RESULTSNoninvasive intravascular glucose measuring principle and the skin-like biosensorsHere, we present a strategy for a fully noninvasive biosensor system for intravascular blood glucose monitoring.The system consists of a flexible biocompatible paper battery and ultrathin skin-like biosensors. The paper battery is first attached to the skin to generate subcutaneouselectrochemical twin channels (ETCs).The ETCs act through hyaluronic acid (HA) penetration into the ISF (anode channel), intravascular blood glucose refiltration from vessels, and glucose reverse iontophoresis to the skin surface (cathode channel).Under the paper battery anode, high-density positively charged HA is transdermally repelled into the ISF. Extra HA increases the ISF osmotic pressure and breaks the balance between ISF filtration and reabsorption, thus promoting intravascular blood glucose refiltration at the arterial ends and reducing the reabsorption at the venous ends.A higher molar glucose concentration in the ISF also increases the flux of reverse iontophoresis in low-current occasions.As a result, more intravascular blood glucose is driven out of the vessel and is transported to the skin surface. The measurement of “real” blood glucose (that is, the glucose previously existed in the blood together with the glucose previously in the ISF) greatly improves the blood glucose correlation.Next, the ultrathin skin-like biosensors completely conform to the skin and measure the outward-transported glucose driven by ETCs.These biosensors are multilayered with “sand dune” nanostructures, which exhibit better electrochemical properties and higher sensitivity.The layers of the biosensor, from bottom to top, are polymethylmethacrylate (PMMA) (80 nm), polyimide (PI) (1.6 mm), a nanostructured deposited gold thin film (100 nm), an electrochemically deposited nanometer transducer layer (51.8 nm), and a transfer/glucose oxidase (GOx) immobilization layer (~1 mm). We first fabricate the biosensors on the silicon wafers with various shapes and then transfer-printed (26–28) them by bionic “capillary grabbing.” The transfer-printed biosensors are ultrathin, skin-like, and flexible .The total thickness of the multilayer biosensor is approximately 3 mm so that the biosensor fully conforms to the skin with intimate contact.The conformal contact with dermal ridges increases the contact areas between the biosensor and outward-transported glucose on the skin. A larger surface energy reinforces the absorption of glucose on the biosensor surface. As a result, we can collect more glucose and measure it by such biosensors, thereby improving them easurement accuracy and signal-to-noise ratio of in vivo measurements.