Tumor acidification and GSH depletion by bimetallic composite nanoparticles for enhanced chemodynamic therapy of TNBC.

Chemodynamic therapy (CDT) based on intracellular Fenton reaction to produce highly cytotoxic reactive oxygen species (ROS) has played an essential role in tumor therapy. However, this therapy still needs to be improved by weakly acidic pH and over-expression of glutathione (GSH) in tumor microenvironment (TEM), which hinders its future application. Herein, we reported a multifunctional bimetallic composite nanoparticle MnO2@GA-Fe@CAI based on a metal polyphenol network (MPN) structure, which could reduce intracellular pH and endogenous GSH by remodeling tumor microenvironment to improve Fenton activity. MnO2 nanoparticles were prepared first and MnO2@GA-Fe nanoparticles with Fe3+ as central ion and gallic acid (GA) as surface ligands were prepared by the chelation reaction. Then, carbonic anhydrase inhibitor (CAI) was coupled with GA to form MnO2@GA-Fe@CAI. The properties of the bimetallic composite nanoparticles were studied, and the results showed that CAI could reduce intracellular pH. At the same time, MnO2 could deplete intracellular GSH and produce Mn2+ via redox reactions, which re-established the TME with low pH and GSH. In addition, GA reduced Fe3+ to Fe2+. Mn2+ and Fe2+ catalyzed the endogenous H2O2 to produce high-lever ROS to kill tumor cells. Compared with MnO2, MnO2@GA-Fe@CAI could reduce the tumor weight and volume for the xenograft MDA-MB-231 tumor-bearing mice and the final tumor inhibition rate of 58.09 ± 5.77%, showing the improved therapeutic effect as well as the biological safety. Therefore, this study achieved the high-efficiency CDT effect catalyzed by bimetallic through reshaping the tumor microenvironment.

Reoxygenation Modulates the Adverse Effects of Hypoxia on Wound Repair.

Hypoxia is a major stressor and a prominent feature of pathological conditions, such as bacterial infections, inflammation, wounds, and cardiovascular defects. In this study, we investigated whether reoxygenation has a protective effect against hypoxia-induced acute injury and burn using the C57BL/6 mouse model. C57BL/6 mice were exposed to hypoxia and treated with both acute and burn injuries and were in hypoxia until wound healing. Next, C57BL/6 mice were exposed to hypoxia for three days and then transferred to normoxic conditions for reoxygenation until wound healing. Finally, skin wound tissue was collected to analyze healing-related markers, such as inflammation, vascularization, and collagen. Hypoxia significantly increased inflammatory cell infiltration and decreased vascular and collagen production, and reoxygenation notably attenuated hypoxia-induced infiltration of inflammatory cells, upregulation of pro-inflammatory cytokine levels (IL-6 and TNF-α) in the wound, and remission of inflammation in the wound. Immunofluorescence analysis showed that reoxygenation increased the expression of the angiogenic factor α-SMA and decreased ROS expression in burn tissues compared to hypoxia-treated animals. Moreover, further analysis by qPCR showed that reoxygenation could alleviate the expression of hypoxic-induced inflammatory markers (IL-6 and TNF), increase angiogenesis (SMA) and collagen synthesis (Col I), and thus promote wound healing. It is suggested that oxygen can be further evaluated in combination with oxygen-releasing materials as a supplementary therapy for patients with chronic hypoxic wounds.

Curcumin-loaded chitosan-based hydrogels accelerating S. aureus-infected wound healing.

The damaged skin for some reasons is vulnerable to invasion by bacteria and other harmful microorganisms, leading to delay of the wound healing. In order to promote the infected wound healing, curcumin was loaded with chitosan-based hydrogel was formed through phenylborate ester bonding and its properties and effects on the S. aureus-infected wound healing was tested. It was found the hydrogel showed good antioxidation on the intracellular reactive oxygen species, inhibition on the growth of S. aureus, and acceleration the infected skin healing. The ablity of hydrogel due to its regulating inflammation, promoting angiogenesis and collagen synthesis in the wound site. This research work suggested that the developed multifunctional hydrogel might be a beneficial treatment for the infected wound healing.

