Biophysical Regulation of Macrophages Through Engineered Material Platforms

About This Grant

PROJECT ABSTRACT/SUMMARY Macrophages, vital regulators of inflammation and tissue repair, are profoundly influenced by mechanical cues in their microenvironments, such as stiffness, spatial architecture, and dynamic forces. These cues are disrupted in aging, injury, and diseases like fibrosis and cancer, driving maladaptive immune responses. While stiffness has been studied, the independent roles of geometry, viscoelasticity, and intracellular force in shaping macrophage states remain unexplored. Current models oversimplify these dynamics and fail to capture the translational complexity of living tissues. To close this gap, we will develop and apply dynamic, cell-instructive biomaterials that emulate native mechanics while benchmarking their outputs against macrophage states from in vivo injury and fibrotic datasets. Our program integrates three innovations: (1) Curvature platforms spanning fibril- to tissue-scale geometries to dissect cytoskeletal partitioning and MRTF-A-driven transcription; (2) Viscoelastic hydrogels under cyclic loading to identify mechanical “tipping points” between regenerative versus fibrotic polarization; and (3) Intracellular nanomaterial actuation to test whether direct cytoskeletal force alone reprograms inflammatory and fibrotic transcription. Predefined success metrics and alternative approaches will ensure rigor and reproducibility. These platforms will serve dual roles: (i) as foundational tools to reveal mechanoimmunology principles, and (ii) as translational blueprints for “mechanotherapies.” For example, curvature-tuned scaffolds may suppress tissue fibrosis, viscoelastic implants may accelerate wound repair, and intracellular force actuators may silence chronic inflammation in arthritis. By merging engineering with immunology and grounding models in physiologic benchmarks, this research establishes macrophages as sentinels of mechanical dysfunction and opens new therapeutic avenues for fibrosis, chronic wounds, and cancer.