High-Intensity Blue Light (450-460 nm) Phototherapy for Pseudomonas aeruginosa-Infected Wounds.

Background: Nosocomial wound infection with Pseudomonas aeruginosa (PA) is a serious complication often responsible for septic mortality of burn patients. High-intensity antimicrobial blue light (aBL) treatment may represent an alternative therapy for PA infections. Methods: Antibacterial effects of an light-emitting diode (LED) array (450-460 nm; 300 mW/cm2; 15/30 min; 270/540J/cm2) against PA were determined by suspension assay, biofilm assay, and a human skin wound model and compared with 15-min topically applied 3% citric acid (CA) and wound irrigation solution (Prontosan®; PRT). Results: The aBL reduced the bacterial number (2.51-3.56 log10 CFU/mL), whereas PRT or CA treatment achieved a 4.64 or 6.60 log10 CFU/mL reduction in suspension assays. The aBL reduced biofilm formation by 60%-66%. PRT or CA treatment showed reductions by 25% or 13%. In this study, aBL reduced bacterial number in biofilms (1.30-1.64 log10 CFU), but to a lower extent than PRT (2.41 log10 CFU) or CA (2.48 log10 CFU). In the wound skin model, aBL (2.21-2.33 log10 CFU) showed a bacterial reduction of the same magnitude as PRT (2.26 log10 CFU) and CA (2.30 log10 CFU). Conclusions: The aBL showed a significant antibacterial efficacy against PA and biofilm formation in a short time. However, a clinical application of aBL in wound therapy requires effective active skin cooling and eye protection, which in turn may limit clinical implementation.

Experimental evidence for Parthanatos-like mode of cell death of heat-damaged human skin fibroblasts in a cell culture-based in vitro burn model.

The cellular mechanisms of burn conversion of heat damaged tissue are center of many studies. Even if the molecular mechanisms of heat-induced cell death are controversially discussed in the current literature, it is widely accepted that caspase-mediated apoptosis plays a central role. In the current study we wanted to develop further information on the nature of the mechanism of heat-induced cell death of fibroblasts in vitro. We found that heating of human fibroblast cultures (a 10 s rise from 37 °C to 67 °C followed by a 13 s cool down to 37 °C) resulted in the death of about 50% of the cells. However, the increase in cell death started with a delay, about one hour after exposure to heat, and reached the maximum after about five hours. The lack of clear evidence for an active involvement of effector caspase in the observed cell death mechanism and the lack of observation of the occurrence of hypodiploid nuclei contradict heat-induced cell death by caspase-mediated apoptosis. Moreover, a dominant heat-induced increase in PARP1 protein expression, which correlated with a time-delayed ATP synthesis inhibition, appearance of double-strand breaks and secondary necrosis, indicate a different type of cell death than apoptosis. Indeed, increased translocation of Apoptosis Inducing Factor (AIF) and Macrophage Migration Inhibitory Factor (MIF) into cell nuclei, which correlates with the mentioned enhanced PARP1 protein expression, indicate PARP1-induced, AIF-mediated and MIF-activated cell death. With regard to the molecular actors involved, the cellular processes and temporal sequences, the mode of cell death observed in our model is very similar to the cell death mechanism via Parthanatos described in the literature.

The Antimicrobial Efficacy of Topically Applied Mafenide Acetate, Citric Acid and Wound Irrigation Solutions Lavanox and Prontosan against Pseudomonas aeruginosa.

Since burn wound infections caused by Pseudomonas aeruginosa (PA) lead to major complications and sepsis, this study evaluates the antimicrobial efficacy of the wound irrigation solutions Prontosan (PRT), Lavanox (LAV), citric acid (CA) and mafenide acetate (MA) using microbiology assays and an ex vivo skin wound model. In suspension assays, all the solutions showed significant reductions in bacterial number (log10 reduction: CA 5.77; LAV 4.91; PRT 4.74; MA 1.23). The biofilm assay revealed that PRT and LAV reduced biofilm formation by ~25% after a 15 min treatment, while PRT was most effective after a 24 h treatment (~68%). The number of PA in biofilms measured directly after a 15 min treatment was reduced most effectively with CA and LAV (log10 reductions ~2.5), whereas after a 24 h treatment, all solutions achieved only 1.36-1.65 log10 reductions. In the skin wound model, PRT and LAV provided the highest bacterial reduction after a 15 min treatment (log10 reduction 1.8-1.9), while MA was more effective after a 22 h treatment (log10 reduction 3.6). The results demonstrated the antimicrobial efficacy of all solutions against PA. Further investigation is needed to explore the potential clinical applications of a combination or alternating use of these solutions for infection prophylaxis and treatment of wound infections caused by PA.

