A Whole-Course-Repair System Based on Stimulus-Responsive Multifunctional Hydrogels for Myocardial Tissue Regeneration.

Myocardial infarction (MI) has emerged as the predominant cause of cardiovascular morbidity globally. The pathogenesis of MI unfolds as a progressive process encompassing three pivotal phases: inflammation, proliferation, and remodeling. Smart stimulus-responsive hydrogels have garnered considerable attention for their capacity to deliver therapeutic drugs precisely and controllably at the MI site. Here, a smart stimulus-responsive hydrogel with a dual-crosslinked network structure is designed, which enables the precise and controlled release of therapeutic drugs in different pathological stages for the treatment of MI. The hydrogel can rapidly release curcumin (Cur) in the inflammatory phase of MI to exert anti-apoptotic/anti-inflammatory effects. Recombinant humanized collagen type III (rhCol III) is loaded in the hydrogel and released as the hydrogel swelled/degraded during the proliferative phase to promote neovascularization. RepSox (a selective TGF-ß inhibitor) releases from Pluronic F-127 grafted with aldehyde nanoparticles (PF127-CHO@RepSox NPs) in the remodeling phase to against fibrosis. The results in vitro and in vivo suggest that the hydrogel improves cardiac function and alleviates cardiac remodeling by suppressing inflammation and apoptosis, promoting neovascularization, and inhibiting myocardial fibrosis. A whole-course-repair system, leveraging stimulus-responsive multifunctional hydrogels, demonstrates notable effectiveness in enhancing post-MI cardiac function and facilitating the restoration of damaged myocardial tissue.

Development of an injectable oxidized dextran/gelatin hydrogel capable of promoting the healing of alkali burn-associated corneal wounds.

The cornea serves as an essential shield that protects the underlying eye from external conditions, yet it remains highly vulnerable to injuries that could lead to blindness and scarring if not promptly and effectively treated. Excessive inflammatory response constitute the primary cause of pathological corneal injury. This study aimed to develop effective approaches for enabling the functional repair of corneal injuries by combining nanoparticles loaded with anti-inflammatory agents and an injectable oxidized dextran/gelatin/borax hydrogel. The injectability and self-healing properties of developed hydrogels based on borate ester bonds and dynamic Schiff base bonds were excellent, improving the retention of administered drugs on the ocular surface. In vitro cellular assays and in vivo animal studies collectively substantiated the proficiency of probucol nanoparticle-loaded hydrogels to readily suppress proinflammatory marker expression and to induce the upregulation of anti-inflammatory mediators, thereby supporting rapid repair of rat corneal tissue following alkali burn-induced injury. As such, probucol nanoparticle-loaded hydrogels represent a prospective avenue to developing long-acting and efficacious therapies for ophthalmic diseases.

An injectable carrier for spatiotemporal and sequential release of therapeutic substances to treat myocardial infarction.

Myocardial infarction (MI) has become the primary cause of cardiovascular mortality, while the current treatment methods in clinical all have their shortcomings. Injectable biomaterials have emerged as a promising solution for cardiac tissue repair after MI. In this study, we designed a smart multifunctional carrier that could meet the treatment needs of different MI pathological processes by programmatically releasing different therapeutic substances. The carrier could respond to inflammatory microenvironment in the early stage of MI with rapid release of curcumin (Cur), and then sustained release recombinant humanized collagen type III (rhCol III) to treat MI. The rapid release of Cur reduced inflammation and apoptosis in the early stages, while the sustained release of rhCol III promoted angiogenesis and cardiac repair in the later stages. In vitro and in vivo results suggested that the multifunctional carrier could effectively improve cardiac function, promote the repair of infarcted tissue, and inhibit ventricular remodeling by reducing cell apoptosis and inflammation, and promoting angiogenesis in the different pathological processes of MI. Therefore, this programmed-release carrier provides a promising protocol for MI therapy.

Injectable polyaniline nanorods/alginate hydrogel with AAV9-mediated VEGF overexpression for myocardial infarction treatment.

