This chapter provides a comprehensive analysis of the dynamic relationship between cells and their external material context, emphasizing the implications of sustainable practices in biomedical engineering. It starts with an examination of the crucial components of cellular interactions with the extracellular matrix (ECM). This includes adhesion sites, integrins, cadherins, and mechano-transduction in guiding cellular activities like adhesion, spreading, polarization, and migration. The chapter elucidates the reciprocal signalling pathways that enable communication between cells and their extracellular milieu. A notable emphasis is placed on the influence of synthetic materials on these cellular interactions, specifically how surface chemistry, including hydrophobicity, hydrophilicity, and ligand spacing, affects cellular behaviour. The discourse further investigates the significance of surface topography, particularly the implications of nanostructures on cellular guidance and the differentiation of stem cells. The mechanics of materials are analysed concerning the replication of tissue stiffness in vitro, investigating how matrix rigidity impacts cell signalling, receptor interactions, and stem cell differentiation. The chapter also encompasses various cellular activities reliant on interactions with the environment, such as survival, proliferation, differentiation, and protein synthesis. In conclusion, the chapter addresses the immune response elicited by implanted biomaterials, examining acute inflammation, macrophage activity, foreign body responses, and the development of a fibrotic capsule. Through a detailed analysis, the chapter emphasizes the critical importance of comprehending cell-material interactions to promote the advancement of sustainable and biocompatible materials in biomedical engineering.