Diabetes mellitus (DM) is a metabolic disorder that is one of the most common health problems in the world, primarily type 2 DM (T2DM). Metformin (MTF), as the first-line treatment of DMT2, is effective in lowering glucose levels, but its oral administration causes problems, including gastrointestinal side effects, low bioavailability, and the risk of hypoglycemia. In this study, we formulated MTF into microparticles incorporating a glucose-responsive polymer (MP−MTF−GR), which could potentially increase the bioavailability and extend and control the release of MTF according to glucose levels. This system was delivered by dissolving microneedles (MP−MTF−GR−DMN), applied through the skin, thereby preventing gastrointestinal side effects of orally administered MTF. MP−MTF−GR was formulated using various concentrations of gelatin as a polymer combined with phenylboronic acid (PBA) as a glucose-responsive material. MP−MTF−GR was encapsulated in DMN using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as DMN polymers. The physicochemical evaluation of MP−MTF−GR showed that MTF could be completely entrapped in MP with the percentage of MTF trapped increasing with increasing gelatin concentration without changing the chemical structure of MTF and producing stable MP. In addition, the results of the physicochemical evaluation of MP−MTF−GR−DMN showed that DMN had adequate mechanical strength properties and penetration ability and was stable to environmental changes. The results of the in vitro release and ex vivo permeation study on media with various concentrations of glucose showed that the release and permeation of MTF from the formula increased with increasing glucose levels in the media. The MP−MTF−GR−DMN formula successfully delivered MTF through the skin at 11.30 ± 0.29, 23.31 ± 1.64, 36.12 ± 3.77, and 53.09 ± 3.01 μg from PBS, PBS + glucose 1%, PBS + glucose 2%, and PBS + glucose 4%, respectively, at 24 h, which indicates glucose-responsive permeation and release behavior. The formula developed was also proven to be nontoxic based on hemolysis tests. Importantly, the in vivo study on the rat model showed that this combination approach could provide a better glucose reduction compared to other routes, reducing the blood glucose level to normal levels after 3 h and maintaining this level for 8 h. Furthermore, this approach did not change the skin moisture of the rats. This MP−MTF−GR−DMN is a promising alternative to MTF delivery to overcome MTF problems and increase the effectiveness of T2DM therapy.

Numerous diseases have been reported to affect the lymphatic system. As such, several strategies have been developed to deliver chemotherapeutics to this specific network of tissues and associated organs. Nanotechnology has been exploited as one of the main approaches to improve the lymphatic uptake of drugs. Different nanoparticle approaches utilized for both active and passive targeting of the lymphatic system are discussed here. Specifically, due to the rich abundance of lymphatic capillaries in the dermis, particular attention is given to this route of administration, as intradermal administration could potentially result in higher lymphatic uptake compared to other routes of administration. Recently, progress in microneedle research has attracted particular attention as an alternative for the use of conventional hypodermic injections. The benefits of microneedles, when compared to intradermal injection, are subsequently highlighted. Importantly, microneedles exhibit particular benefit in relation to therapeutic targeting of the lymphatic system, especially when combined with nanoparticles, which are further discussed. However, despite the apparent benefits provided by this combination approach, further comprehensive preclinical and clinical studies are now necessary to realize the potential extent of this dual‐delivery platform, further taking into consideration eventual usability and acceptability in the intended patient end‐users. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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Extracellular tissue fluids are interesting biomatrices that have recently attracted scientists' interest. Many significant biomarkers for localized external organ diseases have been isolated from this biofluid. In the diagnostic and disease monitoring context, measuring biochemical entities from the fluids surrounding the diseased tissues may give more important clinical value than measuring them at a systemic level. Despite all these facts, pushing tissue fluid-based diagnosis and monitoring forward to clinical settings faces one major problem: its accessibility. Most extracellular tissue fluid, such as interstitial fluid (ISF), is abundant but hard to collect, and the currently available technologies are invasive and expensive. This is where novel microneedle technology can help tackle this significant obstacle. The ability of microneedle technology to minimally invasively access tissue fluid-containing biomarkers will enable ISF and other tissue fluid utilization in the clinical diagnosis and monitoring of localized diseases. This review attempts to present the current pursuit of the application of microneedle systems as a diagnostic and monitoring platform, along with the recent progress of biomarker detection in diagnosing and monitoring localized external organ diseases. Then, the potential use of various microneedles in future clinical diagnostics and monitoring of localized diseases is discussed by presenting the currently studied cases.

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