General Semi‐Solid Freeze Casting for Uniform Large‐Scale Isotropic Porous Scaffolds: An Application for Extensive Oral Mucosal Reconstruction

Abstract Ice‐templated porous biomaterials possess transformative potential in regenerative medicine; yet, scaling up ice‐templating processes for broader applications—owing to inconsistent pore formation—remains challenging. This study reports an innovative semi‐solid freeze‐casting technique that draws inspiration from semi‐solid metal processing (SSMP) combined with ice cream‐production routines. This versatile approach allows for the large‐scale assembly of various materials, from polymers to inorganic particles, into isotropic 3D scaffolds featuring uniformly equiaxed pores throughout the centimeter scale. Through (cryo‐)electron microscopy, X‐ray tomography, and finite element modeling, the structural evolution of ice grains/pores is elucidated, demonstrating how the method increases the initial ice nucleus density by pre‐fabricating a semi‐frozen slurry, which facilitates a transition from columnar to equiaxed grain structures. For a practical demonstration, as‐prepared scaffolds are integrated into a bilayer tissue patch using biodegradable waterborne polyurethane (WPU) for large‐scale oral mucosal reconstruction in minipigs. Systematic analyses, including histology and RNA sequencing, prove that the patch modulates the healing process toward near‐scarless mucosal remodeling via innate and adaptive immunomodulation and activation of pro‐healing genes converging on matrix synthesis and epithelialization. This study not only advances the field of ice‐templating fabrication but sets a promising precedent for scaffold‐based large‐scale tissue regeneration.