Temperature-Induced Assembly of Monodisperse, Covalently Cross-Linked, and Degradable Poly(N-isopropylacrylamide) Microgels Based on Oligomeric Precursors

Abstract

A simple, rapid, solvent-free, and scalable thermally driven self-assembly approach is described to produce monodisperse, covalently cross-linked, and degradable poly(N-isopropylacrylamide) (PNIPAM) microgels based on mixing hydrazide (PNIPAM-Hzd) and aldehyde (PNIPAM-Ald) functionalized PNIPAM precursors. Preheating of a seed PNIPAM-Hzd solution above its phase transition temperature produces nanoaggregates that are subsequently stabilized and cross-linked by the addition of PNIPAM-Ald. The ratio of PNIPAM-Hzd:PNIPAM-Ald used to prepare the microgels, the time between PNIPAM-Ald addition and cooling, the temperature to which the PNIPAM-Hzd polymer solution is preheated, and the concentration of PNIPAM-Hzd in the initial seed solution can all be used to control the size of the resulting microgels. The microgels exhibit similar thermal phase transition behavior to conventional precipitation-based microgels but are fully degradable into oligomeric precursor polymers. The microgels can also be lyophilized and redispersed without any change in colloidal stability or particle size and exhibit no significant cytotoxicity in vitro. We anticipate that microgels fabricated using this approach may facilitate translation of the attractive properties of such microgels in vivo without the concerns regarding microgel clearance that exist with other PNIPAM-based microgels.

Fabricating Degradable Thermoresponsive Hydrogels on Multiple Length Scales via Reactive Extrusion, Microfluidics, Self-assembly, and Electrospinning

“…Self-assembly driven by the nanoaggregation of a hydrazide-functionalized PNIPAM polymer in a heated solution followed by crosslinking with an aldehyde-functionalized PNIPAM polymer results in highly monodisperse nanogels (polydispersity <0.1) on the size range of 180-300 nm, depending on the process conditions used ( Figure 7 A ) 28 . The nanogels retain the typical thermoresponsive behavior of conventional free-radical crosslinked PNIPAM nanogels, with lower degrees of thermal deswelling observed as more cross-linking polymer was added ( Figure 7 B ).…”

“…(A) Particle size distributions of nanogels prepared with different aldehyde:hydrazide polymer mass ratios from dynamic light scattering (inset: transmission electron micrograph confirming the spherical nature of the nanogels); (B) Thermosensitivity of self-assembled particles as a function of the mass ratio between aldehyde:hydrazide polymer used to prepare the nanogels (from dynamic light scattering), with error bars representing the standard deviation of n=4 replicates; (C) Visual confirmation of the lack of nanogel aggregation both pre and post-lyophilization; (D) Visual confirmation of the acid-catalyzed degradation of nanogels (here in 1 M HCl for consistency with other studies above); (E) Gel permeation chromatograph traces of nanogel degradation products indicating their similarity to the hydrazide and aldehyde-functionalized precursor polymers. Adapted with permission from reference 28 . Copyright 2015, American Chemical Society.…”

“…In response to this limitation, we have recently reported extensively on the application of hydrazone chemistry ( i.e ., the reaction between hydrazide and aldehyde-functionalized pre-polymers) to prepare degradable analogues of thermoresponsive hydrogels 24 25 26 27 28 29 . The rapid and reversible reaction between hydrazide and aldehyde groups upon mixing of the functionalized precursor polymers 30 enables both in situ gelation (enabling facile injection of these materials without the need for surgical implantation or any type of external polymerization stimulus such as UV irradiation or chemical initiation) as well as hydrolytic degradation of the network at a rate controlled by the chemistry and density of the crosslinking sites.…”

“…The rapid and reversible reaction between hydrazide and aldehyde groups upon mixing of the functionalized precursor polymers 30 enables both in situ gelation (enabling facile injection of these materials without the need for surgical implantation or any type of external polymerization stimulus such as UV irradiation or chemical initiation) as well as hydrolytic degradation of the network at a rate controlled by the chemistry and density of the crosslinking sites. Furthermore, by maintaining the molecular weight of the pre-polymers used to prepare the hydrogels below the renal filtration limit, hydrogels made using this approach degrade back into the oligomeric precursor polymers that can be cleared from the body 25 27 28 . Coupled with the low cytotoxicity and low inflammatory tissue response induced by these materials 25 26 27 , this approach offers a potentially translatable method for the use of thermoresponsive smart hydrogels in medicine, particularly if well-controlled degradable analogues of such hydrogels on all length scales (bulk, micro, and nano) can be fabricated.…”

“…To create degradable gel particles on the nanoscale, a thermally-driven reactive self-assembly method is described in which a solution of one of the reactive precursor polymers (the "seed" polymer) is heated above its LCST to form a stable nanoaggregate that is subsequently crosslinked by the addition of the complementary reactive precursor polymer (the "crosslinking" polymer); the resulting hydrazone crosslinked nanogel has a size templated directly by the nanoaggregate ( Figure 3 ) 28 .…”