Biophotonic sensor platform for diagnostics
The purpose of the Lab-on-a-chip sensor platform for a diagnostics project is to develop a generic lab-on-a-chip (LOC), label-free sensor platform capable of performing highly sensitive and selective multiplexed quantitative diagnostic tests. LOC technology has unique characteristics that enable fast analysis for point-of care-testing. Early and reliable detection of diseases is highly desirable because it dramatically increases the chances of successful treatment.
During 2020, our research focused on developing photonic sensor designs to improve the limit-of-detection (LOD), micro-nanofluidics for efficient mass transport of minute volumes of sample fluid to the sensor, and new protocols for fabrication of polymer microfluidics to enable upscaling using OSTE+ (off-stoichiometry thiol-ene-epoxies). The advantage of OSTE+ polymers is that they are hydrophilic, cure quickly at low temperatures and have low solvent permeability. Two novel photonic sensor designs have been developed, one based on grating waveguides and the other ring resonator based. C-reactive protein and Cod-vitellogenin biomarkers were measured with ug-ng/ml LOD. To increase the mass transport of the analyte to the sensor, we have investigated different passive mixing structure designs that are integrated in the ceilings of the microfluidic channels. Herringbone and other micromixers have been realised and a robust design has been identified.
One highlight in 2020 is that in collaboration with NTNU Transfer Technology Office, we applied for a patent for the Mach-Zehnder assisted ring resonator configuration (MARC). MARC can realise transmission spectra with unique spectral signatures and is favourable for multiplexing of sensors. Other advantages are the low LOD and large dynamic range.
The added value of being part of a transdisciplinary centre is derived from the unique network that has been built up and the support from the centre. There is project collaboration between the DIAP and LOC biosensor projects, especially within photonics. Cross-project activities with the dCod project have been established and future collaboration is being pursued.
No PhD candidates in 2020, Ingrid Haga Øvreeide held her defence 16 February 2021.
Scientific publications 2020: 1 conference proceeding and 2 journal articles (2 more in 2021)
Project lead: Astrid Aksnes
Partners: Department of Electronic Systems NTNU (host), Department of Cancer Research and Molecular Medicine NTNU, Department of Physics NTNU, Microsystems and Nanotechnology SINTEF Digital, og Centre of Molecular Inflammation Research (CEMIR) at NTNU/S
Funding: NOK 22.8 mill.
Silicon photonic waveguide sensor (2019)
Mukesh Yadav, Jens Høvik, Jong Wook Noh, Dag Roar Hjelme, Astrid Aksnes
High-throughput measurements of red blood cell deformation in microfluidic channels (2019)
Diego A. Huyke, Diego I. Oyarzun, Amir Saadat, Ingrid Haga Øvreeide, Paulina V. Escobar, Eric S.G. Shaqfeh, Juan G. Santiago
Nina Bjørk Arnfinnsdottir
Biofunctionalization of a photonic ring resonator sensor (2019)
Nina Bjørk Arnfinnsdottir
Photonics activities at IES: LOC biosensor project and Artificial intraperitoneal pancreas project (2019)
Astrid Aksnes, Jens Høvik, Mukesh Yadav, Jong Wook Noh, Dag Roar Hjelme, Karolina Barbara Milenko, Ine Larsen Jernelv, Silje Skeide Fuglerud, Reinold Ellingsen
Lab-on-a-chip photonic biosensor for detection of antigens (2018)
Jens Høvik, Nina Bjørk Arnfinnsdottir, Mukesh Yadav, Astrid Aksnes
Experimental validation of a 2D approximation method for investigating photonic components: case study refractive index sensor (2018)
Jens Høvik, Astrid Aksnes
Loss reduction of electron-beam lithography fabricated strip wire waveguide bends (2018)
Jens Høvik, Astrid Aksnes
A comparative study of photonic transducers for lab-on-a-chip biosensors (2018)
Jens Høvik, Nina Bjørk Arnfinnsdottir, Astrid Aksnes
- Bjørn Torger Stokke
- Dag Roar Hjelme
Ingrid Haga Øvreeide
Jong Wook Noh
Nina Bjørk Arnfinnsdottir
- Project lead: Astrid Aksnes
- Trude Helen Flo
Tests for many diseases simultaneouslyDoctors can make accurate diagnoses much faster if they have access to a microlaboratory in their office that can analyze samples from a patient in minutes. Scientists from NTNU in Trondheim and SINTEF in Oslo are developing a lab-on-a-chip, which is only a few square centimeters. This tiny device will be able to reveal a number of different diseases from the same patient sample, whether it is blood, saliva or urine.
This microlaboratory, also called lab-on-a-chip (LOC), draws the patient sample through thin channels, only a few tens of micrometers thick. The microfluidic channels deliver the samples to the sensors, which are surface functionalized for attachment of different biomarkers. These biomarkers are specific for the diseases one wishes to check. The design of the LOC sensor platform enables a single chip to analyze many substances within tens of minutes. Today, samples are usually sent to a laboratory and it takes many hours or even several days until the doctor will get an answer.
