Siqi Li

Development of boronic acid grafted random copolymer sensing fluid for continuous glucose monitoring

We have previously presented a microelectromechanical system (MEMS) based viscometric sensor for continuous glucose monitoring using protein Concanavalin A (Con A). To address its drawbacks, including immunotoxicity and instability issues, we have synthesized stable, biocompatible copolymers poly(acrylamide-ran-3-acrylamidophenylboronic acid) (PAA-ran-PAAPBA) for viscosity based glucose sensing. We found that PAA-ran-PAAPBA showed very high binding specificity to glucose. Several key factors such as polymer compositions, polymer molecular weights and polymer concentrations have been investigated to optimize viscometric responses. This polymer is able to detect glucose under physiological pH conditions in a reversible manner. Therefore, it has the potential to enable a highly reliable, continuous monitoring of glucose in subcutaneous tissue using the MEMS device.

A MEMS viscometric sensor for continuous glucose monitoring

We present a MEMS sensor aiming to enable continuous monitoring of glucose levels in diabetes patients. The device features a magnetically-driven vibrating microcantilever, which is situated in a microchamber and separated from the environment by a semi-permeable membrane. Glucose sensing is based on affinity binding principles using a solution of dextran concanavalin-A (Con A) as the sensing fluid. The glucose concentration is determined by detecting viscosity changes induced by the binding of glucose to Con A through the measurement of the cantilevers vibration parameters. The device is capable of measuring physiologically relevant glucose concentrations from 0 to 25 mM with a resolution better than 0.025 mM and a phase sensitivity better than 0.4° mM−1. The response of the sensor to glucose concentration changes has a time constant down to 4.27 min, and can be further improved with optimized device designs.

A Capacitive MEMS Viscometric Sensor for Affinity Detection of Glucose

This paper presents a capacitively based microelectromechanical systems affinity sensor for continuous glucose monitoring (CGM) applications. This sensor consists of a vibrating Parylene diaphragm, which is remotely driven by a magnetic field and situated inside a microchamber. A solution of poly(acrylamide-ran-3-acrylamidophenylboronic acid) (PAA-ran-PAAPBA), a biocompatible glucose-sensitive polymer, fills the microchamber, which is separated from its surroundings by a semipermeable membrane. Glucose permeates through the membrane and binds reversibly to the phenylboronic acid moiety of the polymer. This results in a viscosity change of the sensing solution, causing a detectable change in the Parylene diaphragm vibration which can be measured capacitively. Experimental results demonstrate that the device is capable of detecting glucose at physiologically relevant concentrations ranging from 30 to 360 mg/dL. The response time of the sensor to glucose concentration changes is approximately 1.5 min, which can be further improved with optimized device designs. Excellent reversibility and stability are observed in sensor responses, as highly desired for long-term CGM.

A dielectric affinity microbiosensor

We present an affinity biosensing approach that exploits changes in dielectric properties of a polymer due to its specific, reversible binding with an analyte. The approach is demonstrated using a microsensor comprising a pair of thin-film capacitive electrodes sandwiching a solution of poly(acrylamide-ran-3-acrylamidophenylboronic acid), a synthetic polymer with specific affinity to glucose. Binding with glucose induces changes in the permittivity of the polymer, which can be measured capacitively for specific glucose detection, as confirmed by experimental results at physiologically relevant concentrations. The dielectric affinity biosensing approach holds the potential for practical applications such as long-term continuous glucose monitoring.

A MEMS differential viscometric sensor for affinity glucose detection in continuous glucose monitoring

Micromachined viscometric affinity glucose sensors have been previously demonstrated using vibrational cantilever and diaphragm. These devices featured a single glucose detection module that determines glucose concentrations through viscosity changes of glucose-sensitive polymer solutions. However, fluctuations in temperature and other environmental parameters might potentially affect the stability and reliability of these devices, creating complexity in their applications in subcutaneously implanted continuous glucose monitoring (CGM). To address these issues, we present a MEMS differential sensor that can effectively reject environmental disturbances while allowing accurate glucose detection. The sensor consists of two magnetically driven vibrating diaphragms situated inside microchambers filled with a boronic-acid based glucose-sensing solution and a reference solution insensitive to glucose. Glucose concentrations can be accurately determined by characteristics of the diaphragm vibration through differential capacitive detection. Our in-vitro and preliminary in-vivo experimental data demonstrate the potential of this sensor for highly stable subcutaneous CGM applications.

Development of Novel Glucose Sensing Fluids with Potential Application to Microelectromechanical Systems-Based Continuous Glucose Monitoring

