Biophysical‐Inspired Interpenetrated Fibrillar and Reticular Collagen Scaffold with Vascular Endothelial Cell Membrane Incorporation for Guided In Situ Spleen Tissue Regeneration

Abstract The spleen's complex structure and limited regenerative ability hinder its regrowth at the site of injure, affecting patient quality of life and risk severe complications. The spleen's stroma primarily consists of reticular and fibrillar collagen, supporting its microvascular network. Inspired by such biophysical environment, this work develops an inducible scaffold featuring an interpenetrating network structure of fibrous and reticular collagen, which is loaded with vascular endothelial cell membranes to facilitate in situ regeneration. The regenerated parenchyma includes red pulp, white pulp, and a vascular system. The scaffold effectively reduces oxidative stress at the injury site, recruits cells to degrade the scaffold, and promotes tissue integration, thereby accelerating spleen regeneration. Additionally, the regenerated tissue compensates for the spleen's functions, enhancing its ability to clear abnormal red blood cells and platelets. Proteomics and RNA sequencing analyses reveal that the scaffold induced the upregulation of key pathways, including the Wnt signalling pathway, Statin pathway, and amino acid metabolism pathway. This activation mobilizes splenic cells metabolism, enhances immune cell activity, and facilitates the remodeling of the extracellular matrix. Moreover, the incorporated cell membrane components promote splenic blood vessels regeneration by upregulating the neural crest cell differentiation pathway within the tissue.