Engineering the Structure and Rheological Properties of P407 Hydrogels via Reverse Poloxamer Addition

Abstract

Aqueous solutions of poloxamer 407 (P407), a commercially available and nontoxic ABA triblock polymer (PEO-PPO-PEO), undergo a solution-to-gel transition with increasing temperature and are promising candidates for injectable therapeutics. The gel transition temperature, modulus, and structure are all dictated by polymer concentration, preventing independent tuning of these properties. Here, we show that addition of BAB reverse poloxamers (RPs) to P407-based solutions dramatically alters the gelation temperature, modulus, and morphology. Gelation temperature and RP localization within the hydrogel are dictated by RP solubility. Highly soluble RPs increase gelation temperature and incorporate primarily into the micelle corona regions. Alternatively, RPs with low aqueous solubility decrease gelation temperature and associate within the micelle core and core−corona interface. These differences in RP localization have significant implications for the hydrogel modulus and microstructure. The ability to tune gelation temperature, modulus, and structure through RP addition allows for the design of thermoresponsive materials with specific properties that are unobtainable with neat P407-based hydrogels.

Effect of Chain Architecture on the Structure, Dynamics, and Rheology of Thermoresponsive Poloxamer Hydrogels and Associated Blends

“…Formulations with intermediate blend compositions display two peaks in the DSC traces upon heating (Figure a). Similar DSC traces have also been reported for blends of two ABA poloxamers, or P407 and lower-molecular-weight RPs, where the T mic values between the two components are significantly different. ,,,,,, In these cases, the two features in the DSC traces have been attributed to a two-step dehydration process with increasing temperature. In the first step, one component forms micelles while the other component remains as hydrated unimers in solution.…”

“…Unfortunately, commercially available RPs are not large enough for a single chain to span between P407 micelles but instead form multi-chain bridges. This bridging mechanism prevents strong network formation at lower polymer concentrations, as observed in other BAB triblock systems …”

“…In the first step, one component forms micelles while the other component remains as hydrated unimers in solution. In the second step, all PPO blocks dehydrate to form mixed micelles at elevated temperatures. ,,, …”

“…As the temperature is increased past the CMT, the PPO blocks dehydrate to form spherical micelles. ,,,,− In solutions with >13–15% (w/w) P407, further increases in temperature cause these micelles to rearrange into ordered cubic phases. Such ordering leads to a liquid-to-gel transition, which can be exploited for the design of injectable therapeutics that behave as liquids at room temperature but gel when heated to body temperature. ,,− While thermoresponsive gels have major promise in the health sector, only a limited number of systems, including those containing P407, have undergone clinical trials due to the limited tunability within the currently available systems …”

“…Previously, P407 has been blended with other lower-molecular-weight, commercially available poloxamers or RPs to alter micellization and solution gelation. ,,,− Because the same chemistries were utilized for both blocks, these blends formed mixed micelles at elevated temperatures; however, the micelle size and packing differed based on the block fractions and architecture of the polymers. ,,− For example, when 25R4, an RP with 40% PEO and M n = 3.8 kDa, was blended with P407, the CMT increased relative to P407 alone and the RP chains localized at the interfacial and coronal regions to form bridges composed of multiple RP chains associating between P407 micelles. ,, These bridges served as weak physical crosslinks, enhancing the gel moduli when added to formulations with a constant P407 concentration. Unfortunately, commercially available RPs are not large enough for a single chain to span between P407 micelles but instead form multi-chain bridges.…”