Chitosan and hyaluronic-based hydrogels could promote the infected wound healing.

The most important function of skin is to prevent biological dehydration and protect internal structures from the environment. When a wound becomes infected, the bacteria cause a sustained inflammatory response at the infected site, further delaying the healing process. Therefore, the search for better antibacterial strategies has become a topic of great concern. Therefore, the development of multifunctional hydrogels with antibacterial properties, ROS removal, and hemostasis is urgently required for promoting wound healing process. Chitosan is the only cationic natural polysaccharide with good biocompatibility, antibacterial and hemostatic ability. It is a candidate material to prepare hydrogel wound dressing. Hyaluronic acid (HA) is a natural biological macromolecule that belongs to a group of heteropolysaccharides known as non-sulfated glycosaminoglycans. It is a major component of the skin extracellular matrix (ECM) and is involved in inflammation, angiogenesis, and tissue regeneration. Here, the hydrogel was designed with the natural macromolecular of the gallic acid-grafted quaternized chitosan (GA-QCS) and oxidized hyaluronic acid (OHA) via Schiff base and/or Michael addition reaction. It was found that the GA-QCS/OHA hydrogel exhibited multifunctional capabilities with injectable, hemostasis, degradation, and release of medicines. In addiation, GA-QCS/OHA hydrogels exhibited remarkable antioxidant and migration promoting effects in vitro. And the mupirocin-loaded GA-QCS/OHA hydrogels had inhibitory effects on E. coli (Gram-negative bacterium) and S. aureus (Gram-positive bacterium) in vitro. A full-thickness skin of S. aureus infection mouse wound model was used to test the bioactive effect of the hydrogels and the accelerated wound healing was obtained due to the inhibiting the proinflammatory factor TNF-α and upregulating the vascularization factor CD31. This study proposed an effective strategy based on antioxidant, antibacterial, self-healing multifunctional hydrogel for wound healing under various infectious complications. This natural macromolecular hydrogel could act as an effective reactive oxygen species scavenger to promote the wound healing in the future.

Smart microneedle patches for wound healing and management.

The number of patients with non-healing wounds is generally increasing globally, placing a huge social and economic burden on every country. The complexity of the wound-healing process remains a major health challenge despite the numerous studies that have been reported on conventional wound dressings. Therefore, a therapeutic system that combines diagnostic and therapeutic modalities is essential to monitor wound-related biomarkers and facilitate wound healing in real time. Microneedles, as a multifunctional platform, are promising for transdermal diagnostics and drug delivery. Their advantages are mainly reflected in painless transdermal drug delivery, good biocompatibility, and ease of self-administration. In this work, we review recent advances in the use of microneedle patches for wound healing and monitoring. The paper first provides a brief overview of the skin structure and the wound healing process, and then discusses the current state of research and prospects for the development of wound-related biomarkers and their real-time monitoring based on microneedle sensors. It summarizes the current state of research based on the unique design of microneedle patches, including biomimetic, conductive, and environmentally responsive, to achieve wound healing. It further summarizes the prospects for the application of different microneedle-based drug delivery modalities and drug delivery substances for wound healing, due to their superior transdermal drug delivery advantages. It concludes with challenges and expectations for the use of smart microneedle patches for wound healing and management.

Photocatalytic Ag/AgBr-MBG for Rapid Antibacterial and Wound Repair.

In daily life and during surgery, the skin, as the outermost organ of the human body, is easily damaged to form wounds. If the wound was infected by the bacteria, especially the drug-resistant bacteria such as methicillin-resistant staphylococcus aureus (MRSA), it was difficult to recover. Therefore, it was important to develop the safe antimicrobial strategy to inhibit bacterial growth in the wound site, in particular, to overcome the problem of bacterial drug resistance. Here, the Ag/AgBr-loaded mesoporous bioactive glass (Ag/AgBr-MBG) was prepared, which had excellent photocatalytic properties under simulated daylight for rapid antibacterial activity within 15 min by generating reactive oxygen species (ROS). Meanwhile, the killing rate of Ag/AgBr-MBG against MRSA was 99.19% within 15 min, which further reduced the generation of drug-resistant bacteria. In addition, Ag/AgBr-MBG particles could disrupt bacterial cell membranes, showing the broad-spectrum antibacterial properties and promoting tissue regeneration and infected wound healing. Ag/AgBr-MBG particles might have potential applications as a light-driven antimicrobial agent in the field of biomaterials.

