STOMP_ISO_ARPA-H-SOL-26-152.pdf

ARPA-H-SOL-26-152

STOMP

INNOVATIVE SOLUTIONS OPENING

FOR

SYSTEMATIC TARGETING OF MICROPLASTICS

(STOMP)

HEALTH SCIENCE FUTURES

April 2nd, 2026

Table of Contents

1 INTRODUCTION

1.1 Background

1.2 Program Goals and Timeline

2 THE PROGRAM

2.1 Technical Area 1: Measurement

2.1.1 Technical Area 1.1: Best-in-class MNP Quantification Method

2.1.2 Technical Area 1.2: Clinical Quantification Method

2.1.3 Technical Area 1.3: Biofluids and Tissue Correlation Study

2.2 Technical Area 2: Understanding

2.2.1 Technical Area 2.1: Bioaccumulation and health impacts

2.2.2 Technical Area 2.2: Establish Mechanistic Framework for MNP Toxicity

2.3 Technical Area 3: Removal

2.4 Independent Validation and Verification

2.5 Microplastics Samples

2.6 Special STOMP Requirements

2.7 Commercialization Requirements

3 ELIGIBILITY INFORMATION

3.1 Eligible Proposers

3.1.1 Prohibition of Performer Participation from Federally Funded Research and Development Centers (FFRDCs) and other Government Entities

3.1.2 Current Professional Support

3.1.3 Non-U.S. Entities

3.2 System for Award Management (SAM)

4 SUBMISSION PROCESS

4.1 Submission Process Overview

4.2 Solution Summary Submissions

4.3 Full Proposal Submissions

4.4 Submission Information

4.5 Proprietary Information

5 SUBMISSION REVIEW AND EVALUATION PROCESSES

5.1 Conforming Proposals

5.2 Solution Summary Review Process

5.3 Proposal Review Process

5.4 Evaluation Criteria for Proposals

5.4.1 Criteria 1: Overall Scientific and Technical Merit

5.4.2 Criteria 2: Proposer’s Capabilities and/or Related Experience

5.4.3 Criteria 3: Assessment of Proposed Cost/Price

5.5 Handling Competition-Sensitive Information

5.6 Evaluation and Award Disclaimers

6 POLICY REQUIREMENTS AND MISCELLANEOUS OTHER INFORMATION

6.1 Controlled Unclassified Information (CUI) on Non-Federal Information Systems

6.2 Organizational Conflicts of Interest (OCI)

6.2.1 Agency Supplemental OCI Policy

6.2.2 Research Security Disclosures

6.3 Intellectual Property

6.4 Data Sharing

6.5 Human Subjects Research

6.6 Animal Subjects Research

6.7 Electronic Invoicing and Payments

6.8 Procurement of Synthetic Nucleic Acids or Benchtop Synthesizers

7 APPENDIX A: SOLUTION SUMMARY TEMPLATE

8 APPENDIX B: FULL PROPOSAL CONTENT AND INSTRUCTIONS

8.1 VOLUME I: TECHNICAL AND MANAGEMENT PROPOSAL

8.2 VOLUME II: COST PROPOSAL

8.3 VOLUME III: DRAFT OT RESPONSE

8.4 VOLUME IV: ADMINISTRATIVE AND NATIONAL POLICY REQUIREMENTS

Innovative Solutions Opening (ISO) Overview Information

FEDERAL AGENCY: Advanced Research Projects Agency for Health (ARPA-H)

PROGRAM TITLE: Systematic Targeting of MicroPlastics (STOMP)

ANNOUNCEMENT TYPE: ISO Solicitation Number: ARPA-H-SOL-26-152

ISO CONTACT: https://solutions.arpa-h.gov/Ask-A-Question/

ANTICIPATED AWARDS AND TYPE(S): Multiple Other Transaction (OTs) Agreements

DATES: (All times listed are Eastern Time)

PROPOSERS’ DAY: April 22nd, 8:30 AM – 5:00 PM

QUESTIONS & ANSWERS (Q&A) DUE DATE: May 4th, 5:00 PM

SOLUTION SUMMARIES (TA1, TA2) DUE DATE: May 6th, 5:00 PM

FULL PROPOSALS (TA1, TA2) DUE DATE: June 22nd, 5:00 PM

Where to Submit:

Solution Summaries: https://solutions.arpa-h.gov/Submit-Solution/

Proposals: https://solutions.arpa-h.gov/Submit-Proposal/

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

ISO PURPOSE

ARPA-H seeks proposals from all eligible entities (see Section 3 for eligibility information) to accomplish the STOMP Program goals as described in this solicitation package. Ultimately, ARPA- H intends to negotiate OT Agreements with the team(s) whose proposal(s) are most advantageous to the Government.

ARPA-H is not currently soliciting Technical Area 3 (TA3) proposals. TA3 proposals submitted alongside TA1 and TA2 will not be reviewed. A Special Notice and amended ISO for TA3 will be released prior to completion of initial TA1 and TA2 Phase 1 studies.

ISO QUESTIONS AND ANSWERS

All questions regarding this ISO must be submitted to https://solutions.arpa-h.gov/Ask-A- Question/. ARPA-H will not respond directly to email inquiries but will post Q&As to the ARPA-H ISO Website and SAM.gov on an on-going basis. All questions must be in English and must include the name, email address, and telephone number of a point of contact, and must be submitted by the Q&A deadline posted with other dates identified in Section 1, Innovative Solutions Opening Overview Information. Proposers submitting questions to individual Government team members (e.g., PM) should not expect a response. ARPA-H will attempt to answer questions via FAQ updates in a timely manner. Questions submitted after the due date may not be answered. Further, duplicative questions may be combined and rephrased to streamline responses.

