Design, characterization, and mechanistic study of electro-responsive PANI-based conductive hydrogels integrated with microneedles for transdermal insulin delivery

Transdermal delivery of macromolecular drugs offers significant potential for continuous and stable administration in chronic disease management. We developed a non-invasive double-layer drug delivery platform integrating a sodium hyaluronate (SH) dissolving microneedle (MN) patch and a polyaniline-based conductive hydrogel both loaded with insulin, featuring multiple release kinetics with rapid passive release and electro-driven controlled release. By varying initial concentration and molecular weight (Mw) of SH, the mechanical properties of the MN patches could become optimized to a Young's modulus of 138.5 ± 3.0 MPa, exceeding 3 times the maximum failure stress of the stratum corneum, thereby ensuring efficient puncture and delivery properties at the same time. A conductive hydrogel was developed as a second layer, composed of quaternized chitosan grafted with polyaniline (QCSPA), polyvinyl alcohol (PVA) and boronic acid (BA), that undergoes dynamic crosslinking via borate ester groups and ionic interactions, which possesses well-controlled electric conductivity and viscoelastic properties. In vitro models demonstrated that the MN patch effectively established transport channels and enabled rapid insulin release, providing the necessary conditions for transdermal delivery of the conductive hydrogel layer and accelerating transport efficiency. Meanwhile, the electro-driven mode enhanced the insulin delivery rate by 225% and maintained continuous, stable and efficient release behavior over the 24 h treatment period. The behavior of conductive polymer networks under applied electric field plays a critical role in the electro-driven drug release of conductive hydrogels. We therefore investigated the structural evolution of the PVA-BA-QCSPA conductive hydrogel under varying electric fields. Small-angle X-ray scattering (SAXS), analyzed with the correlation length model and Gaussian domain fitting, was used to quantitatively characterize the multiscale structure of the hydrogel network. Under natural swelling, the spacing between network chains gradually increased, accompanied by a slow expansion of domain radius and correlation length, while maintaining a surface fractal, random coil-like structure. At 3 V, electric field-induced chain aggregation and swelling-driven expansion resulted in an initial slight contraction of domains followed by gradual expansion, reflecting a transition from mass to surface fractal behavior. Under a 5 V high electric field, chain aggregation intensified, leading to rapid formation of larger, denser domains and an accelerated shift to surface fractal structures. The aggregation and densification of spherical domains reduced the correlation length and accelerated polymer chain breakage and network erosion. Consequently, electric field stimulation drives a transformation of the hydrogel network from a microscopically disordered, loose state to an ordered, more densely packed multiscale structure, accompanied by accelerated macroscopic degradation and a significant reduction in mechanical performance. This result reveals the core mechanism underlying the drug release kinetics of the polyaniline-based conductive hydrogel under electrical stimulation and provides a mechanistic basis for the rational design of electro-responsive transdermal delivery systems. Crosslinker length is a key parameter in regulating the properties of borate-ester-based dynamic conductive hydrogels. Therefore, we subsequently synthesized BA-based crosslinkers of different lengths using polyethylene glycol (PEG) with 2 kDa and 20 kDa. The dynamic borate ester hydrogels were constructed from PVA and QCSPA using three crosslinkers of different lengths (BA, 2kPEGPBA and 20kPEGPBA). Rheological measurements reveal distinct viscoelastic responses governed by the interplay between crosslinking density, network defects, and additional physical reinforcement through chain entanglements. SAXS further shows systematic changes in correlation length, network heterogeneity, and multiscale domain organization with crosslinker length and concentration. In vitro insulin release from all three hydrogels follows a first-order kinetic model, where BA gels combine a relatively high apparent rate with the largest releasable fraction, 2kPEGPBA gels exhibit rapid early release but reduced overall capacity due to local trapping, and 20kPEGPBA gels show the slowest and most incomplete release. These results demonstrate that crosslinker length can influence the macroscopic mechanical properties and drug release behavior of dynamic hydrogels by regulating their underlying micro-network structure.