Cascade Mesophase Transitions of Multi-enzyme Responsive Polymeric Formulations.

Studying how synthetic polymer assemblies respond to sequential enzymatic stimuli can uncover intricate interactions in biological systems. Using amidase- and esterase-responsive PEG-based diblock (DBA) and triblock amphiphiles (TBAs), we created two distinct formulations: amidase-responsive DBA with esterase-responsive TBA and vice versa. We studied their cascade responses to the two enzymes and the sequence of their introduction. These formulations underwent cascade mesophase transitions upon the addition of the DBA-degrading enzyme, transitioning from (i) coassembled micelles to (ii) triblock-based hydrogel, and ultimately to (iii) dissolved polymers when exposed to the TBA hydrolyzing enzyme. The specific pathway of the two mesophase transitions depended on the compositions of the formulations and the enzyme introduction sequence. The results highlight the potential for designing polymeric formulations with programmable multistep enzymatic responses, mimicking the complex behavior of biological macromolecules.

Hydrogel Microneedles with Programmed Mesophase Transitions for Controlled Drug Delivery.

Microneedle-based drug delivery offers an attractive and minimally invasive administration route to deliver therapeutic agents through the skin by bypassing the stratum corneum, the main skin barrier. Recently, hydrogel-based microneedles have gained prominence for their exceptional ability to precisely control the release of their drug cargo. In this study, we investigated the feasibility of fabricating microneedles from triblock amphiphiles with linear poly(ethylene glycol) (PEG) as the hydrophilic middle block and two dendritic side-blocks with enzyme-cleavable hydrophobic end-groups. Due to the poor formation and brittleness of microneedles made from the neat amphiphile, we added a sodium alginate base layer and tested different polymeric excipients to enhance the mechanical strength of the microneedles. Following optimization, microneedles based on triblock amphiphiles were successfully fabricated and exhibited favorable insertion efficiency and low height reduction percentage when tested in Parafilm as a skin-simulant model. When tested against static forces ranging from 50 to 1000 g (4.9-98 mN/needle), the microneedles showed adequate mechanical strength with no fractures or broken segments. In buffer solution, the solid microneedles swelled into a hydrogel within about 30 s, followed by their rapid disintegration into small hydrogel particles. These hydrogel particles could undergo slow enzymatic degradation to soluble polymers. In vitro release study of dexamethasone (DEX), as a steroid model drug, showed first-order drug release, with 90% released within 6 days. Eventually, DEX-loaded MNs were subjected to an insertion test using chicken skin and showed full penetration. This study demonstrates the feasibility of programming hydrogel-forming microneedles to undergo several mesophase transitions and their potential application as a delivery system for self-administration, increased patient compliance, improved efficacy, and sustained drug release.

Directional actuation and phase transition-like behavior in anisotropic networks of responsive microfibers.

Two-dimensional shape-morphing networks are common in biological systems and have garnered attention due to their nontrivial physical properties that emanate from their cellular nature. Here, we present the fabrication and characterization of anisotropic shape-morphing networks composed of thermoresponsive polymeric microfibers. By strategically positioning fibers with varying responses, we construct networks that exhibit directional actuation. The individual segments within the network display either a linear extension or buckling upon swelling, depending on their radius and length, and the transition between these morphing behaviors resembles Landau's second-order phase transition. The microscale variations in morphing behaviors are translated into observable macroscopic effects, wherein regions undergoing linear expansion retain their shape upon swelling, whereas buckled regions demonstrate negative compressibility and shrink. Manipulating the macroscale morphing by adjusting the properties of the fibrous microsegments offers a means to modulate and program morphing with mesoscale precision and unlocks novel opportunities for developing programmable microscale soft robotics and actuators.

Architecture-Based Programming of Polymeric Micelles to Undergo Sequential Mesophase Transitions.

Di- and triblock amphiphiles can form different mesophases ranging from micelles to hydrogels depending on their chemical structures, hydrophilic to hydrophobic ratios, and their ratio in the mixture. In addition, their different architectures dictate their exchange rate between the assembled and unimer states and consequently affect their responsiveness toward enzymatic degradation. Here we report the utilization of the different reactivities of di- and triblock amphiphiles, having exactly the same hydrophilic to lipophilic balance, toward enzymatic degradation as a tool for programming formulations to undergo sequential enzymatically induced transitions from (i) micelles to (ii) hydrogel and finally to (iii) dissolved polymers. We show that the rate of transition between the mesophases can be programmed by changing the ratio of the amphiphiles in the formulation, and that the hydrogels can maintain encapsulated cargo, which was loaded into the micelles. The reported results demonstrate the ability of molecular architecture to serve as a tool for programming smart formulations to adopt different structures and functions.

Controlling Nano-to-Microscale Multilevel Architecture in Polymeric Microfibers through Polymerization-Induced Spontaneous Phase Separation.

Hierarchically structured polymeric fibers, composed of structural nanoscale motifs that assemble into a microscale fiber are frequently found in natural fibers including cellulose and silk. The creation of synthetic fibers with nano-to-microscale hierarchical structures represents a promising avenue for the development of novel fabrics with distinctive physical, chemical, and mechanical characteristics. In this work, we introduce a novel approach for creating polyamine-based core-sheath microfibers with controlled hierarchical architectures. This approach involves a polymerization-induced spontaneous phase separation and subsequent chemical fixation. Through the use of various polyamines, the phase separation process can be manipulated to produce fibers with diverse porous core architectures, ranging from densely packed nanospheres to segmented "bamboo-stem" morphology. Moreover, the nitrogen-rich surface of the core enables both the chemisorption of heavy metals and the physisorption of proteins and enzymes. Our method offers a new set of tools for the production of polymeric fibers with novel hierarchical morphologies, which has a high potential for a wide range of applications such as filtering, separation, and catalysis.