Background: We have previously presented a microelectromechanical systems (MEMS) viscometric sensor for continuous glucose monitoring. The sensing fluid used therein was based on protein concanavalin A, which is known to have significant drawbacks, such as immunotoxicity and instability. To address this issue, a stable, biocompatible polymeric sensing fluid has been developed. Methods: In the polymeric sensing system, glucose reversibly formed strong ester bonds with the phenylboronic acid moiety on the poly(acrylamide-ran-3-acrylamidophenylboronic acid) (PAA-ran-PAAPBA) polymer backbone, resulting in cross-linking of the copolymers and an increase in the solution viscosity. The copolymers were synthesized via classic free radical copolymerization processes. The viscosity of the PAA-ran-PAAPBA, dissolved in phosphate-buffered saline buffer and in the presence of glucose at physiologically relevant concentrations, was measured by an Ubbelodhe viscometer and a prototype MEMS viscometric device. Results: Experimental results showed that the polymer molecular weight and composition depended on the solvent quantity, while the sensing fluid viscosity was determined by the polymer molecular weight and percentage composition of PAAPBA. The study of the temperature effect on viscosity showed that the polymer sensed glucose effectively under physiological conditions, although the high temperature lowered its sensitivity. Through proper adjustment of these parameters, a distinctive viscosity increase was observed when the glucose concentration increased from 0 to 450 mg/dl, which was detectable by our prototype MEMS device. Conclusions: We have successfully developed a stable, biocompatible polymeric system for the sensitive detection of glucose. MEMS experiments demonstrated that the sensing fluid was able to sense glucose at different concentrations. This sensing system can potentially enable highly reliable, continuous monitoring of glucose in interstitial fluid from subcutaneous tissue.

Synthesis and development of poly(N-hydroxyethyl acrylamide)-ran-3-acrylamidophenylboronic acid polymer fluid for potential application in affinity sensing of glucose.

Background: In previous work, we described viscosity and permittivity microelectromechanical systems (MEMS) sensors for continuous glucose monitoring (CGM) using poly[acrylamide-ran-3-acrylamidophenylboronic acid (PAA-ran-PAAPBA). In order to enhance our MEMS device antifouling properties, a novel, more hydrophilic polymer-sensing fluid was developed. Method: To optimize sensing performance, we synthesized biocompatible copolymers poly(N-hydroxyethyl acrylamide)-ran-3-acrylamidophenylboronic acid (PHEAA-ran-PAAPBA) and developed its sensing fluid for viscosity-based glucose sensing. Key factors such as polymer composition and molecular weight were investigated in order to optimize viscometric responses. Results: Compared with PAA-ran-PAAPBA fluid of a similar binding moiety percentage, PHEAA-ran-PAAPBA showed comparable high binding specificity to glucose in a reversible manner and even better performance in glucose sensing in terms of glucose sensing range (27–468 mg/ml) and sensitivity (within 3% standard error of estimate). Preliminary experiment on a MEMS viscometer demonstrated that the polymer fluid was able to sense the glucose concentration. Conclusions: Our MEMS systems using PHEAA-ran-PAAPBA will possess enhanced implantable traits necessary to enable CGM in subcutaneous tissues.

A MEMS Dielectric Affinity Glucose Biosensor

Continuous glucose monitoring (CGM) sensors based on affinity detection are desirable for long-term and stable glucose management. However, most affinity sensors contain mechanical moving structures and complex design in sensor actuation and signal readout, limiting their reliability in subcutaneously implantable glucose detection. We have previously demonstrated a proof-of-concept dielectric glucose sensor that measured pre-mixed glucose-sensitive polymer solutions at various glucose concentrations. This sensor features simplicity in sensor design, and possesses high specificity and accuracy in glucose detection. However, lack of glucose diffusion passage, this device is unable to fulfill real-time in-vivo monitoring. As a major improvement to this device, we present in this paper a fully implantable MEMS dielectric affinity glucose biosensor that contains a perforated electrode embedded in a suspended diaphragm. This capacitive-based sensor contains no moving parts, and enables glucose diffusion and real-time monitoring. The experimental results indicate that this sensor can detect glucose solutions at physiological concentrations and possesses good reversibility and reliability. This sensor has a time constant to glucose concentration change at approximately 3 min, which is comparable to commercial systems. The sensor has potential applications in fully implantable CGM that require excellent long-term stability and reliability.

A MEMS Sensor for Continuous Monitoring of Glucose in Subcutaneous Tissue

We present a MEMS sensor for continuous glucose monitoring for diabetes management. The device consists of a microcantilever, which is driven by remote magnetic field and situated in a microchamber separated from the sensing environment by a semi-permeable membrane. As glucose concentration varies, viscosity changes induced by glucose/copolymer binding in a poly(acrylamide-ran-3-acrylamidophenylboronic acid) (PAA-ran-PAAPBA) copolymer solution produce a measurable change in cantilever vibration. The device has been used to measure physiologically relevant glucose concentrations from 0 to 324 mg/dL. The response time of the sensor to glucose concentration changes was 3 minutes and can be further improved with optimized device designs.

A capacitively based MEMS affinity glucose sensor

This paper presents a capacitively based MEMS affinity sensor for continuous glucose monitoring applications. This sensor consists of a vibrating Parylene diaphragm, which is remotely driven by a magnetic field and situated inside a microchamber. A solution of poly(acrylamide-ran-3-acrylamidophenylboronic acid) (PAA-ran-PAAPBA), a biocompatible glucose-sensitive polymer, fills the microchamber, which is separated from its surroundings by a semi-permeable membrane. As glucose concentration is varied, viscosity changes induced by glucose/polymer binding cause a detectable change in the Parylene diaphragm vibration which can be measured capacitively. The response time of the sensor to glucose concentration changes is approximately 3 minutes which can be further improved with optimized device designs. The device has been tested at physiologically relevant glucose concentrations ranging from 27 to 324 mg/dL, showing excellent reversibility and stability.