PROPOSERS’ DAY

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

ARPA-H will host a Proposers’ Day in support of the Technical Areas 1 and 2 of the STOMP Program as described in Special Notice ARPA-H-SN-26-150. The purpose is to provide potential proposers with information on the STOMP program, promote additional discussions, and encourage teaming and networking.

ARPA-H will host a Proposers’ Day in support of Technical Area 3 later, and a separate Special Notice will be published announcing the TA3 Proposers’ Day event.

Interested parties are not required to attend Proposers’ Day in order to propose to Technical Areas 1 and 2, and materials formally presented during Proposers’ Day will be posted to the ARPA-H Program Website along with a recording of the proceedings. One-on-one meetings between the program manager and prospective applicants will not occur.

ARPA-H will not reimburse potential proposers for participation at Proposers’ Day (or time and effort related to submissions in response to this ISO).

1 INTRODUCTION

A growing body of evidence suggests that micro- and nano-plastics (MNPs) harm human health. The Systematic Targeting Of MicroPlastics (STOMP) program seeks to better quantify MNPs in humans; understand the mechanisms of MNP deposition; and, ultimately, improve human health by developing means to limit uptake and remove MNPs from the body.

1.1 Background

Plastics are ubiquitous in modern life, and the amount of plastic in the world increases every year1. With plastic comes plastic waste, and with plastic waste, microscopic plastics, or microplastics. Microplastics (also referred to in this ISO as MNPs (micro- and nano-plastics)) are fragments nanometers to microns in size, which are often degradation products of plastic materials. They can also be manufactured deliberately (e.g.

microbeads in exfoliating products) or be generated inadvertently. MNPs vary in size, shape, and chemical composition. They can be fibers, spheres or fragments of various shapes; their chemical composition includes polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polyurethane (PU), polycarbonate (PC), styrene-butadiene rubber (SBR), nylon 6 (N6), and others. They usually contain additives such as stabilizers, plasticizers, and pigments; indeed, the characteristics listed here are far from exhaustive.

MNPs are found in food and drinks, soil and air, indoors and outdoors. They enter the body mainly through ingestion and inhalation, and are deposited in most, if not all, tissues and organs. MNPs have been found in blood2, brain3, colon4, liver5 and others. Recently, the scientific community has investigated the impact of MNPs on human health, with many studies showing correlation between presence of MNPs and deleterious health effects. For example, 80-fold higher levels of MNPs were found in human femoral artery atherosclerotic plaques as compared with healthy, non-diseased human carotid arteries;

in particular, three- and eight-fold higher PP and PU levels respectively were associated

1 OECD (2022), Global Plastics Outlook: Economic Drivers, Environmental Impacts and Policy Options, OECD Publishing, Paris, https://doi.org/10.1787/de747aef-en.

2 Heather A et al, Discovery and quantification of plastic particle pollution in human blood, Environment International, 163, 2022,107199, ISSN 0160-4120,https://doi.org/10.1016/j.envint.2022.107199.

3 Nihart AJ et al, Bioaccumulation of microplastics in decedent human brains. Nat Med. 2025 Apr;31(4):1114-1119. doi: 10.1038/s41591- 024-03453-1. Epub 2025 Feb 3. Erratum in: Nat Med. 2025 Apr;31(4):1367. doi: 10.1038/s41591-025-03675-x. PMID: 39901044; PMCID:

PMC12003191.

4 Ibrahim YS et al, Detection of microplastics in human colectomy specimens. JGH Open. 2020 Nov 21;5(1):116-121. doi:

10.1002/jgh3.12457. PMID: 33490620; PMCID: PMC7812470.

5 Horvatits et al, Microplastics detected in cirrhotic liver tissue. EBioMedicine. 2022 Aug;82:104147. doi: 10.1016/j.ebiom.2022.104147.

Epub 2022 Jul 11. PMID: 35835713; PMCID: PMC9386716.

with chronic limb-threatening ischemia compared to less severe disease6. Higher MNP levels were found in tissue obtained from cervical cancer patients compared to normal controls, and the highest accumulation was noted in patients with advanced disease7.

MNPs were also detected in livers of liver cirrhosis patients, but not in the livers of subjects without liver disease8. Correlation, however, does not demonstrate causation, but causation is difficult to prove in humans. Exposure studies in animals, however, demonstrate that MNP exposure causes harm. Mice exposed to polystyrene nanoplastics exhibited learning and memory impairments compared to normal controls9; MNPs induced cardiovascular toxicity and led to atherosclerotic plaque formation in mice fed a PS-spiked diet10. Acute exposure to MNPs induced changes in animal behavior and inflammation11;

ingestion of MNPs was shown to promote inflammation and tumorigenesis in the mouse colon12. The examples listed above represent only a small fraction of those documented in the literature.

Despite this concerning evidence, questions about MNP-related harm remain. Transit at systemic and cellular scales is not clear: how do MNPs get into organ systems? How do they get into cells? Where do they accumulate within cells? Is there an innate removal mechanism, or an equilibrium between the blood and organ levels? Toxicity mechanisms are only now beginning to be elucidated: which biochemical pathways do MNPs dysregulate, and how? How do MNPs dysregulate the microbiome? How do MNPs disrupt tissue structure and function? Furthermore, it is still not clear which MNPs are most harmful, at what dose, and why. Is it the size, shape, or chemical composition—or all the above?

There are many reasons why these questions remain unanswered. First, measuring MNPs in biological tissue is very challenging. Existing technologies require intensive sample preparation, data analysis, and/or imaging workflows that can take hours to days, with limited standardization across laboratories. No single analytical technique can determine

6 Massie PL et al, Micro- and nanoplastics are elevated in femoral atherosclerotic plaques compared with undiseased arteries. JVS Vasc Sci. 2025 Aug 28;6:100393. doi: 10.1016/j.jvssci.2025.100393. PMID: 41069702; PMCID: PMC12506576.

