Functional Hydrogel Microneedle Sensors Integrated with Different Recognition Probes for Continuous In Vivo Monitoring

Microneedle (MN) assays have been extensively reported and applied to a variety of wearable biosensing. These devices can penetrate through the skin, allowing access to the interstitial fluid (ISF) which contains biomolecules of great clinical significance. Traditional MN biosensors utilize solid and rigid MNs as the device electrodes which are not compatible with mechanically soft and curved skin. To address this unmet need, we are developing novel wearable platforms that use, for the first time, flexible, hydrogel microneedle(HMN) electrodes for continuous, real-time measurement of patient health status. Our electrodes utilize state-of-the-art conductive and flexible yet mechanically strong polymers to tackle the problems associated with rigid MN biosensors. The backbone of our HMN electrodes is hyaluronic acid (HA), a highly biocompatible polymer. To enhance the electrical conductivity of the electrode patches, we introduced doping into the polymer by incorporating PEDOT:PSS, a highly conductive and biocompatible polymer. We linked dopamine (DA) with HA to create an HMN-based pH meter, capitalizing on DA's pH-dependent behavior (published in Small, 2022). Additionally, by exploiting DA's redox properties, we generated platinum nanoparticles (Pt NP) in situ for non-enzymatic glucose detection and reported the first HMN-continuous glucose monitoring (CGM) device(published in Advanced Healthcare Materials, 2022).


Additionally, we leveraged our HMN electrodes to develop a new continuous ketone monitoring (CKM) device which measures β-HB, the main ketone bodies. Patients with T1D need to track their ketone levels in addition to their glucose to avoid complications such as diabetes ketoacidosis (DKA). However, currently, no CKM device is available commercially. Our CKM aims to address this important need. The β-HB sensor integrates innovative chemistry principles with engineered HMN electrodes. The backbone of this novel β-HB sensor is DA-HA doped with PEDOT:PSS, similar to our previous glucose and pH sensor. In addition to its role in crosslinking, DA is utilized as the redox mediator to measure the byproduct of β-HB catalysis. Ex vivo characterization of the HMN-CKM using a skin model showed that the sensor can accurately measure the ketone levels with a sensitivity of 0.08 mM. Specifically, our sensor measures the ketone levels within the range of 0.6 - 1.5 mM to monitor the early onset of DKA. Subsequent experiments in diabetic rats along with a machine learning model confirmed the HMN-CKM capacity to continuously monitor in vivo changes in ketone levels in real-time and highlighted its capability to accurately decipher the delay between ISF and blood measurements in individual rats, a crucial aspect for clinical adoption. Importantly, the HMN-CKM measurements closely matched those obtained with standard ketone meters considering the time lag (published in Advanced Materials, 2024).

We also integrated our biocompatible HMN arrays for ISF extraction with an electrochemical aptamer-based biosensor for in situ monitoring of blood analytes. The use of aptamers enables continuous monitoring of a wide range of analytes, beyond what is possible with enzymatic monitoring. The system, called Wearable Aptalyzer, is used for real-time and multiplexed monitoring of glucose and lactate in ISF. Validation experiments using live mice and rat models of Type 1 Diabetes demonstrate a strong correlation between the measurements collected from the Wearable Aptalyzer in ISF and those obtained from gold-standard techniques for blood glucose and lactate, for each analyte alone and in combination. The Wearable Aptalyzer effectively addresses the limitations inherent in enzymatic detection methods as well as solid MN biosensors and addresses the need for reliable and multiplexed bioanalytical monitoring in vivo (published in Advanced Materials, 2024).