Intramyocardial injection of hydrogels possesses great potential in the minimally invasive treatment of myocardial infarction (MI), but the current injectable hydrogels lack conductivity, long-term angiogenesis inductive ability, and reactive oxygen species (ROS)-scavenging ability, which are essential for myocardium repair. In this study, lignosulfonate-doped polyaniline (PANI/LS) nanorods and adeno-associated virus encoding vascular endothelial growth factor (AAV9-VEGF) are incorporated in the calcium-crosslinked alginate hydrogel to develop an injectable conductive hydrogel with excellent antioxidative and angiogenic ability (Alg-P-AAV hydrogel). Due to the special nanorod morphology, a conductive network is constructed in the hydrogel with the conductivity matching the native myocardium for excitation conduction. The PANI/LS nanorod network may also have large specific surfaces and effectively scavenges ROS to protect cardiomyocytes from oxidative stress damage. AAV9-VEGF transfects the surrounding cardiomyocytes for continuously expressing VEGF, which significantly promotes the proliferation, migration and tube formation of endothelial cells. After injecting the Alg-P-AAV hydrogel around the MI area in rats, the generation of gap junctions and angiogenesis are greatly improved with reduced infarct area and recovered cardiac function. The remarkable therapeutic effect indicates the promising potential of this multi-functional hydrogel for MI treatment.

Microneedles for in situ tissue regeneration.

Tissue injury is a common clinical problem, which may cause great burden on patients' life. It is important to develop functional scaffolds to promote tissue repair and regeneration. Due to their unique composition and structure, microneedles have attracted extensive attention in various tissues regeneration, including skin wound, corneal injury, myocardial infarction, endometrial injury, and spinal cord injury et al. Microneedles with micro-needle structure can effectively penetrate the barriers of necrotic tissue or biofilm, therefore improving the bioavailability of drugs. The use of microneedles to deliver bioactive molecules, mesenchymal stem cells, and growth factors in situ allows for targeted tissue and better spatial distribution. At the same time, microneedles can also provide mechanical support or directional traction for tissue, thus accelerating tissue repair. This review summarized the research progress of microneedles for in situ tissue regeneration over the past decade. At the same time, the shortcomings of existing researches, future research direction and clinical application prospect were also discussed.

Responsive multifunctional hydrogels emulating the chronic wounds healing cascade for skin repair.

It remains challenging to cure chronic diabetic wounds due to its' harsh microenvironment and poor tissue regeneration ability. At present, bacteria elimination, inflammatory response suppression and angiogenesis orderly render an important paradigm for chronic diabetic wound treatment. Herein, smart-responsive multifunctional hydrogels were developed to improve chronic diabetic wound healing, which could quickly respond to the acidic environment of the diabetic wound site and mediate multistage sequential delivery of silver and curcumin-loaded polydopamine nanoparticles (PDA@Ag&Cur NPs) and vascular endothelial growth factor (VEGF). PDA@Ag&Cur NPs and VEGF endowed the hydrogels with antibacterial, anti-inflammatory and angiogenesis performances, respectively. The in vitro and in vivo experiments confirmed that our multistage drug delivery hydrogels could effectively eliminate bacteria, relieve inflammatory response, and induce angiogenesis, hence accelerating the closure of chronic diabetic wounds. In conclusion, we highlighted the importance of multistage manipulation in wound healing and offered a combinatorial therapeutic strategy to sequentially deliver drugs exactly aiming at the dynamic wound healing stages.

Regeneration of infarcted hearts by myocardial infarction-responsive injectable hydrogels with combined anti-apoptosis, anti-inflammatory and pro-angiogenesis properties.

Current treatments including drug therapy, medical device implantation, and organ transplantation have considerable shortcomings for myocardial infarction (MI), such as high invasiveness, the scarce number of donor organs, easy thrombosis, immune rejection, and poor therapeutic effects. Therefore, the development of new solutions to repair infarcted hearts is urgently needed. Smart responsive injectable hydrogels have served as a good foundation in biomedical engineering, especially for cardiac regeneration. Herein, we synthesized an injectable hydrogel that responds to the inflammatory microenvironment at the site of MI to provide the drug curcumin (Cur) and tailored recombinant humanized collagen type III (rhCol III) in a controlled manner for myocardial repair. The excellent antioxidant and anti-inflammatory properties of Cur could effectively reduce the ROS level and cell apoptosis and inhibit inflammatory reactions after MI. The tailored rhCol III promoted cell proliferation, migration, and angiogenesis. The therapeutic hydrogel resulted in the rapid recovery of cardiac function after MI by elevating the expression of the cardiac markers α-actinin and CX 43. In vitro and in vivo data showed that the combined anti-apoptosis, anti-inflammatory and pro-angiogenesis treatment strategies were an auspicious tactic for the treatment of MI, and had significant clinical application value. Furthermore, the work also demonstrated the great application potential of our tailored rhCol III in promoting the repair and regeneration of infarcted hearts.

