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.

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, 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.

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.

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.

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.

Recognition-mediated assembly of quantum dot polymer conjugates with controlled morphology.

We have demonstrated a polymer mediated "bricks and mortar" method for the self-assembly of quantum dots (QDs). This strategy allows QDs to self-assemble into structured aggregates using complementary three-point hydrogen bonding. The resulting nanocomposites have distinct morphologies and inter-particle distances based on the ratio between QDs and polymer. Time resolved photoluminescence measurements showed that the optical properties of the QDs were retained after self-assembly.

Poly(glycerol sebacate)-co-poly(ethylene glycol)/Gelatin Hybrid Hydrogels as Biocompatible Biomaterials for Cell Proliferation and Spreading.

Synthetic polymers have been widely employed to prepare hydrogels for biomedical applications, such as cell culture, drug delivery, and tissue engineering. However, the activity of cells cultured in the synthetic polymer-based hydrogels faces the challenges of limited cell proliferation and spreading compared to cells cultured in natural polymer-based hydrogels. To address this concern, a hybrid hydrogel strategy is demonstrated by incorporating thiolated gelatin (GS) into the norbornene-functionalized poly (glycerol sebacate)-co-polyethylene glycol (Nor_PGS-co-PEG, NPP) network to prepare highly biocompatible NPP/GS_UV hydrogels after the thiol-ene photo-crosslinking reaction. The GS introduces several desirable features (i.e., enhanced water content, enlarged pore size, increased mechanical property, and more cell adhesion sites) to the NPP/GS_UV hydrogels, facilitating the cell proliferation and spreading inside the network. Thus, the highly biocompatible NPP/GS_UV hydrogels are promising materials for cell encapsulation and tissue engineering applications. Taken together, the hybrid hydrogel strategy is demonstrated as a powerful approach to fabricate hydrogels with a highly friendly environment for cell culture, expanding the biomedical applications of hydrogels.

Engineering nanocomposite hydrogels using dynamic bonds.

Nanocomposite (NC) hydrogels are promising biomaterials that possess versatile properties and functions for biomedical applications such as drug delivery, biosensor development, imaging and tissue engineering. Different strategies and chemistries have been utilized to define the structure and properties of NC hydrogels. In this review, we discuss NC hydrogels synthesized using dynamic bonds, including dynamic covalent bonds (e.g., Schiff base and boronate ester bond) and non-covalent bonds (e.g., hydrogen bonds and metal-ligand coordination). Dynamic bonds can reversibly break and reform to provide self-healing properties to NC hydrogels as well as be influenced by external factors to allow NC hydrogels with stimulus-responsiveness. The presence of dynamic bonds in NC hydrogels can occur at the polymer-polymer or polymer-particle interfaces, which also determines whether the particles act as fillers or crosslinkers in hydrogels. Several representative examples of NC hydrogels fabricated using dynamic bonds are discussed here, focusing on their design, preparation, properties, applications and future prospects. STATEMENT OF SIGNIFICANCE: This review provides an overview of the current progress in NC hydrogel development using dynamic bonds, summarizing the material design, fabrication approaches, unique performance and promising biomedical applications. The presence of both nanoparticles and dynamic bonds in hydrogels shows a combined or synergistic effect to provide hydrogels with dynamic features, definable properties, multi-functionality and stimulus-responsiveness for advanced applications. We believe that this review will be of interest to the hydrogel community and inspire researchers to develop next-generation hydrogels.

Smart near infrared-responsive nanocomposite hydrogels for therapeutics and diagnostics.

