Translating Sex- and Disease-Informed Design Criteria from Human Lung into Engineered Biomaterials

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by pathological extracellular matrix (ECM) remodeling, and a pronounced sex disparity, with approximately 70% of cases occurring in males. Despite these differences, biomaterials used to model fibrosis are commonly designed to replicate disease state or stiffness alone and rarely account for biological sex. Here, we derived sex- and disease-informed biomaterial design criteria from female and male control and IPF human lungs and translated these criteria into engineered hybrid-hydrogels containing human lung decellularized ECM (dECM) and poly(ethylene glycol) alpha methacrylate (PEG⍺MA). Matrisome-focused reanalysis of our previously published region-resolved human lung proteomic dataset revealed region- and sex-associated differences in fibrillar collagens, matricellular proteins, and structural proteoglycans. Complementary characterization of human lung tissue further identified sex- and disease-associated differences in fibrillar collagen architecture, proteoglycan and glycosaminoglycan (GAG) remodeling, and tissue mechanics. Male IPF lungs exhibited the highest levels of disease-associated stiffening and fibrillar collagen remodeling, while female IPF tissue showed comparatively modest mechanical changes despite biochemical remodeling. These measurements established tissue-informed design criteria spanning matrix composition, architecture, and mechanics. We next evaluated whether tissue-derived properties were reproduced or retained following decellularization, processing, and incorporation of donor-derived dECM into hybrid-hydrogels. Engineered hybrid-hydrogels closely recapitulated sex- and disease-associated mechanical relationships, while COL1A1-associated abundance patterns were more consistently preserved than fibrillar collagen organization. Matricellular proteins and GAG-rich matrix remained detectable, although condition-dependent biochemical fidelity varied. This work establishes a human tissue-informed framework for engineering sex- and disease-specific biomaterials, highlighting the importance of defining sex-associated ECM properties and validating individual features following material fabrication to advance human models of IPF and other diseases with sex-associated differences in susceptibility and progression.