Analysis of Structural Changes of pH-Thermo-Responsive Nanoparticles in Polymeric Hydrogels.

The pH- and thermo-responsive behavior of polymeric hydrogels MC-co-MA have been studied in detail using dynamic light scattering DLS, scanning electron microscopy SEM, nuclear magnetic resonance (1H NMR) and rheology to evaluate the conformational changes, swelling-shrinkage, stability, the ability to flow and the diffusion process of nanoparticles at several temperatures. Furthermore, polymeric systems functionalized with acrylic acid MC and acrylamide MA were subjected to a titration process with a calcium chloride CaCl2 solution to analyze its effect on the average particle diameter Dz, polymer structure and the intra- and intermolecular interactions in order to provide a responsive polymer network that can be used as a possible nanocarrier for drug delivery with several benefits. The results confirmed that the structural changes in the sensitive hydrogels are highly dependent on the corresponding critical solution temperature CST of the carboxylic (-COOH) and amide (-CONH2) functional groups and the influence of calcium ions Ca2+ on the formation or breaking of hydrogen bonds, as well as the decrease in electrostatic repulsions generated between the polymer chains contributing to a particle agglomeration phenomenon. The temperature leads to a re-arrangement of the polymer chains, affecting the viscoelastic properties of the hydrogels. In addition, the diffusion coefficients D of nanoparticles were evaluated, showing a closeness among with the morphology, shape, size and temperature, resulting in slower diffusions for larger particles size and, conversely, the diffusion in the medium increasing as the polymer size is reduced. Therefore, the hydrogels exhibited a remarkable response to pH and temperature variations in the environment. During this research, the functionality and behavior of the polymeric nanoparticles were observed under different analysis conditions, which revealed notable structural changes and further demonstrated the nanoparticles promising high potential for drug delivery applications. Hence, these results have sparked significant interest in various scientific, industrial and technological fields.

Solvent Engineering of Thermo-Responsive Hydrogels Facilitates Strong and Large Contractile Actuations.

Thermo-responsive hydrogels can generate the actuation force through volumetric transitions in response to temperature changes. However, their weak mechanical properties and fragile actuation performance limit robust applications. Existing approaches to enhance these properties have typically depended on additional components, leading to an unavoidable interference to the actuation performance. In this work, robust thermo-responsive hydrogels are fabricated through solvent engineering. A particular solvent, N-methylformamide, interacts affinitively with the carbonyl group of N-isopropylacrylamide monomer, solubilizes the monomer with extremely high concentration, stabilizes chain propagation during polymerization, and greatly increases chain lengths and entanglements of the resulting polymer. The synthesized hydrogels are highly elastic, strong, and tough, displaying remarkable thermo-responsive contractile actuation. The simple synthetic process can broaden its applicability in designing robust functional hydrogel applications.

Bioinspired Genetic and Chemical Engineering of Protein Hydrogels for programable Multi-responsive Actuation.

Protein hydrogels with tailored stimuli-responsive features and tunable stiffness have garnered considerable attention due to the growing demand for biomedical soft robotics. However, integrating multiple responsive features toward intelligent yet biocompatible actuators remains challenging. Here, we report a facile approach that synergistically combines genetic and chemical engineering for the design of protein hydrogel actuators with programable complex spatial deformation. Genetically engineered silk-elastin-like proteins (SELPs) were encoded with stimuli-responsive motifs and enzymatic crosslinking sites via simulation-guided genetic engineering strategies. Chemical modifications of the recombinant proteins were also used as secondary control points to tailor material properties, responsive features, and anisotropy in SELP hydrogels. As a proof-of-concept example, diazonium coupling chemistry was exploited to incorporate sulfanilic acid groups onto the tyrosine residues in the elastin domains of SELPs to achieve patterned SELP hydrogels. These hydrogels can be programmed to perform various actuations, including controllable bending, buckling, and complex deformation under external stimuli, such as temperature, ionic strength, or pH. With the inspiration of genetic and chemical engineering in natural organisms, this work offers a predictable, tunable, and environmentally sustainable approach for the fabrication of programmed intelligent soft actuators, with implications for a variety of biomedical materials and bio-robotics needs. This article is protected by copyright. All rights reserved.

