Fabrication of Multiresponsive Magnetic Nanocomposite Double-Network Hydrogels for Controlled Release Applications.

Nanocomposite double-network hydrogels (ncDN hydrogels) have been demonstrated as promising biomaterials to present several desired properties (e.g., high mechanical strength, stimuli-responsiveness, and local therapy) for biomedicine. Here, a new type of ncDN hydrogels featuring definable microstructures and properties as well as multistimuli responsiveness for controlled release applications is developed. Amine-functionalized iron oxide nanoparticles (IOPs_NH2 ) are used as nanoparticle cross-linkers to simultaneously connect the dual networks of gelatin (Gel) and polydextran aldehyde (PDA) through hydrogen bonding, electrostatic interactions, and dynamic imine bonds. The pH- and temperature-responsive Gel/PDA/IOP_NH2 ncDN hydrogels present a fast release profile of proteins at acidic pH and high temperature. Besides, IOP_NH2 also contributes the magnetic-responsiveness to the ncDN hydrogels, allowing the use of magnetic field to generate heat to facilitate the structural change of hydrogels and the subsequent applications. Taken together, a versatile ncDN hydrogel platform capable of multistimuli responsiveness and local heating for controlled release is developed for advanced biomedical applications.

Co-delivery of protein and small molecule therapeutics using nanoparticle-stabilized nanocapsules.

Combination therapy employing proteins and small molecules provides access to synergistic treatment strategies. Co-delivery of these two payloads is challenging due to the divergent physicochemical properties of small molecule and protein cargos. Nanoparticle-stabilized nanocapsules (NPSCs) are promising for combination treatment strategies since they have the potential to deliver small molecule drugs and proteins simultaneously into the cytosol. In this study, we loaded paclitaxel into the hydrophobic core of the NPSC and self-assembled caspase-3 and nanoparticles on the capsule surface. The resulting combination NPSCs showed higher cytotoxicity than either of the single agent NPSCs, with synergistic action established using combination index values.

Fabrication of functional nanofibers through post-nanoparticle functionalization.

A facile method is developed to functionalize nanofiber surfaces with nanoparticles (NPs) through dithiocarbamate chemistry. Gold nanoparticles (AuNPs) and quantum dots (QDs) are immobilized on the nanofiber surface. These surfaces provide scaffolds for further supramolecular functionalization, as demonstrated through the Förster resonance energy transfer (FRET) pairing of QD-decorated fibers and fluorescent proteins.

Mass spectrometric detection of nanoparticle host-guest interactions in cells.

Synthetic host-guest chemistry is a versatile tool for biomedical applications. Characterization and detection of host-guest complexes in biological systems, however, is challenging due to the complexity of the biological milieu. Here, we describe and apply a mass spectrometric method to monitor the association and dissociation of nanoparticle (NP)-based host-guest interactions that integrates NP-assisted laser desorption/ionization (LDI) and matrix assisted laser desoption/ionization (MALDI) mass spectrometry. This LDI/MALDI approach reveals how NP surface functionality affects host-guest interactions in cells, information difficult to achieve using other techniques.

Fabrication of multiresponsive bioactive nanocapsules through orthogonal self-assembly.

Multifunctional self-assembled systems present platforms for fundamental research and practical applications as they provide tunability of structure, functionality, and stimuli responsiveness. Pragmatic structures for biological applications have multiple design requirements, including control of size, stability, and environmental response. Here we present the fabrication of multifunctional nanoparticle-stabilized capsules (NPSCs) by using a set of orthogonal supramolecular interactions. In these capsules, fluorescent proteins are attached to quantum dots through polyhistidine coordination. These anionic assemblies interact laterally with cationic gold nanoparticles that are anchored to the fatty acid core through guanidinium-carboxylate interactions. The lipophilic core then provides a reservoir for hydrophobic endosome-disrupting agents, thereby generating a system featuring stimuli-responsive release of a payload into the cytosol with fluorescence monitoring.

Luminescent lanthanide-containing gelatin/polydextran/laponite nanocomposite double-network hydrogels for processing and sensing applications.