Initially, the researchers will create a prototype that measures three biomarkers used in the analysis of blood samples. These biomarkers are inflammation markers that indicate different conditions, inflammation from bacteria or viruses, potentially cancer and kidney failure. The goal is to create a lab-on-a-chip that is so cheap that it can be discarded after use, and be used both in doctors' offices and in the Third World.
This groundbreaking project combines expertise from medicine, bioengineering, micro-/ nanofluidics (deals with the behavior and precise control of fluids) and nanophotonics (a branch of optical engineering where light interacts with nanoscale structures).
The project is managed by the Department of Electronic Systems at NTNU. Partners are the Department of Physics at NTNU, Department of Cancer Research and Molecular Medicine at NTNU, Department of Microsystems and Nanoelectronics (MiNaLab) at SINTEF Digital, and Centre of Molecular Inflammation Research (CEMIR) at NTNU / St. Olav's Hospital.
More about the project
Biomarkers and nanosensors on lab-on-a-chip
In the Lab-on-a-chip (LOC) Biophotonic Sensor Platform for Diagnostics project, scientists will develop a medical analysis lab-on-a-chip, only a few square centimeters large. To achieve this goal the project combines knowledge of medicine, bioengineering, nanophotonics, micro-/nanofluidics and electronics.
When a person is sick, blood or other bodily fluids may contain proteins specific to an illness or group of diseases. This is called a disease biomarker, and is useful for diagnosis of disease from infections and cancer to kidney failure. By measuring the amount of such biomarkers physicians can obtain quantitative information to help make the diagnosis and choose the right course of treatment.
In this project, the researchers miniaturize the components comprising the analysis equipment. A prototype chip will be developed containing four multiplexed sensors with different surface functionalization. Each sensor will be sensitive to one specific biomarker. Microfluidic channels will transport the fluids containing target biomarkers to these sensors.
The prototype will contain one reference sensor and three sensors with different biomarkers: C-reactive protein (CRP) showing bacterial inflammation in the body, lipocalin 2 (LCN2) as a potential marker of kidney failure, and tumor necrosis factor (TNF) that is elevated by inflammation in the body by arthritis, but may also indicate early stage cancer.
The three selected biomarkers were chosen partly because of their difference in blood concentration, from micrograms per milliliter down to a few picograms (trillion gram), which requires very sensitive measuring equipment. Today, such biomarkers are mainly analyzed in well-equipped laboratories. Here they require relatively large sample volume and it may take hours before the result is ready.
In the project, the researchers will create a LOC demonstrator the size of a postage stamp, where the smallest components are a few hundred nanometers. The advantage of making the LOC so little is that it only needs small sample volumes, approximately 15 microliters. Further, the samples are analyzed quickly with a goal of maximum 20 minutes. In the long term, the goal is to develop a chip with a large number of multiplexed sensors that can measure the biomarkers simultaneously.
Results from the analysis of samples using the LOC will be compared with the gold standard for blood samples in hospitals today - ELISA (Enzyme-linked Immunosorbent Assay).
The project will develop all the three main components integrated on a chip:
- Photonic sensors that are micro- to nanometer in size.
- Surface functionalized sensors with molecules that capture the target biomarkers.
- Microfluidic channels that guide the transport of fluids (patient samples) containing biomarkers to the sensors.
NTNU Nanolab is an important infrastructure needed to fabricate the minute chip, as well as the MiNaLab at SINTEF in Oslo.
To succeed with such a dramatic reduction in size of a «laboratory» the project gathers scientists from different fields combining competence within nanophotonics, bioengineering, nanofluidics, immunology, and clinical applications. Each field has its own jargon (language) where even the same word may have a different meaning between disciplines. Through several two-day seminars, project participants from the various disciplines and institutions meet, discuss and make specifications for the physical prototype of lab-on-a-chip. This has generated better understanding for each other's disciplines.
Two PhD students and two postdoctoral fellows are funded by the Digital Life project while another PhD student is funded by a NTNU strategic enabling technology project. Some of them are physically in the same environment as PhD students and post-docs in another Digital Life project, the Double Intraperitoneal Artificial Pancreas project. Several of the students are affiliated to the PhD Network for Nanotechnology and Microsystems Research School and the Digital Life Research School.
The project collaborates with the Center for Digital Life Norway on responsible research and innovation (RRI). A number of dissemination activities aim at creating awareness, triggering interaction, and collecting valuable feedback from target stakeholder groups (industry, patient associations, medical practitioners, health personnel, health decision makers) thus maximizing the impact and exploitation opportunities of the LOC Biosensor. The vision for the lab-on-a-chip project is to contribute to an analysis equipment, which is so simple and cheap to use that it is found at any doctor’s office.
The lab-on-a-chip project extends the existing technology to the limit. Five years is therefore a too short timeframe for development of these pioneering lab-on-a-chips to a commercial product. However, the project has an Advisory Board with representatives from industry, several with experience in start-ups. This panel will provide advice on how the results can be developed commercially beyond the end of this project.