Preparation and Hemostatic Effect of Micro-Nanograded Porous Particles Doped with Dopamine-Based Water-Triggered Intelligent Composite Adhesives.

The wet environment of water or tissue in bleeding wounds poses significant challenges to the adhesion performance of existing hemostatic adhesives. An intelligent composite adhesive prepared by doping starch-based silicate micro-nanograded porous particles (MBC@CMS) with dopamine-hyperbranched polymers (HPD, 7800 Mw) synthesized by the Michael addition reaction could be triggered by water to form a glue (MBC@CMS-HPD). The results indicated that MBC@CMS-HPD could still have adhesion properties under running water washing and water immersion and could effectively seal the water outlet. The results of the glue-forming mechanism showed that MBC@CMS-HPD had better wettability than water, which could eliminate water molecules at the wet adhesive surface. When contacted with water, the agglomeration of the HPD hydrophobic chain increases the exposure of the catechol group, and the relative atomic mass of the N element on the surface increases from 2.8 to 4.8%. The adhesion of MBC@CMS-HPD was enhanced and stable. MBC@CMS-HPD showed significant hemostasis effects in five injury bleeding models of Sprague-Dawley (SD) rats and New Zealand rabbits. Especially in the fatal femoral artery bleeding model of New Zealand rabbits, MBC@CMS-HPD reduced the amount of bleeding by 75% and shortened the bleeding time by 78% compared with the a-cyanoacrylate adhesives. The results of the coagulation mechanism showed that compared with HPD, MBC@CMS-HPD could activate both endogenous and exogenous coagulation pathways. Among them, after contact with blood, HPD formed a gel to close the blood outlet, and MBC@CMS entered the wound to activate the internal and external coagulation pathways. In addition, HPD and MBC@CMS had good histocompatibility and degradability, which has the potential to be applied to different wounds.

Research Progress on Improving the Efficiency of CDT by Exacerbating Tumor Acidification.

In recent years, chemodynamic therapy (CDT) has received extensive attention as a novel means of cancer treatment. The CDT agents can exert Fenton and Fenton-like reactions in the acidic tumor microenvironment (TME), converting hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (·OH). However, the pH of TME, as an essential factor in the Fenton reaction, does not catalyze the reaction effectively, hindering its efficiency, which poses a significant challenge for the future clinical application of CDT. Therefore, this paper reviews various strategies to enhance the antitumor properties of nanomaterials by modulating tumor acidity. Ultimately, the performance of CDT can be further improved by inducing strong oxidative stress to produce sufficient ·OH. In this paper, the various acidification pathways and proton pumps with potential acidification functions are mainly discussed, such as catalytic enzymes, exogenous acids, CAIX, MCT, NHE, NBCn1, etc. The problems, opportunities, and challenges of CDT in the cancer field are also discussed, thereby providing new insights for the design of nanomaterials and laying the foundation for their future clinical applications.

Application of Metal-Organic Framework in Diagnosis and Treatment of Diabetes.

Diabetes-related chronic wounds are often accompanied by a poor wound-healing environment such as high glucose, recurrent infections, and inflammation, and standard wound treatments are fairly limited in their ability to heal these wounds. Metal-organic frameworks (MOFs) have been developed to improve therapeutic outcomes due to their ease of engineering, surface functionalization, and therapeutic properties. In this review, we summarize the different synthesis methods of MOFs and conduct a comprehensive review of the latest research progress of MOFs in the treatment of diabetes and its wounds. State-of-the-art in vivo oral hypoglycemic strategies and the in vitro diagnosis of diabetes are enumerated and different antimicrobial strategies (including physical contact, oxidative stress, photothermal, and related ions or ligands) and provascular strategies for the treatment of diabetic wounds are compared. It focuses on the connections and differences between different applications of MOFs as well as possible directions for improvement. Finally, the potential toxicity of MOFs is also an issue that we cannot ignore.

The contribution of pore size and porosity of 3D printed porous titanium scaffolds to osteogenesis.

