Hydrogels are extensively used in medical applications and they are an important class of biomaterials that are under significant study for regenerative medicine applications. They are cross-linked, three-dimensional, hydrophilic polymer networks that can swell but not dissolve in water. Hydrogels derived from biological macromolecules such as proteins and polysaccharides are of great interest to the biomedical community as they can contain intrinsic biological information or serve as an extracellular matrix mimic. The study of the properties of functional and responsive hydrogels presents a fundamental challenge with important practical applications. What are the molecular factors that determine the structure of the gel? What is the activity of specific ligands within the gel? How do pH sensitive groups respond within the network structure? In order to study these complex systems we are carrying out a combined experimental and theoretical effort aimed at the fundamental understanding of the mechanism of formation and properties of hydrogels formed by mixtures of proteins and polymers. We have developed a novel family of water-soluble poly(diol citrates) that can mediate the formation of a protein gel via complexation. Protein-polymer gels with water content of up to 90% have been fabricated with bovine and human serum albumin, fibrinogen, and hemoglobulin without covalently modifying the protein. The gels can form within 10 minutes, depending on the protein and temperature of the gelation and degrade within 4 to 8 weeks. The overall objectives of this project include the understanding at the fundamental level of the driving forces for the formation of this class of hydrogels, the mechanism of gel formation and the identification of design criteria that would allow the formation of the protein gels for tissue engineering applications. Toward this goal, we are using a combination of theoretical studies and experimental observations to investigate the formation and properties of the gels as well as the feasibility of using these protein gels for controlled release of proteins and cell encapsulation. The results of this research will lead to a new paradigm on the mechanism for protein gel formation and protein delivery.