Designing a unique feedback mechanism for hydrogel-forming microneedle array patches: a concept study

Although microneedle array patch (MAP) technology is reaching ever closer to regulatory approval, it remains imperativethat approaches to further improve patient acceptance are still explored. Addressing this perception, a water-flled reservoirwas incorporated into a hydrogel-forming MAP system to provide a novel feedback mechanism. To confrm successful MAPskin insertion, the end user would both hear and feel the rupture of the water-flled reservoir. Interestingly, a 50-µL waterflled reservoir ruptured at 30.27±0.39 N, which has previously been shown as the mean application force for MN insertionin human subjects following appropriate instruction. Importantly, no signifcant diference in % cumulative permeation ofFITC-dextran 10 kDa and fuorescein sodium after 24 h was observed between a 50-µL reservoir and the current method ofapplication that has been successfully used in both in vitro and in vivo studies (p>0.05). Therefore, as drug delivery was notafected, this proof-of-concept study has shown that a water-flled reservoir feedback mechanism has the potential to serveas a viable tool for consistent MAP skin insertion

Influence of molecular weight on transdermal delivery of model macromolecules using hydrogel-forming microneedles: Potential to enhance the administration of novel low molecular weight biotherapeutics

With a view to improve the current monoclonal antibody-based therapies dominating the pharmaceutical market, low molecular weight (MW) protein-based macromolecules, such as recombinant antibody fragments, typically within the range of 10–70 kDa, have been developed. Previously, our group successfully delivered Avastin®, a monoclonal antibody (mAb) across the skin using hydrogel-forming microneedles (MN). However, it is thought that this delivery system can be further enhanced using novel, lower MW biomolecules. To address this perception, in the current study, FITC–dextran of different MWs (10, 70 and 150 kDa) was used to model the transdermal delivery of low MW biotherapeutics and mAbs with MWs of approximately 150 kDa. Conversely, fluorescein sodium was the compound selected to model hydrophilic, low MW drugs. As expected, fluorescein sodium produced the greatest cumulative permeation (637.4 ± 42.69 μg). The amounts of FITC–dextran 10 kDa and 150 kDa which permeated across neonatal porcine skin in vitro were 462.17 ± 65.85 μg and 213.54 ± 15.19 μg after 24 h, respectively. The results collated here suggest that the delivery of emerging novel biotherapeutics, via ‘super swelling’ hydrogel-forming MNs, have the potential to result in greater permeation across human skin, compared to the delivery of mAbs delivered via the same route

Enhancing the Transdermal Delivery of ‘Next Generation’ Variable New Antigen Receptors Using Microarray Patch Technology: a Proof-of-Concept Study

Heavy chain only binding proteins, such as variable new antigen receptors (VNARs), have emerged as an alternative to the highly successful therapeutic monoclonal antibodies (mAb). Owing to their small size (» 11 kDa)and single chain only architecture, they are amenable to modular reformatting and can be produced using inexpensive expression systems. Furthermore, due to their low molecular weight (MW) and high stability, theymay be suitable for alternative delivery strategies, such as microarray array patches (MAPs). In this study, thetransdermal delivery of ELN22-104, a multivalent anti-hTNF-a VNAR, was examined using both dissolving andhydrogel-forming MAPs. For dissolving MAPs, the cumulative in vitro permeation of ELN22-104 reached a plateau after 2 h (12.24 § 0.17 mg). This could be important for bolus dosing. Assessing two hydrogel-formingMAPs in vitro, PVP/PVA hydrogel-forming MAPs delivered significantly higher drug doses when compared to‘super swelling’ MAPs, equivalent to 43.13 § 10.36 mg and 23.13 § 5.66 mg, respectively (p < 0.05). Consequently, this study has proven that by modifying the MAP system, the transdermal delivery of a VNAR acrossthe skin can be enhanced. Furthermore, this proof-of-concept study has shown that transdermal delivery of‘next generation’ biotherapeutics is achievable using MAP technology