Porous titanium implants were popularly fabricated to promote bone formation. A desirable porous scaffold was recommended to be with porosity of >60% or/and pore size of >300 µm for better osteointegration. However, whether the pore size and porosity could be randomly selected within the recommended values? And what is the correlation between pore size and porosity for accelerating osteointegration? In this study, porous titanium with cubic cell structure was produced by selective laser melting. The designed porosities of scaffolds with 700-µm pore size were 40%, 70% and 90%; and the pore sizes of scaffolds with 70% porosity were 400, 700 and 900 µm. The in vitro osteogenic potential and in vivo bone formation were investigated. Results showed that porosity and pore size could be tuned by altering strut size, which was further directly responsible for mechanical properties. Besides, pore size and porosity synergistically contributed to osteogenic activity in vitro and new bone formation in vivo. In regard to pore sizes herein, the optimized one for better osteogenic response and bone forming ability was ~600-700 µm (p70). Too smaller or too larger pore size might more or less hinder cellular behaviors and bone regeneration, even if both pore size (300-900 µm) and porosity (70%) were within the recommended value range. At a constant pore size (~600-700 µm), p70 and p90 with higher porosity was more conductive to biological effects, compared with p40. As a result, pore-size variation revealed more significant influence on osteogenesis, compared with variation of porosity within recommended values. However, the applicable porosity within recommended values should be designed with the consideration of specific load-bearing conditions. This study helps to provide guidance for designing porous scaffolds with appropriate mechanical strengths and effective bone-forming ability, so as to develop better custom-made bone substitutes.

Recent molecular design strategies for efficient photodynamic therapy and its synergistic therapy based on AIE photosensitizers.

Cancer seriously endangers human life and health. Recently, the development of AIEgens with aggregation-induced emission (AIE) effect as a new generation of photosensitizers (PSs) to circumvent aggregation-induced fluorescence quenching and reduction of ROS generation has received extensive attention in photodynamic therapy (PDT), a non-invasive anticancer therapy. Rational molecular design can enhance the photosensitization of AIE PSs to achieve effective PDT and can realize the construction of functionalized AIE PSs and synergistic therapy based on AIE PSs. To improve the efficacy of AIE PSs for cancer treatment, many groups have conducted molecular design studies and produced exciting results. This review summarizes the molecular design strategies of three types of AIE PSs for effective photodynamic therapy, focusing on the design strategies of pure organic small molecule type AIE PSs, and reviews the existing design strategies of metal complexes and conjugated polymers. Subsequently, the design strategy to achieve synergistic treatment of AIE PSs from molecular modifications is summarized. The challenges and prospects of the AIE PSs research field are further discussed.

Oxygen-releasing hydrogels promote burn healing under hypoxic conditions.

Hypoxic nonhealing wounds are a common complication in chronic patients, and chronic hypoxia is the main reason for delayed wound healing, so local wound oxygenation may be an effective way to address this problem. Here, we proposed a system consisting of oxygen-releasing microsphere (GC) and self-healing hydrogel (QGO). QGO/GC hydrogel could promote survival, migration and tube formation of human umbilical vein endothelial cells under hypoxic conditions. Moreover, QGO/GC hydrogels exhibited biocompatibility in vitro and in vivo. The hypoxic mouse burn model further confirmed that QGO/GC hydrogel could promote tissue repair by reducing inflammation (TNF-α and IL-1ß), increasing angiogenesis (CD31, VEGF and α-SMA) and collagen deposition. This study provided an effective oxygen-releasing hydrogel that could offer a simple and effective method for the clinical treatment of chronic hypoxic wounds. STATEMENT OF SIGNIFICANCE: Burn injury is caused by various exogenous factors such as friction, cold, radiations, electricity, chemicals, hot surfaces or liquids. Severe burn can damage the entire skin layer, and the healing process is delayed due to an unbalanced inflammatory response, excessive reactive oxygen species, lack of angiogenesis (insufficient nutrient and oxygen availability), and susceptibility to infection. In the present study, we proposed an oxygen-releasing hydrogel (QGO/GC). QGO/GC hydrogel could promote survival, migration, and tube formation of human umbilical vein endothelial cells under hypoxic conditions. And QGO/GC hydrogels could promote tissue repair by reducing inflammation, increasing angiogenesis and collagen deposition. This work provided an effective oxygen-releasing hydrogel for the clinical management of chronic hypoxic wounds.

