaper and faster than R&D on Earth, decreasing the time and costs currently hindering the drug development pipeline.

Comprehensive Organ System Modeling in Outer Space (COSMOS) centers on quantifying the Tissue Aging Rate in Space (TARIS) relative to the Tissue Aging Rate on Earth (TAROE) for human tissues affiliated with diseases that have the highest morbidity and mortality across multiple adult age groups. COSMOS will establish if there is an accelerated aging rate in LEO flight across four critical tissues—brain, cardiac, uterine, and kidney—using microphysiological systems (organs-on-chips) and organoids.

COSMOS will definitively prove or disprove if exposure to microgravity in LEO truly accelerates tissue aging across these four tissue types and across representative adult age brackets. Provided TARIS exceeds TAROE at a rate that exceeds the on Earth breakeven cost for new drug R&D, COSMOS will create a first-in-class platform for fully autonomous, high-throughput drug screening in LEO that would be more cost effective and faster than new drug R&D on Earth.

Current State of R&D in Low Earth Orbit:

Space based research has, until recently, been limited by the issue of reliable, repeatable access. The International Space Station (ISS) and the ISS National Lab have provided a platform for scientific research for decades, enabling proof-of-concept demonstrations of numerous space-based methods and biologic phenomena. The ISS will be decommissioned in ~2030, adding time pressure to the already limited availability of experimental locker space and ascent/descent payloads. A number of new entrants into the commercial space industry, also known as Commercial LEO Destinations or CLDs, are building a thriving, private sector market that promises to allow for a high cadence of LEO flights with plentiful R&D space on board, reducing experimental costs and risk over time while opening the opportunity for further biotechnology R&D in space. These CLDs will range from fully crewed to fully autonomous, providing optionality and healthy market competition. With commercial space entities and commercial LEO destinations, it is now feasible to plan and execute experiments at the scale that can generate robust evidence in LEO and compel large biopharma entities to consider entering the arena.

Age-related Disease:

Age-related diseases—including neurodegenerative, cardiovascular, chronic kidney, and female reproductive conditions—are overwhelming our current healthcare and drug development systems, with no regenerative cures in sight. The following tissue types are affiliated with the highest morbidity and mortality rates Nationwide and deserve particular focus in the quest for regenerative therapies:

Brain. Neurodegenerative diseases (ND) including Alzheimer’s, Parkinson’s and other dementias affect an estimated 8-11 million Americans (~200,000 deaths) and cost more than $435 billion dollars when considering direct and indirect costs[footnoteRef:1]. [1: Centers for Disease Control (CDC) and Prevention. (2026c). About chronic diseases. https://www.cdc.gov/chronic-disease/about/index.html CDC. (2006). Dementia and its implications for public health. Preventing Chronic Disease, 3(2). https://www.cdc.gov/pcd/issues/2006/apr/05_0167.html]

Heart. Cardiovascular diseases (CVD) including stroke, heart disease and arterial pathologies affect an estimated 127 million Americans (~843,000 deaths) and cost more than $400B in direct and indirect costs1.

Uterus. The uterus goes through a series of poorly understood changes across a lifespan. Organ-specific pathologies such as fibroids, the effects of polyendocrine metabolic ovarian syndrome, and abnormal bleeding conditions. Though difficult to define, estimates on healthcare and quality of life costs associated with non-fertility related reproductive ailments ballpark $17-35B annually with attributable deaths greater than 30,000 per year[footnoteRef:2]. [2: Centers for Disease Control (CDC) and Prevention. (1987). Hysterectomies in the United States, 1965–84 (Series 13, No. 92). National Center for Health Statistics. https://www.cdc.gov/nchs/data/series/sr_13/sr13_092.pdf; CDC. (2025b, June 10). Cervical cancer statistics; CDC (2025c, August 15). Health and economic benefits of cervical cancer interventions https://www.cdc.gov/nccdphp/priorities/cervical-cancer.html. Nature Reviews Endocrinology, 18(5), 290–308. https://www.nature.com/articles/s41574-021-00629-4; Frontiers in Cell and Developmental Biology, 9. https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.633180/full https://www.cdc.gov/cervical-cancer/statistics/index.html; De Corte, P., Klinghardt, M., von Stockum, S., & Heinemann, K. (2025). Time to diagnose endometriosis: Current status, challenges and regional characteristics—A systematic literature review. BJOG: An International Journal of Obstetrics and Gynaecology, 132(2), 118–130. https://pubmed.ncbi.nlm.nih.gov/39373298/]