Nanocomposite (NC) hydrogels are emerging biomaterials that possess desirable and defined properties and functions for therapeutics and diagnostics. Particularly, nanoparticles (NPs) are employed as stimulus-transducers in NC hydrogels to facilitate the treatment process by providing controllable structural change and payload release under internal and external simulations. Among the various external stimuli, near-infrared (NIR) light has attracted considerable interest due to its minimal photo-damage, deep tissue penetration, low auto-fluorescence in living systems, facile on/off switch, easy remote and spatiotemporal control. In this study, we discuss four types of transducing nanomaterials used in NIR-responsive NC hydrogels, including metal-based nanoparticles, carbon-based nanomaterials, polydopamine nanoparticles (PDA NPs), and upconversion nanoparticles (UCNPs). This review provides an overview of the current progress in NIR-responsive NC hydrogels, focusing on their preparation, properties, applications, and future prospects.

In situ formation of nanocomposite double-network hydrogels with shear-thinning and self-healing properties.

Nanocomposite double-network hydrogels (ncDN hydrogels) are recently introduced to address the limitations of traditional DN hydrogels, such as the lack of diversity in the network structure and the restricted functionalities. However, two challenges remain, including the time-consuming preparation and the lack of shear-thinning and self-healing properties. Here, our approach to developing versatile ncDN hydrogels is through the use of multiple interfacial crosslinking chemistries (i.e., noncovalent interactions of electrostatic interaction and hydrogen bonds as well as dynamic covalent interactions of imine bonds and boronate ester bonds) and surface functionalized nanomaterials (i.e. phenylboronic acid modified reduced graphene oxide (PBA-rGO)). PBA-rGO was used as a multivalent gelator to further crosslink the two polymer chains (i.e. triethylene glycol-grafted chitosan (TEG-CS) and polydextran aldehyde (PDA)) in DN hydrogels, forming the TEG-CS/PDA/PBA-rGO ncDN hydrogels in seconds. The microstructures (i.e. pore size) and properties (i.e. rheological, mechanical, and swelling properties) of the ncDN hydrogels can be simply modulated by changing the amount of PBA-rGO. The dynamic bonds in the polymeric network provided the shear-thinning and self-healing properties to the ncDN hydrogels, allowing the hydrogels to be injected and molded into varied shapes as well as self-repair the damaged structure. Besides, the designed TEG-CS/PDA/PBA-rGO ncDN hydrogels were cytocompatible and also exhibited antibacterial activity. Taken together, we hereby provide a nanomaterial approach to fabricate a new class of ncDN hydrogels with tailorable networks and favorite properties for specific applications.

Formation of highly elastomeric and property-tailorable poly(glycerol sebacate)-co-poly(ethylene glycol) hydrogels through thiol-norbornene photochemistry.

Poly(glycerol sebacate) (PGS) is a synthetic biorubber that presents good biocompatibility, excellent elasticity and desirable mechanical properties for biomedical applications; however, the inherent hydrophobicity and traditional thermal curing of PGS restrict its use in the fabrication of hydrogels for advanced bioapplications. Here, we designed a new class of hydrophilic PGS-based copolymers that allow hydrogel formation through thiol-norbornene chemistry. Poly(glycerol sebacate)-co-polyethylene glycol (PGS-co-PEG) macromers were synthesized through a stepwise polycondensation reaction, and then the norbornene functional groups were introduced to the PGS-co-PEG structure to form norbornene-functionalized PGS-co-PEG (Nor_PGS-co-PEG). Nor_PGS-co-PEG macromers can be crosslinked using dithiols to prepare hydrogels in the presence of light and photoinitiators. The mechanical, swelling and degradation properties of Nor_PGS-co-PEG hydrogels can be controlled by altering the crosslinker amount. In particular, the elongation of Nor_PGS-co-PEG hydrogels can be modulated up to 950%. Nor_PGS-co-PEG can be processed using electrospinning and 3D printing techniques to generate microfibrous scaffolds and printed structures, respectively. In addition, the cytocompatibility of Nor_PGS-co-PEG was also demonstrated using in vitro cellular viability studies. These results indicate that Nor_PGS-co-PEG is a promising biomaterial with definable properties for scaffold manufacturing, presenting a great potential for biomedical applications.

