Introduction
Polymer gel is defined as an elastic random network of flexible chains in a liquid solution1. In the fields of pharmacy and medicine, three-dimensional (3D) polymeric gel matrices which are swollen in aqueous solvents, termed as hydrogels, have been widely used for drug delivery and tissue scaffolding2. Tissue mimicry is achieved when tissue-derived biopolymers, including collagen and gelatin, are adopted as the base material for the gel fabrication, which serves as an engineered extracellular matrix (ECM), providing tunable physicochemical properties with complete cytocompatibility3. In a different viewpoint, when a hydrogel is synthesized with thermoresponsive polymers, such as poly(N-isopropylacrylamide) (pNIPAM) and its copolymers, the reversible swelling-deswelling behavior can be conferred to the hydrogel matrix in a temperature-sensitive manner4.
Thermodynamic understanding of the polymeric gel system has been achieved using a mean-field approach, called the Flory-Huggins-Rehner theory5-8. In this lattice theory, if we limit the scope for non-ionic gels, the total Gibbs free energy of the system is a summation of two main contributions: the free energy of mixing between polymer segments and solvent molecules, and the elastic free energy of crosslinked polymer network. In the former, the polymer-solvent interaction is represented by a non-dimensional multiplication coefficient, called the Flory-Huggins interaction parameter. The Flory-Huggins parameter reflects both entropic and enthalpic interactions, and the temperature responsivity of a polymer chain or network is mediated by this parameter. Thermoresponsive hydrogels have primarily been modeled for pNIPAM systems, considering binary mixing free energy between polymer and solvent9. Because a single chain of pNIPAM exhibits coil-to-globule transition above lower critical solution temperature, the pNIPAM gel collapses in the same critical temperature. This reversible collapsing is called volume phase transition, which is a first-order-like phase transition. A variety of biosensors and drug delivery platforms have been developed based on the deswelling (shrinking) behavior of miniaturized pNIPAM gels. Nevertheless, synthetic stimuli-responsive polymers, including pNIPAM, predominantly have few tissue-relevant features10.
Hence it is strongly required to use the tissue-derived biopolymers for implementing artificial ECMs, albeit those biopolymers are lacking thermoresponsivity in the room temperature range. To overcome this limitation, doping pNIPAM chains in the biopolymer network through chemical conjugations can be an efficient way to combine the advantages of both types of polymers in a single gel matrix. In this work, we theoretically design a new type of engineered ECM-like hydrogel where thermoresponsive synthetic polymer chains are doped in a 3D ECM biopolymer gel (Fig. 1). Considering the ternary mixing free energy of the biopolymer-solvent system and by assuming a generalized form of the gel elastic free energy, we derive a simple analytical relation to show well-defined volume phase behaviors of the tissue-resembling gel as a function of temperature. We calculate optimized numerical parameter sets of the hybrid gel matrix for biomedical applications in vivo andin vitro , which are aimed to operate at human body temperature.