Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery.

Analogous to an assembly line, we employed a modular design for the high-throughput study of 1,536 structurally distinct nanoparticles with cationic cores and variable shells. This enabled elucidation of complexation, internalization, and delivery trends that could only be learned through evaluation of a large library. Using robotic automation, epoxide-functionalized block polymers were combinatorially cross-linked with a diverse library of amines, followed by measurement of molecular weight, diameter, RNA complexation, cellular internalization, and in vitro siRNA and pDNA delivery. Analysis revealed structure-function relationships and beneficial design guidelines, including a higher reactive block weight fraction, stoichiometric equivalence between epoxides and amines, and thin hydrophilic shells. Cross-linkers optimally possessed tertiary dimethylamine or piperazine groups and potential buffering capacity. Covalent cholesterol attachment allowed for transfection in vivo to liver hepatocytes in mice. The ability to tune the chemical nature of the core and shell may afford utility of these materials in additional applications.

Development of an intervention to support parents receiving treatment in psychiatric inpatient hospital using participatory design methods.

Introduction: When parents of dependent children are treated in psychiatric inpatient hospital, it typically involves separation of parent and child for the duration of treatment, which can be highly distressing to the dyad and can result in disruption to the parent-child relationship. Parents who have experienced hospitalisation have expressed a desire for their parenting identity to be recognized and appropriately engaged with during their treatment. This recognition includes provision of interventions which support them as parents to limit the impact of their mental health on their children. The current study, the first of its kind known to have taken place, details a collaborative intervention development project for parents receiving inpatient care. Methods: The current study, the first of its kind known to have taken place, details a collaborative intervention development project for parents receiving inpatient care. This project involved the adaptation and extension of a prior parenting-focused course for parents high in anxiety to meet the needs of parents being treated in inpatient settings. In the first two stages of the three-phase project, patients, carers and mental health practitioners contributed to the revision and delivery plan for the course including developing new content for the intervention. In the final stage, which took the form of a participatory evaluation, the intervention was delivered to 11 parents receiving inpatient treatment who then provided extensive feedback. A series of iterative adaptations to the intervention were made in response to this feedback alongside stakeholder input. Results: The final intervention comprises five modules focused on exploring the experience of parents alongside specific learning and skills orientated toward boosting their connection with their children during hospitalisation and in readiness for discharge. Preliminary feedback from patients and ward staff has been positive and the process of delivering the project on inpatient wards was associated with no increase in negative clinical outcomes. Discussion: The successful development of a targeted intervention within inpatient psychiatric units offers a signal that parents treated in this setting welcome the opportunity to be supported in their parenting role. As the first known UK intervention of its kind to be developed in partnership with patients, ward staff and management, it is specifically tailored to the context and needs of this group with the potential to be delivered by a range of health professionals in this setting.

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates.

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.