How did the COVID-19 pandemic affect burn centres in German-speaking countries?

The exponential growth of COVID-19 cases in early 2020 presented a massive challenge for healthcare systems and called for the adaptation of emergency care routines and intensive care capacities. We, therefore, analyzed a possible impact of the COVID-19 pandemic on the general structure and emergency preparedness of burn centers in German-speaking countries through a cross-sectional descriptive survey questionnaire. The survey was conducted for the first time in January 2019 by Al-Shamsi et al. before the beginning of the COVID-19 pandemic. It was performed for a second time in November 2020 during the second wave of COVID-19 infections in German-speaking countries. We noticed a pronounced increase in the preparation for a great number of patients in need of intensive care including the enlargement of overall capacity when necessary. We also showed a notable decrease in the specific preparation for burn disasters and also reduced communication with first responders and other burn centers. To what extent these alterations were caused by the impact the pandemic had on healthcare systems could not be determined in this study and should be the subject of future research.

Which Moisturizer to Use in Scar Therapy after Burn Injuries? A Subjective and Objective Skin and Scar Evaluation after Topical Treatment with Dexpanthenol, Aloe Vera, and Plant Oil.

Background and Objectives: Good scar management in burn care is essential. Nevertheless, there are no consistent recommendations regarding moisturizers for scar management. Our aim was to investigate and compare the effects of commonly used products on normal skin and burn scars. Materials and Methods: A total of 30 skin-healthy (control group) and 12 patients with burn scars were included in this study. For an intraindividual comparison, each participant received creams consisting of dexpanthenol (P), aloe vera (A), and a natural plant oil (O) with instructions to apply them daily to a previously defined area for at least 28 days. Objective scar evaluation was performed with Visioscan®; Tewameter®; Cutometer®, and the Oxygen To See® device. Subjective evaluation was performed with an "application" questionnaire, the Patient and Observer Scar Assessment Scale (POSAS), and with the "best of three" questionnaire. Results: After (A) a high trend of amelioration of +30%, TEWL was detected on the scar area. Blood flow increased slightly on healthy skin areas after (A) application to +104%. The application of (A) on healthy skin demonstrated a positive effect on the parameters of scaliness (+22%, p < 0.001), softness (+14%, p = 0.046), roughness R1 (+16%, p < 0.001) and R2 (+17%, p = 0.000), volume (+22%, p < 0.001), and surface area (+7%, p < 0.001) within the control group. After (P), a significant improvement of the baseline firmness parameter of +14.7% was detected (p = 0.007). (P) also showed a beneficial effect on the parameters of R1 (+7%, p = 0.003), R2 (+6%, p = 0.001), and volume (+17%, p = 0.001). (O) lead to a statistically significant improvement of volume (+15%, p = 0.009). Overall, most study participants stated (A) to be the "best of three". Conclusions: (A) performed statistically best, and is a well-tolerated moisturizing product. However, further quantitative studies are needed to provide statistically significant clarification for uniform recommendations for scar therapy.

Can Cold Atmospheric Plasma Be Used for Infection Control in Burns? A Preclinical Evaluation.

