Optimization of 3D hydrogel microenvironment for enhanced hepatic functionality of primary human hepatocytes.

Although primary human hepatocytes (PHHs) are the gold standard in drug efficacy and metabolism studies, long-term survival of PHHs and maintenance of their hepatic function are still challenging. In this study, we focused on the effect of the initial microenvironment on upregulation and long-term preservation of hepatic function of PHHs encapsulated within biodegradable hydrogel systems. PHHs were encapsulated in RGD-functionalized hybrid hydrogels with various degrees of degradability, and their hepatic functionality was analyzed. Regardless of the hydrogel elastic modulus, the combination with nondegradable hydrogels had a predominantly negative effect on the prompt engraftment of PHHs, whereas a degradable hydrogel with intermediate initial degradability was most effective in maintaining hepatic function. Efficient network formation by PHHs and cocultured cells, along with the control of hydrogel degradation, governed the hepatic functionality at an early stage and upon long-term cultivation. Under optimized conditions, expression of genes involved in biological processes such as focal adhesions, cell survival, cytoskeleton formation, and extracellular matrix interactions was significantly higher than that in a control with relatively delayed initial degradation. Thus, we suggest that the orchestrated control of initial cellular remodeling may play an important role in the maintenance of hepatic function in a three-dimensional PHH culture.

Photo-crosslinking methacrylated-amylopectin/polyacrylamide hydrogels loading curcumin for applications as degradable, injectable, and antibacterial wound dressings.

The preparation of biodegradable and antibacterial hydrogels has important clinical value. In this work, a novel strategy has been developed to prepare degradable hydrogel dressings without chemical crosslinking agent using methacrylate anhydride (MA)-modified amylopectin (APMA) and polyacrylamide (PAM). After introducing CC bonds, APMA/PAM hydrogels can be formed under light irradiation. This strategy improves the gelling ability of AP and degradation properties of the hydrogel by avoiding the addition of crosslinking agent. The degradation rate of APMA/PAM hydrogel is 74.04 ± 0.69 % within 12 weeks, while that of APMA/PAM hydrogel containing crosslinking agent is only 38.5 ± 0.1 %. The APMA/PAM hydrogel loading curcumin (Cur) (APMA/PAM-Cur) exhibits high antibacterial efficiency of 98.29 ± 0.41 % and 97.18 ± 0.81 % against S. aureus and E. coli, respectively, with light irradiation. Animal experiments show that the APMA/PAM-Cur hydrogel reduces the infiltration of inflammatory factors, increases the density of collagen, and makes the newly formed granulation tissue thicker and tighter. This study not only proves the promising potential of the APMA/PAM-Cur hydrogel as degradable and antibacterial wound dressing for clinical treatment, but also provides a new strategy for developing low-cost, degradable, and antibacterial wound dressings and reducing antibiotic abuse and environmental pollution caused by medical waste.

A 4D Printed Adhesive, Thermo-Contractile, and Degradable Hydrogel for Diabetic Wound Healing.

Chronic wound healing remains a substantial clinical challenge. Current treatments are often either prohibitively expensive or insufficient in meeting the various requirements needed for effective diabetic wound healing. A 4D printing multifunctional hydrogel dressing is reported here, which aligns perfectly with wounds owning various complex shapes and depths, promoting both wound closure and tissue regeneration. The hydrogel is prepared via digital light process (DLP) 3D printing of the mixture containing N-isopropylacrylamide (NIPAm), curcumin-loaded Pluronic F127 micelles (Cur-PF127), and poly(ethylene glycol) diacrylate-dopamine (PEGDA575-Do), a degradable crosslinker. The use of PEGDA575-Do ensures tissue adhesion and degradability, and cur-PF127 serves as an antibacterial agent. Moreover, the thermo-responsive mainchains (i.e., polymerized NIPAm) enables the activation of wound contraction by body temperature. The features of the prepared hydrogel, including robust tissue adhesion, temperature-responsive contraction, effective hemostasis, spectral antibacterial, biocompatibility, biodegradability, and inflammation regulation, contribute to accelerating diabetic wound healing in Methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness skin defect diabetic rat models and liver injury mouse models, highlighting the potential of this customizable, mechanobiological, and inflammation-regulatory dressing to expedite wound healing in various clinical settings.