7 Xu H et al, Microplastic changes during the development of cervical cancer and its effects on the metabolomic profiles of cancer tissues. J Hazard Mater. 2025 Feb 5;483:136656. doi: 10.1016/j.jhazmat.2024.136656. Epub 2024 Nov 26. PMID: 39603134.

8 Horvatits T et al, Microplastics detected in cirrhotic liver tissue. EBioMedicine. 2022 Aug;82:104147. doi:

10.1016/j.ebiom.2022.104147. Epub 2022 Jul 11. PMID: 35835713; PMCID: PMC9386716.

9 Sun M et al, Polystyrene nanoplastics induced learning and memory impairments in mice by damaging the glymphatic system.

Ecotoxicol Environ Saf. 2024 Oct 1;284:116874. doi: 10.1016/j.ecoenv.2024.116874. Epub 2024 Aug 16. PMID: 39153278.

10 Wang B et al, Long-Chain Acyl Carnitines Aggravate Polystyrene Nanoplastics-Induced Atherosclerosis by Upregulating MARCO. Adv Sci (Weinh). 2023 Jul;10(19):e2205876. doi: 10.1002/advs.202205876. Epub 2023 May 5. PMID: 37144527; PMCID: PMC10323628.

11 Gaspar L, et al, Acute Exposure to Microplastics Induced Changes in Behavior and Inflammation in Young and Old Mice. Int J Mol Sci.

2023 Aug 1;24(15):12308. doi: 10.3390/ijms241512308. PMID: 37569681; PMCID: PMC10418951.

12 Djouina M et al. Ingestion of a human-relevant mixture of environmentally sourced microplastics promotes inflammation and tumorigenesis in the mouse colon. Environ Pollut. 2026 Feb 9;395:127794. doi: 10.1016/j.envpol.2026.127794. Epub ahead of print.

PMID: 41672396.

MNP particle mass, count, size, and chemical composition simultaneously, nor is there a standard workflow for labeling and tracking MNPs in vivo. Furthermore, the biological matrix— the complex mixture of proteins, salts, lipids, and other materials that comprise a biological sample— interferes significantly with measurement. Notably, under pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS), lipids and some types of polymers break down into similar hydrocarbons13, complicating data analysis; and for Stimulated Raman Spectroscopy (SRS), spectra from the biological matrix require disentangling by bespoke statistical and machine learning pipelines. These are problems that need to be addressed in order to develop a gold standard quantification method. In addition, experiments are often performed with animals exposed to varying, and sometimes unreasonably high, MNP levels, which do not recapitulate human exposure. Last, but not least, there are no good MNP reference materials enabling scientists to perform experiments that can be directly compared to each other. Polystyrene spheres are used in most studies, as they are one of the few commercially available solutions, even though it is generally agreed upon that this is not a good model of human exposure. Fibers and irregular fragments may produce stronger biological effects than spheres, because they are retained longer and cause more direct membrane damage, while also potentially triggering stronger innate immune activation14.

1.2 Program Goals and Timeline

STOMP has three technical areas (TAs) and is structured as two 30-month Phases. Note that not all program activities span the full period of performance. TA3 proposals are not being solicited in this ISO; a subsequent solicitation for TA3 proposals will be released later in Phase 1. All information pertaining to TA3 in this ISO is meant to frame and provide context for the technologies solicited for now in TA1 and TA2.

Phase 1 Phase 2 6 12 18 24 30 36 42 48 54 60

TA1: Measurement

TA2: Understanding

Apply to TA3 TA3: Removal

Figure 1: STOMP program structure by phase and month.

13 Rauert, Cassandra, et al. "Extraction and Pyrolysis-GC-MS analysis of polyethylene in samples with medium to high lipid content." Journal of Environmental Exposure Assessment 1.2 (2022): N-A 14 Choi D et al. In vitro toxicity from a physical perspective of polyethylene microplastics based on statistical curvature change analysis.

Sci Total Environ. 2021 Jan 15;752:142242. doi: 10.1016/j.scitotenv.2020.142242. Epub 2020 Sep 7. PMID: 33207500.

TA1: Measurement

Without reliable detection, characterization, and quantification of MNPs, it is not possible to understand where MNPs are in the human body (and why/how), nor is it possible to develop and/or validate removal methods. STOMP TA1 performers will:

a. Develop a best-in-class research-grade MNP measurement technique, including sample preparation, measurement, and analysis methodology, to be used by STOMP teams to quantify data and validate results starting before the end of the first year of the STOMP period of performance. Because of the accelerated timeline, performers will likely develop techniques that overcome challenges with existing instrumentation, but novel approaches are welcomed with justification.

b. Develop a novel, clinically-focused measurement system capable of quantifying MNPs in human biospecimens quickly, cheaply, and at scale. This may involve the development of entirely new devices and modalities for rapid MNP detection and quantification.

c. Conduct a study in human participants, acquiring paired MNP data from biological fluids and tissue samples, to determine if tissue MNP concentration correlates with the MNP concentration in the more accessible biological fluids.

TA2: Understanding

To target the most harmful MNPs in the most effective way, it is necessary to understand which MNPs drive adverse health effects, and how. TA2 performers will:

a. Conduct acute and chronic MNP exposure studies in animal models to assess bioaccumulation and impacts to system- and organ-level harm.

b. Prioritize organ systems with the greatest MNP accumulation and indications of harm to investigate and define trafficking and accumulation mechanisms to key organ systems.

c. Determine cell types and cellular pathways impacted by MNPs, including outlining when intracellular internalization occurs and mechanisms of toxicity (oxidative stress, inflammation, protein dyshomeostasis, etc.).

d. Identify any innate mechanisms for MNP removal and degradation.