Kidney. “Kidney disease” includes chronic kidney disease (often caused by diabetes, hypertension, and obesity), nephritis, nephrosis and other medium to long-term kidney conditions affect ~35 million Americans. Though the annual death rate is relatively lower than CVD (~55,000), the annual cost of Medicare-based dialysis alone is greater than $6.7 billion annually[footnoteRef:3]. [3: Hassan, M.B. et al; Chronic kidney disease and cardiovascular risk: Pathophysiology and interventional approaches – systematic review. Medicine, 104(49), e46189. https://doi.org/10.1097/MD.0000000000046189; National Institute of Diabetes and Digestive and Kidney Diseases. (n.d.). Kidney disease statistics for the United States. https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease; United States Renal Data System. (2024). Healthcare expenditures for persons with CKD. Annual Data Report. https://usrds-adr.niddk.nih.gov/2024/chronic-kidney-disease/6-healthcare-expenditures-for-persons-with-ckd; National Institute of Diabetes and Digestive and Kidney Diseases. (n.d.). United States Renal Data System. https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/usrds]

Microphysiological Systems / Organs on Chips:

An organ-on-a-chip is a small microphysiological system (MPS) that recreates key functions of a specific organ using living cells. MPSs are three-dimensional microfluidic devices that incorporate living human cells to replicate the structural, mechanical, and biochemical conditions of specific tissues and organs in vitro. These controlled environments can mimic dynamic fluid flow, shear stress, and biochemical gradients more closely approximate in vivo conditions than conventional two-dimensional cell culture.

Due to their biological complexity and scale, robust microfluidic support is required to keep MPSs healthy. Engineering microfluidics for support of MPSs in LEO has been achieved on small scales (up to 16 MPSs), and many of the optimizations made for terrestrial studies are adaptable to LEO. Commercial service providers (CSP), in fact, now offer fully autonomous lab units compatible with commercial launch cargo parameters. In addition to the engineering advances needed, MPS technology continues to be refined, and MPSs of greater complexity featuring multiple organ systems working together are routinely produced. The field has developed to the point where the semi-mass or mass production of many MPSs is achievable on a predictable timeline. Leveraging the maturation of MPSs as a biological proxy for human tissues, they present a potential path to modeling aging in human tissues.

Regenerative Medicine:

Regenerative medicine refers to the science of repairing, replacing, or restoring the biological function of damaged tissues and organs. Currently, approaches include cellular therapies, biomaterials, gene editing, and tissue engineering. Rather than managing symptoms, its core aim is to address the underlying structural and functional deficits that arise from disease or injury. While regenerative medicine is agnostic to the reason that restoration is needed, it is not agnostic to the mechanisms of functional decay. "Aging" is biologically defined by a collection of changes to cells and tissues that include genomic instability, telomere attrition, epigenetic alterations, protein dysfunction (from translation through correct turnover), mitochondrial dysfunction, cellular senescence, and stem cell exhaustion. Individually (or more frequently in combinations) these changes degrade cell function and converge to impair the body's intrinsic capacity for tissue repair and homeostasis.

Age-related disease reflects, in part, a failure of endogenous repair mechanisms, and regenerative strategies offer a framework for restoring those mechanisms at the cellular and tissue levels. The loss of maintenance and renewal creates conditions favorable to chronic diseases such as neurodegeneration, cardiovascular diseases, and metabolic syndromes. By design, regenerative therapies would encompass therapeutics that could intervene in multiple degradative cascades from the molecular to systemic scale. There are at least two paths to humans living longer healthier lives: finding ways to treat the changes caused by aging or preventing those changes in the first place. It is unclear which path may be more effective. The road to an answer starts with reliable and reproducible models of human aging.