Construction of multifunctional wound dressings with their application in chronic wound treatment.

As the prevalence of diabetes increases year by year and the aging population continues to intensify in the world, chronic wounds such as diabetic foot ulcers and pressure ulcers have become serious problems that threaten people's health, and have brought an enormous burden to the world healthcare system. Conventional clinical treatment of chronic wounds relies on non-specific topical care (including debridement, infection/inflammation control, and frequent wound dressing changes), which can alleviate disease progression and reduce patient suffering to a certain extent, but the overall cure rate is less than 50% and the recurrence rate is high. Traditional wound dressings such as gauze, hydrocolloids, films and foams are single-function, acting as a physical barrier or absorbing exudates, and cannot meet all the needs of the entire chronic wound healing process. Recently, a large number of novel functional dressings have been reported for chronic wound repair. Based on the progress on wound dressings in recent years and the relevant research experience of our group, the review summarizes and discusses the progress on multifunctional wound dressings (such as microneedles, sponges and hydrogels) with anti-inflammatory, antioxidant, antibacterial, pro-angiogenic and tissue adhesive functions in detail. At the same time, the various responsive mechanisms (in vivo microenvironment or in vitro stimulation) of the smart multifunctional wound dressing are also analyzed in detail. It is expected that the review could provide some inspiration and suggestions for research on dressings for chronic wound treatment.

Microfibrillated cellulose-enhanced carboxymethyl chitosan/oxidized starch sponge for chronic diabetic wound repair.

Herein, a novel microfibrillated cellulose (MFC) reinforced natural polymer-based sponge composed of carboxymethyl chitosan (CMC) and oxidized starch (OS) with hemostatic, repairing-promoting, and antimicrobial performances was fabricated for chronic wound repair. When the content of MFC reached 1.2 wt%, the prepared sponge exhibited ultra-fast water or blood-trigged shape recovery property within 3 s. Moreover, sponge was functionally modified with silver nanoparticles (AgNPs) and recombinant humanized collagen type III (rhCol III). The AgNPs and rhCol III loaded sponge (A-Ag/III) could effectively kill a broad spectrum of pathogenic microbes, promote the proliferation and migration of L929 cells in vitro. Due to their erythrocyte-aggregating ability and positive-charge feature of CMC, the A-Ag/III displayed rapid hemostasis ability. Furthermore, the in vivo animal experiment demonstrated the A-Ag/III could promote wound repair by inhibiting inflammation, promoting angiogenesis, and cell proliferation.

Injectable multifunctional hyaluronic acid/methylcellulose hydrogels for chronic wounds repairing.

Herein, an injectable multifunctional hydrogel based on dopamine grafted hyaluronic acid and phenylboric acid grafted methylcellulose was fabricated for promoting the repair of diabetic wounds. The prepared hydrogel possessed multifunctional properties including rapid gelation time (less than 10 s), self-healing, high water absorbency, tissue adhesiveness and excellent antioxidant activity. After loading Ag nanoparticles and the recombinant humanized collagen type III with high affinity to cells, the hydrogel exhibited properties of pH-/H2O2-responsive drug release profile, promoting cell proliferation and ideal antibacterial activity. Moreover, the in vivo experimental results demonstrated the prepared hydrogel could significantly accelerate wound repair by enhancing the collagen deposition and granulation tissue regeneration, reducing the expression of CD68 and improving the production of Ki67 and CD31 simultaneously. In conclusion, these multifunctional injectable hydrogels possessed great potential in chronic wound dressings.

Injectable conductive and angiogenic hydrogels for chronic diabetic wound treatment.