Degradable and self-luminescence porous silicon particles as tissue adhesive for wound closure, monitoring and accelerating wound healing.

Tissue adhesives have received much attention for their effectiveness in sealing wounds or incisions in clinical surgery, especially in minimally invasive surgery. To meet the safe and smart wound management requirements, ideal tissue adhesives are expected to have high biocompatibility, and be able to accelerate wound closing and healing, and monitor wound healing process. However, few adhesives fit all of the above descriptions. It has been demonstrated that inorganic nanoparticles can directly glue biological tissue based on nano-bridging effect. In this study, self-luminescence porous silicon (LPSi) particles were prepared with degradable and biocompatible properties. In addition, the self-luminescence property of LPSi particles was discovered by In Vivo Imaging System (IVIS) for the first time, which can avoid the limitations of photoluminescence imaging. Due to the oxidation and degradation reaction, LPSi particles not only can be degraded completely in several days, but also showed satisfactory biocompatibility. And their degradation product could promote tube formation of HUVECs. Moreover, owing to the high specific surface area and the outer oxide layer of LPSi particles, LPSi tissue adhesive exhibited strong adhesive strength to pig livers. Furthermore, this adhesive closed wound rapidly, promoted angiogenesis and epidermal regeneration, and facilitated wound healing in a mouse skin incision model. Importantly, the wound healing ratio can be monitored by measuring the self-luminescence intensity of LPSi particles in the wound site. This study reveals that LPSi particles could be employed as a safe and smart wound management tissue adhesive for wound closure, as well as accelerating and monitoring wound healing.

Gelatin-based adhesive hydrogel with self-healing, hemostasis, and electrical conductivity.

As a kind of natural protein derived material, gelatin has been widely used in the preparation of medical hydrogels due to its good biocompatibility, non-immunogenicity and the ability of promoting cell adhesion. Functionalization of gelatin-based hydrogels is a hot topic in research and its clinic application. Herein, a novel gelatin-based adhesive hydrogel was prepared via mussel-inspired chemistry. Gelatin was firstly functionalized by dopamine to form dopamine grafted gelatin (GelDA). After the mixture with 1,4-phenylenebisboronic acid and graphene oxide (GO), the GelDA/GO hydrogels were obtained by H2O2/HRP (horseradish peroxidase) catalytic system. Based on the self-healing and tissue adhesion of the hydrogels, the hemostatic property has been exhibited in the rat hepatic hemorrhage model. Additionally, the incorporation of GO endowed conductivity and enhanced the mechanical property of GelDA/GO hydrogels. The electromyography (EMG) signals of finger movement were successfully monitored by using hydrogel as the adhesive electrodes of EMG monitor. L929 cell experiments showed that the hydrogels had good cytocompatibility. The results indicated the potential application of GelDA/GO hydrogels in tissue adhesives, wound dressings, and wearable devices.

Study on hemostatic effect and mechanism of starch-based nano-microporous particles.

The powdered hemostatic particles have broad application prospects in large open wounds, internal organ injuries and penetrating injuries of the body. In this study, nanoscale mescoporous and macroporous silica (MMSN), nanoscale mescoporous and macroporous bioactive glass (MBG), micron-scale cross-linked corn starch porous microspheres (CMS), MMSN@CMS and MBG@CMS starch-based nano-microporous particles were synthesized and their hemostatic effect and hemostatic mechanism were studied. The results showed that comparted with the single particle of CMS, the combination particles MBG@CMS and MMSN@CMS significantly increased the water absorption rate, activated both internal and external coagulation pathways, significantly shortened CBT, as well as the improved hemostatic effects in vitro. The immediately released Ca2+ from MBG@CMS in the blood to participate in the coagulation pathway, and MMSN@CMS activated platelets by concentrating blood coagulation factors, might be the main hemostatic mechanisms for the starch-based nano-microporous particles. Furthermore, the hemostatic efficacy of particles, both in the model of tail-amputation and liver injury in SD rats, showed the starch-based nano-microporous particles, especial MBG@CMS, could significantly reduce the weight of blood loss and shorten the bleeding time. Our research work stated that the starch-based nano-microporous particles MBG@CMS might be a hemostasis biomaterial with the potential applications for the emergency bleeding.