Wound infection with Pseudomonas aeruginosa (PA) is a serious complication and is responsible for higher rates of mortality in burn patients. Because of the resistance of PA to many antibiotics and antiseptics, an effective treatment is difficult. As a possible alternative, cold atmospheric plasma (CAP) can be considered for treatment, as antibacterial effects are known from some types of CAP. Hence, we preclinically tested the CAP device PlasmaOne and found that CAP was effective against PA in various test systems. CAP induced an accumulation of nitrite, nitrate, and hydrogen peroxide, combined with a decrease in pH in agar and solutions, which could be responsible for the antibacterial effects. In an ex vivo contamination wound model using human skin, a reduction in microbial load of about 1 log10 level was observed after 5 min of CAP treatment as well as an inhibition of biofilm formation. However, the efficacy of CAP was significantly lower when compared with commonly used antibacterial wound irrigation solutions. Nevertheless, a clinical use of CAP in the treatment of burn wounds is conceivable on account of the potential resistance of PA to common wound irrigation solutions and the possible wound healing-promoting effects of CAP.

[Academic Careers in Medicine: a Sex-Related Analysis of Career Goals]. / Akademische Karriere in der Medizin: eine geschlechterbezogene Analyse zu beruflichen Zielen.

AIM OF THE STUDY: For female and male physicians of the clinical-academic mid-level staff, working conditions as well as the attitude towards profession and career play a decisive role. For years, there has been an increasing proportion of women in medicine. Despite this increase, a significant sex incongruence is still evident, especially in academic medicine. The aim of this work was to analyze current opinions of female and male physicians on sex-related aspects for career. METHODS: By means of an online survey, medical mid-level staff from university and peripheral hospitals were asked about professional biographical as well as career-related topics and the data analyzed in terms of the sexes. RESULTS: Compared to their male counterparts, female physicians had lower career goals and mainly aimed to qualify as senior physicians. Women planned to have families and raise children earlier in their careers. Men were more likely to have their professional careers in mind during the same time period. Although only just under 47% of respondents considered an academic career to be worthwhile, 65% continued to rate the acquisition of an academic title highly. When evaluating equal treatment by superiors, female physicians tended to feel disadvantaged in their professional careers compared to male physicians. Thus, physicians rated the treatment by their respective superiors as characterized by the quality of the work (44% for both genders of superiors) or dependent on sympathy (female superiors 30%; male superiors 24%). Female physicians, however, saw a preference for male colleagues in 37% of male superiors. CONCLUSION: Despite a significantly larger proportion of women in medicine for decades, there is still an incongruence in sexes in favor of men in management positions. The professional and private goals of women and men differ significantly depending on their age decade. The academic career per se is increasingly losing importance, although the acquisition of academic degrees still seems to be desirable. Therefore, to improve the future of academic medicine, significant structural changes are needed to enable projectable career paths (e. g., tenure track, assistant professorship, young medical professionals model) for mid-level academic staff.

[Balancing Family and Career in Medicine: Greatly Desired but Given Little Consideration Results of the Study Arm VI of the KARiMED Study]. / Vereinbarkeit von Familie und Beruf in der Medizin: vom großen Wunsch und wenig Berücksichtigung.

AIM OF THE STUDY: Family life and professional practice are both highly important for young physicians. Accordingly, a good balancing of both areas of life is necessary. Despite political framework conditions and legal requirements that have been in place for years, implementation of measures to achieve this seems to be difficult, especially in medicine, and is associated with great reservations and problems on the part of those involved. METHODS: By means of an online survey, the medical mid-level staff from university and peripheral hospitals was questioned on topics related to family, children and professional biographical as well as career-relevant topics and subsequently analyzed on a gender-specific basis. RESULTS: Of the study participants, 65.1% were married and already had children or expressed a desire to have children (86.0%). Most were employed full-time (80.8%). The majority of part-time employees were female (87.4%). For 34.6%, there was a career break of 18.5±21.3 months, 87.8% of which were taken due to pregnancy or children. Female physicians generally took significantly more parental leave than male physicians (6-12 months: females 62.2%; males 22.4%; 12 months or more: females 25.2%; males 6.6%). Family planning received little support from superiors (21.2% much to very much support) and 45.6% reported having experienced problems with their return to work or career advancement. Almost 60% of the participants did not have any specific working time models in their own hospital for employees with children who need to be cared for. CONCLUSION: In order to implement a work-life balance for physicians, changes are first and foremost necessary on the part of the institutions. In addition, the respective superiors must rethink in order to enable a parallelization of these two areas of their employees' lives. However, young physicians must also rethink their view of this issue. Demanding changes in labor law while continuing traditional family constellations at home does not seem to do address this issue adequately.