Biomedical Trends in Stimuli-Responsive Hydrogels with Emphasis on Chitosan-Based Formulations.

Biomedicine is constantly evolving to ensure a significant and positive impact on healthcare, which has resulted in innovative and distinct requisites such as hydrogels. Chitosan-based formulations stand out for their versatile utilization in drug encapsulation, transport, and controlled release, which is complemented by their biocompatibility, biodegradability, and non-immunogenic nature. Stimuli-responsive hydrogels, also known as smart hydrogels, have strictly regulated release patterns since they respond and adapt based on various external stimuli. Moreover, they can imitate the intrinsic tissues' mechanical, biological, and physicochemical properties. These characteristics allow stimuli-responsive hydrogels to provide cutting-edge, effective, and safe treatment. Constant progress in the field necessitates an up-to-date summary of current trends and breakthroughs in the biomedical application of stimuli-responsive chitosan-based hydrogels, which was the aim of this review. General data about hydrogels sensitive to ions, pH, redox potential, light, electric field, temperature, and magnetic field are recapitulated. Additionally, formulations responsive to multiple stimuli are mentioned. Focusing on chitosan-based smart hydrogels, their multifaceted utilization was thoroughly described. The vast application spectrum encompasses neurological disorders, tumors, wound healing, and dermal infections. Available data on smart chitosan hydrogels strongly support the idea that current approaches and developing novel solutions are worth improving. The present paper constitutes a valuable resource for researchers and practitioners in the currently evolving field.

3D Printable Active Hydrogels with Supramolecular Additive-Driven Adaptiveness.

Smart hydrogels are a promising candidate for the development of next-generation soft materials due to their stimuli-responsiveness, deformability, and biocompatibility. However, it remains challenging to enable hydrogels to actively adapt to various environmental conditions like living organisms. In this work, supramolecular additives are introduced to the hydrogel matrix to confer environmental adaptiveness. Specifically, their microstructures, swelling behaviors, mechanical properties, and transparency can adapt to external environmental conditions. Moreover, the presence of hydrogen bonding provides the hydrogel with applicable rheological properties for 3D extrusion printing, thus allowing for the facile preparation of thickness-dependent camouflage and multistimuli responsive complex. The environmentally adaptive hydrogel developed in this study offers new approaches for manipulating supramolecular interactions and broadens the capability of smart hydrogels in information security and multifunctional integrated actuation.

Smart/stimuli-responsive chitosan/gelatin and other polymeric macromolecules natural hydrogels vs. synthetic hydrogels systems for brain tissue engineering: A state-of-the-art review.

Currently, there are no viable curative treatments that can enhance the central nervous system's (CNS) recovery from trauma or illness. Bioengineered injectable smart/stimuli-responsive hydrogels (SSRHs) that mirror the intricacy of the CNS milieu and architecture have been suggested as a way to get around these restrictions in combination with medication and cell therapy. Additionally, the right biophysical and pharmacological stimuli are required to boost meaningful CNS regeneration. Recent research has focused heavily on developing SSRHs as cutting-edge delivery systems that can direct the regeneration of brain tissue. In the present article, we have discussed the pathology of brain injuries, and the applicable strategies employed to regenerate the brain tissues. Moreover, the most promising SSRHs for neural tissue engineering (TE) including alginate (Alg.), hyaluronic acid (HA), chitosan (CH), gelatin, and collagen are used in natural polymer-based hydrogels and thoroughly discussed in this review. The ability of these hydrogels to distribute bioactive substances or cells in response to internal and external stimuli is highlighted with particular attention. In addition, this article provides a summary of the most cutting-edge techniques for CNS recovery employing SSRHs for several neurodegenerative diseases.

Harnessing the power of biological macromolecules in hydrogels for controlled drug release in the central nervous system: A review.

