Determining the factors affecting dynamic insertion of microneedles into skin.

Microneedles are extremely small and minimally-invasive intradermal drug delivery devices that require controlled, accurate, and repeatable insertions into human skin to perform their functions. Due to high variability and elasticity of human skin, dynamic insertion methods are being sought to ensure success in microneedle insertions into the skin passed the tough stratum corneum layer. Dynamic microneedle insertions have not been thoroughly studied to identify and assess the key parameters influencing the skin fracture to date. Here, we have utilized a previously validated artificial mechanical human skin model to identify and evaluate the factors affecting microneedle insertion. It was determined that a microneedle's velocity at impact against the skin played the most crucial role in successfully inserting microneedle devices of different geometrical features (i.e., tip area) and array size (i.e., number of projections). The findings presented herein will facilitate the development of automated microneedle insertion devices that will enable user-friendly and error-free applications of microneedle technologies for medicine delivery.

Precise measurement of intradermal fluid delivery using a low activity technetium-99m pertechnetate tracer.

A method was developed and validated to determine the intradermal (ID) fluid delivery potential of several ID devices, including hollow microneedles. The novel method used water soluble technetium-99 m pertechnetate (99mTcO4-) diluted in normal saline to measure the volume of fluid delivered to and remaining in the skin. The fluid that back-flowed to the skin surface and the fluid left on the device surface were also quantified, thus capturing all fluid volumes deposited during intradermal injections. The technique described in this manuscript was used to assess the injection performance of conventional hypodermic needles and hollow microneedles ex vivo using porcine skin and in vivo with a rat model. Since only a small fraction, 1.1%, of the water-soluble tracer remained bound to the skin when applied topically, the technique can be used to differentiate between injected fluid and backflow. Counting of gamma radiation from 99mTcO4- provided sub-nanoliter resolution for volume measurements, making the proposed method powerful, sensitive, and suitable for the assessments of ID injection devices, particularly for vaccine delivery.

Revolutionizing Therapeutic Drug Monitoring with the Use of Interstitial Fluid and Microneedles Technology.

While therapeutic drug monitoring (TDM) that uses blood as the biological matrix is the traditional gold standard, this practice may be impossible, impractical, or unethical for some patient populations (e.g., elderly, pediatric, anemic) and those with fragile veins. In the context of finding an alternative biological matrix for TDM, this manuscript will provide a qualitative review on: (1) the principles of TDM; (2) alternative matrices for TDM; (3) current evidence supporting the use of interstitial fluid (ISF) for TDM in clinical models; (4) the use of microneedle technologies, which is potentially minimally invasive and pain-free, for the collection of ISF; and (5) future directions. The current state of knowledge on the use of ISF for TDM in humans is still limited. A thorough literature review indicates that only a few drug classes have been investigated (i.e., anti-infectives, anticonvulsants, and miscellaneous other agents). Studies have successfully demonstrated techniques for ISF extraction from the skin but have failed to demonstrate commercial feasibility of ISF extraction followed by analysis of its content outside the ISF-collecting microneedle device. In contrast, microneedle-integrated biosensors built to extract ISF and perform the biomolecule analysis on-device, with a key feature of not needing to transfer ISF to a separate instrument, have yielded promising results that need to be validated in pre-clinical and clinical studies. The most promising applications for microneedle-integrated biosensors is continuous monitoring of biomolecules from the skin's ISF. Conducting TDM using ISF is at the stage where its clinical utility should be investigated. Based on the advancements described in the current review, the immediate future direction for this area of research is to establish the suitability of using ISF for TDM in human models for drugs that have been found suitable in pre-clinical experiments.

Fluorescence spectroscopy and principal component analysis of soy protein hydrolysate fractions and the potential to assess their antioxidant capacity characteristics.

The potential of intrinsic fluorescence and principal component analysis (PCA) to characterize the antioxidant capacity of soy protein hydrolysates (SPH) during sequential ultrafiltration (UF) and nanofiltration (NF) was evaluated. SPH was obtained by enzymatic hydrolysis of soy protein isolate. Antioxidant capacity was measured by Oxygen Radical Absorbance Capacity (ORAC) and Folin Ciocalteau Reagent (FCR) assays together with fluorescence excitation-emission matrices (EEM). PCA of the fluorescence EEMs revealed two principal components (PC1-tryptophan, PC2-tyrosine) that captured significant variance in the fluorescence spectra. Regression models between antioxidant capacity and PC1 and PC2 displayed strong linear correlations for NF fractions and a weak linear correlation for UF fractions. Clustering of UF and NF fractions according to ORACFPCA and FCRFPCA was observed. The ability of this method to extract information on contributions by tryptophan and tyrosine amino acid residues to the antioxidant capacity of SPH fractions was demonstrated.

Integrated hollow microneedle-optofluidic biosensor for therapeutic drug monitoring in sub-nanoliter volumes.

Therapeutic drug monitoring (TDM) typically requires painful blood drawn from patients. We propose a painless and minimally-invasive alternative for TDM using hollow microneedles suitable to extract extremely small volumes (<1 nL) of interstitial fluid to measure drug concentrations. The inner lumen of a microneedle is functionalized to be used as a micro-reactor during sample collection to trap and bind target drug candidates during extraction, without requirements of sample transfer. An optofluidic device is integrated with this microneedle to rapidly quantify drug analytes with high sensitivity using a straightforward absorbance scheme. Vancomycin is currently detected by using volumes ranging between 50-100 µL with a limit of detection (LoD) of 1.35 µM. The proposed microneedle-optofluidic biosensor can detect vancomycin with a sample volume of 0.6 nL and a LoD of <100 nM, validating this painless point of care system with significant potential to reduce healthcare costs and patients suffering.