Pharmaceutical Drug Screening:

Traditional drug candidate screening requires a broad assessment of potential therapeutics across a library of assets, lead asset selection and optimization, and validation within an animal model of disease. The preclinical stage alone can take more than 5 years, assuming relevant in vivo models have even been established. Adding to that potential time, the translation through small animal, large animal, and non-human primate models each offers an opportunity for failure. Recent FDA guidance (New Approach Methodologies (2026), Roadmap to Reducing Animal Testing in Preclinical Safety Studies (2025)) has incentivized a more streamlined process that relies heavily upon robust, in vitro tissue models of disease that would limit both animal and human testing. High fidelity, naturally aged models made from human cells could both shorten the lead development and pre-clinical timelines. The potential advantages of LEO remain unrealized, as no TARIS has been definitively established and no current platform exists for autonomous LEO-based pharmaceuticals, and, therefore, the value proposition for private industry remains unproven. Opening a LEO-based bioeconomy rests on demonstrating the utility, feasibility, and extensibility of a LEO-based pharmaceuticals platform which inspires pharmaceutical manufacturers to co-invest.

COSMOS Overview Comprehensive Organ System Modeling in Outer Space (COSMOS) centers on quantifying Tissue Aging Rate in Space (TARIS) relative to Tissue Aging Rate on Earth (TAROE) for human tissues affiliated with diseases that have the highest morbidity and mortality across multiple adult age groups impacting four critical tissues—brain, heart, uterus, and kidney—using microphysiological systems (organs-on-chips) and organoids. Accelerating the drug discovery process via COSMOS will mean more treatments in the development pipeline can be screened faster and more cost effectively than on Earth, expediting both the pathway to patients and decreasing downstream pharmaceutical costs.

COSMOS will definitively prove or disprove if exposure to microgravity in LEO truly accelerates tissue aging across these four tissue types and across representative adult age brackets. Provided TARIS exceeds TAROE at a rate that exceeds the breakeven cost on Earth for new drug R&D, COSMOS will then create a first-in-class platform for fully autonomous, high-throughput drug screening in LEO that would be more cost effective and faster than new drug R&D on Earth.

COSMOS will not only accelerate the creation of best-in-class MPSs across the largest donor pool in history for tissues affiliated with the leading causes of death but will also use that MPS platform for biopharmaceutical R&D at a scale never seen before. In turn, COSMOS will generate downstream pharmaceutical and private space interest and investment that can create a sustainable pathway for drug testing and, ultimately, development and clinical trials in space.

COSMOS DETAILS

COSMOS Structure and Timeline COSMOS includes two sequential phases. See Attachment C: COSMOS Schedule for more granular details of the schedule.

Phase I is 27 months and includes establishing and validating an MPS system based on a selected target organ with the objective of definitively establishing the TARIS and TAROE in four tissues (heart, brain, uterus, and kidney) across a range of representative ages that cover all adult populations.

PH II is 15 months. Phase II performers will use the MPSs or organoids (tissue and age range) in which the TARIS substantially exceeds TAROE to develop models of age-related pathology. These models will be used to justify LEO R&D for targeted, pro-regenerative drug testing on validated and unvalidated therapeutic assets in partnership with commercial biopharmaceutical partner(s) (CBPs). The objective is to demonstrate that MPSs can offer an in vitro high fidelity test bed for regenerative medicines that either directly counteract age-related tissue changes or prevent those tissue changes even as tissue ages.Figure 1 COSMOS schedule; for granular schedule see Attachment C

Phase I Details During Phase I, proposers shall establish and validate an MPS system based on their selected target organ (each proposer can only select one organ). The MPS design, cell types, and interactions must recapitulate structures and functions that change with age. Phase I experiments consist of a terrestrial MPS set and a LEO MPS set. There will be two scheduled spaceflights for performers to fly their MPSs: one at month 19 and one at month 23. Each flight will remain in LEO for 4 total weeks but requires that fifty percent of MPS tissues are preserved at 2 weeks in LEO, and the remainder at 4 weeks in LEO, prior to descent.

All experimentation in LEO will be fully autonomous, requiring no human input or interaction from launch through splashdown. All twinned LEO experiments performed on Earth will also be autonomous. This must be accounted for in each proposer’s experimental design and plans. A Hardware Validation Launch will occur at Month 12 Ffter Contract (MAC) but will not involve MPSs or organoids as it is intended to ensure all non-biology logistics are in lockstep prior to the month 19 launch.