Hydrogels have immense potential in revolutionizing central nervous system (CNS) drug delivery, improving outcomes for neurological disorders. They serve as promising tools for controlled drug delivery to the CNS. Available hydrogel types include natural macromolecules (e.g., chitosan, hyaluronic acid, alginate), as well as hybrid hydrogels combining natural and synthetic polymers. Each type offers distinct advantages in terms of biocompatibility, mechanical properties, and drug release kinetics. Design and engineering considerations encompass hydrogel composition, crosslinking density, porosity, and strategies for targeted drug delivery. The review emphasizes factors affecting drug release profiles, such as hydrogel properties and formulation parameters. CNS drug delivery applications of hydrogels span a wide range of therapeutics, including small molecules, proteins and peptides, and nucleic acids. However, challenges like limited biodegradability, clearance, and effective CNS delivery persist. Incorporating 3D bioprinting technology with hydrogel-based CNS drug delivery holds the promise of highly personalized and precisely controlled therapeutic interventions for neurological disorders. The review explores emerging technologies like 3D bioprinting and nanotechnology as opportunities for enhanced precision and effectiveness in hydrogel-based CNS drug delivery. Continued research, collaboration, and technological advancements are vital for translating hydrogel-based therapies into clinical practice, benefiting patients with CNS disorders. This comprehensive review article delves into hydrogels for CNS drug delivery, addressing their types, design principles, applications, challenges, and opportunities for clinical translation.

Stimuli-Responsive Hydrogels for Protein Delivery.

Proteins and peptides are potential therapeutic agents, but their physiochemical properties make their use as drug substances challenging. Hydrogels are hydrophilic polymeric networks that can swell and retain high amounts of water or biological fluids without being dissolved. Due to their biocompatibility, their porous structure, which enables the transport of various peptides and proteins, and their protective effect against degradation, hydrogels have gained prominence as ideal carriers for these molecules' delivery. Particularly, stimuli-responsive hydrogels exhibit physicochemical transitions in response to subtle modifications in the surrounding environment, leading to the controlled release of entrapped proteins or peptides. This review is focused on the application of these hydrogels in protein and peptide delivery, including a brief overview of therapeutic proteins and types of stimuli-responsive polymers.

Porous silicon embedded in a thermoresponsive hydrogel for intranasal delivery of lipophilic drugs to treat rhinosinusitis.

Intranasal delivery is the most preferred route of drug administration for treatment of a range of nasal conditions including chronic rhinosinusitis (CRS), caused by an infection and inflammation of the nasal mucosa. However, localised delivery of lipophilic drugs for persistent nasal inflammation is a challenge especially with traditional topical nasal sprays. In this study, a composite thermoresponsive hydrogel is developed and tuned to obtain desired rheological and physiochemical properties suitable for intranasal administration of lipophilic drugs. The composite is comprised of drug-loaded porous silicon (pSi) particles embedded in a poloxamer 407 (P407) hydrogel matrix. Mometasone Furoate (MF), a lipophilic corticosteroid (log P of 4.11), is used as the drug, which is loaded onto pSi particles at a loading capacity of 28 wt%. The MF-loaded pSi particles (MF@pSi) are incorporated into the P407-based thermoresponsive hydrogel (HG) matrix to form the composite hydrogel (MF@pSi-HG) with a final drug content ranging between 0.1 wt% to 0.5 wt%. Rheomechanical studies indicate that the MF@pSi component exerts a minimal impact on gelation temperature or strength of the hydrogel host. The in-vitro release of the MF payload from MF@pSi-HG shows a pronounced increase in the amount of drug released over 8 h (4.5 to 21-fold) in comparison to controls consisting of pure MF incorporated in hydrogel (MF@HG), indicating an improvement in kinetic solubility of MF upon loading into pSi. Ex-vivo toxicity studies conducted on human nasal mucosal tissue show no adverse effect from exposure to either pure HG or the MF@pSi-HG formulation, even at the highest drug content of 0.5 wt%. Experiments on human nasal mucosal tissue show the MF@pSi-HG formulation deposits a quantity of MF into the tissues within 8 h that is >19 times greater than the MF@HG control (194 ± 7 µg of MF/g of tissue vs. <10 µg of MF/g of tissue, respectively).