Chronic diabetic wounds are lack of angiogenesis and susceptible to bacterial infections due to their high sugar microenvironment, making them difficult to heal. Here, a conductive and intrinsically antibacterial hydrogel with pH responsiveness has been developed. This hydrogel has good mechanical properties, self-healing ability and biocompatibility, and can smartly release the pro-angiogenic drug, deferoxamine. Application of the hydrogel promotes the proliferation and migration of endothelial cells and enhances vascularization by upregulating the expression of hypoxia-inducible factor-1α and vascular endothelial growth factor. The hydrogel dressing combined with electrical stimulation improves angiogenesis and significantly accelerates the healing of infected diabetic wounds, which would lead to a promising therapeutic strategy.

Dissolving microneedle-encapsulated drug-loaded nanoparticles and recombinant humanized collagen type III for the treatment of chronic wound via anti-inflammation and enhanced cell proliferation and angiogenesis.

Nowadays, diabetic chronic wounds impose a heavy burden on patients and the medical system. Persistent inflammation and poor tissue remodeling severely limit the healing of chronic wounds. For these issues, the first recombinant humanized collagen type III (rhCol III) and naproxen (Nap) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticle incorporated hyaluronic acid (HA) microneedle (MN) was fabricated for diabetic chronic wound therapy. As the tailored rhCol III was synthesized based on the Gly483-Pro512 segment, which contained the highly adhesive fragments (GER, GEK) in the human collagen type III sequence, it possessed strong cell adhesion. The mechanical strength of the prepared MN was enough to overcome the tissue barrier of necrosis/hyperkeratosis in a minimally invasive way after being applied in wounds. Subsequently, rhCol III and Nap@PLGA nanoparticles were rapidly released to the wound site within a few minutes. The prepared MN possessed favourable biocompatibility and could effectively facilitate the proliferation and migration of fibroblasts and endothelial cells. Furthermore, the regenerative efficacy of the MN was evaluated in vivo using the diabetic rat full-thickness skin wound model. These results illustrated that the prepared MN could accelerate wound closure by reducing the inflammatory response and enhancing angiogenesis or collagen deposition, indicating their significant application value in wound dressings for chronic wound repair.

A spatiotemporal release platform based on pH/ROS stimuli-responsive hydrogel in wound repairing.

Fabricating injectable hydrogel with multifunctions that matchs the highly ordered healing process of skin regeneration has greatly desired in treatment of chronic diabetic wounds. Herein, a pH/reactive oxygen species (ROS) dual responsive injectable glycopeptide hydrogel based on phenylboronic acid-grafted oxidized dextran and caffeic acid-grafted ε-polylysine was constructed, which exhibited inherent antibacterial and antioxidant capacities. The mangiferin (MF) with the ability to promote angiogenesis was encapsulated into pH-responsive micelles (MIC). Subsequently, diclofenac sodium (DS) with anti-inflammatory activities and MIC@MF were embedded into the hydrogel. The hydrogel possessed good biodegradability, stable rheological property and self-healing ability, and could realize the spatiotemporal delivery of DS and MF. The in vitro and in vivo data showed that the hydrogel was biocompatible with effective anti-infection, anti-oxidation and anti-inflammation at early stages, then further promoted angiogenesis and accelerated wound repairing. Collectively, this novel glycopeptide hydrogel provides a facile and effective strategy for chronic diabetic wound repairing.

Correction: Microenvironment-responsive multifunctional hydrogels with spatiotemporal sequential release of tailored recombinant human collagen type III for the rapid repair of infected chronic diabetic wounds.

Correction for 'Microenvironment-responsive multifunctional hydrogels with spatiotemporal sequential release of tailored recombinant human collagen type III for the rapid repair of infected chronic diabetic wounds' by Cheng Hu et al., J. Mater. Chem. B, 2021, 9, 9684-9699, DOI: 10.1039/D1TB02170B.

Microenvironment-responsive multifunctional hydrogels with spatiotemporal sequential release of tailored recombinant human collagen type III for the rapid repair of infected chronic diabetic wounds.