Each team must present a plan to develop MPSs at the scale required for the terrestrial arm, and a plan to develop no fewer than 384 single-donor MPSs that will mature in parallel (matched 192 LEO: 192 Terrestrial) and be delivered as a LEO payload by the established launch dates(s) for the LEO Twin Study (See Figure 2: Phase I Experimental Design requirements). The ‘twin’ in this instance refers to a set of MPSs derived from the same donor (n=384), constructed under the same protocols and conditions, and housed in autonomous laboratory housings. One of the sets will remain on earth (n=192), the other will launch and achieve flight for a specified amount of time (n=192). All MPSs will be preserved using identical technology and then analyzed for LEO-associated variances.

Phase I Launch Schedule Phase I includes two (2) space launches tentatively scheduled for months 19 and 23. Both hardware for housing MPS systems and launch vehicles will be provided by ARPA-H selected Commercial Service Providers.

Phase I Results Showcase Phase I culminates in a 3-month window where the ARPA-H team will convene a research forum (date to be determined, 25-27 MAC) where performer teams will share the completed results of their Phase I efforts including TARIS: TAROE modeling.

Phase I Commercialization Requirements See Section 3.5

Phase II Details Success in Phase II requires that each team have an established partnership (e.g., signed contractual agreement) with a commercial biopharmaceutical partner (CBP) that has drugs of interest applicable to the selected organ type and age brackets in which TARIS>TAROE.

Phase II: Establishing Rapid Drug Screening for Age-Related Diseases Phase II performers will use the MPSs or organoids (tissue and age range) in which the TARIS substantially exceeds TAROE to develop models of age-related pathology. These models will be used to justify LEO R&D for targeted, pro-regenerative drug testing on validated and unvalidated therapeutic assets in partnership with CBP(s).

Phase II Launch Cadence Phase II includes two (2) space launches tentatively scheduled for months 39 and 41. No less than 50% of MPS and drug combinations described in Table 1 (Section 4.2) must be launch capable simultaneously (e.g., 50% of the selected MPSs need to launch on the first launch and the remaining 50% need to fly on the second launch).

Phase II Results Showcase The format and schedule of the end of program meeting will be established during Phase II, but the general intention is an all-COSMOS showcase of results of the second phase.

Drug Candidate Selection Drug libraries licensed or acquired should have relevance to any biological variances discovered in the LEO Twin Study data of Phase I. Ideal libraries or candidates would target tissue/organ processes, mechanisms, or phenotypes known to contribute to pathology.

Phase II Commercialization Requirements See Section 3.5

The following experimental design, technical, personnel, scale, and timing requirements must be met by a successful performer team.

Performer Reporting, Evaluation and Progress Monitoring To ensure success, each COSMOS phase will include regular performance evaluations, including (but not limited to) monthly, semi-annual, and annual progress reports. Specifics regarding deliverables will be stipulated in any award made under this solicitation.

In addition to the technical requirements associated with each phase, COSMOS also includes additional metrics designed to guide and monitor each Performer’s progress towards biopharma partnerships and regulatory buy-in for sustained, post-program biopharma and biotechnology work in LEO (e.g., in vitro clinical trials, drug development, and continued drug screening).

Performer progress evaluation will be an ongoing process over the duration of COSMOS. Written deliverables, meetings, schedule and financial management, and achievement of milestones are some of the information that is integrated into progress evaluation. The ARPA-H model requires active performer management and a high degree of involvement by the PM and their technical team. Performers should expect regular interactions with the ARPA-H team. Further details will be available in any awards made under this solicitation.

Required Meetings Kickoff Meeting (Include in travel budget) - ARPA-H will convene a kickoff meeting at the beginning of COSMOS, after contract award. Details will be forthcoming, but the meeting is likely to be held at a TBD CONUS space launch facility.

Scientific Reviews (Include in travel budget) – Semi-annual all-performer (technical and CSP) meetings with locations TBD to discuss progress, hurdles, key findings, etc. Current tentative schedule is for months 7,14, 21 (Phase I) and 34 (Phase II). Further details and a template for deliverables will be provided at kick-off.

Site visits - At the discretion of the GOV team with the expectation key personnel are present at their prime location. ARPA-H will travel to you at a cadence TBD.

MPS/Organoid and CSP Hardware/Flight Team Meetings: Regular touchpoints between MPS/Organoid teams and Commercial Service Partner Engineering teams are required. It is understood that the physical support of MPS for flight is complex and will require iteration and testing. Immediately following award, Performer teams must initiate material transfer agreements and data-sharing agreements to allow full cooperation on the design, build, and testing of autonomous experimental MPS support hardware and MPS design teams.