Stimuli-responsive hydrogels: smart state of-the-art platforms for cardiac tissue engineering.

Biomedicine and tissue regeneration have made significant advancements recently, positively affecting the whole healthcare spectrum. This opened the way for them to develop their applications for revitalizing damaged tissues. Thus, their functionality will be restored. Cardiac tissue engineering (CTE) using curative procedures that combine biomolecules, biomimetic scaffolds, and cells plays a critical part in this path. Stimuli-responsive hydrogels (SRHs) are excellent three-dimensional (3D) biomaterials for tissue engineering (TE) and various biomedical applications. They can mimic the intrinsic tissues' physicochemical, mechanical, and biological characteristics in a variety of ways. They also provide for 3D setup, adequate aqueous conditions, and the mechanical consistency required for cell development. Furthermore, they function as competent delivery platforms for various biomolecules. Many natural and synthetic polymers were used to fabricate these intelligent platforms with innovative enhanced features and specialized capabilities that are appropriate for CTE applications. In the present review, different strategies employed for CTE were outlined. The light was shed on the limitations of the use of conventional hydrogels in CTE. Moreover, diverse types of SRHs, their characteristics, assembly and exploitation for CTE were discussed. To summarize, recent development in the construction of SRHs increases their potential to operate as intelligent, sophisticated systems in the reconstruction of degenerated cardiac tissues.

Synthesis, Characterization, Properties, and Biomedical Application of Chitosan-Based Hydrogels.

The prospective applications of chitosan-based hydrogels (CBHs), a category of biocompatible and biodegradable materials, in biomedical disciplines such as tissue engineering, wound healing, drug delivery, and biosensing have garnered great interest. The synthesis and characterization processes used to create CBHs play a significant role in determining their characteristics and effectiveness. The qualities of CBHs might be greatly influenced by tailoring the manufacturing method to get certain traits, including porosity, swelling, mechanical strength, and bioactivity. Additionally, characterization methods aid in gaining access to the microstructures and properties of CBHs. Herein, this review provides a comprehensive assessment of the state-of-the-art with a focus on the affiliation between particular properties and domains in biomedicine. Moreover, this review highlights the beneficial properties and wide application of stimuli-responsive CBHs. The main obstacles and prospects for the future of CBH development for biomedical applications are also covered in this review.

Stimuli-bioresponsive hydrogels as new generation materials for implantable, wearable, and disposable biosensors for medical diagnostics: Principles, opportunities, and challenges.

Hydrogels are excellent water-swollen polymeric materials for use in wearable, implantable, and disposable biosensors. Hydrogels have unique properties such as low cost, ease of preparation, transparency, rapid response to external conditions, biocompatibility and self-adhesion to the skin, flexibility, and strain sensitivity, making them ideal for use in biosensor platforms. This review provides a detailed overview of advanced applications of stimuli-responsive hydrogels in biosensor platforms, from hydrogel synthesis and functionalization for bioreceptor immobilization to several important diagnostic applications. Emphasis is placed on recent advances in the fabrication of ultrasensitive fluorescent and electrically conductive hydrogels and their applications in wearable, implantable, and disposable biosensors for quantitative measurements. Design, modification, and assembly techniques of fluorescent, ionically conductive, and electrically conductive hydrogels to improve performance will be addressed. The advantages and performance improvements of immobilizing bioreceptors (e.g., antibodies, enzymes, and aptamers), and incorporating fluorescent and electrically conductive nanomaterials are described, as are their limitations. Potential applications of hydrogels in implantable, wearable, disposable portable biosensors for quantitative detection of the various bioanalytes (ions, molecules, drugs, proteins, and biomarkers) are discussed. Finally, the global market for hydrogel-based biosensors and future challenges and prospects are discussed in detail.

Polyurethane Shape Memory Polymer/pH-Responsive Hydrogel Hybrid for Bi-Function Synergistic Actuations.

