Mesenchymal stromal cells (MSCs) possess potent immunomodulatory, pro-angiogenic, and regenerative capacities, offering broad clinical promise in regenerative medicine. However, clinical application is constrained by low in vivo survival, poor targeting, variable efficacy, replicative senescence and insufficiently characterized in vivo cell fate. The accelerating global aging trend further complicates MSC therapy for age-associated diseases. Biomaterials have emerged as powerful tools to enhance MSC function and direct cell fate. This review adopts a materiobiology perspective to detail how biomaterial design—across physical (stiffness, topography), chemical (surface chemistry, ion release), and biological (growth factor release, gene delivery) parameters, can proactively steer MSC fate and function to amplify therapeutic efficacy. Subsequently, focusing on the characteristics of aging-related diseases from three perspectives—reactive oxygen species scavenging, epigenetic regulation, and telomere protection—this review summarizes the anti-aging functional design of biomaterials. To bridge biomaterial-driven MSC regulation with in vivo therapeutic outcomes, we systematically review post-transplant fate-tracking technologies, including imaging-based approaches (MRI, CT, fluorescent probes) and transcriptomic monitoring, which enable quantitative evaluation and causal understanding of MSC survival, biodistribution, functional states, and aging trajectories in vivo. Building on these methodological foundations, we summarize engineering solutions for MSC-biomaterial combination therapies in representative aging-related diseases, such as fibrosis, osteoarthritis, heart failure, and wound healing. Importantly, in vivo outcomes can in turn guide subsequent biomaterial design. Finally, we discuss policy and technical hurdles, current limitations, and future directions—including mitochondrial homeostasis control, microfluidics-based dynamic culture, and machine learning for structure-function prediction—to inform next-generation, intelligent MSC-biomaterial combination therapies. Materiobiology-Guided Regulation of Mesenchymal Stromal Cell (MSC) Fate This schematic summarizes a materiobiology-guided framework in which rational biomaterial design regulates MSC fate and therapeutic function. Basic material parameters-including stiffness, topography, surface chemistry, ion release, and bioactive factor or gene delivery-govern MSC sensing, adhesion, and early fate commitment. These foundational designs further enable anti-aging functionalization strategies, such as reactive oxygen species (ROS) scavenging, epigenetic regulation, and telomere protection, to restore or maintain MSC functionality in aged microenvironments. In vivo position tracking and cell fate tracking serve as a functional validation layer, providing critical insight into MSC biodistribution, persistence, and therapeutic outcomes. Biomaterial-modulated MSCs are subsequently applied to the treatment of aging-related diseases, including fibrosis, osteoarthritis, heart failure, and impaired wound healing, thereby forming a feedback loop that guides next-generation biomaterial design. • Parameter-to-function framing of physics, chemistry, biomolecules. • Multimodal imaging-MRI/CT/fluorescence plus transcriptomics to map in vivo MSC fates. • Aging diseases integrate Fibrosis, HF, OA, Wounds into a clinical engineering loop. • Roadmap: mitochondrial tuning, microfluidic cell culture, machine learning-based inversion.
Feng et al. (Thu,) studied this question.