Encapsulation of ß-Glucosidase within PVA Fibers by CCD-RSM-Guided Coelectrospinning: A Novel Approach for Specific Mogroside Sweetener Production.

Siamenoside I is a rare mogroside in Siraitia grosvenorii Swingle and has become one of the target ingredients in natural sweetener production. However, the complex structure of siamenoside I has hindered its production in various ways. Here, a yeast cell that produces a specific ß-glucosidase for siamenoside I conversion from mogroside V was constructed, and the enzymes were coelectrospun with poly(vinyl alcohol) followed by phenylboronic acid cross-linking to provide potential usage in the batch production process of Siamenoside I. A central composite design (CCD)-response surface methodology (RSM) was used to find the optimum coelectrospinning parameters. The pH stability and sodium dodecyl sulfate tolerance increased for the entrapped enzymes, and positive correlations between the fiber diameter and enzymatic activity were confirmed. The batch process showed an average siamenoside I production rate of 118 ± 0.08 mg L-1 h-1 per gram of fiber. This is the first research article showing specific siamenoside I production on enzyme-loaded electrospun fibers.

Mechanically dynamic PDMS substrates to investigate changing cell environments.

Mechanics of the extracellular matrix (ECM) play a pivotal role in governing cell behavior, such as cell spreading and differentiation. ECM mechanics have been recapitulated primarily in elastic hydrogels, including with dynamic properties to mimic complex behaviors (e.g., fibrosis); however, these dynamic hydrogels fail to introduce the viscoelastic nature of many tissues. Here, we developed a two-step crosslinking strategy to first form (via platinum-catalyzed crosslinking) networks of polydimethylsiloxane (PDMS) and then to increase PDMS crosslinking (via thiol-ene click reaction) in a temporally-controlled manner. This photoinitiated reaction increased the compressive modulus of PDMS up to 10-fold within minutes and was conducted under cytocompatible conditions. With stiffening, cells displayed increased spreading, changing from ∼1300 to 1900 µm2 and from ∼2700 to 4600 µm2 for fibroblasts and mesenchymal stem cells, respectively. In addition, higher myofibroblast activation (from ∼2 to 20%) for cardiac fibroblasts was observed with increasing PDMS substrate stiffness. These results indicate a cellular response to changes in PDMS substrate mechanics, along with a demonstration of a mechanically dynamic and photoresponsive PDMS substrate platform to model the dynamic behavior of ECM.

3D printing of photocurable poly(glycerol sebacate) elastomers.

Three-dimensional (3D) printed scaffolds have great potential in biomedicine; however, it is important that we are able to design such scaffolds with a range of diverse properties towards specific applications. Here, we report the extrusion-based 3D printing of biodegradable and photocurable acrylated polyglycerol sebacate (Acr-PGS) to fabricate scaffolds with elastic properties. Two Acr-PGS macromers were synthesized with varied molecular weights and viscosity, which were then blended to obtain photocurable macromer inks with a range of viscosities. The quality of extruded and photocured scaffolds was dependent on the initial ink viscosity, with flow of printed material resulting in a loss of structural resolution or sample breaking observed with too low or too high viscosity inks, respectively. However, scaffolds with high print resolution and up to ten layers were fabricated with an optimal ink viscosity. The mechanical properties of printed scaffolds were dependent on printing density, where the scaffolds with lower printing density possessed lower moduli and failure properties than higher density scaffolds. The 3D printed scaffolds supported the culture of 3T3 fibroblasts and both spreading and proliferation were observed, indicating that 3D printed Acr-PGS scaffolds are cytocompatible. These results demonstrate that Acr-PGS is a promising material for the fabrication of elastomeric scaffolds for biomedical applications.

Rapid coating of surfaces with functionalized nanoparticles for regulation of cell behavior.

A robust monolayer of nanoparticles is formed via dip-coating of cell culture plates. These surfaces provide cell type-specific modulation of growth behavior without the uptake of nanoparticles.