Recently, the incidence of chronic diabetic wounds increases continuously, and the existing clinical treatment is less effective. Thus, it is an urgent need to solve these problems for better clinical treatment effects. Herein, we prepared a brand-new tailored recombinant human collagen type III (rhCol III) and constructed a multifunctional microenvironment-responsive hydrogel carrier based on multifunctional antibacterial nanoparticles (PDA@Ag NPs) and our tailored rhCol III. The multifunctional smart hydrogel disintegrated quickly at the chronic diabetic wound sites and achieved the programed on-demand release of different therapeutic substances. The first released PDA@Ag NPs showed great antibacterial properties against S. aureus and E. coli. They could kill bacteria rapidly, and also showed antioxidant and anti-inflammatory effects at the wound site. The subsequent release of our tailored rhCol III could promote the proliferation and migration of mouse fibroblasts and endothelial cells during the proliferation and remodeling process of wound healing. Relevant results showed that the multifunctional smart hydrogel could promote the expression levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), decrease the inflammatory response, accelerate the deposition of collagen and increase cell proliferation and angiogenesis, thereby speeding up the healing of infected chronic wounds. In a word, the hydrogel, which took into consideration the complex microenvironment at the wound site and multi-stage healing process, could achieve programmed and responsive release of different therapeutic substances to meet the treatment needs in different wound healing stages. More importantly, our work illustrated the great application potential of our brand-new rhCol III in promoting chronic wound repair and regeneration.

Intrinsic Antibacterial and Conductive Hydrogels Based on the Distinct Bactericidal Effect of Polyaniline for Infected Chronic Wound Healing.

Most chronic wounds suffer from infections, and their treatment is challenging. The usage of antibiotics may lead to bacterial resistance and adverse side effects. Positively charged substances have shown promise, but their applications are usually limited by certain cytotoxicity or complex synthesis. Doped polyaniline that carries a high density of positive charges would be a promising candidate due to its good biocompatibility and easy availability, but its interaction with bacteria has not been elucidated. Herein, the distinct bactericidal effect of polyaniline against Gram-positive bacteria has been verified. The antibacterial activity may result from the specific interaction with lipoteichoic acid to destroy the Gram-positive bacterial cell wall. Polyaniline and a macromolecular dopant (sulfonated hyaluronic acid) are used to construct a flexible hydrogel with skin-mimic electrical conductivity. The in vivo results demonstrate that electrical stimulation (ES) through this hydrogel is superior to ES via separated electrodes (the ES strategy used clinically) for promoting infected chronic wound healing.

Microneedle-mediated vascular endothelial growth factor delivery promotes angiogenesis and functional recovery after stroke.

Ischemic stroke is still the major cause of disability worldwide. Although vascular endothelial growth factor (VEGF) is able to promote both angiogenesis and functional recovery, its use is limited by needle-induced injury, nonhomogenous VEGF distribution, and limited VEGF retention in the brain after intracranial or intravenous injection. Here, we first present a gelatin methacryloyl (GelMA) microneedle (MN)-based platform for the sustained and controlled local delivery of an adeno-associated virus (AAV) expressing human VEGF (AAV-VEGF) that achieves homogenous distribution and high transfection efficiency in ischemic brains. An ischemic stroke model was established in adult rats, and MNs loaded with AAV-VEGF were epicortically inserted into both the ischemic core and penumbra of these rats one day after the onset of ischemia. One week later, the inflammatory response and microneedle biocompatibility were assessed by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence. Eight weeks later, angiogenesis and neural stem cell proliferation and migration were assessed. GelMA MN implantation did not elicit an obvious inflammatory response and had good biocompatibility in the brain. AAV-green fluorescent protein (GFP)-loaded MNs could achieve successful transfection and homogeneous distribution in the brain cortex three weeks postoperatively. MNs loaded with AAV-VEGF increased VEGF expression and enhanced functional angiogenesis and neurogenesis. In summary, MNs might emerge as a promising platform for delivering various therapeutics to treat ischemic stroke and repair other neurologically diseased tissues.

Inflammation-Responsive Drug-Loaded Hydrogels with Sequential Hemostasis, Antibacterial, and Anti-Inflammatory Behavior for Chronically Infected Diabetic Wound Treatment.

