Differential aperture modulation enables high-fidelity 3D photoacoustic imaging.

High-fidelity volumetric imaging of vascular structures at depth remains challenging for practical biomedical imaging systems, where performance is fundamentally constrained by limited detection aperture and insufficient spatial sampling. Photoacoustic imaging provides label-free vascular contrast at clinically relevant depths, yet achieving high-quality three-dimensional (3D) imaging typically requires complex and customized transducer geometries, limiting accessibility and translational potential. Here, we introduce differential aperture modulation photoacoustic computed tomography (DAM-PACT), a volumetric imaging framework that enhances 3D photoacoustic imaging fidelity using standard linear-array transducers. By synthesizing complementary receive apertures through differential modulation, DAM-PACT increases effective apertures and improves recovery of elevational spatial information, enabling large field-of-view imaging with improved resolution uniformity. Simulations and phantom experiments demonstrate up to four-fold improvement in the elevational resolution without hardware modifications, approaching near-isotropic resolution. In vivo imaging of human arm and palm further shows sharper vascular delineation and improved vessel visibility compared to conventional delay-and-sum reconstruction. By leveraging intrinsic acoustic information in linear-array acquisitions, DAM-PACT provides a practical and scalable strategy for high-fidelity volumetric photoacoustic imaging, with potential for broad adoption in preclinical and clinical settings.