# Using experimentally-guided multi-scale modeling to determining the mechanism of FLASH tissue sparing

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $710,252

## Abstract

Abstract
FLASH irradiations, irradiations with dose rates >40 Gy/s, have been shown to greatly reduce
radiation damage for normal tissue while not affecting tumor control. This sparing effect was
demonstrated in multiple animal models, mostly using electron FLASH irradiations. The pre-
clinical data generated a strong push to translate FLASH radiation therapy (RT) into the clinic.
Only a few human patients have so far been treated with FLASH-RT. The first patient, a
single cutaneous lymphoma lesion was treated with electron FLASH-RT. Recently, Varian an-
nounced the first clinical trial of proton FLASH-RT (phase 1) and treated the first patients with
symptomatic bone metastases.
Yet many questions remain unanswered. Most significantly, the underlying mechanism of
FLASH induced sparing of healthy tissue still remain elusive. As corollary, the constraints im-
posed on the clinical parameters (e.g. dose, dose rate and time within and between treatment
fields) to induce the FLASH tissue sparing effect are still not determined.
While there are many experimental efforts currently being pursued, my team has worked on
understanding FLASH both from an experimental as well as theoretical point of view. Our ex-
perimental preliminary data show proton FLASH tissue sparing in intestine, brain and skin.
Our theoretical preliminary data include modeling oxygen depletion and simulations of radi-
ochemistry using TOPAS-nBio, a mechanistic Monte Carlo framework developed by our group.
Our central hypothesis is that the FLASH effect is caused by a combination of (stem) cells in
a low-oxygen niche and long-lived (µs to ms) daughter products of chemical reactions involving
oxygen. We propose an interplay between experiments and modeling to determine the under-
lying mechanism of FLASH-RT tissue sparing by employing TOPAS-nBio to investigate the
involved chemical reactions based on their intrinsic time features.
We propose to test the hypothesis and validate the model with the following aims:
SA 1: Investigate the mechanisms of proton FLASH-RT
 1. Conduct multi-scale experiments to guide the modeling efforts.
 2. Model the mechanism and chemical processes at relevant time scales in TOPAS-nBio.
SA 2: Validate the model and determine clinical parameters for FLASH tissue sparing.

## Key facts

- **NIH application ID:** 10519648
- **Project number:** 1R01CA266419-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jan Patrick Oscar Schuemann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $710,252
- **Award type:** 1
- **Project period:** 2022-09-05 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519648

## Citation

> US National Institutes of Health, RePORTER application 10519648, Using experimentally-guided multi-scale modeling to determining the mechanism of FLASH tissue sparing (1R01CA266419-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10519648. Licensed CC0.

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