TA3: Removal

The ultimate aim of STOMP is to develop methods to remove toxic MNPs from the human body to improve health outcomes. Although TA3 solutions will not be solicited until closer to Month 24, it is anticipated that TA3 performers will develop and preclinically validate technologies that prevent further accumulation and reduce MNP burden.

2 THE PROGRAM

2.1 Technical Area 1: Measurement

For Technical Area 1 of STOMP, performers will perform three activities:

TA1.1: Develop a best-in-class, standardized, validated measurement methodology for MNP in animal and human samples, for immediate (Month 9) use during STOMP.

Measurements must be provided as a service to other STOMP TA1 and TA2 performers;

alternatively, assistance must be provided, so that they can replicate the optimal methodology in their own labs.

TA1.2: Develop a novel, fast, cheap, and easy-to-use system to quantify MNPs from clinical human samples at scale. While TA1.1 may extend existing technology, TA1.2 will likely involve significant technological development to reach the ambitious goal of MNP quantification for less than $50 in less than 15 minutes. The final method may lack the precision of the research-grade TA1.1 measurements but will still provide a quantitative measurement of patient MNP burden.

TA1.3: Conduct a study evaluating the correlation between MNP content in biopsy/excised tissues and bodily fluids. To determine if bodily fluid MNP levels are a valid reporter for MNPs deposition in tissues, STOMP TA1 performers will use TA1.1 measurement methods to conduct a study of clinically obtained tissue (surgical, biopsy, etc.) and bodily fluids and determine the level of correlation.

TA1 performers must address TA1.1, TA1.2, and TA1.3; teaming is likely necessary as the three goals require different approaches and expertise.

As described in Section 2.5, samples of MNPs with known composition and size distribution will be provided to TA1 performers to establish common references.

Performers may develop and use their own MNP samples, but these will come in addition to the ARPA-H provided materials.

The table below illustrates the timeline for TA1 activities. Milestones are presented in more detail in the following subsections.

TA1 Activities Year 1 Year 2 Year 3 Year 4 Year 5

Month after award 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

TA1.1: Best-in-class research quantification

Method dev. and validation Sample analysis for TA2 and TA3 performers

TA1.2: Clinical assay development

Prototype 1 Prototype 2 Preclinical device/assay Premarket FDA submission

TA1.3: Biofluids and tissue study

IRB

submission and approval

Clinical study and data analysis

Figure 1: Notional schedule for TA1 activities. Deviation from this schedule must be described and justified in the proposals.

2.1.1 Technical Area 1.1: Best-in-class MNP Quantification Method MNP quantification in biological samples pushes the limits of modern instrumentation and methodologies. Biological matrix hydrocarbons generate similar spectra to polymers; non-specific binding confounds attempts at fluorescent labeling; and small signal-to-noise ratios make data processing difficult. Technical Area 1 requires performers to overcome these challenges to create a best-in-class approach that will be used by the STOMP program starting in Month 9, and that will be disseminated to the broader scientific community to benefit MNP research.

Given the aggressive timeline, methodology for research-grade MNP quantification developed under TA1.1 will likely extend and enhance existing instrumentation and sample preparation methodology. It is expected that teams will already have completed significant work on this capability at time of proposal submission, but may need to improve, standardize, and document workflow. Pyrolysis gas chromatography mass spectrometry (Py-GC-MS), Stimulated Raman Spectroscopy (SRS) or flow cytometry (with correspondingly high-performance labeling strategy) may be proposed, with strategies to ameliorate current challenges. Other methods will be considered with justification15.

Techniques must quantify, at the minimum, mass and chemical composition, or number of particles and chemical composition. Proposers must describe measures taken to avoid interference and contamination from environmental MNPs.

TA1 performers may be asked to provide measurement services to TA2 and TA3 groups, and/or assist them in deploying the best-in-class methodology with their own instruments.

The exact number of samples to be processed for other performers, or extent of help to be

15 Zhao, Jian, et al. "Detection and characterization of microplastics and nanoplastics in biological samples." Nature Reviews Bioengineering (2025): 1-15.

provided to other teams, along with associated costs, will be finalized in the negotiations prior to award (See General Program Requirements).

TA1.1: Best-in-Class Quantification Method

Phase 1: Months 1-30

Month 1 Establish preliminary methodology

• Protocol to minimize MNP contamination established and validated.

Controls show <10% of measured MNP signal relative to lowest experimental dose in three independent replicates

Month 3

Demonstrate initial setup:

• Water-based samples

• Intra-assay Coefficient of Variation (CV) <25% across ten replicates

• Quantify mass or number of particles 500 nm – 1 µm

• Identify chemical composition of four - six different polymer types

• Characterize limit of detection/quantification

Month 9

Demonstrate best-in class method:

• Sample preparation methods for blood and tissue, including quantification of purification efficiency

• Intra-assay Coefficient of Variation < 10% across ten replicates

• Quantify mass or number of particles 100 nm – 1 µm

• Identify chemical composition of eight - ten different polymer types

• Characterize limit of detection/quantification

• Dissemination of full documentation to all STOMP teams

Month 12 Submit best-in-class method for publication

Month 12-

TA1 performers will use the best-in-class method to analyze samples from TA2 performers as needed and update the methodology if further optimization becomes possible.

Phase 2: Months 30-60

Month 30-

TA1 performers will use the best-in-class method to analyze samples from TA3 performers as needed and update the methodology if further optimization becomes possible.

Figure 3: TA1.1 metrics

2.1.2 Technical Area 1.2: Clinical Quantification Method

Existing MNP measurement methods are currently intended for research, not for clinical use. The goal of TA1.2 is to develop a measurement system capable of rapidly and cheaply quantifying MNPs in relevant human tissue at scale. This clinical system complements STOMP’s goal of clinically removing MNPs from the human body; in the future, if patients undergo the removal treatment, their MNP levels will need to be measured before and after.