Phototherapy of Pseudomonas aeruginosa-Infected Wounds: Preclinical Evaluation of Antimicrobial Blue Light (450-460 nm) Using In Vitro Assays and a Human Wound Skin Model.

Objective: To determine effective treatment strategies against bacterial infections of burn wounds with Pseudomonas aeruginosa, we tested different treatment regimens with antibacterial blue light (BL). Background: Infections of burn wounds are serious complications and require effective and pathogen-specific therapy. Hereby, infections caused by P. aeruginosa pose a particular challenge in clinical practice due to its resistance to many antibiotics and topical antiseptics. Methods: LED-based light sources (450-460 nm) with different intensities and treatment times were used. Antibacterial effects against P. aeruginosa were determined by colony-forming unit (CFU) assays, human skin wound models, and fluorescence imaging. Results: In suspension assays, BL (2 h, 40 mW/cm2, 288 J/cm2) reduced bacterial number (>5 log10 CFU/mL). Applying 144 J/cm2, using 40 mW/cm2 for 1 h was more effective (>4 log10 CFU) than using 20 mW/cm2 for 2 h (>1.5 log10 CFU). BL with low irradiance (24 h, 3.5 mW/cm2, 300 J/cm2) only revealed bacterial reduction in thin bacteria-containing medium layers. In infected in vitro skin wounds only BL irradiation (2 h, 40 mW/cm2, 288 J/cm2) exerted a significant antimicrobial efficacy (2.94 log10 CFU/mL). Conclusions: BL treatment may be an effective therapy for P. aeruginosa-infected wounds to avoid radical surgical debridement. However, a significant antibacterial efficacy can only be achieved with higher irradiances and longer treatment times (min. 40 mW/cm2; >1 h), which cannot be easily integrated into regular clinical treatment protocols, for example, during a dressing change. Further studies are necessary to establish BL therapy for infected burns among tissue compatibility and interactions with previous therapeutic agents.

The effect of paste composition, aggregate mineralogy and temperature on the pore solution composition and the extent of ASR expansion.

The reaction kinetics of the alkali silica reaction depends on the composition of the pore solution. The evolution of the pore solution composition in different cement pastes and concretes was studied. Pastes containing silica fume or metakaolin had the lowest amount of alkalis in the pore solution. In addition, metakaolin increased the aluminium concentrations. The lowest expansion was measured for the concretes made of blended cement pastes with low alkali and hydroxide content in their pore solution, for the duration of the present study, no additional aluminium effect was observed due to the already low pH. Addition of 400 mM of Li slowed down expansion rate of concrete prisms at 40 and 60 °C, however, similar expansion was observed for samples with and without Li at 60 °C after 1 year. Temperature, alkali concentration and pH of pore solution all have a major effect on ASR expansion.

Utility of Intravenous Curcumin Nanodelivery Systems for Improving In Vivo Pharmacokinetics and Anticancer Pharmacodynamics.

Curcumin nanoformulations for intravenous injection have been developed to offset poor absorption, biotransformation, degradation, and excessive clearance associated with parenteral delivery. This review investigates (1) whether intravenous nanoformulations improve curcumin pharmacokinetics (PK) and (2) whether improved PK yields greater therapeutic efficacy. Standard PK parameters (measured maximum concentration [Cmax], area under the curve [AUC], distribution volume [Vd], and clearance [CL]) of intravenously administered free curcumin in mice and rats were sourced from literature and compared to curcumin formulated in nanoparticles, micelles, and liposomes. The studies that also featured analysis of pharmacodynamics (PD) in murine cancer models were used to determine whether improved PK of nanoencapsulated curcumin resulted in improved PD. The distribution and clearance of free and nanoformulated curcumin were very fast, typically accounting for >80% curcumin elimination from plasma within 60 min. Case-matched analysis demonstrated that curcumin nanoencapsulation generally improved curcumin PK in terms of measured Cmax (n = 27) and AUC (n = 33), and to a lesser extent Vd and CL. However, when the data were unpaired and clustered for comparative analysis, only 5 out of the 12 analyzed nanoformulations maintained a higher relative curcumin concentration in plasma over time compared to free curcumin. Quantitative analysis of the mean plasma concentration of free curcumin versus nanoformulated curcumin did not reveal an overall marked improvement in curcumin PK. No correlation was found between PK and PD, suggesting that augmentation of the systemic presence of curcumin does not necessarily lead to greater therapeutic efficacy.

