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Integrated microsystems for continuous glucose monitoring, interstitial fluid sampling and digital microfluidics
KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems.ORCID iD: 0000-0002-3549-0228
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Interdisciplinary research between medicine and microsystem engineering creates new possibilities to improve the quality of life of patients or to further enhance the performance of already existing devices. In particular, microsystems show great potential for the realization of biosensors and sampling devices to monitor bioanalytes with minimal patient discomfort. Microneedles offer a minimally invasive and painless solution to penetrate the epidermis and provide access to dermal interstitial fluid (ISF), to monitor various substances without the need for more invasive and painful extraction of blood. Diabetes, for example, requires continuous monitoring of the glucose levels in the body (CGM) to avoid complications. Although glucose is traditionally measured in finger-prick blood, CGM, which is performed in ISF, has been proven to be beneficial in the management of the disease. However, current commercial solutions are still relatively large and invasive. In this work, an electrochemical glucose sensor 50 times smaller than competing commercial devices was combined with a hollow silicon microneedle and shown to be able to measure glucose levels in the dermis in vivo. A scalable manufacturing method for the assembly of the two separately fabricated components and their electrical interconnection was also demonstrated. At the same time, a single data point may be sufficient in other situations, such as when only the presence of a certain biomarker or drug needs to be assessed. Although continuous monitoring is not required in these cases, the patient would still benefit by avoiding blood extraction. However, there are no simple devices currently available to reliably sample and store ISF. A painless microneedle-based sampling device designed to extract 1 μL of ISF from the dermis was realized. The sampled liquid is metered and stored in a paper matrix embedded in a microfluidic chip. The sample could then be analyzed using state-of-the-art tools, such as mass spectrometry.On the other hand, device miniaturization also creates issues for sensor performance. In certain types of electrochemical gas sensors, such as nitric oxide sensors used for asthma monitoring, the reduced size results in a shorter device lifetime. These sensors typically operate with a liquid electrolyte, subject to evaporation, and their long-term stability tends to be proportional to the electrode size. To address this issue, a gas diffusion and evaporation controlling platform to be integrated with this type of sensors was proposed. Such a platform opens or seals the sensing compartment on demand, potentially enabling sensor recalibration and evaporation reduction when the sensor is not in use. The device is based on electrowetting-on-dielectric actuation of low-vapor-pressure ionic liquid microdroplets on partially perforated membranes. The platform was then modified to create a zero-insertion loss and broad-band-operation laser shutter.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2020. , p. 96
Series
TRITA-EECS-AVL ; 2020:7
Keywords [en]
Microelectromechanical systems (MEMS), biosensors, biomedical devices, continuous glucose monitoring (CGM), glucose sensors, microneedles, interstitial fluid sampling, minimally-invasive technologies, electrochemical sensors, heterogeneous integration, wire bonding, magnetic assembly, electrowetting-on-dielectric (EWOD), digital microfluidics, ionic liquids, gas sensors, optical switches, laser shutters.
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Research subject
Electrical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-266803ISBN: 978-91-7873-415-3 (print)OAI: oai:DiVA.org:kth-266803DiVA, id: diva2:1388031
Public defence
2020-02-14, F3, Lindstedtsvägen 64, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20200124

Available from: 2020-01-24 Created: 2020-01-23 Last updated: 2020-01-24Bibliographically approved
List of papers
1. Ultra-miniaturization of a planar amperometric sensor targeting continuous intradermal glucose monitoring
Open this publication in new window or tab >>Ultra-miniaturization of a planar amperometric sensor targeting continuous intradermal glucose monitoring
2017 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 90, p. 577-583Article in journal (Refereed) Published
Abstract [en]

