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.