The final clinical assay must take less than 15 min/sample (not including sample prep), and cost less than $50/sample. It must measure, at minimum, total particle count and chemical composition, or mass and chemical composition of relevant 200 nm – 1 µm MNPs in biological samples. The system, including the data analysis, must be designed to be operated by technicians with minimal advanced training required.

It is anticipated that to meet STOMP requirements for the clinical system, significant instrumentation and/or methods development and innovation will be required. The development of the clinical system will constitute the majority of TA1 activity after the first year.

TA1.2: Clinical Quantification Method

Phase 1: Months 1-30

Month 6 Establish requirements for clinical system

Month 12 First prototype system:

• Simple biological media such as saliva, or biomimetic analogue

• Intra-assay coefficient of variation (CV) ≤ 30% across ten replicates

• Particle count and/or mass error ± 30%

• Detects particles from 500 nm – 1 µm

• Identify chemical composition of at least three MNP types

• 3 hr/sample

Month 24 Second prototype system:

• Biological fluid, including blood or tissue sample

• Intra-assay CV ≤ 25% across ten replicates

• Particle count and/or mass error ± 25%

• Detects particles from 200 nm – 1 µm

• Identify chemical composition of at least five MNP types

• 1 hr/sample

Determine FDA regulatory pathway

Month 30 Initiate FDA pre-submission process

Phase 2: Months 30-60

Month 48 Clinical system:

• Biological fluid (including blood) or tissue sample

• Intra-assay CV ≤ 10% across ten replicates

• Particle count and/or mass error ± 10%

• Detects particles from 200 nm – 1 µm

• Characterization of particle size distribution and detection down to 50 µm is desired but not required.

• Identify chemical composition of at least seven MNP types

• 15 min/sample

Month 60 Validate in 100 relevant human samples

Premarket submission to FDA

Figure 4: TA1.2 metrics; Note that not all milestones may apply to all measurement methods; depending on the method selected, adaptation of these milestones may occur in the award negotiation process.

2.1.3 Technical Area 1.3: Biofluids and Tissue Correlation Study The main purpose of TA1.3 is to clinically validate the correlation (if any) between non-invasively collected bodily fluids and tissue MNP levels. This relationship will inform the final implementation of the clinical system developed under TA1.2. If biofluid MNP levels can be used as a proxy for tissue levels, TA1.2 devices will likely use biofluid samples. If biofluid MNP levels do not correlate well to tissue levels, TA1.2 assays will have to focus on relevant, and accessible, tissues.

Performers must enroll at least 100 subjects (or provide power analysis and justification for proposed sample size) in the study and collect two bodily fluids (urine, blood, etc.) and one type of tissue (surgical, biopsy, etc.), at the minimum. At least 3 geographically distinct clinical sites are desired, as well as a broad distribution of participant demographics, professional occupations, and other attributes, to reflect the variety in MNP exposure types and levels. Proposals may include other approaches to address heterogeneity in MNP exposure with rationale.

ARPA-H does not mandate a specific study design or tissue type; one possible choice is colon biopsies. Colonoscopies are commonly performed outpatient procedures, and the recently suggested correlation between MNP presence and the increasing rate of colon cancers16 make colon biopsies a meaningful target. Regardless of tissue type proposed, the applicability to the clinical system should be considered and justified, addressing whether it would be practical to take a similar sample to measure MNP levels in patients.

16 Djouina M, et al, Ingestion of a human-relevant mixture of environmentally sourced microplastics promotes inflammation and tumorigenesis in the mouse colon. Environ Pollut. 2026 Feb 9;395:127794. doi: 10.1016/j.envpol.2026.127794. Epub ahead of print.

PMID: 41672396.

Including means to decrease blood MNP levels (e.g., through apheresis) in the study design may also be considered.

TA1.3: Biofluids and Tissue Correlation study

Phase 1: Months 1-30

3 IRB submission

9 Initiate clinical study using TA1.1 best-in-class quantification methods

24 Complete clinical study with MNP quantification from two or more bodily fluids (blood, urine, etc.) and tissue from 100 subjects

Phase 2: Months 30-60

TA1.3 has no further activities in Phase 2.

Figure 5: TA1.3 metrics

2.2 Technical Area 2: Understanding

Today, understanding of the mechanisms through which MNPs are taken up, and either excreted, eliminated or stored is sorely lacking. While it is currently generally understood that MNPs larger than 1 µm get excreted, smaller particles tend to accumulate in the human body, particularly in fat-rich regions including the brain, the testes, plaques, etc. An understanding of this accumulation process, its contributors, and the health impacts (TA2) will lead to better specifications and solutions for MNP removal (TA3).

TA2 will first address health effects at the whole-body level to understand systemic-level changes when animals are exposed to different MNPs, then impacts at the organ system level, and lastly effects at the level of individual cells.

Figure 6: TA2 activities should focus broadly on establishing bioaccumulation and adverse health effects across the whole organism, then assessing impacts at the organ system level, and finally determining impacts to individual cells.

Cumulatively, TA2 performers will address the “who, what, where, when, why and how” of MNP adverse health effects:

Who: Which MNP polymer types, sizes, and morphologies bioaccumulate and yield systemic negative health impacts?

What: What harm(s) do MNPs cause across scale: whole body, organ systems, and individual cells?

Where: Where do MNPs bioaccumulate in the body? What organ systems? Which cell types?

When: Are there different types or degrees of harm depending on acute or chronic exposures? On what timescale are MNPs naturally excreted and are there innate clearance pathways that could be leveraged for TA3 solutions?

Why: Why are MNPs harmful to cells and organ systems? Which cellular and organ system processes do they disrupt?

How: How do MNPs reach their organ and cellular targets? Are there specific pathways that we might reverse for MNP removal or prevention of accumulation?

