An Integrated Experimental and Computational Framework for Testing Extracellular Material Memory

This Perspective proposes an integrated experimental and computational framework for investigating extracellular material memory: whether a defined formation or conditioning history leaves persistent material features that influence cells introduced after the original stimulus has been withdrawn. Fibrin serves as an initial demonstrator. The proposed workflow separates encoding, retention, delayed cellular readout, selective material modification, and independent reconstruction of candidate features. It distinguishes extracellular retention from cellular mechanical memory, residual stimuli, and ongoing activity of persistent molecular components. The framework describes two implementation levels. A minimal platform combines controlled matrix preparation, quantitative imaging, mechanical characterization, and a standardized cellular assay. An expanded platform adds automation, multimodal measurements, uncertainty-aware prediction, and active learning to guide experiment and intervention selection. Computational models would be evaluated prospectively against simpler baselines using independently prepared specimens. Within the MMD, TMP, and MME research program, the article connects causal testing of altered microenvironments, investigation of material retention and readout, and controlled modification toward predefined functional targets. Explicit evidence gates distinguish positive findings, adequately supported negative results, and technically inconclusive outcomes. Immediate functional improvement, persistence after intervention withdrawal, and response to a subsequent challenge are assessed separately. Building on established research in fibrin mechanics, cellular mechanical memory, and computational biomaterial discovery, the contribution is an integrated research strategy rather than a claim to have discovered these phenomena. This document is a conceptual Perspective and research roadmap. It reports no new experimental results, validated computational platform, or demonstrated therapeutic efficacy. It does not represent participation or endorsement by any specific laboratory or institution.