Thermoresponsive polymers for cell support: poloxamers as a case study of promise and challenge.

Thermoresponsive biomaterials have the potential to improve the complexity of in vitro models, to generate dynamically controlled extracellular microenvironments and act as in situ forming drug delivery systems. Due to its known biocompatibility and ease of use, poloxamer 407 (P407), also known as pluronic F127, has attracted significant attention as a component for next-generation cell culture and biomedical applications. P407 display rapid gelation into hydrogels with facile ease-of-handling, and which possess good shear-thinning properties that enable 3D printability with high fidelity. Although P407 has been extensively used as a support matrix for cell proliferation, differentiation and the on-demand release of biomolecules and drugs, significant issues relating to mechanical stability under physiological conditions limit its application. Multiple protocols report the use of P407 'hydrogel' for a variety of applications but often do not emphasise its inherent limitations at the concentrations described. Here we emphasise the disparity between written protocols and what specifically constitutes a hydrogel, showing selected examples from the literature and suggesting clarifications in the language used in describing P407 supports. We describe progress in the field, which is accelerating in part due to development of multi-network hydrogels that include P407 as a stabiliser, for shear-thinning and as a sacrificial component aiding 3D printing. We also contrast P407 to a panel of other promising thermoresponsive systems that have emerged as alternative biomaterials. Finally, we briefly discuss challenges and new opportunities in the field. This includes evaluation of the relative merits of current thermoresponsive polymer systems as they are formulated for use, also by advanced manufacturing, in next-generation 4D-responsive functional hydrogel networks for cell culture automation and as components in responsive-release devices.