A CO-mediated photothermal therapy to kill drug-resistant bacteria and minimize thermal injury for infected diabetic wound healing.

With an increasing proportion of drug-resistant bacteria, photothermal therapy (PTT) is a promising alternative to antibiotic treatment for infected diabetic skin ulcers. However, the inevitable thermal damage to the tissues restricts its clinical practice. Carbon monoxide (CO), as a bioactive gas molecule, can selectively inhibit bacterial growth and promote tissue regeneration, which may be coordinated with PTT for drug-resistant bacteria killing and tissue protection. Herein, a CO-mediated PTT agent (CO@mPDA) was engineered by loading manganese carbonyl groups into mesoporous polydopamine (mPDA) nanoparticles via coordination interactions between the metal center and a catechol group. Compared to the traditional PTT, the CO-mediated PTT increases the inhibition ratio of the drug-resistant bacteria both in vitro and in diabetic wound beds by selectively inhibiting the co-chaperone of the heat shock protein 90 kDa (Hsp90), and lowers the heat resistance of the bacteria rather than the mammalian tissues. Meanwhile, the tissue-protective proteins, such as Hsp90 and vimentin (Vim), are upregulated via the WNT and PI3K-Akt pathways to reduce thermal injury, especially with a laser with a high-power density. The CO-mediated PTT unified the bacterial killing with tissue protection, which offers a promising concept to improve PTT efficiency and minimize the side-effects of PTT when treating infected skin wounds.

The Effect and Evaluation of the Third Military Medical University Fluid Resuscitation Formula.

Background: The clinical efficacy of the third Military Medical University formula (TMMU formula) for fluid resuscitation stage was evaluated to improve the treatment level of adult patients with extensive burns during the shock stage. Methods: Retrospective analysis of the data of 55 patients undergoing fluid resuscitation according to the TMMU formula within six hours after burn injury. The following indicators were collected: (1) demographic and injury information; (2) fluid resuscitation information; (3) efficiency information, including cardiovascular function, liver function, renal function, coagulation function evaluation indicators, blood concentration, and average urine output index. Results: (1) In the first and second 24 hours after injury, the median fluid rehydration coefficient was 1.68 ml/kg·(%) TBSA and 1.15 ml/kg·(%) TBSA, the median ratio of crystal to colloid was 2.24 and 1.67, and the median urine output index was 0.75 ml/kg·h and 1.05 ml/kg·h, respectively. (2) The actual fluid volume during patient resuscitation is higher than the formula calculated volume, and this difference is more obvious in patients with burn area ≥80%. (3) In the second 24 hours, the value of the actual total fluid volume minus the formula total volume in the group with crystal to colloid ratio ≤2 was significantly lower than that in the ratio >2 group. (4) At 24 and 48 hours after injury, the cardiovascular function, liver function, renal function, and coagulation function were better than those before fluid resuscitation. Conclusions: Early application of the TMMU formula for fluid resuscitation in adult patients with extensive burns is safe and effective, but the actual input volume often exceeds the volume calculated by the formula, especially in the second 24 hours after burn injury and in patients with larger burn areas. Increasing the colloid input volume can help reduce the total amount of fluid used for resuscitation.

A multifunctional platform with single-NIR-laser-triggered photothermal and NO release for synergistic therapy against multidrug-resistant Gram-negative bacteria and their biofilms.

BACKGROUND: Infectious diseases caused by multidrug-resistant (MDR) bacteria, especially MDR Gram-negative strains, have become a global public health challenge. Multifunctional nanomaterials for controlling MDR bacterial infections via eradication of planktonic bacteria and their biofilms are of great interest. RESULTS: In this study, we developed a multifunctional platform (TG-NO-B) with single NIR laser-triggered PTT and NO release for synergistic therapy against MDR Gram-negative bacteria and their biofilms. When located at the infected sites, TG-NO-B was able to selectively bind to the surfaces of Gram-negative bacterial cells and their biofilm matrix through covalent coupling between the BA groups of TG-NO-B and the bacterial LPS units, which could greatly improve the antibacterial efficiency, and reduce side damages to ambient normal tissues. Upon single NIR laser irradiation, TG-NO-B could generate hyperthermia and simultaneously release NO, which would synergistically disrupt bacterial cell membrane, further cause leakage and damage of intracellular components, and finally induce bacteria death. On one hand, the combination of NO and PTT could largely improve the antibacterial efficiency. On the other hand, the bacterial cell membrane damage could improve the permeability and sensitivity to heat, decrease the photothermal temperature and avoid damages caused by high temperature. Moreover, TG-NO-B could be effectively utilized for synergistic therapy against the in vivo infections of MDR Gram-negative bacteria and their biofilms and accelerate wound healing as well as exhibit excellent biocompatibility both in vitro and in vivo. CONCLUSIONS: Our study demonstrates that TG-NO-B can be considered as a promising alternative for treating infections caused by MDR Gram-negative bacteria and their biofilms.