Lanthanide-containing nanomaterials have gained significant popularity for their utilization in polymeric networks, enabling the creation of luminescent nanocomposites for advanced applications. In this study, we developed a new type of lanthanide-containing nanocomposite hydrogels by incorporating terbium-containing laponite (Tb3+@Lap) into the networks of polyethyleneimine-modified gelatin/polydextran aldehyde (PG/PDA) through dynamic bonds. The structures and properties of the Tb3+@Lap-containing nanocomposite double-network (ncDN) hydrogels were comprehensively investigated in comparison with the DN hydrogels with a pure polymeric network and the Lap-containing ncDN hydrogels. The PG/PDA/Tb3+@Lap ncDN hydrogels with multiple dynamic bonds (i.e., imine bonds, coordination bonds, hydrogen bonds, and electrostatic interactions) exhibited remarkable characteristics of shear-thinning and self-healing, making them suitable for the construction of hydrogel scaffolds on a macroscale using fabrication techniques such as electrospinning and 3D printing. Moreover, the PG/PDA/Tb3+@Lap ncDN hydrogels have been demonstrated to act as sensitive and selective luminescent sensors for detecting copper ions. Taken together, a versatile lanthanide-containing ncDN hydrogel platform capable of dynamic features is developed for processing and sensing applications.

Injectable pH- and Ultrasound-Responsive Dual-Crosslinked Dextran/Chitosan/TiO2 Nanocomposite Hydrogels for Antibacterial Applications.

Combining exogenous and endogenous antibacterial mechanisms has been demonstrated to enhance therapeutic efficacy significantly. This study constructs an innovative type of exogenous and endogenous antibacterial nanocomposite hydrogels with injectable dual-crosslinked networks and dual-stimuli responsiveness. The primary network establishes imine bonds between the functionalized dextran featuring norbornenes and aldehydes (NorAld-Dex) and the quaternized chitosan (QCS). The imine bonds provide self-healing, injectability, and pH-responsiveness to the hydrogel network. The secondary network is established by integrating thiolated mesoporous silica-coated titanium dioxide nanoparticles (TiO2@MS-SH) into the hydrogel network via an ultrasound-activated thiol-norbornene reaction with NorAld-Dex. The microstructures and properties of NorAld-Dex/QCS/TiO2@MS-SH hydrogels can be fine-tuned by adjusting the sonication time to increase the amount of thiol-norbornene crosslinks in the network. Effective antibacterial performance of NorAld-Dex/QCS/TiO2@MS-SH hydrogels at low pH has been demonstrated with the synergistic effect of the acid-induced dissociation of the hydrogel network, protonated QCS, and the reactive oxygen species (ROS) generated by TiO2@MS-SH nanoparticles under ultrasound irradiation. In summary, NorAld-Dex/QCS/TiO2@MS-SH nanocomposite hydrogel is an advanced dual stimuli-responsive antibacterial platform with customizable microstructures and properties, offering great potential for biomedical applications.

Injectable, Antioxidative, and Tissue-Adhesive Nanocomposite Hydrogel as a Potential Treatment for Inner Retina Injuries.

Reactive oxygen species (ROS) have been recognized as prevalent contributors to the development of inner retinal injuries including optic neuropathies such as glaucoma, non-arteritic anterior ischemic optic neuropathy, traumatic optic neuropathy, and Leber hereditary optic neuropathy, among others. This underscores the pivotal significance of oxidative stress in the damage inflicted upon retinal tissue. To combat ROS-related challenges, this study focuses on creating an injectable and tissue-adhesive hydrogel with tailored antioxidant properties for retinal applications. GelCA, a gelatin-modified hydrogel with photo-crosslinkable and injectable properties, is developed. To enhance its antioxidant capabilities, curcumin-loaded polydopamine nanoparticles (Cur@PDA NPs) are incorporated into the GelCA matrix, resulting in a multifunctional nanocomposite hydrogel referred to as Cur@PDA@GelCA. This hydrogel exhibits excellent biocompatibility in both in vitro and in vivo assessments, along with enhanced tissue adhesion facilitated by NPs in an in vivo model. Importantly, Cur@PDA@GelCA demonstrates the potential to mitigate oxidative stress when administered via intravitreal injection in retinal injury models such as the optic nerve crush model. These findings underscore its promise in advancing retinal tissue engineering and providing an innovative strategy for acute neuroprotection in the context of inner retinal injuries.

Hydrogel-Based Strategies for the Management of Osteomyelitis.

Osteomyelitis is a type of bone infection caused by bacteria, with Staphylococcus sepsis being responsible for most cases. Osteomyelitis treatment generally requires a multifaceted approach that may include intervention of surgery and administration of antibacterial agents, where several materials have been utilized as delivery vehicles for antibiotics and other antibacterial materials. Hydrogel has become a popular candidate for osteomyelitis treatment due to its biocompatibility, water-containing porous structure, and adaptable physicochemical properties. In this review, we discuss several hydrogel-based strategies for osteomyelitis treatment and categorized them based on the encapsulated cargos (i.e., antibiotics, silver nanoparticles, protein and bacteriophage, and reactive oxygen species (ROS) generator). Several representative examples of osteomyelitis treatment using hydrogels are described here, focusing on their design, preparation, properties, and outcomes. We also provide our perspectives on the remaining concerns regarding fabricating advanced hydrogels for osteomyelitis treatment. This review will be valuable to the hydrogel community and inspire researchers to develop next-generation hydrogels for specific and practical clinical applications in osteomyelitis.