Evaluation of Scar Quality after Treatment of Superficial Burns with Dressilk® and Suprathel®-In an Intraindividual Clinical Setting.

BACKGROUND: Various synthetic and biological wound dressings are available for the treatment of superficial burns, and standard care differs among hospitals. Nevertheless, the search for an ideal wound dressing offering a safe healing environment as well as optimal scar quality while being economically attractive is a continuing process. In recent years, Dressilk®, which consists of pure silk, has become the standard of care for the treatment of superficial burns in our hospital. However, no long-term scar-evaluation studies have been performed to compare Dressilk® with the often-used and more expensive Suprathel® in the treatment of superficial burns. METHODS: Subjective and objective scar evaluations were performed three, six, and twelve months after treatment in patients who received simultaneous treatment of 20 superficial burn wounds with both Suprathel® and Dressilk®. The evaluations were performed using the Vancouver Scar Scale, the Cutometer®, Mexameter®, Tewameter®, and the O2C®. RESULTS: Both dressings showed mostly equivalent results in subjective scar evaluations. In the objective scar evaluations, the wounds treated with Dressilk® showed a faster return to the qualities of non-injured skin. Wound areas treated with the two dressings showed no significant differences in elasticity and transepidermal water loss after 12 months. Only oxygen saturation was significantly lower in wound areas treated with Suprathel® (p = 0.008). Subjectively, wound areas treated with Dressilk® showed significantly higher pigmentation after six months, which was not apparent after 12 months. CONCLUSION: Both wound dressings led to esthetically satisfying scar recovery without significant differences from normal uninjured skin after 12 months. Therefore, Dressilk® remains an economically and clinically interesting alternative to Suprathel® for the treatment of superficial burns.

Simultaneous Classification of Both Mental Workload and Stress Level Suitable for an Online Passive Brain-Computer Interface.

Research studies on EEG-based mental workload detection for a passive BCI generally focus on classifying cognitive states associated with the performance of tasks at different levels of difficulty, with no other aspects of the user's mental state considered. However, in real-life situations, different aspects of the user's state such as their cognitive (e.g., level of mental workload) and affective (e.g., level of stress/anxiety) states will often change simultaneously, and performance of a BCI system designed considering just one state may be unreliable. Moreover, multiple mental states may be relevant to the purposes of the BCI-for example both mental workload and stress level might be related to an aircraft pilot's risk of error-and the simultaneous prediction of states may be critical in maximizing the practical effectiveness of real-life online BCI systems. In this study we investigated the feasibility of performing simultaneous classification of mental workload and stress level in an online passive BCI. We investigated both subject-specific and cross-subject classification approaches, the latter with and without the application of a transfer learning technique to align the distributions of data from the training and test subjects. Using cross-subject classification with transfer learning in a simulated online analysis, we obtained accuracies of 77.5 ± 6.9% and 84.1 ± 5.9%, across 18 participants for mental workload and stress level detection, respectively.

A clinical comparison of pure knitted silk and a complex synthetic skin substitute for the treatment of partial thickness burns.

