This paper reports a flexible electronics-based epidermal biomicrofluidics technique for clinical continuous blood glucose monitoring, overcoming the drawback of the present wearables, unreliable measurements. A thermal activation method is proposed to improve the efficiency of transdermal interstitial fluid (ISF) extraction, enabling extraction with a low current density to notably reduce skin irritation. An Na⁺ sensor and a correction model are proposed to eliminate the effect of individual differences, which leads to fluctuations in the amount of ISF extraction. An electrochemical sensor with a 3D nanostructured working electrode surface is designed to enable precise in situ glucose measurement. A differential structure is proposed to eliminate the effect of passive perspiration, which leads to inaccurate blood glucose prediction. Fabrications of the epidermal biomicrofluidic device including formation of flexible electrodes, nanomaterial modification, and enzyme immobilization are fully realized by inkjet printing to enable facile manufacturing with low cost, which benefits practical production.

A novel cylindrical flexible enzyme-electrode sensor was fabricated with a bigger working electrode (WE) surface than the traditional pin-like one for implantable continuous glucose monitoring. On the WE surface, a 3D nanostructure consisting of graphene and platinum nanoparticles was constructed to enhance the sensitivity; in conjunction with the bigger WE, this nanostructure enabled hypoglycemia detection, which is still a big challenge in clinics. The cylindrical sensor was fabricated by rotated inkjet printing which enabled direct patterning of microstructures on a curved surface, thus overcoming the restriction of the traditional planar micromachining by photolithography. Specifically, the cylindrical substrate (polyetheretherketone, PEEK) was modified by (3-aminopropyl) trimethoxysilane and (3-mercaptopropyl) trimethoxysilane to facilitate surface wettability, which discourages the coalescence of adjacent droplets, and to facilitate the adhesion of metals to PEEK in order to construct robust electrodes. A synchronous heating method was used to evaporate the solvent of the droplets quickly to prevent them from running along the cylindrical surface, which affects the formation of the printed electrode significantly. In vitro experimental results showed that the proposed sensor was able to detect the glucose concentration ranging from 0 to 570 mg dL⁻¹ which demonstrated its capability for physiological glucose detection. In vivo experiments were conducted with rats, and the measurement results recorded using the implanted cylindrical sensor showed great compliance to those recorded using a commercial glucometer which exhibited the viability of the proposed sensor for implantable continuous glucose monitoring, even under the hypoglycemic conditions.

This paper presents a continuous glucose monitoring microsystem consisting of a three-electrode electrochemical sensor integrated into a microfluidic chip. The microfluidic chip, which was used to transdermally extract and collect subcutaneous interstitial fluid, was fabricated from five polydimethylsiloxane layers using micromolding techniques. The electrochemical sensor was integrated into the chip for continuous detection of glucose. Specifically, a single-layer graphene and gold nanoparticles (AuNPs) were decorated onto the working electrode (WE) of the sensor to construct a composite nanostructured surface and improve the resolution of the glucose measurements. Graphene was transferred onto the WE surface to improve the electroactive nature of the electrode to enable measurements of low levels of glucose. The AuNPs were directly electrodeposited onto the graphene layer to improve the electron transfer rate from the activity center of the enzyme to the electrode to enhance the sensitivity of the sensor. Glucose oxidase (GOx) was immobilized onto the composite nanostructured surface to specifically detect glucose. The factors required for AuNPs deposition and GOx immobilization were also investigated, and the optimized parameters were obtained. The experimental results displayed that the proposed sensor could precisely measure glucose in the linear range from 0 to 162 mg/dl with a detection limit of 1.44 mg/dl (S/N = 3). The proposed sensor exhibited the potential to detect hypoglycemia which is still a major challenge for continuous glucose monitoring in clinics. Unlike implantable glucose sensors, the wearable device enabled external continuous monitoring of glucose without interference from foreign body reaction and bioelectricity.

Step emulsification for micro- and nano-droplet generation is reviewed in brief, including the emulsion mechanisms and microfluidic devices.