Improving comfort in nursing home residents with dementia and pneumonia: Development, implementation and evaluation of a practice guideline for optimal symptom relief

Hertogh, C.M.P.M. [Promotor]Koopmans, R.C.T.M. [Promotor]Vet, H.C.W. de [Promotor]Steen, J.T. van der [Copromotor

Microneedle-mediated vaccine delivery

Conventional vaccines are administered intramuscularly or subcutaneously via hypodermic needles, causing pain and stress. Since the skin is a powerful immune organ, it is not surprising that intradermal injections result in potent immune responses. However, they are relatively difficult to perform and very painful. Advances in microfabrication techniques make microneedle-based dermal vaccination a viable alternative to traditional injections. Microneedles are micron-sized structures with a length of less than 1 mm that are used to deliver drugs, including vaccines, into the skin. The minimally-invasive, potentially pain free nature and ease of drug delivery can reduce the risk of infections and alleviate the need for trained personnel. This thesis describes several fundamental parameters that influence skin penetration by microneedles as well as factors that affect antigen-specific immune responses in animals following microneedle-based vaccination. Besides, the importance of using a microneedle insertion device for self-administration of microneedles is highlighted. Moreover, ultrathin pH-sensitive surface modifications for microneedles were developed to improve the coating of antigens and the efficiency of microneedle-mediated vaccine delivery. Finally, a method was developed to fabricate hollow microneedles, which were successfully used for polio vaccination. In conclusion, these studies provide important new insights for enabling pain free vaccination via the skin.UBL - phd migration 201

Chemical Modifications of Gold Surfaces with Basic Groups and a Fluorescent Nanoparticle Adhesion Assay To Determine Their Surface pKa

For pharmaceutical, biological, and biomedical applications, the functionalization of gold surfaces with pH-sensitive groups has great potential. The aim of this work was to modify gold surfaces with pH-sensitive groups and to determine the pKa of the modified gold surfaces using a fluorescent nanoparticle adhesion assay. To introduce pH-sensitive groups onto gold surfaces, we modified gold-coated silicon slides with four different bases: 4-mercaptopyridine (4-MP), 4-pyridylethylmercaptan (4-PEM), 4-aminothiophenol (4-ATP), and 2-mercaptoethylamine (2-MEA). To screen whether the modifications were successful, the binding of negatively charged fluorescently labeled nanoparticles to the positively charged surfaces was visualized by fluorescence microscopy and atomic force microscopy. Next, the pKa of the modified surfaces was determined by quantifying the pH-dependent adhesion of the fluorescently labeled nanoparticles with fluorescence spectroscopy. Fluorescence microscopy showed that the gold surfaces were successfully modified with the four different basic molecules. Moreover, fluorescence spectroscopy revealed that fluorescently labeled negatively charged nanoparticles bound onto gold surfaces that were modified with one of the four bases in a pH-dependent manner. By quantifying the adsorption of negatively charged fluorescently labeled nanoparticles onto the functionalized gold surfaces and using the Henderson–Hasselbalch equation, the pKa of these surfaces was determined to be 3.7 ± 0.1 (4-MP), 5.0 ± 0.1 (4-PEM), 5.4 ± 0.1 (4-ATP), and 7.4 ± 0.3 (2-MEA). We successfully functionalized gold surfaces with four different basic molecules, yielding modified surfaces with different pKa values, as determined with a fluorescent nanoparticle adhesion assay.Drug Delivery Technolog

Cationic nanoparticle-based cancer vaccines

Cationic nanoparticles have been shown to be surprisingly effective as cancer vaccine vehicles in preclinical and clinical studies. Cationic nanoparticles deliver tumor-associated antigens to dendritic cells and induce immune activation, resulting in strong antigen-specific cellular immune responses, as shown for a wide variety of vaccine candidates. In this review, we discuss the relation between the cationic nature of nanoparticles and the efficacy of cancer immunotherapy. Multiple types of lipid- and polymer-based cationic nanoparticulate cancer vaccines with various antigen types (e.g., mRNA, DNA, peptides and proteins) and adjuvants are described. Furthermore, we focus on the types of cationic nanoparticles used for T-cell induction, especially in the context of therapeutic cancer vaccination. We discuss different cationic nanoparticulate vaccines, molecular mechanisms of adjuvanticity and biodistribution profiles upon administration via different routes. Finally, we discuss the perspectives of cationic nanoparticulate vaccines for improving immunotherapy of cancer.Tumorimmunolog