Fabrication of triple-crosslinked gelatin/alginate hydrogels for controlled release applications.

Hydrogels have been demonstrated as smart drug carriers to recognize the tumor microenvironment for cancer treatment, where the dynamic crosslinks in the hydrogel network contribute to the stimuli-responsive features but also result in poor stability and weak mechanical property of the hydrogels. Here, phenylboronic acid-grafted polyethyleneimine (PBA-PEI)-modified gelatin (PPG) was synthesized to crosslink alginate dialdehyde (ADA) through imine bonds and boronate ester bonds, and then calcium ions (Ca2+) were added to introduce the third calcium-carboxylate crosslinking in the network to form the triple-crosslinked PPG/ADA-Ca2+ hydrogels. Given the three types of dynamic bonds in the network, PPG/ADA-Ca2+ hydrogels possessed a self-healing manner, stimuli-responsiveness, and better mechanical properties compared to single- or double-crosslinked hydrogels. The controlled release capability of PPG/ADA-Ca2+ hydrogels was also demonstrated, showing the encapsulated molecules can be rapidly released from the hydrogel network in the presence of hydrogen peroxide while the release rate can be slowed down at acidic pH. Furthermore, PPG/ADA-Ca2+ hydrogels presented selected cytotoxicity and drug delivery to cancer cells due to the regulated degradation by the cellular microenvironment. Taken together, PPG/ADA-Ca2+ hydrogels have been demonstrated as promising biomaterials with multiple desirable properties and dynamic features to perform controlled molecule release for biomedical applications.

Fabrication of versatile poly(xylitol sebacate)-co-poly(ethylene glycol) hydrogels through multifunctional crosslinkers and dynamic bonds for wound healing.

Poly(polyol sebacate) (PPS) polymer family has been recognized as promising biomaterials for biomedical applications with their characteristics of easy production, elasticity, biodegradation, and cytocompatibility. Poly(xylitol sebacate)-co-poly(ethylene glycol) (PXS-co-PEG) has been developed to fabricate PPS-based hydrogels; however, current PXS-co-PEG hydrogels presented limited properties and functions due to the limitations of the crosslinkers and crosslinking chemistry used in the hydrogel formation. Here, we fabricate a new type of PXS-co-PEG hydrogels through the use of multifunctional crosslinkers as well as dynamic bonds. In our design, polyethyleneimine-polydopamine (PEI-PDA) macromers are utilized to crosslink aldehyde-functionalized PXS-co-PEG (APP) through imine bonds and hydrogen bonds. PEI-PDA/APP hydrogels present multiple functional properties (e.g., fluorescent, elastomeric, biodegradable, self-healing, bioadhesive, antioxidant, and antibacterial behaviors). These properties of PEI-PDA/APP hydrogels can be fine-tuned by changing the PDA grafting degrees in the PEI-PDA crosslinkers. Most importantly, PEI-PDA/APP hydrogels are considered promising wound dressings to promote tissue remodeling and prevent bacterial infection in vivo. Taken together, PEI-PDA/APP hydrogels have been demonstrated as versatile biomaterials to provide multiple tailorable properties and desirable functions to expand the utility of PPS-based hydrogels for advanced biomedical applications. STATEMENT OF SIGNIFICANCE: Various strategies have been developed to fabricate poly(polyol sebacate) (PPS)-based hydrogels. However, current PPS-based hydrogels present limited properties and functions due to the limitations of the crosslinkers and crosslinking chemistry used in the hydrogel formation. This work describes that co-engineering crosslinkers and interfacial crosslinking is a promising approach to synthesizing a new type of poly(xylitol sebacate)-co-poly(ethylene glycol) (PXS-co-PEG) hydrogels as multifunctional hydrogels to expand the utility of PPS-based hydrogels for advanced biomedical applications. The fabricated hydrogels present multiple functional properties (e.g., fluorescent, biodegradable, elastomeric, self-healing, bioadhesive, antioxidative, and antibacterial), and these properties can be fine-tuned by the defined crosslinkers. The fabricated hydrogels are also used as promising wound dressing biomaterials to exhibit promoted tissue remodeling and prevent bacterial infection in vivo.