Synthesis and Properties of Biodegradable Hydrogel Based on Polysaccharide Wound Dressing.

The metabolic disorder of the wound microenvironment can lead to a series of serious symptoms, especially chronic wounds, which result in significant pain in patients. At present, there is no effective and widely used wound dressing. Therefore, it is important to develop new multifunctional wound dressings. Hydrogel is an ideal wound dressing for medical nursing because of its abilities to absorb exudate and maintain wound wetting, its excellent biocompatibility, and its ability to provide a moist environment for wound repair. Because of these features, hydrogel overcomes the shortcomings of traditional dressings. Therefore, hydrogel has high medical value and is widely studied. In this study, a biodegradable hydrogel based on polysaccharide was synthesized and used as a wound dressing. The swelling degree and degradability of hydrogel were characterized as the characteristics of the wound dressing. The results showed that the prepared hydrogel was degraded with trypsin and in the soil environment. Furthermore, the wound dressing can effectively inhibit the bacterial environment, promote the deposition of the collagen structure of the wound tissue, and accelerate the healing of the wound. The proposed hydrogel has value in practical medical nursing application.

Stop-Flow Lithography for the Continuous Production of Degradable Hydrogel Achiral Crescent Microswimmers.

The small size of robotic microswimmers makes them suitable for performing biomedical tasks in tiny, enclosed spaces. Considering the effects of potentially long-term retention of microswimmers in biological tissues and the environment, the degradability of microswimmers has become one of the pressing issues in this field. While degradable hydrogel was successfully used to prepare microswimmers in previous reports, most hydrogel microswimmers could only be fabricated using two-photon polymerization (TPP) due to their 3D structures, resulting in costly robotic microswimmers solution. This limits the potential of hydrogel microswimmers to be used in applications where a large number of microswimmers are needed. Here, we proposed a new type of preparation method for degradable hydrogel achiral crescent microswimmers using a custom-built stop-flow lithography (SFL) setup. The degradability of the hydrogel crescent microswimmers was quantitatively analyzed, and the degradation rate in sodium hydroxide solution (NaOH) of different concentrations was investigated. Cytotoxicity assays showed the hydrogel crescent microswimmers had good biocompatibility. The hydrogel crescent microswimmers were magnetically actuated using a 3D Helmholtz coil system and were able to obtain a swimming efficiency on par with previously reported microswimmers. The results herein demonstrated the potential for the degradable hydrogel achiral microswimmers to become a candidate for microscale applications.

Modulation of Properties through Covalent Bond Induced Formation of Strong Ion Pairing between Polyelectrolytes in Injectable Conetwork Hydrogels.

In situ simultaneous formation of both covalent linkages and ion pair is challenging yet necessary to control the biological properties of a hydrogel. We report that the generation of covalent linkages (+N-C) facilitates the simultaneous formation of ion pairs between polyelectrolytes (PEs) in a hydrogel network. Co-injection of tertiary amine functional macromolecules and reactive poly(ethylene glycol) (PEG) containing negatively charged PE leads to the formation of hydrogel conetworks consisting of covalent junctions and ion pairs. Our design is based on the gradual appearance of +N-C junctions followed by formation of ion pairs. This strategy provides an easy access to hydrogel networks bearing a predetermined proportion of ion pair and covalent cross-linking junction. The proportion of ion pair could be varied by introducing a precalculated proportion of mono- and difunctional reactive PEG in the hydrogel system. The topology of the prepolymer and the hydrogel could be modulated (graft) during hydrogel formation. This approach is applicable to obtain covalent/ionic, covalent bond induced purely ionic, and purely covalent hydrogels of several macromolecular entities. The effect of ion pairing in the hydrogels is strongly reflected in the modulus, strain bearing, degradation, free volume, swelling, and drug release properties. The hydrogels exhibit microscopic recovery of modulus after application of high amplitude strain depending on the prepolymer concentration (chain entanglement) and nature of hydrogel network. The hydrogels are hemocompatible, and the covalent/ionic hydrogels show a slower release of methotrexate than that of the purely covalent hydrogel. This work provides an understanding for the in situ construction and manipulation of biological properties of hydrogels through the covalent bond induced formation of a strong ion pair.

