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A closed‐loop system that can mini‐invasively track blood glucose and intelligently treat diabetes is in great demand for modern medicine, yet it remains challenging to realize. Microneedles technologies have recently emerged as powerful tools for transdermal applications with inherent painlessness and biosafety. In this work, for the first time to the authors' knowledge, a fully integrated wearable closed‐loop system (IWCS) based on mini‐invasive microneedle platform is developed for in situ diabetic sensing and treatment. The IWCS consists of three connected modules: 1) a mesoporous microneedle‐reverse iontophoretic glucose sensor; 2) a flexible printed circuit board as integrated and control; and 3) a microneedle‐iontophoretic insulin delivery component. As the key component, mesoporous microneedles enable the painless penetration of stratum corneum, implementing subcutaneous substance exchange. The coupling with iontophoresis significantly enhances glucose extraction and insulin delivery and enables electrical control. This IWCS is demonstrated to accurately monitor glucose fluctuations, and responsively deliver insulin to regulate hyperglycemia in diabetic rat model. The painless microneedles and wearable design endows this IWCS as a highly promising platform to improve the therapies of diabetic patients.

One-dimensional nanoneedle-like arrays have emerged as an attractive tool for penetrating the cell membrane to achieve intracellular applications including drug delivery, electrical recording, and biochemical detection. Hollow nanoneedles, also called nanostraws (NSs), combined with nanoelectroporation have been demonstrated as a powerful platform for intracellular drug delivery and extraction of intracellular contents. However, the fabrication technique of nanostraws still requires complicated and expensive atomic layer deposition and etching processes and fails to produce conductive nanostraws. Herein, we developed a commonly accessible and versatile electrodeposition approach to controllably fabricate conductive nanostraw arrays based on various types of metal or conductive polymer materials. Representatively, Pt nanostraws (Pt NSs) with 400 nm diameter were further integrated with a low-voltage nanoelectroporation system to achieve cell detection, intracellular drug delivery, and sensing of intracellular enzymes. Both theoretical simulations and experimental results revealed that the conductive nanostraws in direct contact with cells could induce high-efficiency cell electroporation at relatively low voltage (∼5 V). Efficient delivery of reagents into live cells with spatial control and repeated extraction of intracellular enzymes (e.g., caspase-3) for temporal monitoring from the same set of cells were demonstrated. This work not only pioneers a new avenue for universal production of conductive nanostraws on a large scale but also presents great potential for developing nanodevices to achieve a variety of biomedical applications including cell re-engineering, cell-based therapy, and signaling pathway monitoring.

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A variety of nanomaterial‐based biosensors have been developed to sensitively detect biomolecules in vitro, yet limited success has been achieved in real‐time sensing in vivo. The application of microneedles (MN) may offer a solution for painless and minimally‐invasive transdermal biosensing. However, integration of nanostructural materials on microneedle surface as transdermal electrodes remains challenging in applications. Here, a transdermal H2O2 electrochemical biosensor based on MNs integrated with nanohybrid consisting of reduced graphene oxide and Pt nanoparticles (Pt/rGO) is developed. The Pt/rGO significantly improves the detection sensitivity of the MN electrode, while the MNs are utilized as a painless transdermal tool to access the in vivo environment. The Pt/rGO nanostructures are protected by a water‐soluble polymer layer to avoid mechanical destruction during the MN skin insertion process. The polymer layer can readily be dissolved by the interstitial fluid and exposes the Pt/rGO on MNs for biosensing in vivo. The applications of the Pt/rGO‐integrated MNs for in situ and real‐time sensing of H2O2 in vivo are demonstrated both on pigskin and living mice. This work offers a unique real‐time transdermal biosensing system, which is a promising tool for sensing in vivo with high sensitivity but in a minimally‐invasive manner.

Implantable sensors that detect biomarkers in vivo are critical for early disease diagnostics. Although many colloidal nanomaterials have been developed into optical sensors to detect biomolecules in vitro, their application in vivo as implantable sensors is hindered by potential migration or clearance from the implantation site. One potential solution is incorporating colloidal nanosensors in hydrogel scaffold prior to implantation. However, direct contact between the nanosensors and hydrogel matrix has the potential to disrupt sensor performance. Here, we develop a hollow-microcapsule-based sensing platform that protects colloidal nanosensors from direct contact with hydrogel matrix. Using microfluidics, colloidal nanosensors were encapsulated in polyethylene glycol microcapsules with liquid cores. The microcapsules selectively trap the nanosensors within the core while allowing free diffusion of smaller molecules such as glucose and heparin. Glucose-responsive quantum dots or gold nanorods or heparin-responsive gold nanorods were each encapsulated. Microcapsules loaded with these sensors showed responsive optical signals in the presence of target biomolecules (glucose or heparin). Furthermore, these microcapsules can be immobilized into biocompatible hydrogel as implantable devices for biomolecular sensing. This technique offers new opportunities to extend the utility of colloidal nanosensors from solution-based detection to implantable device-based detection.

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Techniques used to understand the dynamic expression of intracellular proteins are critical in both fundamental biological research and biomedical engineering. Various methods for analyzing proteins have been developed, but these methods require the extraction of intracellular proteins from the cells resulting in cell lysis and subsequent protein purifications from the lysate, which limits the potential of repetitive extraction from the same set of viable cells to track dynamic intracellular protein expression. Therefore, it is crucial to develop novel methods that enable nondestructive and repeated extraction of intracellular proteins. This work reports a hollow nanoneedle-electroporation system for the repeated extraction of intracellular proteins from living cells. Hollow nanoneedles with ∼450 nm diameter were fabricated by a material deposition and etching process, followed by integration with a microfluidic device. Long-lasting electrical pulses were coupled with the nanoneedles to permeate the cell membrane, allowing intracellular contents to diffuse into the microfluidic channels located below the cells via hollow nanoneedles. Using lactate dehydrogenase B (LDHB) as the model intracellular protein, the nanoneedle-electroporation system effectively and repeatedly extracted LDHB from the same set of cells at different time points, followed by quantitative analysis of LDHB via standard enzyme-linked immunosorbent assay. Our work demonstrated an efficient method to nondestructively probe intracellular protein levels and monitor the dynamic protein expression, with great potential to help understanding cell behaviors and functions.