An ultra-miniaturized electrochemical biosensor for continuous glucose monitoring (CGM) is presented. The aim of this work is to demonstrate the possibility of an overall reduction in sensor size to allow minimally invasive glucose monitoring in the interstitial fluid in the dermal region, in contrast to larger state-of-the-art systems, which are necessarily placed in the subcutaneous layer. Moreover, the reduction in size might be a key factor to improve the stability and reliability of transdermal sensors, due to the reduction of the detrimental foreign body reaction and of consequent potential failures. These advantages are combined with lower invasiveness and discomfort for patients. The realized device consists of a microfabricated three-electrode enzymatic sensor with a total surface area of the sensing portion of less than 0.04 mm2, making it the smallest fully integrated planar amperometric glucose sensor area reported to date. The working electrode and counter electrode consist of platinum and are functionalized by drop casting of three polymeric membranes. The on-chip iridium oxide (IrOx) pseudo-reference electrode provides the required stability for measurements under physiological conditions. The device is able to dynamically and linearly measure glucose concentrations in-vitro over the relevant physiological range, while showing sufficient selectivity to known interfering species present in the interstitial fluid, with resolution and sensitivity (1.51 nA/mM) comparable to that of state-of-art commercial CGM systems. This work can therefore enable less invasive and improved CGM in patients affected by diabetes.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Amperometry, Continuous glucose monitoring, Diabetes, Glucose biosensor, Iridium oxide reference electrode, MEMS
National Category
Other Engineering and Technologies
Identifiers
urn:nbn:se:kth:diva-200851 (URN)10.1016/j.bios.2016.10.007 (DOI)000392768000073 ()27825874 (PubMedID)2-s2.0-85006170204 (Scopus ID)
Note

QC 20170206

Available from: 2017-02-06 Created: 2017-02-03 Last updated: 2020-03-09Bibliographically approved
2. Real-time intradermal continuous glucose monitoring using a minimally invasive microneedle-based system
Open this publication in new window or tab >>Real-time intradermal continuous glucose monitoring using a minimally invasive microneedle-based system
2018 (English)In: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781, Vol. 20, no 4, article id 101Article in journal (Refereed) Published
Abstract [en]

Continuous glucose monitoring (CGM) has the potential to greatly improve diabetes management. The aim of this work is to show a proof-of-concept CGM device which performs minimally invasive and minimally delayed in-situ glucose sensing in the dermal interstitial fluid, combining the advantages of microneedle-based and commercially available CGM systems. The device is based on the integration of an ultra-miniaturized electrochemical sensing probe in the lumen of a single hollow microneedle, separately realized using standard silicon microfabrication methods. By placing the sensing electrodes inside the lumen facing an opening towards the dermal space, real-time measurement purely can be performed relying on molecular diffusion over a short distance. Furthermore, the device relies only on passive capillary lumen filling without the need for complex fluid extraction mechanisms. Importantly, the transdermal portion of the device is 50 times smaller than that of commercial products. This allows access to the dermis and simultaneously reduces tissue trauma, along with being virtually painless during insertion. The three-electrode enzymatic sensor alone was previously proven to have satisfactory sensitivity (1.5 nA/mM), linearity (up to 14 mM), selectivity, and long-term stability (up to 4 days) in-vitro. In this work we combine this sensor technology with microneedles for reliable insertion in forearm skin. In-vivo human tests showed the possibility to correctly and dynamically track glycaemia over time, with approximately 10 min delay with respect to capillary blood control values, in line with the expected physiological lag time. The proposed device can thus reduce discomfort and potentially enable less invasive real-time CGM in diabetic patients.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2018
Keywords
Biomedical MEMS, Continuous glucose monitoring system (CGMS), Dermal interstitial fluid (ISF), Diabetes, Electrochemical biosensor, Microneedle, silicon, Article, blood glucose monitoring, capillary, dermis, diffusion, electrochemical analysis, forearm, in vitro study, minimally invasive procedure, priority journal, proof of concept, tissue injury
National Category
Medical Engineering
Identifiers
urn:nbn:se:kth:diva-247011 (URN)10.1007/s10544-018-0349-6 (DOI)000452462600001 ()30523421 (PubMedID)2-s2.0-85058594710 (Scopus ID)
Note

QC 20190626

Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2020-03-09Bibliographically approved
3. Vertical Integration of Microchips by Magnetic Assembly and Edge Wire Bonding
Open this publication in new window or tab >>Vertical Integration of Microchips by Magnetic Assembly and Edge Wire Bonding
Show others...
(English)In: Article in journal (Refereed) Submitted
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:kth:diva-259159 (URN)
Note

QC 20191113

Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2020-03-10Bibliographically approved
4. Minimally invasive and volume-metered extraction of interstitial fluid:bloodless point-of-care sampling for bioanalyte detection
Open this publication in new window or tab >>Minimally invasive and volume-metered extraction of interstitial fluid:bloodless point-of-care sampling for bioanalyte detection
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Sampling of biological fluids is fundamental in health monitoring and, currently, blood analysisis the standard practice. However, blood sampling entails a series of drawbacks including pain,discomfort, and risk of infections. Interstitial fluid, having a good correlation with blood concentrationdynamics for several analytes, is a promising alternative monitoring matrix because it can be sampled ina minimally invasively manner from the skin, without the need for the more invasive and painfulextraction methods used for blood. Currently, there are no simple devices available to sample and storeknown amounts of interstitial fluid. In this work, a painless microneedle-based sampling device designedto extract 1 μL of fluid from the dermis was realized. The sampled liquid is metered and stored in a papermatrix embedded in a microfluidic chip. The sample can then be analyzed using state-of-the-art tools,such as mass spectrometry (LC-MS/MS).