Currently, many dressings are commercially available for the treatment of burn wounds. Some of these wound dressings remain on the wound, prevent painful dressing changes, and reduce tissue scarring. Nevertheless, still a wound dressing that is cost-effective, produces good wound healing properties, and has a high patient satisfaction is needed. Standard care of superficial burn wounds differs between burn centres. This study aimed to determine a dressing with easy appliance, accurate pain control, favourable outcome, and cost-effectiveness. Therefore, we compared the widely used but expensive Suprathel with the rather new but much cheaper Dressilk in the clinical setting. In a prospective clinical study, the healing of partial thickness burn wounds after simultaneous treatment with Suprathel and Dressilk was examined in 20 patients intra-individually. During wound healing, pain, infection, exudation, and bleeding were evaluated. A subjective scar evaluation was performed using the Patient and Observer Scar Scale. Both dressings were easy to apply, remained on the wound in place, and were gradually cut back as reepithelisation proceeded and showed similar times to wound closure. Dressing changes were not necessary, and neither infections nor bleeding was detected. Overall exudation and pain were highest in the beginning but declined during the wound-healing phase without significant differences. In the follow-up scar evaluation after 12 months, patients reported overall high satisfaction. Overall, the modern dressings Suprathel and Dressilk (solely made out of pure silk) led to safe wound healing without infection and rapidly reduced pain. There was no need for dressing changes, and they had similar clinical outcomes in scar evaluation. Therefore, both dressings seem to be ideal for the treatment of superficial burns. Because acquisition costs remain one of the main factors in the treatment of burns, Dressilk, which is ~20 times cheaper than Suprathel, remains a good option for the treatment of partial thickness burns.

Comparison of wound healing and patient comfort in partial-thickness burn wounds treated with SUPRATHEL and epictehydro wound dressings.

Among the available dressings for partial-thickness burn wound treatment, SUPRATHEL has shown good usability and effectiveness for wound healing and patient comfort and has been used in many burn centres in the last decade. Recently, bacterial nanocellulose (BNC) has become popular for the treatment of wounds, and many studies have demonstrated its efficacy. epicitehydro , consisting of BNC and 95% water, is a promising product and has recently been introduced in numerous burn centres. To date, no studies including direct comparisons to existing products like SUPRATHEL have been conducted. Therefore, we aimed to compare epicitehydro to SUPRATHEL in the treatment of partial-thickness burns. Twenty patients with partial-thickness burns affecting more than 0.5% of their total body surface area (TBSA) were enrolled in this prospective, unicentric, open, comparative, intra-individual clinical study. After debridement, the wounds were divided into two areas: one was treated with SUPRATHEL and the other with epicitehydro . Wound healing, infection, bleeding, exudation, dressing changes, and pain were documented. The quality of the scar tissue was assessed subjectively using the Patient and Observer Scar Scale. Wound healing in patients with a mean TBSA of 9.2% took 15 to 16 days for both treatments without dressing changes. All wounds showed minimal exudation, and patients reported decreased pain with the only significant difference between the two dressings on day 1. No infection or bleeding occurred in any of the wounds. Regarding scar evaluation, SUPRATHEL and epicitehydro did not differ significantly. Both wound dressings were easy to use, were highly flexible, created a safe healing environment, had similar effects on pain reduction, and showed good cosmetic and functional results without necessary dressing changes. Therefore, epicitehydro can be used as an alternative to SUPRATHEL for the treatment of partial-thickness burn wounds.

Effect of comorbidities on clinical outcome of patients with burn injury - An analysis of the German Burn Registry.