Stimuli-responsive actuating hydrogels response to the external stimulus with complex deformation behaviors based on the programmable anisotropic structure design are one of the most important smart soft materials, which have great potential applications in artificial muscles, smart values, and mini-robots. However, the anisotropic structure of one actuating hydrogel can only be programmed one time, which can only provide single actuating performance, and subsequently, has severely limited their further applications. Herein, we have explored a novel SMP/hydrogel hybrid actuator through combining polyurethane shape memory polymer (PU SMP) layer and pH-responsive polyacrylic-acid (PAA) hydrogel layer by a napkin with UV-adhesive. Owing to both the super-hydrophilicity and super-lipophilicity of the cellulose-fiber based napkin, the SMP and the hydrogel can be bonded firmly by the UV-adhesive in the napkin. More importantly, this bilayer hybrid 2D sheet can be programmed by designing a different temporary shape in heat water which can be fixed easily in cool water to achieve various fixed shapes. This hybrid with a fixed temporary shape can achieve complex actuating performance based on the bi-functional synergy of temperature-triggered SMP and pH-responsive hydrogel. The relatively high modulus PU SMP achieved high to 87.19% and 88.92% shape-fixing ratio, respectively, correspond to bending and folding shapes. The hybrid actuator can actuate with the 25.71 °/min actuating speed. Most importantly, one SMP/hydrogel bi-layer hybrid sheet was repeatedly programmed at least nine times in our research to fix various temporary 1D, 2D and 3D shapes, including bending, folding and spiraling shapes. As a result, only one SMP/hydrogel hybrid can provide various complex stimuli-responsive actuations, including the reversable bending-straightening, spiraling-unspiraling. A few of the intelligent devices have been designed to simulate the movement of the natural organisms, such as bio-mimetic "paw", "pangolin" and "octopus". This work has developed a new SMP/hydrogel hybrid with excellent multi-repeatable (≥9 times) programmability for high-level complex actuations, including the 1D to 2D bending and the 2D to 3D spiraling actuations, which also provides a new strategy to design other new soft intelligent materials and systems.

Dual-Stimuli-Sensitive Smart Hydrogels Containing Magnetic Nanoparticles as Antitumor Local Drug Delivery Systems-Synthesis and Characterization.

The aim of this study was to develop an innovative, dual-stimuli-responsive smart hydrogel local drug delivery system (LDDS), potentially useful as an injectable simultaneous chemotherapy and magnetic hyperthermia (MHT) antitumor treatment device. The hydrogels were based on a biocompatible and biodegradable poly(ε-caprolactone-co-rac-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-rac-lactide) (PCLA-PEG-PCLA, PCLA) triblock copolymer, synthesized via ring-opening polymerization (ROP) in the presence of a zirconium(IV) acetylacetonate (Zr(acac)4) catalyst. The PCLA copolymers were successfully synthesized and characterized using NMR and GPC techniques. Furthermore, the gel-forming and rheological properties of the resulting hydrogels were thoroughly investigated, and the optimal synthesis conditions were determined. The coprecipitation method was applied to create magnetic iron oxide nanoparticles (MIONs) with a low diameter and a narrow size distribution. The magnetic properties of the MIONs were close to superparamagnetic upon TEM, DLS, and VSM analysis. The particle suspension placed in an alternating magnetic field (AMF) of the appropriate parameters showed a rapid increase in temperature to the values desired for hyperthermia. The MIONs/hydrogel matrices were evaluated for paclitaxel (PTX) release in vitro. The release was prolonged and well controlled, displaying close to zero-order kinetics; the drug release mechanism was found to be anomalous. Furthermore, it was found that the simulated hyperthermia conditions had no effect on the release kinetics. As a result, the synthesized smart hydrogels were discovered to be a promising antitumor LDDS, allowing simultaneous chemotherapy and hyperthermia treatment.

Thiol-Ene Photo-Click Hydrogels with Tunable Mechanical Properties Resulting from the Exposure of Different -Ene Moieties through a Green Chemistry.