TA2 has two separate components and proposers must address both:

TA2.1: Define whole body and organ system bioaccumulation and health impacts of MNPs. TA2.1 will complete both acute and chronic exposure studies in small animals to understand the health impact of MNPs, outlining at the whole body and organ level the:

Who - Which MNPs accumulate across organ systems in the body and induce disease-relevant phenotypes (polymer types, sizes and morphologies)?

What - What harms do MNPs cause at the whole organism and organ level?

Where - To which organ systems do MNPs traffic? Do levels of MNPs in the blood correspond to organ levels of MNPs?

When - Are harmful effects distinct depending on acute or chronic exposures? What is the half-life of MNPs in the body?

TA2.2: Establish the mechanistic framework for MNP trafficking and toxicity at the cellular and subcellular level. TA2.2 will complete studies at the cellular and molecular level to understand in depth how negative health affects manifest and potential cellular processes to leverage for TA3 solutions, specifically answering:

What - What toxic effects do MNPs cause at the cellular level?

Where - Which cell types are specifically affected by MNPs?

When - On what timescale are MNPs naturally degraded or cleared, and do innate clearance pathways exist that can be leveraged for TA3 solutions?

Why - Why are MNPs harmful to cells? Which pathways are disrupted when exposed to MNPs?

How - How do MNPs reach their organ and cellular targets? Are there pathways that we might reverse for TA3 solutions?

To establish a common baseline, solutions for TA2 must utilize, at the minimum, samples of MNPs with known composition and size distribution provided by ARPA-H to performers.

Proposers may choose to include alternative MNP varieties beyond these common reference materials; the type and manner of generating or sourcing alternative MNPs must be described in the proposal.

Figure 7: Notional schedule for TA2 activities. Deviation from this schedule must be described and justified in the proposals. TA2 activities end after Month 36.

2.2.1 Technical Area 2.1: Bioaccumulation and health impacts

To best prioritize MNP removal—which MNPs, and from which organ systems— we need a better understanding of how MNP size, shape, chemical composition, and intake route (inhalation vs ingestion) affect their accumulation throughout the body. Unfortunately, no general approaches currently exist to provide this information. TA2.1 entails a comprehensive study, identifying sites of bioaccumulation for the most relevant plastic types, at relevant doses, with relevant geometries and a characterization of adverse health effects. The results of this study will inform TA2.2 mechanistic studies and TA3 removal strategies (See General Program Requirements on Data Sharing).

Animal models must be exposed to relevant types of MNPs (with relevant geometries) through ingestion and inhalation and evaluated for MNP biodistribution using whole body imaging approaches. Proposers may elect to use different labeling and/or imaging techniques for different MNPs. Justification for proposed labeling and imaging techniques must be provided, along with applicability to longitudinal imaging of live animals, special resolution, and the potential for multiplexing to track more than one MNP type

TA2 activities 3 6 9 12 15 18 21 24 27 30 33 36

TA2.2: Mechanistic framework for MNP trafficking and toxicity

Define MNP internalization and toxicity mechanism in vitro

TA2.1:

Bioaccumulation and health impacts

Acute exposure studies for all MNPs

Chronic exposure studies for all MNPs

Validate MNP internalization and toxicity mechanism in vivo

Method dev. and validation

Complete system- and organ-level measures of adverse health impacts

Year 1 Year 2 Year 3 Years 4-5 simultaneously. Novel methods must be supported by preliminary data justifying viability—particularly for MNPs smaller than 1µm. For positron emission tomography (PET)-based imaging, long-lived radioisotopes must be prioritized.

To address key system and organ-level questions, performers must:

1. Assess accumulation of MNPs across organ systems and across provided polymer types, sizes and morphologies at both acute and chronic exposures.

2. Assess system- and organ-level metrics of harm after MNP exposure by investigating:

a. Systemic changes to body weight, temperature, behavior, etc.

b. Functional, structural, and molecular damage to specific organs (i.e., histological changes, serum enzymes, inflammation, organ weights, molecular markers)

3. Assess levels of MNPs in the blood and a minimum of three impacted organ systems to determine whether blood MNP levels correspond to organ levels.

4. Define the half-life of MNPs in the body following chronic exposure

As described in Section 2.5, ARPA-H will provide reference materials for common types of MNPs. Performers will have to develop their own labeling methodology; if the method cannot be applied to existing samples, performers will have to generate common MNPs similar to those provided by ARPA-H.

Proposers shall describe and justify methods to assess and minimize MNP contamination arising from the laboratory environment (e.g. PPE, water sources, and research equipment).

TA2.1: Bioaccumulation and health impacts

Phase 1: Months 1-30

Month 1 Establish preliminary methodology

• Protocol to minimize MNP contamination established and validated.

Controls show <10% of measured MNP signal relative to lowest experimental dose in three independent replicates

Month 3 Labeling and imaging technique demonstrated and characterized for initial set of MNPs

Exposure concentrations verified within 20% of target dose range

Chronic and acute exposure imaging studies initiated

Month 6 Acute exposure imaging study characterizing differential effects of initial set of MNPs’ tissue distribution in animal model

Labeling and imaging technique demonstrated and characterized for second set of MNPs

Month 9 Acute exposure imaging study characterizing differential effects of second set of MNPs’ tissue distribution in animal model

Labeling and imaging technique demonstrated and characterized for third set of MNPs

Month 12 Acute exposure imaging study characterizing differential effects of third set of MNPs’ tissue distribution in animal model

Month 24 Chronic exposure imaging studies completed for all six MNPs

Month 30 Assess system- and organ-level metrics of toxicity and harm by investigating:

• Systemic changes to body weight, temperature, behavior, etc.

