open-flow microperfusion, are time-consuming, cumbersome, patient-unfriendly, requiring medical expertise and specialized equipment. [2] Microneedles (MNs) have then been proposed for the extraction of skin ISF due to their minimally invasive and easy-to-administrated properties. [3,4,5] Hydrogel-based swellable MNs are especially attractive because of their simplicity, efficiency, and biocompatibility. Samant et al. recently showed that polyvinyl alcohol (PVA)-based hydrogel patch could collect ISF from ex vivo pig skin [4] {[(Samant, 2018 #7)]} while our group developed the methacrylated hyaluronic acid (MeHA)-based hydrogel patch for ISF extraction from mouse skin in vivo without external devices. [5] Although the results from both systems were exciting, they were limited to the sampling time for the collection of the sufficient volume of ISF (1-10 µL) and the additional steps for quantifying the biomarkers in ISF. Assuming that both aforementioned systems maintain their performance in human skin as those in pig/mouse skin, PVA patch with 100 MNs can only extract 0.3 µL ISF after 12 h, while MeHA patch with 100 MNs required 20 min to collect 2.5 µL ISF. 20 min collection time is acceptable for the examination of biomarkers like cancer biomarkers or cholesterol that are relatively stable during this collection period but is definitely too long for biomarkers like O 2 and glucose whose concentration Hydrogel microneedle patch enables the extraction of skin interstitial fluid (ISF) through in situ swelling in a minimally invasive manner without assistance of mechano-chemical peripherals. However, existing hydrogel microneedles require tens of minutes with multistep process to collect sufficient volume (1 mL) for effective analysis. This study introduces an osmolyte-powered hydrogel microneedle patch that can extract ISF three times faster than the existing platforms and provide in situ analysis of extracted biomarkers. The microneedle patch is composed of osmolytes (i.e., maltose) and hydrogel (i.e., methacrylated hyaluronic acid). During the extraction process, the osmolytes dissolve in the matrix and provide the osmotic pressure that increases the diffusion of ISF from skin to the hydrogel matrix. A patch with 100 microneedles can extract 7.90 µL of ISF from pig skin ex vivo and 3.82 µL of ISF from mouse skin in vivo within 3 min, whereas the control (i.e., hydrogel microneedle without osmolytes) requires >10 min to achieve similar results. The extracted ISF allows the quantification of biomarkers such as glucose and/or drugs such as insulin in vivo. Through the integration with the electronic glucose sensors, the whole system permits the direct and rapid analysis of the extracted glucose.

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These MN platforms have been intensively explored for transdermal drug delivery in the treatment of both local and systemic diseases. [1c,12] They function as carriers for small molecular drugs, [13] peptides and proteins (e.g., insulin, vaccines, and antibodies), [8a,14] oligonucleotides, [11d] and nanomedicines [10a,b] and deliver them into peripheral tissues like skin, eyes, mouth, vascular wall, vagina etc. [15] Recently, MNs also receive attention from medical diagnosis and health monitoring, as they can easily access skin interstitial fluid (ISF) that is formed by blood transcapillary filtration and contains numerous biomarkers of clinical interest. [16] They can either directly sample ISF for postanalysis, [9e,11b,17] or integrate with sensing components for in situ real-time monitoring. [18] This article summarizes the recent advances in the MN field including the design, fabrication, and biomedical applications (Figure 1). The challenges and future perspectives are also discussed.

Development of siRNA-loaded mesoporous Silica nanoparticles coated with poly-l-lysine for enhanced transdermal drug delivery in skin cancer treatment.

The development of potent antibiotic alternatives with rapid bactericidal properties is of great importance in addressing the current antibiotic crisis. One representative example is the topical delivery of predatory bacteria to treat ocular bacterial infections. However, there is a lack of suitable methods for the delivery of predatory bacteria into ocular tissue. This work introduces cryomicroneedles (cryoMN) for the ocular delivery of predatory Bdellovibrio bacteriovorus (B. bacteriovorus) bacteria. The cryoMN patches are prepared by freezing B. bacteriovorus containing a cryoprotectant medium in a microneedle template. The viability of B. bacteriovorus in cryoMNs remains above 80% as found in long‐term storage studies, and they successfully impede the growth of gram‐negative bacteria in vitro or in a rodent eye infection model. The infection is significantly relieved by nearly six times through 2.5 days of treatment without substantial effects on the cornea thickness and morphology. This approach represents the safe and efficient delivery of new class of antimicrobial armamentarium to otherwise impermeable ocular surface and opens up new avenues for the treatment of ocular surface disorders.

Topical drug delivery has inherent advantages over other administration routes. However, the existence of stratum corneum limits the diffusion to small and lipophilic drugs. Fortunately, the advancement of nanotechnology brings along opportunities to address this challenge. Taking the unique features in size and surface chemistry, nanocarriers such as liposomes, polymeric nanoparticles, gold nanoparticles, and framework nucleic acids have been used to bring drugs across the skin barrier to epidermis and dermis layers. This article reviews the development of these formulations and focuses on their applications in the treatment of skin disorders such as acne, skin inflammation, skin infection, and wound healing. Existing hurdles and further developments are also discussed.

Microneedles (MNs) offer a rapid method of transdermal drug delivery through penetration of the stratum corneum. However, commercial translation has been limited by fabrication techniques unique to each drug. Herein, a broadly applicable platform is explored by drug-loading via swelling effect of a hydrogel MN patch. A range of small molecule hydrophilic, hydrophobic, and biomacromolecule therapeutics demonstrate successful loading and burst release from hydrogel MNs fabricated from methacrylated hyaluronic acid (MeHA). The post-fabrication drug loading process allows MeHA MN patches with drug loadings of 10 μg cm −2 . Additional post-fabrication processes are explored with dendrimer bioadhesives that increase work of adhesion, ensuring stable fixation on skin, and allow for additional drug loading strategies.

Cellular reprogramming, the process by which somatic cells regain pluripotency, is relevant in many disease modeling, therapeutic, and drug discovery applications. Molecular evaluation of reprogramming (e.g., polymerase chain reaction, immunostaining) is typically disruptive, and only provides snapshots of phenotypic traits. Gene reporter constructs facilitate live-cell evaluation but is labor intensive and may risk insertional mutagenesis during viral transfection. Herein, the utilization of a non-integrative nanosensor is demonstrated to visualize key reprogramming events in situ within live cells. Principally based on sustained intracellular release of encapsulated molecular probes, nanosensors successfully monitored mesenchymal-epithelial transition, pluripotency acquisition, and transdifferentiation events. Tracking the dynamic expression of four pivotal biomarkers (i.e., THY1, E-CADHERIN, OCT4, and GATA4 mRNA), nanosensor signal showed great agreement with polymerase chain reaction and gene reporter imaging (R > 0.9). Overall, such facile, versatile nanosensor enables real-time monitoring of low-frequency reprogramming events, thereby useful for high-throughput assessment, optimization, and biomarker-specific cell enrichment.