Developing superporous hemostatic sponges with simultaneously enhanced permeability and mechanical properties remains challenging but highly desirable to achieve rapid hemostasis for non-compressible hemorrhage. Typical approaches to improve the permeability of hemostatic sponges by increasing porosity sacrifice mechanical properties and yield limited pore interconnectivity, thereby undermining the hemostatic efficacy and subsequent tissue regeneration. Herein, we propose a temperature-assisted secondary network compaction strategy following the phase separation-induced primary compaction to fabricate the superporous chitosan sponge with highly-interconnected porous structure, enhanced blood absorption rate and capacity, and fatigue resistance. The superporous chitosan sponge exhibits rapid shape recovery after absorbing blood and maintains sufficient pressure on wounds to build a robust physical barrier to greatly improve hemostatic efficiency. Furthermore, the superporous chitosan sponge outperforms commercial gauze, gelatin sponges, and chitosan powder by enhancing hemostatic efficiency, cell infiltration, vascular regeneration, and in-situ tissue regeneration in non-compressible organ injury models, respectively. We believe the proposed secondary network compaction strategy provides a simple yet effective method to fabricate superporous hemostatic sponges for diverse clinical applications.

Mesenchymal condensation, characterized by rapid proliferation and aggregation of precursor cells within a restructured mesodermal extracellular matrix, is critical for skeletal tissue development, including articular cartilage. This process establishes a hypoxic microenvironment that drives metabolic shifts and epigenetic modifications essential for cartilage development. To replicate this, we engineer a cell-adaptable supramolecular hydrogel that accommodates the extensive volumetric and morphological changes of encapsulated mesenchymal stromal cells, facilitating the rapid formation of large multicellular cartilaginous organoids. This adaptation fosters a hypoxic environment and induces metabolic shifts toward glycolysis, increasing lactate accumulation and histone lysine lactylation. Enhanced lactylation on Lysine 18 of Histone H3 promotes chondrogenesis and cartilage matrix deposition by improving the accessibility of chondrogenic genes, while the inhibition of histone lactylation disrupts these processes. Implantation of the ultradynamic hydrogel in large animal cartilage defects results in superior repair compared to less dynamic alternatives, providing insights for effective biomaterial delivery in cell therapies. Our findings reveal how matrix biophysical cues influence cellular development, metabolic reprogramming, and epigenetic modifications.

The native extracellular matrix is continuously remodeled to form complex interconnected network structures that reversibly regulate stem cell behaviors. Both regulation and understanding of its intricate dynamicity can help to modulate numerous cell behaviors. However, neither of these has yet been achieved due to the lack of designing and modeling such complex structures with dynamic controllability. Here we report modularity-based mathematical modeling of extracellular matrix-emulating ligand inter-cluster connectivity using the graph theory. Increasing anisotropy of magnetic nano-blockers proportionately disconnects arginine-glycine-aspartic acid ligand-to-ligand interconnections and decreases the number of ligand inter-cluster edges. This phenomenon deactivates stem cells, which can be partly activated by linearizing the nano-blockers. Remote cyclic elevation of high-anisotropy nano-blockers flexibly generates nano-gaps under the nano-blockers and augments the number of ligand inter-cluster edges. Subsequently, integrin-presenting stem cell infiltration is stimulated, which reversibly intensifies focal adhesion and mechanotransduction-driven differentiation both in vitro and in vivo. Designing and systemically modeling extracellular matrix-mimetic geometries opens avenues for unraveling dynamic cell-material interactions for tissue regeneration.