Temperature and light responsiveness are widely exploited stimuli to tune the physico-chemical properties of double network hydrogels. In this work, new amphiphilic poly(ether urethane)s bearing photo-sensitive moieties (i.e., thiol, acrylate and norbornene functionalities) were engineered by exploiting the versatility of poly(urethane) chemistry and carbodiimide-mediated green functionalization procedures. Polymers were synthesized according to optimized protocols maximizing photo-sensitive group grafting while preserving their functionality (approx. 1.0 × 1019, 2.6 × 1019 and 8.1 × 1017 thiol, acrylate and norbornene groups/gpolymer), and exploited to prepare thermo- and Vis-light-responsive thiol-ene photo-click hydrogels (18% w/v, 1:1 thiol:ene molar ratio). Green light-induced photo-curing allowed the achievement of a much more developed gel state with improved resistance to deformation (ca. 60% increase in critical deformation, γL). Triethanolamine addition as co-initiator to thiol-acrylate hydrogels improved the photo-click reaction (i.e., achievement of a better-developed gel state). Differently, L-tyrosine addition to thiol-norbornene solutions slightly hindered cross-linking, resulting in less developed gels with worse mechanical performances (~62% γL decrease). In their optimized composition, thiol-norbornene formulations resulted in prevalent elastic behavior at lower frequency compared to thiol-acrylate gels due to the formation of purely bio-orthogonal instead of heterogeneous gel networks. Our findings highlight that exploiting the same thiol-ene photo-click chemistry, a fine tuning of the gel properties is possible by reacting specific functional groups.

Designing Multistimuli-Responsive Anisotropic Bilayer Hydrogel Actuators by Integrating LCST Phase Transition and Photochromic Isomerization.

Stimuli-responsive hydrogel actuators have attracted tremendous interest in switches and microrobots. Based on N-isopropylacrylamide (NIPAM) monomers with LCST phase separation and photochromic molecule spiropyran which can respond to ultraviolet light and H+, we develop a novel multistimuli-responsive co-polymer anisotropic bilayer hydrogel, which can undergo complex deformation behavior under environmental stimuli. Diverse bending angles were achieved based on inhomogeneous swelling. By controlling the environmental temperature, the bilayer hydrogels achieved bending angles of 83.4° and -162.4° below and above the critical temperature of PNIPAM. Stimulated by ultraviolet light and H+, the bilayer hydrogels showed bending angles of -19.4° and -17.3°, respectively. In addition, we designed a strategy to enhance the mechanical properties of the hydrogel via double network (DN). The mechanical properties and microscopic Fourier transform infrared (micro-FTIR) spectrum showed that the bilayer hydrogel can be well bonded at the interfaces of such bilayers. This work will inspire the design and fabrication of novel soft actuators with synergistic functions.

Untethered Soft Microrobots with Adaptive Logic Gates.

Integrating adaptative logic computation directly into soft microrobots is imperative for the next generation of intelligent soft microrobots as well as for the smart materials to move beyond stimulus-response relationships and toward the intelligent behaviors seen in biological systems. Acquiring adaptivity is coveted for soft microrobots that can adapt to implement different works and respond to different environments either passively or actively through human intervention like biological systems. Here, a novel and simple strategy for constructing untethered soft microrobots based on stimuli-responsive hydrogels that can switch logic gates according to the surrounding stimuli of environment is introduced. Different basic logic gates and combinational logic gates are integrated into a microrobot via a straightforward method. Importantly, two kinds of soft microrobots with adaptive logic gates are designed and fabricated, which can smartly switch logic operation between AND gate and OR gate under different surrounding environmental stimuli. Furthermore, a same magnetic microrobot with adaptive logic gate is used to capture and release the specified objects through the change of the surrounding environmental stimuli based on AND or OR logic gate. This work contributes an innovative strategy to integrate computation into small-scale untethered soft robots with adaptive logic gates.

Ultrasensitive hydrogel grating detector for real-time continuous-flow detection of trace threat Pb2.

