FLASH radiotherapy utilizing ultra-high dose rate has the potential of being a substantial evolutionary advancement for cancer treatment. Ultra-high dose rate radiation provides a benefit of decreased normal tissue toxicities while maintaining equivalent tumor killing effect. Among different modalities, particle therapy has been an active area of research to integrate its unique characteristics with the FLASH effect because proton therapy remains the only clinically assessable modality that can potentially treat deep seated tumors under FLASH conditions. Thus, developing methods to enable FLASH proton therapy with clinically available accelerators is an important step to both unravel the biological mechanism using preclinical studies, clinical trials as well as explore the physical hardware requirements for clinical implementation. In FLASH proton therapy, beam modulation devices are important accessories for enabling ultra-fast dose delivery based on the clinically available cyclotrons and synchrocyclotron systems. These work by transforming an ultra-high dose rate mono-energetic proton pencil to a multi-energy spot after passing through varying thicknesses of modulating material. In this way, a multi-energy layer pencil beam scanning proton plan can be delivered completely in less than a second without the need for beam pausing for energy switching. The most common modulator is the ridge filter, which consists of uniform density spikes of varying height. The limitation of this design includes restricted structure stability and modulation flexibility. We propose to develop a new class of heterogeneous density range modulators based on the novel PixelPrint technology, to facilitate FLASH therapy. By continuously varying the ratio of filament to air, PixelPrint technology is capable of 3D printing phantoms with voxel-wise heterogeneous density. By utilizing material density as an optimization parameter, the new devices will have robust structure and high flexibility in modulation. The hypothesis is that the 3D printed heterogeneous density modulator degrades the beam energy across the transverse plane of the particle beam, based on both local material density and the stopping power distribution of the material. With greater flexibility compared to current binary modulation only design, complex modulation is achievable for application in universal range modulator and patient-specific modulators. Our deliverables will include design methods to optimize density structures for range modulation, and experimentally validated modulators for proton FLASH therapy applications. The specific aims are: Aim 1. Development of density optimization algorithms for range modulation. Aim 2. Experimental validation and characterization of 3D printed heterogeneous range modulators. Aim 3. Development of patient-specific modulators for Proton FLASH therapy. If successful, the approach will enable a new class of range modulators to enable FLASH particle therapy with fl...