The Role of 3D Printing Technology in Microengineering of Microneedles

Microneedles (MNs) are minimally invasive devices, which have gained extensive interest over the past decades in various fields including drug delivery, disease diagnosis, monitoring, and cosmetics. MN geometry and shape are key parameters that dictate performance and therapeutic efficacy, however, traditional fabrication methods, such as molding, may not be able to offer rapid design modifications. In this regard, the fabrication of MNs using 3D printing technology enables the rapid creation of complex MN prototypes with high accuracy and offers customizable MN devices with a desired shape and dimension. Moreover, 3D printing shows great potential in producing advanced transdermal drug delivery systems and medical devices by integrating MNs with a variety of technologies. This review aims to demonstrate the advantages of exploiting 3D printing technology as a new tool to microengineer MNs. Various 3D printing methods are introduced, and representative MNs manufactured by such approaches are highlighted in detail. The development of advanced MN devices is also included. Finally, clinical translation and future perspectives for the development of MNs using 3D printing are discussed

Upward Three-Dimensional Grid Drawings of Graphs

A \emph{three-dimensional grid drawing} of a graph is a placement of the vertices at distinct points with integer coordinates, such that the straight line segments representing the edges do not cross. Our aim is to produce three-dimensional grid drawings with small bounding box volume. We prove that every $n$-vertex graph with bounded degeneracy has a three-dimensional grid drawing with $O(n^{3/2})$ volume. This is the broadest class of graphs admiting such drawings. A three-dimensional grid drawing of a directed graph is \emph{upward} if every arc points up in the z-direction. We prove that every directed acyclic graph has an upward three-dimensional grid drawing with $(n^3)$ volume, which is tight for the complete dag. The previous best upper bound was $O(n^4)$. Our main result is that every $c$-colourable directed acyclic graph ($c$ constant) has an upward three-dimensional grid drawing with $O(n^2)$ volume. This result matches the bound in the undirected case, and improves the best known bound from $O(n^3)$ for many classes of directed acyclic graphs, including planar, series parallel, and outerplanar

Oceanic response to Pliensbachian and Toarcian magmatic events: Implications from an organic-rich basinal succession in the NW Tethys

The Bächental bituminous marls (Bächentaler Bitumenmergel) belonging to the Sachrang Member of the Lower Jurassic Middle Allgäu Formation were investigated using a multidisciplinary approach to determine environmental controls on the formation of organic-rich deposits in a semi-restricted basin of the NW Tethys during the Early Jurassic. The marls are subdivided into three units on the basis of mineralogical composition, source-rock parameters, redox conditions, salinity variations, and diagenetic processes. Redox proxies (e.g., pristane/phytane ratio; aryl isoprenoids; bioturbation; ternary plot of iron, total organic carbon, and sulphur) indicate varying suboxic to euxinic conditions during deposition of the Bächental section. Redox variations were mainly controlled by sea-level fluctuations with the tectonically complex bathymetry of the Bächental basin determining watermass exchange with the Tethys Ocean. Accordingly, strongest anoxia and highest total organic carbon content (up to 13%) occur in the middle part of the profile (upper tenuicostatum and lower falciferum zones), coincident with an increase in surface-water productivity during a period of relative sea-level lowstand that induced salinity stratification in a stagnant basin setting. This level corresponds to the time interval of the lower Toarcian oceanic anoxic event (T-OAE). However, the absence of the widely observed lower Toarcian negative carbon isotope excursion in the study section questions its unrestricted use as a global chemostratigraphic marker. Stratigraphic correlation of the thermally immature Bächental bituminous marls with the Posidonia Shale of SW Germany on the basis of C27/C29 sterane ratio profiles and ammonite data suggests that deposition of organic matter-rich sediments in isolated basins in the Alpine realm commenced earlier (late Pliensbachian margaritatus Zone) than in regionally proximal epicontinental seas (early Toarcian tenuicostatum Zone). The late Pliensbachian onset of reducing conditions in the Bächental basin coincided with an influx of volcaniclastic detritus that was possibly connected to complex rifting processes of the Alpine Tethys and with a globally observed eruption-induced extinction event. The level of maximum organic matter accumulation in the Bächental basin corresponds to the main eruptive phase of the Karoo-Ferrar large igneous province (LIP), confirming its massive impact on global climate and oceanic conditions during the Early Jurassic. The Bächental marl succession is thus a record of the complex interaction of global (i.e., LIP) and local (e.g., redox and salinity variations, basin morphology) factors that caused reducing conditions and organic matter enrichment in the Bächental basin. These developments resulted in highly inhomogeneous environmental conditions in semi-restricted basins of the NW Tethyan domain during late Pliensbachian and early Toarcian time