Ad Hoc Meetings: At the program manager’s discretion, additional meetings will be requested with Performer teams. These requests will be made in writing, listing the team members requested to attend.

Required Commercial Biopharmaceutical Partnernerships Engagement

· Phase I: By the end of Phase 1, each team must establish a signed, contractual commercial public-private partnership (PPP) with AT LEAST one Fortune 100 biopharmaceutical company to leverage the COSMOS platform for regenerative therapeutic R&D for all tissues where TARIS>TAROE to include: drug screening, in vitro clinical testing, etc. Selected partner must have:

· Each team’s partner(s) must: 1) have ³3 drug candidates that are either approved for age-related disease in the selected tissue type or target aging-relevant molecular pathways in clinical testing and/or 2) have a panel of known and novel drug candidates relevant to the target tissue type. Drugs selected for screening must be relevant to aging and the target tissue and must include drugs with known mechanisms of action and/or drug candidates/leads.

· Proposers must also propose the design, development plan, and substantiating evidence for MPSs of disease in only the ages and tissues demonstrating TARIS>TAROE. Those MPS-based models of disease will be what the CBP will use to screen validated and unvalidated therapeutics of interest in Phase II.

· For each tissue and age group where TARIS>TAROE, the CBP must demonstrate how that rate translates to the discount on the downstream therapeutic MSRP. For instance, if 35-year-old uterine tissue demonstrates TARIS is 5x TAROE, the CBP must clearly demonstrate how that 5x accelerated rate will be recognized by patients benefiting from novel regenerative therapeutics.

Phase II: Technical teams (MPS/Organoids) will establish a commercial public-private partnership (PPP) with a Fortune 100 pharmaceutical company to leverage the COSMOS platform for translational, regenerative therapeutic applications to include: drug screening, in vitro clinical testing, etc.

· Proposers and their CBP(s) shall use the MPSs in which the TARIS substantially exceeds TAROE to utilize LEO R&D for targeted, pro-regenerative drug testing in validated and unvalidated therapeutic assets. De minimis, proposer teams must secure access to a drug library relevant to the cell types, functions, and variance associated with the “accelerated aging” models developed in Phase I.

· Performer teams are expected to coordinate with the selected CBP to develop MPS models of disease relevant to the drugs being screened in LEO. Selected CBP must have three approved drugs which target aging-related pathways proof of concept of the COSMOS as well as a panel of experimental therapeutics for LEO-based drug screening.

· Phase II success includes the creation of a PPP pipeline to utilize the COSMOS platform.

MANDATORY EXPERIMENTAL DESIGN

Each performer team will produce the required number of MPS and organoids from the designated number of donors in each Phase. Each Phase has specific design requirements that are laid out on the following tables. Phase I details are in Section 4.1; Phase II details in Section 4.2.

Phase I Experimental Design The parameters outlined in the infographic, text, and tables below are mandatory. Please ensure your final proposal package includes all the relevant experiments, justifications, and design requirements outlined in Tables 1-3 and sections 4.1 and 4.2.

Figure 2: COSMOS Phase I Design Parameters – note these numbers address the entire period of performance; metric tables in Section 4.1.5 Experimental Age Brackets All Phase I experiments must include cell/tissue donors in the following restricted age brackets: 30 years ± 2 years, 45 years ± 2 years, 60 years ± 2 years. These age brackets have been selected based on emerging evidence that our bodies age in a non-linear pattern, where a large change across the system occurs at relatively predictable timepoints (Liu et al, Nature 2024). An emerging model of aging is that there are non-linear accelerations in age in the mid-30’s, mid-40’s and mid-60s. Around age 30, most adults are past developmental maturation but have not generally hit the first major nonlinear aging shift seen in later adulthood. This makes it a useful reference/baseline state for adult biology.

The mid-40s are the first major adult aging inflection point. In women, this window also often overlaps with perimenopausal transition biology, which can strongly affect metabolism, inflammation, vascular risk, bone, and immune regulation. Midlife is when cardiovascular aging becomes more biologically apparent, with rising arterial stiffness, endothelial dysfunction, vascular inflammation, and subclinical atherosclerotic burden. The late transition point, the mid-60s, is when many aging hallmarks become more integrated at the organism level: immune remodeling, senescence burden, endocrine change, vascular stiffening, and reduced resilience.

