Biological integration of prosthetic materials depends on coupled interactions involving surface chemistry, hydration, electrostatics, molecular adsorption, geometry, and mechanics. Conventional approaches frequently examine these properties independently, limiting their ability to explain biological responses. This study develops a unified thermodynamic theory of prosthesis–biological interfaces by integrating dispersive surface energetics, nonlinear Lewis acid–base interactions, interfacial hydration, charge regulation, curvature-dependent electrostatics, protein adsorption, cellular recognition, nonequilibrium transport, and mechanochemical coupling. Building upon advances in inverse gas chromatography, temperature-dependent molecular surface areas, nonlinear donor–acceptor thermodynamics, and two-dimensional adsorption models, the proposed framework connects molecular interactions with evolving biological organization. A generalized interfacial free-energy functional describes the coupled mechanisms governing molecular recognition, protein conditioning, cellular adhesion, and tissue integration. Dimensionless competition parameters and thermodynamic regime maps identify dominant interaction mechanisms and potentially favorable conditions for biological functionality. Literature-based benchmarking considers representative metallic, ceramic, and polymeric prosthetic materials using surface-energy, electrokinetic, mechanical, and biological descriptors. The analysis reveals limitations of single-parameter correlations and emphasizes environmental conditioning, functional protein organization, and mechanical compatibility. Existing experimental evidence supports the physical relevance of the proposed mechanisms but does not establish complete quantitative validation. The resulting framework provides a mechanistic foundation for multidimensional, tissue-specific prosthesis design. It generates experimentally testable predictions concerning nonlinear molecular recognition, hydration–electrostatic competition, geometry-dependent adsorption, and mechanochemical integration, establishing a systematic pathway toward predictive characterization and rational optimization of dynamically evolving prosthesis–biological interfaces.