Ultrasensitive real-time detection of trace Pb2+ in continuous flow is vital to effectively and timely eliminate the potential hazards to ecosystem health and sustainability. This work reports on a micro-structured smart hydrogel grating with ultra-sensitivity, high selectivity, good transparency and mechanical property for real-time detection of Pb2+ in continuous flow. The hydrogel grating possesses uniform surface relief microstructures with periodic nano-height ridges made of poly(acrylamide-co-benzo-18-crown-6-acrylamide) networks that crosslinked by tetra-arm star poly(ethylene glycol)acrylamide. The hydrogel grating with good optical transparency and mechanical property can change its height via selective host-guest complexation with Pb2+ to output a changed diffraction efficiency. Meanwhile, the periodic nano-ridges with large specific area benefit the contact with Pb2+ for fast Pb2+-induced height change. Thus, with such rationally designed molecular structures and surface relief microstructures, the hydrogel grating integrated in a glass-based mini-chip allows real-time detection of Pb2+ in continuous flow with ultra-sensitivity and high selectivity. The hydrogel grating detector can achieve ultralow detection limit (10-9 M Pb2+), fast response (2 min), and selective detection of Pb2+ from dozens of interfering ions even with high concentrations. This high-performance hydrogel grating detector is general and can be extended to detect many analytes due to the wide choice of responsive hydrogels, thus opening new areas for creating advanced smart detectors in analytical science.

Acousto-Photolithography for Programmable Shape Deformation of Composite Hydrogel Sheets.

Stimuli-responsive hydrogels with programmable shapes produced by defined patterns of particles are of great interest for the fabrication of small-scale soft actuators and robots. Patterning the particles in the hydrogels during fabrication generally requires external magnetic or electric fields, thus limiting the material choice for the particles. Acoustically driven particle manipulation, however, solely depends on the acoustic impedance difference between the particles and the surrounding fluid, making it a more versatile method to spatially control particles. Here, an approach is reported by combining direct acoustic force to align photothermal particles and photolithography to spatially immobilize these alignments within a temperature-responsive poly(N-isopropylacrylamide) hydrogel to trigger shape deformation under temperature change and light exposure. The spatial distribution of particles can be tuned by the power and frequency of the acoustic waves. Specifically, changing the spacing between the particle patterns and position alters the bending curvature and direction of this composite hydrogel sheet, respectively. Moreover, the orientation (i.e., relative angle) of the particle alignments with respect to the long axis of laser-cut hydrogel strips governs the bending behaviors and the subsequent shape deformation by external stimuli. This acousto-photolithography provides a means of spatiotemporal programming of the internal heterogeneity of composite polymeric systems.

Injectable pH Thermo-Responsive Hydrogel Scaffold for Tumoricidal Neural Stem Cell Therapy for Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults and despite recent advances in treatment modalities, GBM remains incurable. Injectable hydrogel scaffolds are a versatile delivery system that can improve delivery of drug and cell therapeutics for GBM. In this report, we investigated an injectable nanocellulose/chitosan-based hydrogel scaffold for neural stem cell encapsulation and delivery. Hydrogels were prepared using thermogelling beta-glycerophosphate (BGP) and hydroxyethyl cellulose (HEC), chitosan (CS), and cellulose nanocrystals (CNCs). We evaluated the impact of neural stem cells on hydrogel gelation kinetics, microstructures, and degradation. Furthermore, we investigated the biomaterial effects on cell viability and functionality. We demonstrated that the incorporation of cells at densities of 1, 5 and 10 million does not significantly impact rheological and physical properties CS scaffolds. However, addition of CNCs significantly prolonged hydrogel degradation when cells were seeded at 5 and 10 million per 1 mL hydrogel. In vitro cell studies demonstrated high cell viability, release of TRAIL at therapeutic concentrations, and effective tumor cell killing within 72 h. The ability of these hydrogel scaffolds to support stem cell encapsulation and viability and maintain stem cell functionality makes them an attractive cell delivery system for local treatment of post-surgical cancers.