Advanced micro and nano manufacturing technologies used in medical domain

This paper focuses on the aspects of advanced manufacturing technologies, namely micro and nano manufacturing (MNM) capabilities which are particularly relevant to medical domain. In recent years, the so called disruptive technologies have enabled engineers and clinicians to collaborate in solving complex problems which require advanced MNM capabilities to develop medical applications. As a result what was nearly impossible a few years ago, due to limitations in machining and manufacturability of micro and nano scale artefacts, are now made possible thanks to innovative manufacturing processes and technologies. The potential medical applications of the new MNM methods are immense and in this paper four potential uses, namely as medical devices, lab on chips, and brain implants are presented and discussed. These works were based on different projects undertaken by researchers at Cardiff University, UK. The manufacturing costs, though initially high, are expected to reduce over time as the technologies mature and become more widely available. Introducing these MNM technologies and disseminating these results to healthcare engineering, for a better quality of medical diagnosis and treatments with cost-effective solutions, will greatly benefit the majority of population who live in the developing countries in receiving appropriate and affordable medical care to achieve improvements in their quality of life

Quantification of lipid and peptide content in antigenic peptide-loaded liposome formulations by reversed-phase UPLC using UV absorbance and evaporative light scattering detection

Antigenic peptide-loaded cationic liposomes have shown promise as cancer vaccines. Quantification of both peptides and lipids is critical for quality control of such vaccines for clinical translation. In this work we describe a reversed phase ultra-performance liquid chromatography (RP-UPLC) method that separates lipids (DOTAP, DOPC and their degradation products) and two physicochemically different peptides within 12 min. Samples were prepared by dilution in a 1:1 (v/v) mixture of methanol and water. Peptide quantifi-cation was done via UV detection and lipids were quantified by an evaporative light scattering detector (ELSD), both coupled to the RP-UPLC system, with high precision (RSD < 3.5%). We showed that the presence of lipids and peptides did not mutually influence their quantification. Limit of detection (LOD) and limit of quantification (LOQ), as determined in the ICH guidelines, were 6 and 20 ng for DOTAP, 12 ng and 40 ng for DOPC, 3.0 ng and 8.0 ng for peptide A and 2.4 ng and 7.2 ng for the more hydrophobic peptide B. Finally, lipid degradation of DOTAP and DOPC was monitored in peptide loaded DOTAP:DOPC liposomes upon storage at 4 degrees C and 40 degrees C.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American Pharmacists Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Drug Delivery Technolog

Rapid, low cost prototyping of transdermal devices for personal healthcare monitoring

The next generation of devices for personal healthcare monitoring will comprise molecular sensors to monitor analytes of interest in the skin compartment. Transdermal devices based on microneedles offer an excellent opportunity to explore the dynamics of molecular markers in the interstitial fluid, however good acceptability of these next generation devices will require several technical problems associated with current commercially available wearable sensors to be overcome. These particularly include reliability, comfort and cost. An essential pre-requisite for transdermal molecular sensing devices is that they can be fabricated using scalable technologies which are cost effective.We present here a minimally invasive microneedle array as a continuous monitoring platform technology. Method for scalable fabrication of these structures is presented. The microneedle arrays were characterised mechanically and were shown to penetrate human skin under moderate thumb pressure. They were then functionalised and evaluated as glucose, lactate and theophylline biosensors. The results suggest that this technology can be employed in the measurement of metabolites, therapeutic drugs and biomarkers and could have an important role to play in the management of chronic diseases

Engineering of an automated nano-droplet dispensing system for fabrication of antigen-loaded dissolving microneedle arrays

Dissolving microneedle arrays (dMNAs) are promising devices for intradermal vaccine delivery. The aim of this study was to develop a reproducible fabrication method for dMNAs based on an automated nano-droplet dispensing system that minimizes antigen waste. First, a polymer formulation was selected to dispense sufficiently small droplets (<18 nL) that can enter the microneedle cavities (base diameter 330 µm). Besides, three linear stages were assembled to align the dispenser with the cavities, and a vacuum chamber was designed to fill the cavities with dispensed droplets without entrapped air. Lastly, the dispenser and stages were incorporated to build a fully automated system. To examine the function of dMNAs as a vaccine carrier, ovalbumin was loaded in dMNAs by dispensing a mixture of ovalbumin and polymer formulation, followed by determining the ovalbumin loading and release into the skin. The results demonstrate that functional dMNAs which can deliver antigen into the skin were successfully fabricated via the automatic fabrication system, and hardly any antigen waste was encountered. Compared to the method that centrifuges the mould, it resulted in a 98.5% volume reduction of antigen/polymer solution and a day shorter production time. This system has potential for scale-up of manufacturing to an industrial scale.Drug Delivery Technolog