National Category
Other Medical Engineering
Identifiers
urn:nbn:se:kth:diva-266802 (URN)
Available from: 2020-01-23 Created: 2020-01-23 Last updated: 2020-01-24Bibliographically approved
5. Gas diffusion and evaporation control using EWOD actuation of ionic liquid microdroplets for gas sensing applications
Open this publication in new window or tab >>Gas diffusion and evaporation control using EWOD actuation of ionic liquid microdroplets for gas sensing applications
2018 (English)In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 267, p. 647-654Article in journal (Refereed) Published
Abstract [en]

The lifetime of electrochemical gas sensors suffers from electrolyte evaporation and from the impracticality to perform recalibration. To tackle these issues, a prototype of a microfabricated gas diffusion controlling system, based on coplanar electrowetting-on-dielectric (EWOD) actuation of ionic liquid microdroplets, is presented. The system is designed to be integrated with electrochemical gas sensors to allow on-demand sealing of the sensing chamber from the environment. The MEMS device can be electrically toggled between an open and a closed state, in which the microdroplets are used to cover or uncover the openings of a perforated membrane connecting to the sensing compartment, respectively. This ON/OFF diffusion-blocking valve mechanism potentially allows for recalibration and for liquid electrolyte evaporation reduction when the sensor is not in use, thus extending the gas sensor lifetime. A one order of magnitude reduction of evaporation rate and a more than three orders of magnitude reduction of gas diffusion time were experimentally demonstrated. Ionic liquid movement can be performed with an applied AC voltage as low as 18 V, using super-hydrophobic cover plates to facilitate droplet motion. Furthermore, the shown ionic liquid micro-droplet manipulation provides a robust and low voltage platform for digital microfluidics, readily adaptable to serve different applications.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Contact angle modulation, Electrochemical gas sensing, Electrowetting on dielectric, Gas diffusion valve, Ionic liquids, MEMS actuator
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:kth:diva-229250 (URN)10.1016/j.snb.2018.04.076 (DOI)000432775600076 ()2-s2.0-85046339371 (Scopus ID)
Funder
EU, European Research Council, 267528Swedish Research Council
Note

QC 20180601

Available from: 2018-06-01 Created: 2018-06-01 Last updated: 2020-01-23Bibliographically approved
6. Zero-insertion-loss optical shutter based on electrowetting-on-dielectric actuation of opaque ionic liquid microdroplets
Open this publication in new window or tab >>Zero-insertion-loss optical shutter based on electrowetting-on-dielectric actuation of opaque ionic liquid microdroplets
Show others...
2019 (English)In: Applied Physics Letters, ISSN 0003-6951, E-ISSN 1077-3118, Vol. 115, no 7, article id 073502Article in journal (Refereed) Published
Abstract [en]

This article reports a broad-band optical shutter based on microdroplet actuation with zero optical insertion loss in the open state. These features are achieved by electrowetting-on-dielectric (EWOD) actuation of opaque ionic liquid microdroplets. The negligible vapor pressure of ionic liquids allows the device to robustly operate in open air, unlike previously proposed EWOD-based systems in which the light crosses several attenuating and reflective layers, preventing broad-band operation and creating insertion losses > 14%. The presented device provides an attenuation of 78dB in the closed state and a transmission of >99.99999% in the open state and can operate in the visible and mid-infrared wavelength range. Moreover, the switch can sustain larger incoming laser powers (5 mW continuous exposure or up to 3h of continuous exposure at similar to 100mW) compared to the values reported for other state-of-the-art EWOD-based shutters. Additionally, the proposed device is compact, operates with low voltage (<25V peak voltage), and features zero static power consumption.

Place, publisher, year, edition, pages
AMER INST PHYSICS, 2019
National Category
Other Physics Topics
Identifiers
urn:nbn:se:kth:diva-257810 (URN)10.1063/1.5108936 (DOI)000481469900019 ()2-s2.0-85070688345 (Scopus ID)
Note

QC 20190912

Available from: 2019-09-12 Created: 2019-09-12 Last updated: 2020-01-23Bibliographically approved

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