• Functional, structural, and molecular damage to specific organs (i.e., histological changes, serum enzymes, inflammation, organ weights, molecular markers)

Define the half-life of MNPs over at least five time points in blood across a >6-month time-course and at least three tissue types based on organ distribution, as well as the organ-to-blood ratio.

Phase 2: Months 30-60

TA2.1 has no further activities in Phase 2

Figure 8: TA2.1 metrics

2.2.2 Technical Area 2.2: Establish Mechanistic Framework for MNP Toxicity A growing body of evidence demonstrates that MNPs accumulate in the body, interfere with bodily systems and correlate with disease states. However, we still do not have a clear understanding of when and how accumulation of MNPs becomes a toxic disease state requiring intervention. Lack of biologically relevant MNP standards, difficulties with quantitative measurements, and heterogeneity in research methods present barriers to consensus. Interdisciplinary research has also been lacking, as cell biology findings from ecology and toxicology researchers focused on marine systems have not been applied to human health.

To address the current gaps in understanding that hinder the ability to develop methods to remove or degrade MNPs from the human body, proposers must assess health impacts of acute and chronic exposure to various MNP types across biological scale – beginning with whole organism responses, zooming in on organ systems, and finally addressing cell type-specific impacts. Performers must:

1. Determine the cellular pathways impacted by prioritized MNPs identified in TA2.1 and mechanisms of toxicity (oxidative stress, inflammation, protein dyshomeostasis, etc.)

2. Determine which cell types and organelles are affected by MNPs

3. Identify innate mechanisms for MNP removal and degradation.

4. Investigate and define trafficking and accumulation mechanisms to key organ systems for prioritized MNP types identified in TA2.1 (endocytosis, M cell uptake, etc.)

5. Define the half-life of prioritized MNPs

Solutions may leverage technology developed in TA1 and advances in gold-standard absorption, distribution, metabolism, and excretion (ADME) methods, high resolution imaging and labeling of MNPs (e.g., stable and radioisotope labeling, near-IR dyes, pH-sensitive dyes, etc.), and multi-omic techniques, as well as advances in high-throughput model systems for human biology (organoids, 3D cell culture systems, etc.) and computational techniques. Proposers should validate in vitro results in a small animal model.

Proposals must include rationale for in vitro (cell lines, organoid models, etc.) and in vivo models used for cellular trafficking, internalization and toxicity studies.

Proposers shall define their methods for down-selecting critical organ systems for TA2.2 mechanistic studies based on TA2.1 results (See General Program Requirements on Data Sharing). Proposers may pre-define quantitative metrics for prioritization based on organ function (i.e., >10% reduction in kidney function) or methods to establish a ranking system (e.g. ranking by toxicity/accumulation, approaches that balance both systems that are highly susceptible and those highly resistant to health effects, etc.).

Proposers must apply three biologically relevant doses of the top three prioritized polymer compositions based on TA2.1 studies for in vivo studies. Proposers must describe and justify exposure routes (inhalation or ingestion), including verification of exposure concentration, homogeneity of exposure, and biological relevance of exposure route (presence of polymer type in airborne particles versus food and water sources). Proposers must measure both acute and long-term exposure to adequately assess toxicity as appropriate based on model system.

TA2.2: Establish mechanistic framework for MNP toxicity

Phase 1: Months 1-30

Months 3-12

Define MNP trafficking and accumulation mechanism hypothesis for prioritized MNP types identified in TA2.1

• Validated translocation assays established for models of three or more prioritized organ systems (proposer shall define metrics for prioritization or methods for establishing a ranking system based on TA2.1 results)

• One or more translocation mechanism identified for three MNP types in three organ-relevant boundary models (i.e., blood-brain barrier, gut epithelium, placenta, etc.) confirmed via two independent methods (e.g.

inhibition of and/or activation of pathways)

Months 6-18

Identify impacted cell types and organelles for internalized MNPs, cellular pathways implicated in MNP toxicity, and innate mechanisms for MNP removal and degradation using in vitro models,

• One or more differentially affected cell type identified per organ system (p<0.05) for three polymer types using at least six doses

• Three or more key mechanisms of toxicity (e.g. oxidative stress, inflammation, protein dyshomeostasis, etc.) identified for hypothesis testing based on results across organ systems (multi-omics, high resolution imaging, etc.)

• Mechanisms of toxicity validated and quantified using two independent assay methods

• Dose-response relationship established for three MNP types in three or more cell types

• Intracellular versus extracellular MNP fraction quantified and organelle localization identified using two independent methods (e.g. high-resolution imaging, flow cytometry, etc.) in three or more cell types at a biologically relevant dose

• Define the half-life of three polymer types over at least 5 time-points in three or more models for different organ systems/cellular environments

• Identify one or more innate degradation mechanisms (if present) for three MNP types in three models of organ systems

Months 19-24

Validate MNP trafficking and toxicity mechanisms in vivo with at least one biologically relevant route of exposure (inhalation or ingestion). Further down-select polymer characteristics to prioritize for TA3 (dose, composition, morphology, size)

• Validate primary translocation route for at least one polymer type.

Modulation of translocation mechanism significantly reduces target organ accumulation

• Validate differentially affected cell types for at least two organ systems for at least one polymer type with at least three biologically relevant doses

• Validate toxicity mechanisms in vivo for at least one prioritized polymer type at three biologically relevant doses over three timepoints (acute, medium and long-term exposure)

• Deliver initial results for TA3 proposer teams informing MNP removal strategies (24 months)

Months 19-30

• Validate innate mechanisms for prioritized polymer type removal and degradation in vivo

Phase 2: Months 30-60

Months 31-36

Complete toxicity and translocation studies outlined in Phase 1 for all three prioritized polymer types. Replicate results with variation across independent experiments of <20%.

Validate hypotheses and refine methods in conjunction with TA3 teams to inform therapeutic strategies and testing (See General Program Requirements on Data Sharing)

• Outline standard operating procedures for core assays for TA3 performer teams

Months 36-60 No further TA2.2 activities occur from months 36-60.

