Injectable Inflammation-Responsive Hydrogels for Microenvironmental Regulation of Intervertebral Disc Degeneration.

Chronic local inflammation and excessive cell apoptosis in nucleus pulposus (NP) tissue are the main causes of intervertebral disc degeneration (IDD). Stimuli-responsive hydrogels have great potential in the treatment of IDD by facilitating localized and controlled drug delivery. Herein, an injectable drug-loaded dual stimuli-responsive adhesive hydrogel for microenvironmental regulation of IDD, is developed. The gelatin methacryloyl is functionalized with phenylboronic acid groups to enhance drug loading capacity and enable dual stimuli-responsive behavior, while the incorporation of oxidized hyaluronic acid further improves the adhesive properties. The prepared hydrogel exhibits an enhanced drug loading capacity for diol-containing drugs, pH- and reactive oxygen species (ROS)-responsive behaviors, excellent radical scavenging efficiency, potent antibacterial activity, and favorable biocompatibility. Furthermore, the hydrogel shows a beneficial protective efficacy on NP cells within an in vitro oxidative stress microenvironment. The in vivo results demonstrate the hydrogel's excellent therapeutic effect on treating IDD by maintaining water retention, restoring disc height, and promoting NP regeneration, indicating that this hydrogel holds great potential as a promising therapeutic approach for regulating the microenvironment and alleviating the progression of IDD.

Naturally Derived Injectable Dual-Cross-Linked Adhesive Hydrogel for Acute Hemorrhage Control and Wound Healing.

Developing biocompatible injectable hydrogels with high mechanical strength and rapid strong tissue adhesion for hemostatic sealing of uncontrolled bleeding remains a prevailing challenge. Herein, we engineer an injectable and photo-cross-linkable hydrogel based on naturally derived gelatin methacrylate (GelMA) and N-hydroxysuccinimide-modified poly(γ-glutamic acid) (γPGA-NHS). The chemically dual-cross-linked hydrogel rapidly forms after UV light irradiation and covalently bonds to the underlying tissue to provide robust adhesion. We demonstrate a significantly improved hemostatic efficacy of the hydrogel using various injury models in rats compared to the commercially available fibrin glue. Notably, the hydrogel can achieve hemostasis in porcine liver and spleen incision, and femoral artery puncture models. Moreover, the hydrogel is used for sutureless repair of the liver defect in a rat model with a significantly suppressed inflammatory response, enhanced angiogenesis, and superior healing efficacy compared to fibrin glue. Together, this study offers a promising bioadhesive for treating severe bleeding and facilitating wound repair.

Injectable pathological microenvironment-responsive anti-inflammatory hydrogels for ameliorating intervertebral disc degeneration.

Chronic local inflammation and resulting cellular dysfunction of nucleus pulposus (NP) cells are important pathogenic factors of intervertebral disc degeneration (IDD). Injectable pathological microenvironment-responsive hydrogels hold significant potential for treating IDD by adapting to dynamic microenvironment of IDD. Herein, we proposed an injectable gelatin-based hydrogel drug delivery system that could respond to the pathological microenvironment of IDD for controlled release of anti-inflammatory drug to promote degenerative NP repair. The hydrogel system was prepared by conjugating phenylboronic acid-modified gelatin methacryloyl (GP) with the naturally extracted anti-inflammatory drug epigallocatechin-3-gallate (EGCG) through dynamic boronic esters. The hydrogel exhibited excellent degradability, injectability, antioxidant properties, anti-inflammatory effects, and biocompatibility. It also displayed responsive-release of EGCG under high reactive oxygen species (ROS) levels and acidic conditions. The hydrogel demonstrated remarkable cytoprotective effects on NP cells in both hyperactive ROS environments and inflammatory cytokine-overexpressed environments in vitro. In vivo studies revealed that the hydrogel injected in situ could effectively ameliorate the intervertebral disc degeneration by maintaining the disc height and NP tissue structure in a rat IDD model. The hydrogel system exhibited excellent biocompatibility and responsive-release of diol-containing drugs in pathological microenvironments, indicating its potential application as a drug delivery platform.

Meniscus-Inspired Self-Lubricating and Friction-Responsive Hydrogels for Protecting Articular Cartilage and Improving Exercise.

Meniscus injuries are associated with the degeneration of cartilage and development of osteoarthritis (OA). It is challenging to protect articular cartilage and improve exercise when a meniscus injury occurs. Herein, inspired by the components and functions of the meniscus, we developed a self-lubricating and friction-responsive hydrogel that contains nanoliposomes loaded with diclofenac sodium (DS) and Kartogenin (KGN) for anti-inflammation and cartilage regeneration. When the hydrogel was injected into the meniscus injury site, the drug-loaded nanoliposomes were released from the hydrogel in a friction-responsive manner and reassembled to form hydration layers that lubricate joints during movement. Meanwhile, DS and KNG were constantly released from the nanoliposomes to mitigate inflammation and promote cartilage regeneration. Additionally, this hydrogel exhibited favorable injectability, mechanical properties, fatigue resistance, and prolonged degradation. In vivo experiments demonstrated that injection of the hydrogel effectively improved exercise performance and protected the articular cartilage of rats, suggesting it as a potential therapeutic approach for meniscal injuries.

Rapidly in situ forming an injectable Chitosan/PEG hydrogel for intervertebral disc repair.

