High-Throughput Interrogation of the Human Hematopoietic Response to Proton Pbs Flash Radiotherapy Using a Bone Marrow-on-a-Chip Platform
Abstract
Purpose
The clinical translation of ultra-high dose rate (FLASH) radiotherapy is hindered by an incomplete understanding of the physical parameter space required to optimize normal tissue sparing. This study utilizes a human bone marrow-on-a-chip (BMoC) platform to map biological response to the unique temporal structures of proton pencil beam scanning (PBS) delivery, which paints dose over time and introduces spatially varying temporal structure to dose deposition.
Methods
A microphysiological BMoC system, which faithfully recapitulates the human marrow’s 3D vascular niche with human-derived hematopoietic stem cells, was used with a FLASH proton PBS system. The BMoC platform consists of a disk array of 205 isolated and independent chiplets which were irradiated at standard (S-PRT) and FLASH (F-PRT) dose rates to 6 and 20 Gy. Spatiotemporal dose distribution and dose rate maps were derived from treatment delivery log files to quantify the varying time structure across BMoC replicates. Vascular integrity was assessed 3.5 days post-irradiation via CD31 immunofluorescence to visualize endothelial networks.
Results
PBS delivery introduced a complex temporal structure to dose deposition due to the profile of individual pencil beams. Preliminary experiments showed sparser microvasculature on S-PRT irradiated tissues. In contrast, tissues irradiated with F-PRT demonstrated highly branched microvascular morphology and lumens. Paired comparisons of vessel volume demonstrated that F-PRT preserved tissue vasculature at levels like unirradiated controls for both 6 and 20 Gy doses, while S-PRT showed a statistically significant reduction in vascular volume.
Conclusion
The BMoC platform successfully recapitulates human marrow toxicity and provides a high-throughput method to interrogate the FLASH effect “phase” space of conformal PBS delivery. These results demonstrate that F-PRT significantly spares the human hematopoietic niche, identifying BMoC as a critical tool for defining the biophysical boundaries of the FLASH effect for future clinical trials with PBS delivered FLASH.