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The advancement and popularity of transdermal drug delivery (TDD) based on the physical transdermal enhancement technique (PTET) has opened a new paradigm for local tumor treatment. The drug can be directly delivered to the tumor site through the skin, thus avoiding the toxic side effects caused by the first-pass effect and achieving high patient compliance. Further development of PTETs has provided many options for antitumor drugs and laid the foundation for future applications of wearable closed-loop targeting drug delivery systems. In this highlight, the different types of PTETs and related mechanisms, and applications of PTET-related tumor detection and therapy are highlighted. According to their type and characteristics, PTETs are categorized as follows: (1) iontophoresis, (2) electroporation, (3) ultrasound, (4) thermal ablation, and (5) microneedles. PTET-related applications in the local treatment of tumors are categorized as follows: (1) melanoma, (2) breast tumor, (3) squamous cell carcinoma, (4) cervical tumor, and (5) others. The challenges and future prospects of existing PTETs are also discussed. This highlight will provide guidance for the design of PTET-based wearable closed-loop targeting drug delivery systems and personalized therapy for tumors. [ABSTRACT FROM AUTHOR]

In the past two decades, microneedles have been extensively studied for transdermal delivery of drug or vaccines and for bio‐fluid extraction. Microneedle‐based devices consist of micron‐size needles that are arranged on a small patch. Despite ongoing advances in microneedle technology, one of the major problems associated with transdermal delivery or sampling is that many of the microneedle patches are not able to fully penetrate the skin surface and reach the epidermis layer of skin. In this regard, for an optimal and effective penetration—painless and safe—it is crucial to consider complex skin mechanics and how it impacts microneedle design and insertion practice. Various types of skin modelling and insertion simulations are considered, followed by discussion of ways of improving microneedle robustness, reduction of insertion force, and enhancement of penetration efficiency. [ABSTRACT FROM AUTHOR]

Microneedles (MNs) are one of intriguing approach for efficient transdermal drug delivery that penetrates the protective skin barrier in a painless and less invasive way. In recent years, multidisciplinary studies have been conducted to improve their properties to meet stringent requirements and obtain market release approval. This review aims to summarize the latest concept design with unique properties in the advancement of transdermal MNs for diagnosis and therapeutic application. Numerous significant innovation strategies in improving MNs in aspects of adhesion ability, dosing capacity, drug‐controlled release, diffusion control ability, site‐targeted and on‐demand drug delivery, and biomarker or drug release monitoring are presented. Given that the majority of technologies used in such design are exclusively laboratory‐based, striving toward commercialization is a critical aspect of the revolution. Key challenges and future perspectives in industrial and economic aspects are identified with the intention of translating the reviewed technologies into marketable products. [ABSTRACT FROM AUTHOR]

Background: Weight loss outcomes after bariatric surgery are less favorable in super morbidly obese patients (BMI ≥50 kg/m2). Non-response, either defined as insufficient weight loss or weight regain after initial successful weight loss, is a matter of serious concern in these patients. The primary banded Roux-en-Y gastric bypass has shown promising results regarding weight loss in the bariatric population. However, up to now, long-term comparative data about the banded and non-banded bypass in superobese patients is lacking. The aim of this study is to assess the added value of the banded Roux-en-Y gastric bypass in superobese patients on long-term weight loss outcomes.Methods: This single center study will evaluate superobese patients who receive a non-banded Roux-en-Y gastric bypass (NB-RYGB) and a banded Roux-en-Y gastric bypass (B-RYGB). Data from the NB-RYGB group will be collected in retrospect, while data from the B-RYGB group will be collected prospectively. When performing a B-RYGB, a 7.0-8.0 cm silastic ring (MiniMizer®) will be placed proximal to the gastrojejunostomy. The main outcomes of this study are weight loss and non-response during a 10 year follow-up period. Secondary outcomes are reduction of obesity related comorbidities and medication, (ring-related) morbidity and mortality, complications, re-operations, patient satisfaction and health-related quality of life. A total of 142 patients will be included in this study.Discussion: This study will help establish the clinical utility of the B-RYGB in superobese patients.Trial Register: NL8093. Registered 15 October 2019 - Retrospectively registered on the Dutch Registry of Clinical trials, www.trialregister.nl. [ABSTRACT FROM AUTHOR]

Hypertrophic scarring is a widespread skin disorder that affects a patient's confidence and quality of life. Intralesional injection of bleomycin is one of the most commonly employed treatments for hypertrophic scars, which, however, always brings pain and requires long-term treatment. To overcome these limitations, new methods for bleomycin delivery enabling painlessness, self-administration, the fast onset of action, and good bioavailability are urgently needed. In this study, we developed bleomycin-loaded dissolving microneedles (BMN) made up of hyaluronic acid (HA) with excellent aqueous solubility and enhanced efficacy for inhibiting hypertrophic scars. The as-obtained BMN possesses sufficient mechanical strength to pierce porcine skin ex vivo with an insertion depth of over 300 μm. Moreover, BMN can dissolve rapidly and release 20% of loaded bleomycin within 1 min and 52% within 10 min, and the BMN-treated skin could recover to its original status within 3 h, demonstrating good biocompatibility. Besides, the HA matrix also maintains the stability and activity of bleomycin. Furthermore, we show that BMN consisting of HA and bleomycin can inhibit the proliferation of human hypertrophic scar fibroblasts (hHSFs) and the secretion of transforming growth factor-β (TGF-β1) in vitro. Therefore, bleomycin-loaded dissolving HA microneedles provide a potential route to treat hypertrophic scars in a convenient, efficient, and minimally invasive manner. [ABSTRACT FROM AUTHOR]