Terrestrial Study This arm of the study will act as a temporal and technical ‘ground’ for the LEO Twin study. The object is to run technical duplicates (2) for each donor for each relevant time point. For example, for kidney MPS from a 30 (+/-2 years) year-old, a total number of 4 MPSs are required. This must be replicated for each required age bracket. The experimental timepoints can be determined by the performer, though the proposer should offer justification as to why timepoints were selected. This study does not require the use of the CSP-provided microfluidics housing.

LEO Twin Study All MPSs for the LEO Twin study (both terrestrial and flight twin) will be housed for the experimental duration in a fully autonomous functional unit provided by a commercial service provider (to be determined by ARPA-H and relayed to selected performers). This arm of the study will determine if there is detectable variance between MPS on earth (at 2 and 4 weeks) and those in flight for the same time points (at 2 and 4 weeks). Each organ will be recapitulated in quadruplicate with 2 for flight and 2 on earth.

Commercial Service Providers (CSP) The government will select and announce two commercial service providers who will work in collaboration with each performer team and will be responsible for flight hardware and logistics. These CSPs will be determined by the Government, and it is expected that selected performers will only work with and use the designated CSPs within COSMOS.

CSP-Hardware will provide experimental housing (with power, imaging, sample preservation, and microfluidic support) compatible with the CSP-Flight LEO platform. At the time of award, performer teams will immediately institute the required agreements with the CSP partners to allow for co-engineering, testing and integration of MPS systems and flight hardware. The ARPA-H technical team will work with performers to determine how many MPS from each team will launch on each launch.

Phase I Design Requirements The following tables (Tables 1, 2, 3) outline the Experimental parameters, MPS requirements, and Computational modeling (Baseline, TARIS/TAROE) requirements.

Table 1: Phase I Mandatory Experimental Parameters

1 Tissue of Interest per team

Brain OR Heart OR Uterus OR Kidney NOTE: Do NOT propose to more than one organ group per proposal

LEO Twin: MPS fixation will occur at 2 weeks flight time and 4 weeks flight time

· ≥50 healthy individuals for the supplemental terrestrial-only study for each age group Teams must ensure that the selected donors have sufficiently large tissue samples to generate the appropriate number of MPSs: ≥2 MPS/tissue sample for the terrestrial-only study and ≥4 MPS/tissue sample for the twin study

NOTE: NO fewer than 75% of the total numbers of the experimental units must be MPS; the use of organoids in some percentage is encouraged to act as a ‘fail safe’ for the MPS cohort

NOTE: NO fewer than 75% of the total numbers of the experimental units must be MPS; the use of organoids in some percentage is encouraged to act as a ‘fail safe’ for the MPS cohort

Mandatory Microphysiological Systems / Organs on Chips & Organoid Parameters

· MPSs must recapitulate key features of the tissue/organ of interest as demonstrated by an analysis of the 3D microarchitecture, cell lineage identity and composition

· MPS cells, structure and maturation conditions must be selected to support the detection of age-related changes over time

· Proposers must offer justification for how both tissue age and tissue physiology is represented in the MPS

· Sex: 50% female (for non-uterine tissues)

· Race/Ethnicity: 56% Non-Hispanic (NH) White, 20.5% Hispanic or Latino of any race; 13.5% NH Black; 6.9% NH Asian; 4.9% multiracial (≥2 races); 2.1% American Indian & Alaskan Native; 0.3% Native Hawaiian/Pacific Islander

NOTE: For LEO Twins, final testing, monitoring, -omics, and extraction processes will be determined and refined in partnership with the commercial service provider for hardware

Any available non-destructive orthogonal approaches for real time data capture prior to MPS preservation should be integrated and that data captured (up to the limit of the autonomous housings for the LEO Study arm) Approaches selected to monitor variance / potential aging for each organ must allow monitoring of ≥2 biomarkers for each of the following: 1) established and potential tissue agnostic and tissue-specific biomarkers of aging, 2) age-related biological pathways (e.g. stress, senescence, inflammation), and 3) tissue agnostic and tissue specific biomarkers of tissue integrity

In Silico Aging Model To establish if there is variance between healthy tissues on the ground and identical tissues in flight, proposers must offer a rational data capture and modeling strategy.

