Hydrogel crosslinking mechanisms influence the release and functional delivery of lipid nanoparticles

Hydrogel formulation controls size-dependent accumulation of proteins and nanoparticles in PEG microparticles

Hydrogels are widely used in sensing, delivery, and tissue engineering because their transport properties can be tuned through material design. However, while hydrogel permeability is often characterized using small molecules, many practical applications depend on the uptake and retention of much larger species, including protein conjugates and nanoparticles. Here, we systematically investigate how polyethylene glycol (PEG)-acrylate hydrogel microparticle formulation influences accumulation of signal-generating probes spanning a broad size range. We fabricated particles across a 36-condition design space varying nominal PEG-acrylate molecular weight, polymer weight percent, and UV crosslinking dose, and related formulation-dependent probe accumulation to particle swelling behavior. Increasing nominal PEG-acrylate molecular weight and decreasing polymer weight percent produced more highly swollen particles and strongly enhanced accumulation of fluorescent streptavidin conjugates, with the largest effects observed for bulky labels such as allophycocyanin and phycoerythrin. Gold nanoparticle accumulation was even more formulation-restricted, with detectable colorimetric signal observed primarily in the most permissive formulations. These findings establish design rules linking PEG hydrogel formulation to size-dependent accumulation and show that formulations suitable for small probes may be inadequate for larger reporters. More broadly, this framework may inform the design of hydrogels for particle-based assays as well as other applications where transport of macromolecules or nanoscale materials is important.

Nanoparticle-reinforced polysaccharide–protein composite hydrogels: synthesis, structural integrity, and sustained release behavior

Targeting calcium-crosslinked alginate hydrogel in a living subject using a synthetic anion receptor

Alginate hydrogels are widely utilized in different medical applications as drug excipients, wound dressings, and tissue engineering scaffolds. However, selective delivery of molecular payload to unmodified alginate hydrogels in complex biological media remains a significant challenge. This study presents a novel supramolecular approach for targeting unmodified alginate hydrogels using synthetic zinc(ii) bis(2,2′-dipicolylamine) (ZnBDPA) coordination complexes. Recognizing the polyanionic nature of alginate, we demonstrate that ZnBDPA receptors exhibit high binding affinity for the carboxylate groups on an alginate polymer backbone. Solution-state titration and dye displacement assays confirmed strong binding of a ZnBDPA receptor to different polycarboxylates including alginate. Subsequent hydrogel loading and leakage experiments found that a fluorescent ZnBDPA receptor molecule readily transferred into calcium-crosslinked alginate microspheres and remained trapped, unlike an untargeted control dye. Moreover, release of the trapped ZnBDPA receptor could be triggered by adding pyrophosphate as a receptor binding and displacement agent. Finally, in vivo fluorescence imaging of a living mouse revealed that intravenously administered ZnBDPA receptor selectively targeted a subcutaneously implanted alginate microsphere. These findings establish ZnBDPA as an effective delivery vehicle for alginate hydrogel implants within a living subject, offering a versatile platform for loading and controlled release of molecular payload.

Structural reinforcement of Pluronic F127/chitosan thermoresponsive hydrogels through polydopamine incorporation for controllable drug transport.

Results establish PDA-mediated non-covalent reinforcement as an effective crosslinker-free strategy for engineering thermoresponsive hydrogels with tunable network mechanics and controllable NIR-responsive drug transport for localized chemo-photothermal therapy.

Gelatin Hydrogel Crosslinking: From Molecular Design to Functional Soft Materials

Gelatin hydrogels combine biological origin, biodegradability, abundant chemical functionality, and broad processability, but their native thermoreversible physical networks generally lack the stability required for sustained operation. Crosslinking overcomes this limitation while regulating hydration, mechanics, transport, degradation, and responsiveness. This review examines gelatin hydrogel crosslinking from a structure–property–function perspective, connecting molecular design with physicochemical characterization and functional performance. Temperature-induced gelation and ion-mediated physical interactions are compared with small-molecule- and coupling-agent-mediated, enzyme-catalyzed, and photoinduced covalent crosslinking strategies, highlighting their different balances among reversibility, stability, processability, and biocompatibility. Particular attention is given to the characterization methods required to relate junction chemistry and network organization to swelling, thermal behavior, mechanical response, degradation, and molecular or ionic transport. These relationships are evaluated across drug delivery and controlled release, tissue engineering and wound healing, food packaging, preservation and delivery, water remediation and environmental management, wearable sensing and bioelectronics, and energy storage. Across these fields, the central challenge is not to maximize crosslinking, but to balance network stability with the molecular mobility required for function. By integrating complementary crosslinking mechanisms with multiscale characterization, gelatin can be engineered as a programmable platform for advanced soft materials.

Response surface optimization of thermosensitive chitosan-polyvinyl alcohol hybrid hydrogels with enhanced betel leaf extract release for localized anti-inflammatory therapy.

Thermoresponsive biopolymer hydrogels offer a versatile platform for localized delivery of bioactive compounds; however, their performance is often limited by the competing requirements of network integrity, mechanical compliance, and stimulus-regulated release. Herein, thermosensitive chitosan/β-glycerophosphate/polyvinyl alcohol (CS/GP/PVA) hybrid hydrogels were optimized for the delivery of anti-inflammatory betel leaf extract (BLE) under in vitro conditions simulating an acute inflammatory microenvironment (pH 6.5 and 39 °C). Non-optimized hydrogels previously released only 61% of the loaded BLE, with negligible lysozyme-triggered release attributed to dense chitosan cross-linking that constrained enzyme-accessible transport pathways. Response surface methodology was applied to balance cumulative BLE release and elastic modulus. The optimized formulation (0.88% CS, 4.76% GP, 0.5% PVA, and 4000 µg mL-1 BLE) achieved a cumulative BLE release of 73.41%, corresponding to a 20% relative increase over the non-optimized hybrid hydrogel, and an elastic modulus of 1.54 kPa. The optimized hydrogel also displayed pronounced microenvironment-responsive release, including an eightfold higher BLE release at pH 6.5 than at pH 8.0 and lysozyme-triggered release within 24 hours, indicating that it restored pH- and enzyme-regulated transport. In cell-free assays, the hydrogel extract inhibited hyaluronidase activity, scavenged DPPH radicals, and suppressed Staphylococcus aureus growth. The hydrogel was cytocompatible and significantly suppressed nitric oxide production in lipopolysaccharide-stimulated macrophages, confirming that anti-inflammatory activity is retained in a cellular model. These findings establish the optimized hybrid hydrogel as a bio-functional, thermo-responsive network capable of coupling elasticity with bioactive extract release behavior, offering a promising candidate towards localized anti-inflammatory therapy.