Microneedle-based vaccination into skin has several advantages over vaccination using conventional needles for intramuscular or subcutaneous injections. Microneedle (MN) arrays allow the vaccine to be delivered in a minimally invasive manner and directly into the skin, whereby the skin's superficial immune cells are not by-passed. Additionally, a systemic distribution of the vaccine may be avoided, which implies less side effects and less amount of vaccine needed. For a successful delivery, the needles need to penetrate the stratum corneum and reach the potent network of antigen-presenting dendritic cells (DCs). In this study, we evaluated patches covered with biodegradable ceramic (calcium sulphate) MNs with a tip diameter of approximately 3 μm and with two different lengths (300 and 600 μm) for their ability to penetrate and transfer the model allergen ovalbumin (OVA) into epidermis. MNs with a length of 600 μm (MN-600) and a volume average pore size of 12 ± 1 μm were more efficient in crossing the stratum corneum and to deliver OVA into CD1a+ DCs residing in the epidermis of human ex vivo skin, in comparison to MNs with a length of 300 μm. Quantitative in vitro release studies showed that approximately 90% of the loaded OVA could be released from MN-600 within 1 h. These findings support the further development of ceramic MNs for transcutaneous immunization. [ABSTRACT FROM AUTHOR]

Since the 1940s, great amounts of Plutonium (Pu) have been produced for both military and civil purposes. Until now, the standard therapy for decorporation following inhalation has been the intravenous injection of diethylenetriaminepentaacetic acid ligand (Ca-DTPA form). This method offers a strong complexing constant for Pu(iv) but has poor chemical specificity, therefore its efficacy is limited to actinides present in the blood. Consequently, there is no decorporation treatment currently available which efficiently removes the intracellular Pu(iv) trapped in the pulmonary macrophages. Our research shows that a nanoparticle approach could be of particular interest due to large contact area and ability to target the retention compartments of the lungs. In this study, we have focused on the inhalation process involving forms of Pu(iv) with poor solubility. We explored the design of biocompatible nanoparticles able to target the macrophages in the lung alveoli and to chelate the forms of Pu(iv) with poor solubility. Nanoparticle formation was achieved through an ionic cross-linking concept using a polycationic polymer and an anionic chelate linker. We chose N-trimethyl chitosan, for its biocompatibility, as the polycationic polymer base of the nanoparticle and the phosphonic analogue of DTPA, diethylenetriamine-pentamethylenephosphonic acid (DTPMP) as the anionic chelating linker in forming NPs TMC-DTPMP. The synthesis and physico-chemical characterization of these NPs are presented. Secondly, the complexation mechanisms of TMC-DTPMP NPs with Thorium (Th(iv)) are discussed in terms of efficiency and structure. The Extended X-Ray Absorption Fine Structure (EXAFS) of the TMC-DTPMP complex with Th(iv) as well as Pu(iv) are defined and completed with DFT calculations to further delineate the plutonium coordination sphere after complexation. Finally, preliminary cytotoxicity tests onto macrophages were assayed. [ABSTRACT FROM AUTHOR]

SUMMARY: Background and Objectives: Previous work has studied barriers to donating blood or plasma among current, lapsed and non‐donors. Still, it remains unclear why donors stop donating and end their donor career voluntarily. A thorough understanding of why donors stop is necessary to develop more effective retention strategies and manage the decline in whole‐blood donors. Methods: An online questionnaire that contained questions about reasons to stop donation was sent out to 7098 Dutch whole‐blood donors who deregistered from the donor pool in 2015 but who were not permanently deferred for medical reasons (response: N = 2490, 35%). Results: The final sample consisted of 1865 stopped blood donors. Of the stopped blood donors, 28·4% reported that negative physical experiences were (partly) the reason to stop. This stopping reason was more often reported by women than men, those aged 19–33 years compared to older groups and those who had donated five times or less compared to those with more donations. Inconvenient opening times (26·1%) was a stopping reason more frequently reported by men compared to women, those aged 34–50 years compared to their younger and older counterparts and those who had donated more than five times. Conclusions: We found that the stopping reasons for blood donors are dependent on gender, age and the number of donations. Stopping reasons differ substantially from barriers experienced by current, lapsed and non‐donors. More research on preventing negative physical experiences and implementing more flexible opening hours are advised. [ABSTRACT FROM AUTHOR]

