Optics miniaturization strategy for demanding Raman spectroscopy applications.

Raman spectroscopy provides non-destructive, label-free quantitative studies of chemical compositions at the microscale as used on NASA's Perseverance rover on Mars. Such capabilities come at the cost of high requirements for instrumentation. Here we present a centimeter-scale miniaturization of a Raman spectrometer using cheap non-stabilized laser diodes, densely packed optics, and non-cooled small sensors. The performance is comparable with expensive bulky research-grade Raman systems. It has excellent sensitivity, low power consumption, perfect wavenumber, intensity calibration, and 7 cm-1 resolution within the 400-4000 cm-1 range using a built-in reference. High performance and versatility are demonstrated in use cases including quantification of methanol in beverages, in-vivo Raman measurements of human skin, fermentation monitoring, chemical Raman mapping at sub-micrometer resolution, quantitative SERS mapping of the anti-cancer drug methotrexate and in-vitro bacteria identification. We foresee that the miniaturization will allow realization of super-compact Raman spectrometers for integration in smartphones and medical devices, democratizing Raman technology.

Customized fast-separable microneedles prepared with the aid of 3D printing for nanoparticle delivery.

3D printing of master molds for soft lithography-based fabrication of microneedles (MNs) is a cost effective, easy and fast method for producing MNs with variable designs. Deviating from the classical geometries of MNs, 'tanto blade'-inspired MNs showed effective skin penetration, acting as sharp structures with low insertion force of 10.6 N, which is sufficient for manual insertion. Additionally, hydrophilic, fluorescent noble metal nanocluster-modified gelatin nanocarriers were loaded in polyvinyl alcohol/sucrose MNs to act as a novel potential theranostic system emitting light in the near-infrared (λem = ~700 nm). Nanoparticles (NPs) distribution within the MNs and release have been monitored using confocal laser scanning microscopy by means of spectral analysis and linear unmixing. Furthermore, the MNs patch was modified by carving a channel at each of the four corners of the patch. This facilitated the separation process of MNs from the patch base into skin, when 15 µL phosphate buffered saline was applied through each channel post-skin insertion of the MNs. Then, the patch base can be removed easily leaving the implanted MNs inside the skin for further release of the NP cargo. This successfully reduced the application time to 1 min for enhanced patient compliance.

Development and characterization of a PDMS-based masking method for microfabricated Oral drug delivery devices.

With the growing popularity and application of microfabricated devices in oral drug delivery (ODD), masking technologies for drug loading and surface modification become highly relevant. Considering the speed of design and fabrication processes and the necessity for continuous alterations of e.g. the shape and sizes of the devices during the optimization process, there is a need for adaptable, precise and low-cost masking techniques. Here, a novel method is presented for masking ODD microdevices, namely microcontainers, using the physical characteristics of polydimethylsiloxane (PDMS). When compared to a rigid microfabricated shadow mask, used for filling drugs in microcontainers, the PDMS masking technique allows more facile and precise loading of higher quantities of an active compound, without the need of alignment. The method provides flexibility and is adjustable to devices fabricated from different materials with various geometries, topologies and dimensions. This user-friendly flexible masking method overcomes the limitations of other masking techniques and is certainly not limited to ODD and is recommended for a wide range of microdevices.

3D Printing of Reservoir Devices for Oral Drug Delivery: From Concept to Functionality through Design Improvement for Enhanced Mucoadhesion.

So far, microdevices for oral drug delivery have been fabricated as square or cylindrical reservoir structures with a localized and unidirectional release. The fabrication is usually carried out using sophisticated and costly microfabrication techniques. Here, 3D printing of microreservoirs on sacrificial substrates is presented. This approach allows the devices to be accurately arranged in predetermined patterns, enabling implementation into batch production schemes in which the fabrication of the devices is linked to processing steps such as automated drug loading and sealing. Moreover, design and 3D printing of alternative geometries of minireservoirs featuring anchor-like surface structures for improved mucoadhesion and intestinal retention is demonstrated. Surface texturing of minireservoirs increases mucoadhesion of the devices up to two-fold compared to a nonstructured control. The structuring also leads to a strong bias in mucoadhesion in different orientations, which can facilitate a correct orientation of the devices and thus lead to unidirectional release of drugs toward the intestinal mucosa for increased drug uptake.

Biodegradable microcontainers - towards real life applications of microfabricated systems for oral drug delivery.

Microfabrication techniques have been applied to develop micron-scale devices for oral drug delivery with a high degree of control over size, shape and material composition. Recently, microcontainers have been introduced as a novel approach to obtain unidirectional release to avoid luminal drug loss, enhance drug permeation, protect drug payload from the harsh environment of the stomach, and explore the ability for targeted drug delivery. However, in order to eventually pave the way for real life applications of these microfabricated drug delivery systems, it is necessary to fabricate them in biodegradable materials approved for similar applications and with strategies that potentially allow for large scale production. In this study, we for the first time evaluate biodegradable microcontainers for oral drug delivery. Asymmetric poly-ε-caprolactone (PCL) microcontainers with a diameter of 300 µm and a volume of 2.7 nL are fabricated with a novel single-step fabrication process. The microcontainers are loaded with the model drug paracetamol and coated with an enteric pH-sensitive Eudragit® S100 coating to protect the drug until it reaches the desired location in the small intestine. In vitro dissolution studies are performed to assess the drug load and release profile of the PCL microcontainers. Finally, in vivo studies in rats showed a higher bioavailability compared to conventional dosage forms and confirm the potential of biodegradable microcontainers for oral drug delivery.

Polymeric Lids for Microcontainers for Oral Protein Delivery.

Oral delivery of proteins and peptides is one of the main challenges in pharmaceutical drug development. Microdevices have the possibility to protect the therapeutics until release is desired, avoiding losses by degradation. One type of microdevice is polymeric microcontainers. In this study, lysozyme is chosen as model protein and loaded into microcontainers with the permeation enhancer sodium decanoate (C10). The loaded microcontainers are sealed and functionalized by applying polymeric lids onto the cavity of the devices. The first lid is poly(lactic-co-glycolic) acid (PLGA) and on top of this either polyethylene glycol (PEG) or chitosan is applied (PLGA+PEG or PLGA+chitosan, respectively). The functionalization is evaluated in vitro for morphology, drug release, and mucoadhesive properties. These are coupled with in vitro and ex vivo studies using Caco-2 cells, Caco-2/HT29-MTX-E12 co-cultures, and porcine intestinal tissue. PLGA+chitosan shows slower release compared to PLGA+PEG or only PLGA in buffer and the transport of lysozyme across cell cultures is not enhanced compared to the bulk powder. Microcontainers coated with chitosan or PEG demonstrate a three times stronger adhesion during ex vivo mucoadhesion studies compared to samples without coatings. Altogether, functionalized microcontainers with mucoadhesive properties and tunable release for oral protein delivery are developed and characterized.