BACKGROUND: Severe burn injuries are associated with high morbidity and mortality. Well-implemented scoring systems for patients with major burns exist in the literature. A major disadvantage of these scores is the partial non-consideration of patient-related comorbidities. Published data on this matter is limited to small study cohorts and/or single center studies. Further, the effect of comorbidities on clinical outcome of patients with severe burn injuries has not yet been examined nationwide in a large cohort in Germany. Hence, the aim of this study was to examine the influence of comorbidities on clinical outcome of these patients based on data from the national registry. METHODS: Anonymized data from a total of 3455 patients with documented burns of 1% or more Total Burn Surface Area (TBSA) and over 16 years of age included in the German Burn Registry between 2017 and 2018 were analyzed retrospectively. Data included burn extent, body weight, age, burn depth, inhalation injury, comorbidities, mortality, number of operations and length of hospital stay (LOS). RESULTS: In the logistic regression analysis age (OR 1.07 [1.06-1.09], p < 0.001), TBSA (OR 1.09 [1.08-1.11], p < 0.001), IHT (OR 2.15 [1.44-3.20], p < 0001), third degree burn (OR 2.08 [1.39-3.11], p < 0.001), Chronic Obstructive Pulmonary Disease (COPD) (OR 2.45 [1.38-4.35], p = 0.002) and renal insufficiency (OR 2.02 [1.13-3.59], p = 0.017) influenced mortality significantly. If a patient had more than one comorbidity, mortality was higher and in-hospital length of stay (LOS) longer. Renal insufficiency was significantly (p < 0.001) associated with the most prolonged LOS by 11.44 days. TBSA (p < 0.001), Abbreviated Burn Severity Index (ABSI) > 3 (p < 0.001) and IHT (p = 0.001) correlated with the amount of required surgeries and significantly predicted the need for intubation. Patients with arrhythmia significantly required more surgeries (p = 0.041), whereas patients with COPD required significantly less surgical interventions (p = 0.013). CONCLUSION: Preexisting comorbidities have a significant impact on the clinical outcome of patients with severe burn injuries. Further investigation is warranted in order to supplement existing prognostic scores with new mortality-associated parameters.

Lyophilization stabilizes clinical-stage core-crosslinked polymeric micelles to overcome cold chain supply challenges.

BACKGROUND: CriPec technology enables the generation of drug-entrapped biodegradable core-crosslinked polymeric micelles (CCPM) with high drug loading capacity, tailorable size, and drug release kinetics. Docetaxel (DTX)-entrapped CCPM, also referred to as CPC634, have demonstrated favorable pharmacokinetics, tolerability, and enhanced tumor uptake in patients. Clinical efficacy evaluation is ongoing. CPC634 is currently stored (shelf life > 5 years) and shipped as a frozen aqueous dispersion at temperatures below -60°C, in order to prevent premature release of DTX and hydrolysis of the core-crosslinks. Consequently, like other aqueous nanomedicine formulations, CPC634 relies on cold chain supply, which is unfavorable for commercialization. Lyophilization can help to bypass this issue. METHODS AND RESULTS: Freeze-drying methodology for CCPM was developed by employing CPC634 as a model formulation, and sucrose and trehalose as cryoprotectants. We studied the residual moisture content and reconstitution behavior of the CPC634 freeze-dried cake, as well as the size, polydispersity index, morphology, drug retention, and release kinetics of reconstituted CPC634. Subsequently, the freeze-drying methodology was validated in an industrial setting, yielding a CPC634 freeze-dried cake with a moisture content of less than 0.1 wt%. It was found that trehalose-cryoprotected CPC634 could be rapidly reconstituted in less than 5 min at room temperature. Critical quality attributes such as size, morphology, drug retention, and release kinetics of trehalose-cryoprotected freeze-dried CPC634 upon reconstitution were identical to those of non-freeze-dried CPC634. CONCLUSION: Our findings provide proof-of-concept for the lyophilization of drug-containing CCPM and our methodology is readily translatable to large-scale manufacturing for future commercialization.

In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin.