Ultrasonic interfacial crosslinking of TiO2-based nanocomposite hydrogels through thiol-norbornene reactions for sonodynamic antibacterial treatment.

Nanocomposite (NC) hydrogels used for sonodynamic therapy (SDT) face challenges such as lacking interfacial interactions between the polymers and nanomaterials as well as presenting uneven dispersion of nanomaterials in the hydrogel network, reducing their mechanical properties and treatment efficiency. Here, we demonstrate a promising approach of co-engineering nanomaterials and interfacial crosslinking to expand the materials construction and biomedical applications of NC hydrogels in SDT. In this work, mesoporous silica-coated titanium dioxide nanoparticles with thiolated surface functionalization (TiO2@MS-SH) are utilized as crosslinkers to react with norbornene-functionalized dextran (Nor-Dex) through ultrasound-triggered thiol-norbornene reactions, forming TiO2@MS-SH/Nor-Dex NC hydrogels. The TiO2@MS-SH nanoparticles act not only as multivalent crosslinkers to improve the mechanical properties of hydrogels under ultrasound irradiation but also as reactive oxygen species (ROS) generators to allow the use of TiO2@MS-SH/Nor-Dex NC hydrogels in SDT applications. Particularly, the TiO2@MS-SH/Nor-Dex NC hydrogels present tailorable microstructures, properties, and sonodynamic killing of bacteria through the modulation of the ultrasound frequency. Taken together, a versatile TiO2-based NC hydrogel platform prepared under ultrasonic interfacial crosslinking reactions is developed for advancing the applications in SDT.

Piperic acid derivative as a molecular modulator to accelerate the IAPP aggregation process and alter its antimicrobial activity.

Piperic acid derivatives were found to affect the islet amyloid polypeptide (IAPP) aggregation process. Structure-activity relationship studies revealed that PAD-13 was an efficient molecular modulator to accelerate IAPP fibril formation by promoting primary and secondary nucleation and reducing its antimicrobial activity.

Evolution of nanostructured skin patches towards multifunctional wearable platforms for biomedical applications.

Recent advances in the field of skin patches have promoted the development of wearable and implantable bioelectronics for long-term, continuous healthcare management and targeted therapy. However, the design of electronic skin (e-skin) patches with stretchable components is still challenging and requires an in-depth understanding of the skin-attachable substrate layer, functional biomaterials and advanced self-powered electronics. In this comprehensive review, we present the evolution of skin patches from functional nanostructured materials to multi-functional and stimuli-responsive patches towards flexible substrates and emerging biomaterials for e-skin patches, including the material selection, structure design and promising applications. Stretchable sensors and self-powered e-skin patches are also discussed, ranging from electrical stimulation for clinical procedures to continuous health monitoring and integrated systems for comprehensive healthcare management. Moreover, an integrated energy harvester with bioelectronics enables the fabrication of self-powered electronic skin patches, which can effectively solve the energy supply and overcome the drawbacks induced by bulky battery-driven devices. However, to realize the full potential offered by these advancements, several challenges must be addressed for next-generation e-skin patches. Finally, future opportunities and positive outlooks are presented on the future directions of bioelectronics. It is believed that innovative material design, structure engineering, and in-depth study of fundamental principles can foster the rapid evolution of electronic skin patches, and eventually enable self-powered close-looped bioelectronic systems to benefit mankind.

Determination of the intracellular stability of gold nanoparticle monolayers using mass spectrometry.

Monolayer stability of core-shell nanoparticles is a key determinant of their utility in biological studies such as imaging and drug delivery. Intracellular thiols (e.g., cysteine, cysteamine, and glutathione) can trigger the release of thiolate-bound monolayers from nanoparticles, a favorable outcome for controllable drug release applications but an unfavorable outcome for imaging agents. Here, we describe a method to quantify the monolayer release of gold nanoparticles (AuNPs) in living cells using parallel measurements by laser desorption/ionization (LDI) and inductively coupled plasma (ICP) mass spectrometry. This combination of methods is tested using AuNPs with structural features known to influence monolayer stability and on cells types with varying concentrations of glutathione. On the basis of our results, we predict that this approach should help efforts to engineer nanoparticle surface monolayers with tunable stability, providing stable platforms for imaging agents and controlled release of therapeutic monolayer payloads.

Ultrasound-triggered hydrogel formation through thiol-norbornene reactions.

An ultrasound-initiated thiol-norbornene reaction has been applied to fabricate hydrogels, and the ultrasound conditions in determining the properties of hydrogels have been systematically investigated.

Synthesis and Processing of Dynamic Covalently Crosslinked Polydextran/Carbon Dot Nanocomposite Hydrogels with Tailorable Microstructures and Properties.

