Continuous Blood Glucose Monitoring Based On Flexible Epidermal Biomicrofluidics

Continuous blood glucose monitoring holds great significance for the diagnosis and treatment of diabetes.However,the present blood glucose detection methods used in clinics are based on venous blood collection and fingertip blood collection,which are invasive and noncontinuous.Invasive detection is inconvenient;and noncontinuous detection leads to missing information about important blood glucose changes.Therefore,noninvasive continuous blood glucose monitoring techniques,mainly based on optics,are promising and have attracted the attention of many researchers in recent years.Unfortunately,due to the complexity of human tissue,these noninvasive techniques are still in the initial stage of research throughout the world,the detection accuracy is still very low,and the measurement results are unreliable.Thus,many researchers are currently focused on developing minimally invasive blood glucose monitoring technology based on measuring the glucose concentration in interstitial fluid(ISF)because the glucose concentration in ISF is closely related to that in blood.According to the detection method,minimally invasive blood glucose monitoring technologies can be divided into two categories: those that use the transdermal extraction method and those that use the subcutaneous implantation method.For the implantation method,minimally invasive operation is frequently required and the in-body environment significantly affects the measurement precision of the sensor.Thus,we think that the transdermal extraction method,which enables detection outside of the body,thereby avoiding the shortcomings of the implantation method,is promising for practical application.Reverse iontophoresis,an ISF extraction method,is easy to achieve,and the device is easy to miniaturize,benefiting for wearable continuous glucose monitoring.However,long-term stimulation with electricity easily leads to skin irritation.Due to the quite small amount of extracted ISF,the glucose monitoring method based on reverse iontophoresis is greatly affected by temperature,humidity,sweat,etc.In particular,a highprecision glucose sensor is required to enable detection of low glucose concentrations in situ.According to the present techniques and challenges,in this dissertation,a continuous blood glucose monitoring technique based on flexible epidermal biomicrofluidics is proposed to overcome the shortcomings of reverse iontophoresis and realize continuous,real-time blood glucose monitoring to satisfy the clinical diagnosis of diabetes.An integrated flexible epidermal biomicrofluidic device is designed,fabricated and characterized.This flexible epidermal biomicrofluidic device includes an extraction electrode pair to transdermally extract ISF through ion transport microchannels of the skin by reverse iontophoresis,an epidermal temperature control component to increase the ISF extraction rate,a flexible epidermal electrochemical sensor to detect the glucose concentration in the extracted ISF in situ and a differential Na+ sensor to calibrate the glucose measurements.This device is fabricated by the direct-writing technique of inkjet printing.The proposed device exhibits the potential for continuous,real-time blood glucose monitoring to satisfy the clinical diagnosis of diabetes.The detailed works are listed as follows:1.A method to transdermally extract ISF based on epidermal biomicrofluidics was introduced.ISF was extracted through ion transport microchannels of the skin by reverse iontophoresis.A four-path inkjet printing system was built to fabricate flexible microelectrodes and decorate electrodes with nanomaterials and biomolecules at the set positions.This system enabled maskless,on-demand,low-temperature and directwriting microfabrication that satisfied the requirements of flexible electronics.2.To overcome the challenges of transdermal ISF extraction by reverse iontophoresis(the large current densities and long-term extraction led to skin irritation),a novel thermal activation method was proposed to facilitate transdermal ISF extraction according to the mechanism of transdermal ISF extraction based on epidermal biomicrofluidics.A skin impedance detection experiment and an ISF extraction experiment were conducted to verify the facilitation effect of the proposed thermal activation method.Then,a flexible epidermal temperature control component was designed and fabricated.An archimedes spiral structure of gold heating wire was designed to enable uniform heating.An archimedes spiral structure of gold resistance wire was designed as a temperature sensor and was embedded inside the gold heating wire to accurately obtain temperature change information.Simultaneously,a flexible proportional-integral-differential(PID)control circuit was designed and fabricated to enable thermal activation as well as temperature maintenance at 37?.The temperature control component enabled thermal activation,thereby reducing skin irritation.The component maintained the temperature at 37?,thereby facilitating electrochemical detection,avoiding the need for temperature compensation and making the glucose oxidase(GOx)more active.3.To overcome the challenge of glucose detection in situ,a flexible epidermal electrochemical glucose sensor was designed for integration with the flexible ISF extraction electrode pair.To overcome the challenge of glucose detection at low levels,a 3D nanostructure of graphene and platinum nanoparticles(Pt NPs)was constructed on the working electrode(WE)surface of the sensor to improve the sensitivity.An additive micromanufacturing method,inkjet printing,was employed to enable electrode fabrication and modification with nanomaterials at the set positions.Electrochemical characterization experiments were conducted to verify that the fabricated glucose sensor had the potential for accurate glucose detection within the physiological range and for hypoglycemia detection.4.To eliminate the effect of individual differences and passive perspiration,a Na+correction model was constructed,and a flexible differential Na+ sensor was designed and fabricated.According to the relatively stable Na+ concentration in ISF,the model eliminated the effect of individual differences using the amount of extracted ISF that could be reflected by the Na+ sensor.A pig skin simulation experiment was conducted to verify the effectiveness of the Na+ correction for the elimination of individual differences.The effect of passive perspiration was eliminated by the differential measurement of Na+.5.A flexible epidermal biomicrofluidic device was integrated for continuous blood glucose monitoring.Oral glucose tolerance test(OGTT)experiments were conducted to characterize the proposed continuous blood glucose monitoring technique.The experiments verified the feasibility of the proposed continuous glucose monitoring technique based on epidermal biomicrofluidics.Differential Na+ correction was also verified to be necessary to eliminate the effect of the individual differences and passive perspiration.