Stimuli-responsive hydrogels possess unique advantages in drug delivery due to their variable performance and status based on the external environment. In the present study, a dual-responsive (pH and reactive oxygen species (ROS)) hydrogel was prepared to realize drug release properties under inflammatory stimulation. By grafting 3-carboxy-phenylboronic acid to the gelatin molecular backbone and cross-linking with poly(vinyl alcohol), we successfully synthesized the inflammation-responsive drug-loaded hydrogels after encapsulation with vancomycin-conjugated silver nanoclusters (VAN-AgNCs) and pH-sensitive micelles loaded with nimesulide (NIM). This novel design not only retained the dynamic functions of hydrogels, such as injectability, self-healing, and remodeling, but also realized sequential and on-demand drug delivery at diabetic-infected wound sites. In this work, we found that the hydrogel exhibited excellent biocompatibility and hemostasis properties owing to the enhanced cell-adhesive property of the gelatin component. The significant antibacterial and anti-inflammatory effect of the hydrogel was demonstrated in an in vitro experiment. Moreover, in the in vivo experiment, the hydrogel was found to play a role in promoting infected wound healing through sequential hemostasis and antibacterial and anti-inflammatory processes. Collectively, this inflammation-responsive hydrogel design containing VAN-AgNCs and NIM-loaded micelles has great potential in the application of chronically infected diabetic wound treatment, as well as in other inflammatory diseases.

Dual-responsive injectable hydrogels encapsulating drug-loaded micelles for on-demand antimicrobial activity and accelerated wound healing.

Disease microenvironment stimuli-responsive hydrogels are of special interests in enhancing the drug delivery specificity for biomedical applications. In order to achieve specific drug release characteristic at the inflammation region, a smart pH- and reactive oxygen species (ROS)-responsive injectable hydrogel with self-healing and remodeling capability was designed in our present work. By grafting phenylboronic acid to the side chain of the alginate polymer, a highly specific dual-responsive hydrogel with low pH and high ROS was obtained. Moreover, the hydrogel was endowed with antibacterial and anti-inflammatory properties respectively via the effective assembly of antibiotic amikacin (AM), and anti-inflammatory drug naproxen (Nap) which were preloaded into the micelles. Such hydrogel formulation not only preserved the structural integrity and excellent rheological properties of the hydrogel but also allowed for a controllable drug release rate at inflammation sites. The antibacterial experiment results in vitro demonstrated that the hydrogel could effectively kill bacteria by amikacin release, with the inhibitive rate reached to 90% for S. aureus and 98% for P.aeruginosa. Furthermore, the anti-inflammatory drug naproxen was also controllably released from the ROS-responsive micelles within 24 h under pH 5.0, and 10 mM H2O2in vitro. Most importantly, the smart hydrogels showed good biocompatibility, and greatly promoted the healing of infected wounds in vitro by cell scratch assay. In addition, it efficiently reduced the levels of TNF-α (the pro-inflammatory cytokine) by 2.80 times, and increased IL-10 (anti-inflammatory cytokine) by 2.41 times than the hydrogel control without antibiotic and anti-inflammatory drug. Within the dual-responsiveness of pH and ROS, the hydrogel reduced the inflammation response of the surrounding tissues significantly and accelerated the healing process of the infected area. Collectively, this smart hydrogel formula containing antibiotic and drug-loaded micelles is very promising to be applied topically against various microbial infections. We believe that this strategy can also be applied to various disease treatments.

Fabrication and Application of Carboxymethyl Cellulose-Carbon Nanotube Aerogels.

In this study, composite aerogels with excellent mechanical properties were prepared by using carboxymethyl cellulose (CMC) as raw materials, with carboxylic carbon nanotubes (CNTs) as reinforcement. By controlling the mass fraction of CNTs, composite aerogels with different CNTs were prepared, and the surface morphology, specific surface area, compressive modulus, density and adsorption capacities towards different oils were studied. Compared to the pure CMC aerogel, the specific surface areas of CMC/CNTs were decreased because of the agglomeration of CNTs. However, the densities of composite aerogels were lower than pure CMC aerogel. This is because the CNTs were first dispersed in water and then added to CMC solution. The results indicated that it was easy for the low CMC initial concentration to be converted to low density aerogel. The compressive modulus was increased from 0.3 MPa of pure CMC aerogel to 0.5 MPa of 5 wt % CMC/CNTs aerogel. Meanwhile, the prepared aerogels showed promising properties as the adsorption materials. Because of the high viscosity, liquid possesses strong adhesion to the pore wall, the adsorption capacity of the CMC aerogel to the liquid increases as the viscosity of the liquid increases.