Strong and Degradable Adhesion of Hydrogels.

Adhesives potentially offer convenient means to close wounds, but existing adhesives do not fulfill many common requirements. Here we demonstrate an approach to develop hydrogel adhesives that are strong initially, remain soft when adhered to soft tissues, and degrade over time. We demonstrate the approach by using a hydrogel that dissipates a large amount of energy during separation, forms strong and interlinks with the soft tissues, and degrades by breaking cross-links. The hydrogel achieves initial adhesion energies of 300-700 J/m2 when adhered to different tissues, can bear huge pressure, and completely degrades in 5 weeks under simulated physiological conditions.

Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery.

Despite great therapeutic potential and development of a repertoire of delivery approaches addressing degradation and cellular uptake limitations, small interfering RNA (siRNA) exhibits poorly controlled tissue-specific localization. To overcome this hurdle, siRNA was complexed to nanoparticles (siRNA/NP) embedded within poly(ethylene glycol)-poly(lactic acid)-dimethacrylate (PEG-PLA-DM) hydrogels with the hypothesis that hydrolytic degradation of ester bonds within the PLA crosslinks would provide tunable, sustained siRNA/NP release. Hydrogels formed from macromers with increasing PLA repeats (e.g., 0 or non-degradable to 5 PLA repeats flanking PEG cores) and mixtures of nondegradable PEG-DM (0 PLA) and degradable PEG-PLA5-DM macromers were investigated. Hydrogels formed only with fully degradable crosslinks degraded rapidly over 6-14 days with limited control over siRNA/NP release. However, hydrogels formed with mixtures of nondegradable and 20%, 50%, and 100% degradable macromers resulted in siRNA/NP release over 3 to 28 days. Subsequently, gene silencing mediated by released siRNA/NP from 20% and 50% degradable hydrogels was sustained for ~28 days. Furthermore, in vivo imaging showed that hydrogel degradation controlled siRNA/NP localization, with sustained siRNA/NP release from 0%, 20% and 50% degradable hydrogels over 28, 21, and 15 days. A model, which accounts for hydrogel degradation rate and siRNA/NP diffusion, was developed to enable rational design of siRNA/NP delivery depots. Overall, this study shows that siRNA/NP release can be sustained via encapsulation in hydrogels with tunable degradation kinetics and modeled for a priori design of delivery depots.

Light-triggered methylcellulose gold nanoparticle hydrogels for leptin release to inhibit fat stores in adipocytes.

Leptin is released in response to increased triglyceride storage in adipocytes and impacts body weight, but has drawbacks such as poor therapeutic effect and side effects when delivered systemically. Leptin also modifies adipocyte sensitivity to insulin to inhibit lipid accumulation. Here, light-triggered degradation of hydrogels was used to improve accuracy and effectiveness for sustained and controllable release. In our approach, leptin was entrapped within methylcellulose (MC)-based hydrogels, with incorporation of gold nanoparticles (NP). The incorporation of gold NP into MC hydrogels led to a tunable light irradiation response that dictated the hydrogel release rate of leptin. This manuscript demonstrates feasibility in designing tunable thermosensitive hydrogels for loading multimodality therapeutic agents to enhance the bioactivity of leptin for obesity therapy.

Poly(ethylene glycol) grafted polylactide based copolymers for the preparation of PLA-based nanocarriers and hybrid hydrogels.

In previous works, poly(D,L-lactide-co-ɛCL-poly(ethylene glycol) (poly(D,L-La-co-αPEGɛCL) amphiphilic graft-copolymers were successfully synthesized according to a copper azide-alkyne cycloaddition (CuAAC) strategy. This paper aims at reporting on the behavior of this amphiphilic copolymer in water, which was not studied in the previous paper. Moreover, the ability of the copolymer to stabilize a PLA nanoparticles aqueous suspension is presented. For this purpose, dynamic light scattering (DLS) and transmission electron microscopy (TEM) are proposed to characterize the nanoparticles in solution. Otherwise, the strategy developed for the synthesis of the amphiphilic copolymers was adapted and extended to the synthesis of PLA-based degradable hydrogel, potentially applicable as drug-loaded degradable polymer implant.