Potential Applications of Nanomaterials and Technology for Diabetic Wound Healing.

Diabetic wound shows delayed and incomplete healing processes, which in turn exposes patients to an environment with a high risk of infection. This article has summarized current developments of nanoparticles/hydrogels and nanotechnology used for promoting the wound healing process in either diabetic animal models or patients with diabetes mellitus. These nanoparticles/hydrogels promote diabetic wound healing by loading bioactive molecules (such as growth factors, genes, proteins/peptides, stem cells/exosomes, etc.) and non-bioactive substances (metal ions, oxygen, nitric oxide, etc.). Among them, smart hydrogels (a very promising method for loading many types of bioactive components) are currently favored by researchers. In addition, nanoparticles/hydrogels can be combined with some technology (including PTT, LBL self-assembly technique and 3D-printing technology) to treat diabetic wound repair. By reviewing the recent literatures, we also proposed new strategies for improving multifunctional treatment of diabetic wounds in the future.

Rice Calcineurin B-Like Protein-Interacting Protein Kinase 31 (OsCIPK31) Is Involved in the Development of Panicle Apical Spikelets.

Panicle apical abortion (PAA) causes severe yield losses in rice production, but details about its development and molecular basis remain elusive. Herein, a PAA mutant, paa1019, was identified among the progeny of an elite indica maintainer rice line Yixiang 1B (YXB) mutagenized population obtained using ethyl methyl sulfonate. The abortion rate of spikelets in paa1019 was observed up to 60%. Genetic mapping combined with Mutmap analysis revealed that LOC_Os03g20380 harbored a single-bp substitution (C to T) that altered its transcript length. This gene encodes calcineurin B-like protein-interacting protein kinase 31 (OsCIPK31) localized into the cytoplasm, and is preferentially expressed in transport tissues of rice. Complementation of paa1019 by transferring the open reading frame of LOC_Os03g20380 from YXB reversed the mutant phenotype, and conversely, gene editing by knocking out of OsCIPK31 in YXB results in PAA phenotype. Our results support that OsCIPK31 plays an important role in panicle development. We found that dysregulation is caused by the disruption of OsCIPK31 function due to excessive accumulation of ROS, which ultimately leads to cell death in rice panicle. OsCIPK31 and MAPK pathway might have a synergistic effect to lead ROS accumulation in response to stresses. Meanwhile the PAA distribution is related to IAA hormone accumulation in the panicle. Our study provides an understanding of the role of OsCIPK31 in panicle development by responding to various stresses and phytohormones.

Mutation in Rice Abscisic Acid2 Results in Cell Death, Enhanced Disease-Resistance, Altered Seed Dormancy and Development.

Lesion mimic mutants display spontaneous cell death, and thus are valuable for understanding the molecular mechanism of cell death and disease resistance. Although a lot of such mutants have been characterized in rice, the relationship between lesion formation and abscisic acid (ABA) synthesis pathway is not reported. In the present study, we identified a rice mutant, lesion mimic mutant 9150 (lmm9150), exhibiting spontaneous cell death, pre-harvest sprouting, enhanced growth, and resistance to rice bacterial and blast diseases. Cell death in the mutant was accompanied with excessive accumulation of H2O2. Enhanced disease resistance was associated with cell death and upregulation of defense-related genes. Map-based cloning identified a G-to-A point mutation resulting in a D-to-N substitution at the amino acid position 110 of OsABA2 (LOC_Os03g59610) in lmm9150. Knock-out of OsABA2 through CRISPR/Cas9 led to phenotypes similar to those of lmm9150. Consistent with the function of OsABA2 in ABA biosynthesis, ABA level in the lmm9150 mutant was significantly reduced. Moreover, exogenous application of ABA could rescue all the mutant phenotypes of lmm9150. Taken together, our data linked ABA deficiency to cell death and provided insight into the role of ABA in rice disease resistance.