Using functionalized nanoparticles to crosslink hydrophilic polymers is a growing theme of directly constructing nanocomposite (NC) hydrogels. Employing dynamic covalent chemistry at the nanoparticle-polymer interface is particularly attractive due to the spontaneous formation and reversible manner of dynamic covalent bonds. However, the structure and property modulation of the dynamic covalently crosslinked NC hydrogels has not been thoroughly discussed. Here, we fabricated NC hydrogels by using amine-functionalized carbon dots (CDs) to crosslink polydextran aldehyde (PDA) polymers through imine bond formation. The role of PDA with different oxidation degrees (i.e., PDA10, PDA30, and PDA50) in affecting the microstructures and properties of PDA@CD hydrogels was systematically investigated, showing that the PDA50@CD hydrogel presented the densest structure and the highest mechanical strength among the three PDA@CD hydrogels. The pH-responsiveness, 3D printing, electrospinning, and biocompatibility of PDA@CD hydrogels were also demonstrated, showing the great promise of using PDA@CD hydrogels for applications in biomedicine and biofabrication.

Progress in the drug encapsulation of poly(lactic-co-glycolic acid) and folate-decorated poly(ethylene glycol)-poly(lactic-co-glycolic acid) conjugates for selective cancer treatment.

Poly(lactic-co-glycolic acid) (PLGA) is a US Food and Drug Administration (FDA)-approved polymer used in humans in the forms of resorbable sutures, drug carriers, and bone regeneration materials. Recently, PLGA-based conjugates have been extensively investigated for cancer, which is the second leading cause of death globally. This article presents an account of the literature on PLGA-based conjugates, focusing on their chemistries, biological activity, and functions as targeted drug carriers or sustained drug controllers for common cancers (e.g., breast, prostate, and lung cancers). The preparation and drug encapsulation of PLGA nanoparticles and folate-decorated poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) conjugates are discussed, along with several representative examples. Particularly, the reactions used for preparing drug-conjugated PLGA and FA-PEG-PLGA are emphasized, with the associated chemistries involved in the formation of structures and their biocompatibility with internal organs. This review provides a deeper understanding of the constituents and interactions of PLGA-conjugated materials to ensure successful conjugation in PLGA material design and the subsequent biomedical applications.

Development of a PCL-PEO double network colorimetric pH sensor using electrospun fibers containing Hibiscus rosa sinensis extract and silver nanoparticles for food monitoring.

Major anthocyanin, cyanidin-3-sophoroside (318.1 mg/mL), and other minor copigments were identified in the ethanol extract of Hibiscus rosa sinensis. The extracts can be coelectrospun with polycaprolactone and polyethylene oxide into fiber mats and were sensitive to pH changes from 1 to 13 with a unique color code (ΔE > 5). The pH sensor was used to monitor shrimp quality under isothermal conditions to obtain the respective activation energy (Ea in kJ/mol) of the sensors' color-change response (20.2), measured pH (20.6), and trimethylamine nitrogen (24.6), indole (27.1), and total microbial counts (30.8). Together with the Pearson correlation coefficient, the results showed high correlations between the sensors' color change and other quality parameters (p < 0.001). The regression equation developed by conducting the kinetic analysis was also suitable for predicting shrimp quality at refrigeration temperatures (4-10 °C) and can be used as a marker to monitor shrimp quality by visually inspecting the item condition.

Dual Dynamic Covalently Crosslinked Alginate Hydrogels with Tunable Properties and Multiple Stimuli-Responsiveness.

Alginate is a biopolymer that can be crosslinked with calcium ions to fabricate cytocompatible hydrogels. However, using calcium ions to crosslink alginate provides limited properties and functions to alginate hydrogels, restricting their biomedical applications. Here, phenylboronic acid-functionalized polyethyleneimine (PBA-PEI) was developed to introduce two orthogonal dynamic covalent crosslinks in the alginate hydrogels, where PBA-PEI was used to crosslink alginate dialdehyde (ADA) through imine bonds and boronate ester bonds. The grafting degree of PBA in the PEI structure was applied to fine-tune the properties of PBA-PEI/ADA hydrogels, including the rheological property, mechanical strength, swelling behavior, and antibacterial activity. In particular, the highly sensitive boronate ester bonds in the network enabled PBA-PEI/ADA hydrogels to be responsive to several stimuli, such as glucose, fructose, and hydrogen peroxide. Taken together, PBA-PEI/ADA hydrogels with tunable properties and multiple stimuli-responsiveness have been demonstrated as smart biomaterials for advanced biomedical applications.