Biomimicry of oil infused layer on 3D printed poly(dimethylsiloxane): Non-fouling, antibacterial and promoting infected wound healing.

The nepenthes-inspired slippery liquid-infused surface has led to multiple potentials in biomedical devices' design. This study aims to develop a biomimetic, environmentally-friendly slippery layer of oil-infused 3D printed polydimethylsiloxane with anti-bacterial nanosilver (iPDMS/AgNPs) for wound dressing. The engineered 3D printed iPDMS can cater the different requirements of wounds with antifouling, anti-blood staining, and kill bacteria. iPDMS/AgNPs not only exhibits biocompatibility, against adherence and effective antibacterial activity but also effectively promotes neo-epithelial and granulation tissue formation to accelerate wound healing in vivo. Optimized rheologic parameters were obtained for the 3D printable iPDMS pre-polymerization condition. Scanning electronic micrograph (SEM) and Energy Dispersive Spectrometer (EDS) show a uniform mesh with AgNPs dotted on the printed dressing. No cytotoxicity of iPDMS/AgNPs has been found via cell Counting Kit-8(CCK-8) assay. Meanwhile, the membranes infused with silicon oil effectively prevented from the adherence of the two standard drug-resistant bacteria, Staphylococcus aureus and Escherichia coli (PDMS vs. PDMS+oil, p < 0.05; PDMS+0.5%AgNPs vs. iPDMS+0.5%AgNPs, p < 0.05; PDMS+2.5%AgNPs vs. iPDMS+2.5%AgNPs, p < 0.05). By bacteria co-culture model iPDMS/AgNPs can kill about 80% of Staphylococcus aureus and Escherichia coli. When applied to a full-thickness wound defect model of murine, iPDMS/AgNPs was effective in anti-infection. It also promotes the epithelialization, the granulation tissue formation, and wound healing. These findings demonstrate that iPDMS/AgNPs may have therapeutic promise as an ideal wound dressing shortly.

An efficient antimicrobial depot for infectious site-targeted chemo-photothermal therapy.

BACKGROUND: Silver and photothermal therapy (PTT) have been widely used for eradicating the drug-resistant bacteria. However, the risks of excess of silver for humans and the low efficiency of PTT still limit their in vivo therapeutic application. Integration of two distinctive bactericides into one entity is a promising platform to improve the efficiency of antimicrobial agents. RESULTS: In this study, a chemo-photothermal therapeutic platform based on polydopamine (PDA)-coated gold nanorods (GNRs) was developed. The PDA coating acquired high Ag+ ions loading efficiency and Cy5-SE fluorescent agent labeled glycol chitosan (GCS) conjugation (Ag+-GCS-PDA@GNRs). This platform became positively charged in the low pH environment of the abscess, allowing their accumulation in local infection site as revealed by thermal/florescence imaging. The loaded Ag+ ions was released in a pH-sensitive manner, resulting in selective Ag+ ions delivery to the abscess environment (pH ~ 6.3). More importantly, the ultralow dose of Ag+ ions could effectively damage the bacterial membrane, causing the permeability increase and the heat resistance reduction of the cell membrane, leading to the large improvement on bactericidal efficiency of PTT. On the other hand, the hyperthermia could trigger more Ag+ ions release, resulting in further improvement on bactericidal efficiency of chemotherapy. Combinational chemo-hyperthermia therapy of Ag+-GCS-PDA@GNRs could thoroughly ablate abscess and accelerate wound healing via a synergistic antibacterial effect. CONCLUSIONS: Our studies demonstrate that Ag+-GCS-PDA@GNRs is a robust and practical platform for use in chemo-thermal focal infection therapy with outstanding synergistic bacteria ablating.

pH-triggered charge-reversible of glycol chitosan conjugated carboxyl graphene for enhancing photothermal ablation of focal infection.

