Living cells are often described as crowded environments because macromolecules occupy a large volume of the fluid. In these systems non-specific interactions are individually weak but cumulatively strong. One particular type that arises from steric repulsion is excluded volume interactions that can increase the free energy of a solution and the chemical potential of the solutes. The same interactions that play a role in the cellular environment are also important for investigation of the interactions at the biotic-abiotic interface. The properties of proteins were investigated in an artificially crowded environment formed by their entrapment in sol-gels. The influence of surface chemistry on the properties of the entrapped biomolecules and their distribution in the sol-gel matrix was investigated. Data will be presented on how sol-gel matrices functionalized with aliphatic, ionic, and uncharged hydrophilic groups affected the folding properties of proteins in sol-gels. These studies were complimented with small angle scattering and fluorescence techniques to investigate the distribution of the entrapped proteins. These studies are important for enzyme based-diagnostic and biosensing applications.