Microneedles are an efficient and minimally invasive approach to transdermal drug delivery and extraction of skin interstitial fluid. Compared to solid microneedles made of silicon, metals and ceramics, polymeric microneedles have attracted extensive attention due to their excellent biocompatibility, biodegradability and nontoxicity. They are easy to fabricate in large scale and can load drugs in high amounts. More importantly, polymers with different degradation profiles, swelling properties, and responses to biological/physical stimuli can be employed to fabricate polymeric microneedles with different mechanical properties and performance. This review provides a guideline for the selection of polymers and the corresponding fabrication methods for polymeric microneedles while summarizing their recent application in drug delivery and fluid extraction. It should be noted that although polymeric microneedles can achieve efficient transdermal delivery of drugs, their wide applications were limited by their unsatisfactory transdermal therapeutic efficiency. Delivery of nanomedicines that incorporate drugs into functional nanoparticles/capsules can address this problem and thus may be an interesting direction in the future. [ABSTRACT FROM AUTHOR]

Dissolving microneedles are transdermal delivery systems designed to mechanically penetrate the skin and fully dissolve in the skin in a minimally invasive manner. In this study, the skin permeability of compounds encapsulated in microneedles was controlled by changing the composition of microneedle materials. Sodium hyaluronate (SH) and carboxymethyl cellulose (CMC) were chosen as structural materials and amylopectin was used to increase the mechanical strength of microneedles. To determine the effect of microneedle composition on skin permeability, microneedle properties such as mechanical strength and solubility were investigated according to various compositions of SH and CMC. When the CMC fraction in the needle increased, the mechanical strength of the microneedle increased, leading to high skin permeability of rhodamine B, a model compound. Using microneedles, significantly higher skin permeability of niacinamide was also obtained. These results indicate that the microneedles developed in this study improved the skin permeability of compounds loaded in the needle, and the skin permeability could be tuned by changing the composition of microneedle materials. [ABSTRACT FROM AUTHOR]

Purpose: Determine the effect of minute quantities of sub-visible aggregates on the in vitro immunogenicity of clinically relevant protein therapeutics. Methods: Monoclonal chimeric (rituximab) and humanized (trastuzumab) antibodies were subjected to fine-tuned stress conditions to achieve low levels (<3% of total protein) of sub-visible aggregates. The effect of stimulating human dendritic cells (DC) and CD4 T cells with the aggregates was measured in vitro using cytokine secretion, proliferation and confocal microscopy. Results: Due to its intrinsic high clinical immunogenicity, aggregation of rituximab had minimal effects on DC activation and T cell responses compared to monomeric rituximab. However, in the case of trastuzumab (low clinical immunogenicity) small quantities of aggregates led to potent CD4 T cell proliferation as a result of strong cytokine and co-stimulatory signals derived from DC. Consistent with this, confocal studies showed that stir-stressed rituximab was rapidly internalised and associated with late endosomes of DC. Conclusions: These data link minute amounts of aggregates with activation of the innate immune response, involving DC, resulting in T cell activation. Thus, when protein therapeutics with little or no clinical immunogenicity, such as trastuzumab, contain minute amounts of sub-visible aggregates, they are associated with significantly increased potential risk of clinical immunogenicity. [ABSTRACT FROM AUTHOR]

Purpose: To determine the immunogenicity of diphtheria toxoid (DT) formulated in two types of vesicles following transcutaneous immunization (TCI) of mice onto microneedle array-treated skin. Methods: DT-containing cationic liposomes or anionic surfactant-based vesicles were prepared by extrusion and sonication. The physicochemical properties were characterized in terms of size, ζ-potential, vesicle elasticity and antigen association. TCI was performed by applying formulations onto intact or microneedle array-pretreated mice skin, using cholera toxin as an adjuvant. Subcutaneous and intradermal immunizations were as control. Immune responses were evaluated by IgG and neutralizing antibody titers, and the immune-stimulatory properties were assessed using cultured dendritic cells. Results: Stable DT-containing cationic liposomes (∼150 nm) and anionic vesicles (∼100 nm) were obtained. Incorporation of Span 80 increased liposome elasticity. About 90% and 77% DT was associated with liposomes and vesicles, respectively. TCI of all formulations resulted in substantial antibody titers only if microneedle pretreatment was applied. Co-administration of cholera toxin further augmented the immune responses of TCI. However, vesicle formulations didn't enhance the immunogenicity on either intact or microneedle-treated skin and showed low stimulatory activity on dendritic cells. Conclusions: Microneedle pretreatment and cholera toxin, but not antigen association to vesicles, enhances the immunogenicity of topically applied DT. [ABSTRACT FROM AUTHOR]

To compare college students' opinions of computer-based melodic dictation instruction and classroom instruction, 75 students enrolled in sophomore music theory who had been exposed to both approaches were surveyed. A 34-item questionnaire evaluated students' opinions of the hardware, software, and departmental requirements regarding the computer-based instruction and asked for comparisons of this tutelage with the classroom instruction they had subsequently received. While hardware and software received generally favorable reviews; students basically related a negative opinion of the computer-based melodic dictation instruction. This opinion was based on the following three points: The computer program required too much time outside class, too much progress was expected in too little time, and pacing (the increase in difficulty levels) was not consistent throughout the program. On the basis of student comments, several suggestions regarding construction of computer-based instructional materials are presented. [ABSTRACT FROM PUBLISHER]