Figure 9: TA2.2 metrics

2.3 Technical Area 3: Removal

ARPA-H is not currently accepting proposals for TA3. TA3 proposals submitted alongside TA1 and TA2 will not be reviewed. A Special Notice and amended ISO will be released upon completion of initial TA1 and TA2 Phase 1 studies.

To our knowledge, the only existing technique to remove MNPs from the human body is based on apheresis, a dialysis-like technique that separates and filters blood outside the body. This type of treatment is not FDA-approved, and insufficient evidence has been offered to support its efficacy17. It is unclear if these treatments reduce levels of MNP in blood —and even if they do, it is unclear if this translates to reduced levels in organs.

Furthermore, these treatments are expensive, invasive and time-consuming.

The development and clinical translation of MNP removal methods have been limited by a lack of measurement methods to characterize the MNP burden and validate removal, and a lack of mechanistic understanding of how these MNPs transit, localize, and cause harm in the human body. By leveraging well-characterized, biologically relevant reference materials, TA1 detection technologies, and TA2 knowledge of MNP trafficking and bioaccumulation (See General Program Requirements on Data Sharing), TA3 performers will develop technologies to minimize accumulation, remove and/or degrade MNPs from living human patients in a clinically impactful fashion: fast, cheaply and safely.

17 E.g., Bornstein et. al. 2025 and Scholkmann & Gatti 2022 https://doi.org/10.61373/bm025l.0056 https://doi.org/10.3390/compounds2040030

Environmental bioremediation research and understanding of MNP degradation and clearance in other species provide possible avenues for translation to human therapeutics. Multiple bacteria and fungus species are innately capable of degrading plastics in the environment, with some species able to degrade large-scale quantities of plastics on the order of weeks to months18. Several researchers focused on bioremediation have demonstrated the ability to engineer microorganisms to degrade MNPs and hydrolyze polymers into neutral degradation products safe for aquatic ecosystems19. While such techniques have not been validated in living systems, MNP degradation and clearance occurring in other species in vivo suggest potential pathways that could be leveraged and translated to human biology. For example, waxworms are capable of digesting large quantities of MNPs, demonstrated to occur via initial degradation via enzymes in the saliva20, followed by further breakdown by bacteria in the gut21. Mice treated with bacterial strains demonstrating a high degree of binding to polystyrene particles exhibited increased excretion of particles, demonstrating increased clearance in a vertebrate system22.

TA3 solutions may: 1) degrade MNPs into non-toxic byproducts; 2) expel MNPs from cells and tissues for excretion by reversing internalization and trafficking pathways; or 3) prevent MNPs from invading tissues in the first place.

Solutions may include in vivo delivery of clearance agents to intended anatomical locations. Biomimicry could serve as the guide by adapting existing organismal capabilities to break down plastics in the human body, or it may be possible to use genetically engineered enzyme-secreting bacteria in a controlled fashion. Beyond this, novel drugs that promote the removal of MNPs (analogous to chelation) or use the body’s own immune system may be viable.

TA3 metrics below are notional and will be revised when soliciting for TA3 proposals.

TA3: Removing MNPs from the Body

Phase 2: Months 30-60

18 Gao R, et al. A marine fungus Alternaria alternata FB1 efficiently degrades polyethylene. J Hazardous Materials. 2022 June 431:

128617. doi: 10.1016/j.jhazmat.2022.128617.

19 Tian J, et al. Discovery and remodeling of Vibrio natriegens as a microbial platform for efficient formic acid biorefinery. Nat Commun.

2023 Nov 27;14(1):7758. doi: 10.1038/s41467-023-43631-2. PMID: 38012202; PMCID: PMC10682008.

20 Sanluis-Verdes, A., et al. Wax worm saliva and the enzymes therein are the key to polyethylene degradation by Galleria mellonella. Nat Commun. 2022; 13(1): 5568.

21 Ali SS, et al. Biodegradability of polyethylene by efficient bacteria from the guts of plastic-eating waxworms and investigation of its degradation mechanism. J Hazard Mater. 2023 Feb 5;443(Pt B):130287. doi: 10.1016/j.jhazmat.2022.130287. Epub 2022 Oct 31. PMID:

36335905.

22 Teng X et al. Novel probiotics adsorbing and excreting microplastics in vivo show potential gut health benefits. Front. Microbiol. 2025;

15:1522794. doi: 10.3389/fmicb.2024.1522794

Months 30-

Demonstrate proof of concept (e.g. MNP digestion) with 50% efficacy for one polymer type in vitro (cell lines, organoid models, etc.)

Months 36-

Refine MNP removal candidate and demonstrate 50% efficacy for removal, degradation or prevention of uptake to key organ systems of one polymer type in vivo

Demonstrate 50% efficacy for two additional polymer types in vitro

Initiate safety screening studies

Determine the regulatory pathway

Months 48-

Refine MNP removal candidate and demonstrate 80% efficacy for removal, degradation or prevention of uptake to key organ systems of one polymer type in vivo

Demonstrate 50% efficacy for two additional polymer types in vivo

Figure 10: Notional TA3 metrics

2.4 Independent Verification and Validation

Qualified US Government personnel will serve as advisers to ARPA-H during Phase 1 of the STOMP program (months 1-30). They will be part of program review meetings and provide independent verification and validation of the measurement methods developed by TA1 performers.

2.5 Microplastics Samples

ARPA-H is aware that no reference standards currently exist for MNPs. ARPA-H will arrange to provide awardees with relevant MNP materials; these will have various shapes, with sizes including sub-micron.

Throughout the program, STOMP performers should expect to receive annual supplies of at least six MNP polymer types, tentatively polyethylene (PE), polyethylene…