Subcutaneous abscesses infected by multidrug-resistant bacteria are becoming an increasing challenge to human health. To address this challenge, a surface-adaptive and biocompatible glycol chitosan conjugated carboxyl graphene (GCS-CG) is developed, which exhibits unique self-adaptive target to the acidic microenvironment of abscess (∼pH 6.3) and no damage to the healthy tissue (pH 7.4) around the abscess. Originally, following conjugated with GCS, the absorbance of CG obviously increases in the near-infrared (NIR) region, enabling GCS-CG to generate an increment amount of heat. GCS-CG shows fast pH-responsive surface charge transition from negative to positive, which presents strong adherence to negatively charged bacteria surface in abscess, while exhibits poor affinity to host cells in healthy tissues. The local temperature of NIR-irradiated GCS-CG is estimated to be higher than their ambient temperature, ensuring targeted heating and eradicating the bacteria to reduce the damage to tissue; hence, wound healing is accelerated. Moreover, the in vitro and in vivo biosafety results demonstrate that GCS-CG presents greatly biocompatible even at a high concentration of 1 mg·mL-1. Given the above advantages as well as the simple preparation, graphene developed here may provide a new potential application as a useful antibacterial agent in the areas of healthcare. STATEMENT OF SIGNIFICANCE: A surface-adaptive nanomaterial, glycol chitosan conjugated carboxyl graphene (GCS-CG) is developed, which realizes the acidity-triggered bacteria targeting. GCS-CG can result in direct thermal ablation of bacteria and enhancement of the infected wound healing, but exhibit no damage to healthy tissues. The pH-responsive GCS-CG described here, containing no antibiotics, has great potentials in treating bacterial infection and even multidrug-resistant bacteria.

Effective symptomatic treatment for severe and intractable pruritus associated with severe burn-induced hypertrophic scars: A prospective, multicenter, controlled trial.

BACKGROUND: Burn-induced hypertrophic scars are disfiguring and can be associated with severe and intractable pruritus. No effective treatment modalities are currently available for symptomatic control of pruritus for most patients. We assessed the effect of the Antipruritic Hydrogel (CQ-01) in the symptomatic treatment of severe and intractable pruritus associated with burn-induced hypertrophic scars in a prospective, multicenter, controlled trial. METHODS: A pilot study was conducted in healthy adult volunteers to identify the most appropriate hydrogel formulation. A selected preparation called Chongqing No. 1 (CQ-01; a guar gum-based hydrogel impregnated with peppermint oil, menthol, and methyl salicylate by a nanoemulsion), showed an excellent symptomatic relief in an exploratory study in 2 patients with intractable pruritus. A statistically powered, prospective, multicenter, controlled study was then conducted in 74 patients to evaluate the efficacy and safety of a 24-h application of CQ-01 compared to a gel control and a negative control on three separate areas in each patient. Symptom assessment was based on our visual analog JW scale (ranging from 0 to 100) at baseline and various time points up to 7 days after application. Follow-up studies were conducted to determine the reproducibility of CQ-01 in repeated applications. RESULTS: Of the 74 enrolled subjects, the only observed adverse event was skin irritation reported in 6 patients (8%) and resolved shortly after gel removal. Compared to the baseline, the gauze negative control had a mean JW score reduction of 7; while the gel control and CQ-01 had a drop of 18 (p<0.001) and 36 (p<0.001), respectively. The CQ-01 clinical effect was significant for up to 3 days and waned slowly from 3 to 7 days. There was no statistical correlation between the treatment response and any of the demographic, patient or burn-related factors. Further studies showed a trend that repeated applications might be more effective, suggesting the absence of tachyphylaxis. CONCLUSIONS: This prospective, multicenter, controlled study showed that this novel hydrogel CQ-01 is safe and provides significant symptomatic relief for severe and intractable pruritus associated with hypertrophic scars, an unmet medical need for these patients. This effect is independent of the etiology of the burn trauma, extent of the scarring, and duration of the scar formation.

A randomized and controlled multicenter prospective study of the Chinese medicinal compound Fufang Xuelian Burn Ointment for the treatment of superficial and deep second-degree burn wounds.

The objective of this study was to evaluate the efficacy and safety of a traditional Chinese medicine, Fufang Xuelian Burn Ointment (FXBO), to treat superficial and deep second-degree burn wounds. A four-center, randomized, controlled, and prospective study was conducted. Overall, 240 patients with either superficial or deep second-degree burn wounds were enrolled consecutively in this study. Patients who were randomly assigned to the control group (superficial: 72, deep: 48) underwent common burn wound therapy, whereas those randomized to the treatment group (superficial: 72, deep: 48) received common burn wound therapy plus topical FXBO. The healing rate, healing time, effective rate, and safety data were compared between the two groups. The baseline characteristics were comparable for the two groups. The healing rate was 94.79(±7.50) in the control group and 98.60(±5.69) in the FXBO group after 14 days for patients with superficial second-degree burn wounds (P = 0.000), and 95.17(±9.68) versus 97.44(±9.81) at 28 for deep second-degree burn wounds (P = 0.025). The median healing time in the FXBO group were 9 and 21 days for superficial and deep second-degree burns, respectively, compared to 10.5 and 22.5 days, respectively, in control group (P(superficial) = 0.000 and P(deep) = 0.009). The results of the effective rate showed that comprehensive efficacy of the FXBO group was improved compared to the control group for either superficial or deep second-degree burns (P(superficial) = 0.035 and P deep = 0.003). There were no reported drug-related adverse events in both groups. Therefore, FXBO was well tolerated and more effective than control group for treating superficial and deep second-degree burn wounds.