Curcumin-loaded polymeric micelles composed of poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) were prepared to solubilize and improve the pharmacokinetics of curcumin. Curcumin-loaded micelles were prepared by a nanoprecipitation method using mPEG5kDa-b-p(HPMA-Bz) copolymers with varying molecular weight of the hydrophobic block (5.2, 10.0, and 17.1 kDa). At equal curcumin loading, micelles composed of mPEG5kDa-b-p(HPMA-Bz)17.1kDa showed better curcumin retention in both phosphate-buffered saline (PBS) and plasma at 37 °C than micelles based on block copolymers with smaller hydrophobic blocks. No change in micelle size was observed during 24 h incubation in plasma using asymmetrical flow field-flow fractionation (AF4), attesting to particle stability. However, 22-49% of the curcumin loading was released from the micelles during 24 h from formulations with the highest to the lowest molecular weight p(HPMA-Bz), respectively, in plasma. AF4 analysis further showed that the released curcumin was subsequently solubilized by albumin. In vitro analyses revealed that the curcumin-loaded mPEG5kDa-b-p(HPMA-Bz)17.1kDa micelles were internalized by different types of cancer cells, resulting in curcumin-induced cell death. Intravenously administered curcumin-loaded, Cy7-labeled mPEG5kDa-b-p(HPMA-Bz)17.1kDa micelles in mice at 50 mg curcumin/kg showed a long circulation half-life for the micelles (t1/2 = 42 h), in line with the AF4 results. In contrast, the circulation time of curcumin was considerably shorter than that of the micelles (t1/2α = 0.11, t1/2ß = 2.5 h) but ∼5 times longer than has been reported for free curcumin (t1/2α = 0.02 h). The faster clearance of curcumin in vivo compared to in vitro studies can be attributed to the interaction of curcumin with blood cells. Despite the excellent solubilizing effect of these micelles, no cytostatic effect was achieved in neuroblastoma-bearing mice, possibly because of the low sensitivity of the Neuro2A cells to curcumin.

Ultrasonic-assisted production of zero-valent iron-decorated graphene oxide/activated carbon nanocomposites: Chemical transformation and structural evolution.

Nanotechnology has revolutionized many fields and produced nanostructures are promising materials for different industries. Nanoadsorbents as an emerging class of nanostructures can have potential applications for the separation and removal of both hazardous materials (such as heavy metals from water) and useful ingredients (such as vitamins and natural pigments from food wastes). The present study introduces a novel nanoadsorbent based on the ternary combination of zero valent iron/graphene oxide/active carbon (nZVI/GO-AC) with different formulations and using ultrasonication for improved physical properties. The nanocomposites were prepared by sodium borohydride reduction of graphene oxide, active carbon and ferrous sulfate under a nitrogen atmosphere and ultrasonication. Characterization of the developed nanocomposites was done by instrumental techniques, such as FTIR, VSM, FE-SEM, XRD, EDS, AFM and Raman analysis. The results indicated that the size of particles was 50 nm in the blank sample; however, when GO entered the composition, the particle size switched to <10 nm (either with or without ultrasonication). Also, the crystallinity of the ultrasound-assisted prepared nanocomposites enhanced by rapid nucleation in this method. Interestingly, the nanocomposites were superparamagnetic at ambient temperature and were separated by an external magnetic field. Altogether, at lower concentrations of GO in comparison to active carbon, the space between the GO sheets was higher and thus, there was more space for the accommodation of nZVI, which raises the rate of adsorbance. The immobilization process of nZVI on the composite platform improves the stability of the nZVI, whereas graphene coupling accelerates the transfer of electrons in nZVI and hinders the surface passivation of nZVI, resulting in the adsorption of target compounds.

Tuning Size and Morphology of mPEG-b-p(HPMA-Bz) Copolymer Self-Assemblies Using Microfluidics.

The careful design of nanoparticles, in terms of size and morphology, is of great importance to developing effective drug delivery systems. The ability to precisely tailor nanoparticles in size and morphology during polymer self-assembly was therefore investigated. Four poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) mPEG-b-p(HPMA-Bz) block copolymers with a fixed hydrophilic block of mPEG 5 kDa and a varying molecular weight of the hydrophobic p(HPMA-Bz) block (A: 17.1, B: 10.0, C: 5.2 and D: 2.7 kDa) were self-assembled into nanoparticles by nanoprecipitation under well-defined flow conditions, using microfluidics, at different concentrations. The nanoparticles from polymer A, increased in size from 55 to 90 nm using lower polymer concentrations and slower flow rates and even polymer vesicles were formed along with micelles. Similarly, nanoparticles from polymer D increased in size from 35 to 70 nm at slower flow rates and also formed vesicles along with micelles, regardless of the used concentration. Differently, polymers B and C mainly self-assembled into micelles at the different applied flow rates with negligible size difference. In conclusion, this study demonstrates that the self-assembly of mPEG-b-p(HPMA-Bz) block copolymers can be easily tailored in size and morphology using microfluidics and is therefore an attractive option for further scaled-up production activities.