· This model should serve as the grounding for MPS-derived data from the terrestrial experimental set, as well as for the future integration and comparison of data form the LEO twin set

· Performers must: establish the data sources to be used, training and test data, integrated assumptions in the model build, describe the model and establish how it will be used to inform the TARIS/TAROE analyses

· Performers may leverage extant models of aging for their specific organ provided they can justify the model selected, and clearly detail how new data will be added, or the model will be modified with TAROE and TARIS data

· Using the in silico model of aging in the specific organ type, each team should put forth a list of prospective biopharma partners with relevant drug libraries for their organ

Phase II Experimental Design Each performer team selected for Phase II will generate testable disease model(s) using the organ and age bracket(s) (up to 2 brackets per performer team) that showed the greatest TARIS:TAROE ratio. The design parameters for Phase II are listed in Table 4.Figure 3: COSMOS Phase II

MPS-based Disease Model Each performer team selected for Phase II will generate testable disease model(s) using the organ and age bracket(s) (up to 2 brackets per performer team) that showed the greatest TARIS:TAROE ratio. Technical details for Phase II MPS-based disease models are not required at time of proposal submission, however a generalized technical plan for no more than 2 models per organ team is required in the proposal. Model designs and specifics are not part of this current proposal beyond budgeting for the potential of 1-2 disease models per team. Technical description and justification of the MPS-based disease model will be finalized in the final quarter of Phase I (18 MAC). It is expected that disease models would be developed with specific pharmaceutical partner(s) in mind.

Teams must ensure that the selected donors have sufficiently large tissue samples to generate the appropriate number of MPSs

COSMOS METRICS

To evaluate how effectively a proposed solution will achieve the stated objectives, the government hereby promulgates the following metrics that may serve as the basis for determination of satisfactory progress to warrant continued funding.

Although the COSMOS metrics are specified below, Proposers should note that the government has identified these goals with the intention of bounding the scope of effort while affording maximum flexibility, creativity, and innovation of proposed solutions to the stated problem. Proposals should cite the quantitative and qualitative success criteria that the effort will achieve by each Phase’s milestone and intermediary metric measurement.

Phase I Metrics

· Licensable data set comprising the Terrestrial Arm data and LEO Twin Data

· Commercial CSP Hardware integration plan with MPSs for timely spaceflight

· Baseline In Silico Aging Model pre-flight

· Final In Silico Aging Model of tissue changes in LEO

· Signed, contractual partnership and licensing agreement with AT LEAST one CBP that has drugs of interest that are applicable to the organ type with the greatest TARIS:TAROE

· ≥3 drug candidates that are either approved for age-related disease in the selected tissue type or target aging-relevant molecular pathways in clinical testing,

· Have a panel of known and novel drug candidates relevant to the target tissue type.

· Drug Screening: Drugs selected for screening must be relevant to aging and the target tissue and must include drugs with known mechanisms of action and drug candidates

Phase II Metrics

· Demonstration of proof-of-concept high throughput drug testing using microgravity-leveraged MPS models of aging to identify drugs that can prevent and/or reverse age-related tissue dysfunction and/or disease

· Commercial CSP Hardware integration with MPSs for timely spaceflight

· Successful collaboration with a CBP with three approved drugs which target aging-related pathways proof of concept of the COSMOS as well as a panel of experimental therapeutics for LEO-based drug screening.

· For each tissue and age group showing TARIS>TAROE, the CBP must demonstrate how that rate translates to the discount on the downstream therapeutic MSRP. For instance, if 35-year-old uterine tissue demonstrates TARIS is 5x TAROE, the CBP must clearly demonstrate how that 5x accelerated rate will be recognized by patients benefiting from novel regenerative therapeutics.

· Evidence of post-program investment from at least one of the team’s CBP for continued use of the COSMOS platform in the commercial sector following contract conclusion

COSMOS Team Requirements Teams must present a plan to have a qualified team of expert advisors with adequate levels of effort and subject matter expertise to ensure the success of the effort.

Successful proposers and performer teams will be comprised of, at minimum, the following experts and specialists. Unless sufficiently justified otherwise, the government’s assumption is that the Project Manager is full-time, and the other key personnel (KP) will be proposed for at least a minimum of a 0.5 full-time equivalent and cannot be the same person. KPs require Research Security Review (RSR). See Section 14.5 for RSR details.