Intervertebral disc (IVD) degeneration occurred with the increasing age or accidents has puzzled peoples in daily life. To seal IVD defect by injectable hydrogels is a promising method for slowing down IVD degeneration. Herein, we reported a rapidly in situ forming injectable chitosan/PEG hydrogel (CSMA-PEGDA-L) through integrating photo-crosslink of methacrylate chitosan (CSMA) with Schiff base reaction between CSMA and aldehyde polyethylene glycol (PEGDA). The CSMA-PEGDA-L possessed a stronger compressive strength than the photo-crosslinked CSMA-L hydrogel and Schiff-base-crosslinked CSMA-PEGDA hydrogel. This chitosan/PEG hydrogel showed low cytotoxicity from incubation experiments of nucleus pulpous cells. When implanted on the punctured IVD of rat's tail, the CSMA-PEGDA-L hydrogel could well retard the progression of IVD degeneration through physical plugging, powerfully proven by radiological and histological evaluations. This work demonstrated the strategy of in situ injectable glue may be a potential solution for prevention of IVD degeneration.

A Choline Phosphoryl-Conjugated Chitosan/Oxidized Dextran Injectable Self-Healing Hydrogel for Improved Hemostatic Efficacy.

The development of injectable hydrogels with good biocompatibility, self-healing, and superior hemostatic properties is highly desirable in emergency and clinical applications. Herein, we report an in situ injectable and self-healing hemostatic hydrogel based on choline phosphoryl functionalized chitosan (CS-g-CP) and oxidized dextran (ODex). The CP groups were hypothesized to accelerate hemostasis by facilitating erythrocyte adhesion and aggregation. Our results reveal that the CS-g-CP/ODex hydrogels exhibit enhanced blood clotting and erythrocyte adhesion/aggregation capacities compared to those of the CS/ODex hydrogels. The CS-g-CP50/ODex75 hydrogel presents rapid gelation time, good mechanical strength and tissue adhesiveness, satisfactory bursting pressure, and favorable biocompatibility. The hemostatic ability of the CS-g-CP50/ODex75 hydrogel was significantly improved compared to that of the CS/ODex hydrogel and commercial fibrin sealant in the rat tail amputation and liver/spleen injury models. Our study highlights the positive and synergistic effects of CP groups on hemostasis and strongly supports the CS-g-CP50/ODex75 hydrogel as a promising adhesive for hemorrhage control.

In situ forming injectable γ-poly(glutamic acid)/PEG adhesive hydrogels for hemorrhage control.

Rapidly in situ forming adhesive hydrogels are promising candidates for efficient hemostasis due to their easy administration and minimal invasion. However, development of biocompatible and high-performance hemostatic hydrogels without any additional toxic agents remains a challenge. Herein, a series of novel injectable adhesive hydrogels based on N-hydroxysuccinimide (NHS) modified γ-poly(glutamic acid) (γPGA-NHS) and tetra-armed poly(ethylene glycol) amine (Tetra-PEG-NH2) were developed. Among all samples, PGA10-PEG15 and PGA10-PEG20 hydrogels with higher PEG contents exhibited rapid gelation time (<20 s), strong mechanical strength (compression modulus up to ∼75 kPa), good adhesive properties (∼15 kPa), and satisfactory burst pressure (∼18-20 kPa). As a result, PGA10-PEG15 and PGA10-PEG20 hydrogels showed a remarkable reduction in hemostasis time and blood loss compared with gauze and fibrin glue. More importantly, the PGA10-PEG20 hydrogel was also successfully used to seal femoral arterial trauma. Subcutaneous implantation experiments indicated a good biocompatibility of the hydrogels in vivo. All these results strongly support that the developed PGA-PEG hydrogels could serve as promising hemostatic agents in emergency and clinical situations.

A simple and cost-effective approach to fabricate tunable length polymeric microneedle patches for controllable transdermal drug delivery.

Polymeric microneedles (MNs) are attractive transdermal drug delivery systems because of their efficient drug delivery and minimal invasiveness. Master template fabrication is the most time-consuming and costly step in producing polymeric MNs using a micromoulding approach. Herein, this issue is addressed by modifying tattoo needle cartridges by adjusting the volume of a PDMS spacer, thus streamlining polymeric MN fabrication and significantly reducing its manufacturing cost. Using the fabricated master template, dissolvable polymeric MN systems containing poly(vinyl pyrrolidone) (PVP) and poly(vinyl alcohol) (PVA) were developed. This MN system exhibits several advantages, including controllable MN length, uniform distribution of each needle, and controllable drug release profiles. Overall, polymeric MN fabrication using this method is inexpensive, simple, and yields controllable and effective transdermal drug delivery.

Multifunctional Graphene-Oxide-Reinforced Dissolvable Polymeric Microneedles for Transdermal Drug Delivery.

Dissolvable polymeric microneedles (DPMNs) are promising transdermal drug delivery systems with minimal invasiveness and improved patient compliance. Incorporation of a small amount of graphene oxide (GO) in the biocompatible polymers for microneedle fabrication results in important new DPMN properties, that is, dramatically enhanced mechanic strength (10-17 times at 500 mg/mL GO), improved moisture resistance, self-sterilization, antibacterial and anti-inflammatory properties (demonstrated in vitro), and near-infrared light-activated controlled drug release (demonstrated in vitro and in vivo), which were exploited for the transdermal delivery of the chemotherapeutic, HA15, to melanoma-bearing mouse models. These new properties improve their efficacy of transdermal drug delivery and ease of use, enhance their capability of controlled drug release, enlarge the scope of the polymers that can be used for DPMN fabrication, prevent microbial contamination during storage and transportation, and reduce infection risk in clinical applications.