Anja Boisen

Submitted by: Peter Grutter

General area of research: Biochemical sensing systems using micromechanics

McGill courses: 102/142, 534 (I’m adding 117, 107, 251 for centrifuge stuff)

Why you chose to feature this researcher: Solves real-world problems using physics, chemistry insights and great engineering.

More info: https://dg.dk/en/dtu-writes-article-about-the-career-of-head-of-center-anja-boisen/ https://kvinderifysik.dk/2020/12/06/professor-anja-boisen-is-awarded-the-order-of-the-dannebrog/

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Slides PDF

Speaker Notes

Introduction slide / General speaker notes:

Synopsis of work:

Anja Boisen leads a research group (IDUN) working on micro and nano sensor development and microdevices for drug delivery. The IDUN sensor projects focus on developing and analyzing new nanomechanical sensor systems to study the behavior and physical properties of molecules and cells. They utilize centrifugal microfluidics on a lab-on-a-disk device. Boisen co-founded the company BluSense Diagnostics, which manufactures machines based on Blu-ray technology that can diagnose infectious diseases in 10 minutes using a single drop of blood. The IDUN drug projects focus on investigating the use of micrometer sized containers as a way of delivering drugs (such as insulin, vaccines, and antibiotics) orally. Their goal is to make administering drugs easier and less invasive for patients.

Researcher's background:

Boisen received her Master’s degree in Physics and Mathematics from Roskilde University. She worked as a highschool teacher for almost a year before starting an industrial PhD with the company “Danish Micro Engineering”, which she finished in 1997. She was hired as a postdoc at the Technical University of Denmark (DTU) and was awarded a research grant to begin her research group: the DNRF Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN), where she is currently the Head of Sections. She became an Associate Professor at DTU in 1999 and a Professor in 2005. IDUN has several spinout companies including Cantion, Silmeco, and BluSense Diagnostics.

Boisen was awarded the largest research prize in Denmark: the Villum Kann Rasmussen award. In 2012 she was awarded the EliteForsk Award from the Danish Ministry of Research, Innovation and Higher Education. In 2013 she received the Sapere Aude Top Researcher Award from the Danish Council for Independent Research.

Societal relevance:

Boisen’s work in micro and nanotechnology is innovating the way drugs are delivered and characterized. Her two research areas (biochemical sensing and drug delivery via microdevices) work synergistically and have the potential to both better monitor the treatment of diseases such as cancer and safely deliver the treatments.

Tests for dengue can often take several days to receive results and the cost can prevent patients from seeking a diagnosis, which is critical to reduce the spread of the virus. Boisen’s lab-on-a-disk research is an example of remarkable engineering of a bottom-up design, which has led to increased access to accurate and affordable testing done by the BluBox machine from BluSense Diagnostics.

General citations and resources:

https://dg.dk/en/centers/center-for-intelligent-drug-delivery-og-nanomekaniske-sensorer-idun/

https://www.healthtech.dtu.dk/english/research/research-sections/section-idun

https://www.su.org/experts/anja-boisen

https://kvinderifysik.dk/2020/12/06/professor-anja-boisen-is-awarded-the-order-of-the-dannebrog/

https://dg.dk/en/dtu-writes-article-about-the-career-of-head-of-center-anja-boisen/

Slide 1: Centrifugation

Science details:

Centrifugation is a mechanical process that utilizes the centrifugal force to separate particles in a solution based on their physical properties, the viscosity of the medium, and the rotor speed. The solution (a liquid suspension of particles in a liquid medium) is placed in a centrifuge tube which is then placed in a rotor and spun at a particular speed. Centrifugation speeds along the process of gravity separating the larger/denser particles via sedimentation, wherein the particles are drawn to the bottom of the container along the axis of the centrifuge. As the suspension is rotated at a certain angular velocity or revolutions per minute (RPM), the centrifugal force acts on the particles and allows them to travel away from the rotation axis in the radial direction. The sedimentation rate of a particle is proportional to its molecular weight and the difference between the particle’s density and the density of the solution.

The general formula for the RPM of a centrifuge is a function of the respective force of the centrifuge (g) and the radius from the center of the rotor to a point in the suspension (r).

The magnitude of a centrifugal force F on an object of mass m is a function of m, the angular velocity of the rotating object (ω), and the distance from the origin of the rotating object’s reference frame to the object of mass m (r).

Citations and resources:

https://www.fishersci.se/se/en/scientific-products/centrifuge-guide/centrifugation-theory.html

https://en.wikipedia.org/wiki/Centrifugation

https://en.wikipedia.org/wiki/Centrifugal_force

Figures:

Top: Schematic of a centrifuge (left). An armored casing houses the centrifuge tube which contains a mixture of supernatant (blue liquid) and pellets (dark blue dots). The armored casing is attached to a rapidly rotating rotor. The solution is separated after centrifugation, with the denser components at the bottom of the centrifuge tube (right). https://microbiologynote.com/centrifugation/

Bottom: Diagram of the centrifugal force (red arrow) pointing radially outward from the axis of an object rotating with angular speed ω (black arrow). The velocity (dark blue arrow) of the object is perpendicular to centrifugal force acting on it. Adapted from https://microbiologynote.com/centrifugation/

Slide 2: Lab-on-a-disk

Science details:

Boisen is the Head of Sections at IDUN: a Copengagen-based research group working on micro and nano sensor development and microdevices for drug delivery. The IDUN sensor projects focus on developing and analyzing new nanomechanical sensor systems to study the behavior and physical properties of molecules and cells. They research and develop sensing using centrifugal microfluidics on a lab-on-a-disk device.

Boisen co-founded several spin-out companies from her research group, including BluSense Diagnostics. Her research led the company to develop a machine that is able to diagnose dengue and COVID-19 (and they intend to expand to other infectious diseases) from a drop of blood using technology based on a Blu-ray player. The test is run by taking a blood sample and mixing it with magnetic nanoparticles, then loaded onto the BluSense machine which uses a small turntable to centrifuge the sample for 10 minutes. The turntable is coated with biomolecules that will bind to biomarker particles if they are present in the sample, causing them to collect together. The results are not visible to the naked eye, but can be seen using a blue laser (the same as the laser of a Blu-ray player).

Because they have repurposed existing technology, it only took four years from building the prototype to selling their first machines in Thailand. Medical facilities can run diagnostics using the machines for a cost of $20 per patient - significantly cheaper and more accessible than private testing.

Citations and resources:

https://www.su.org/experts/anja-boisen

https://idun.dtu.dk/Research/Sensor

https://www.healthtech.dtu.dk/english/research/research-sections/section-idun

https://www.engadget.com/2017-05-30-zika-test-machine-needs-just-a-drop-of-blood.html

https://www.youtube.com/watch?v=itn1CpCA8z0

https://www.blusense-diagnostics.com/products/#blubox

Figures:

Left: Photo of a spinning disk used for centrifugal microfluidics. https://idun.dtu.dk/Research/Sensor

Right: Photo of BluSense’s BluBox machine used to diagnose infectious diseases. A health professional is shown inserting a disk into the machine. https://good-design.org/projects/blubox/

Slide 3: Microcontainers: concepts

Science details:

Boisen is the Head of Sections at IDUN: a Copenhagen-based research group working on micro and nano sensor development and microdevices for drug delivery. The IDUN drug projects focus on investigating the use of micrometer sized containers as a way of delivering drugs (such as insulin, vaccines, and antibiotics) orally. They use existing drug formulations but aim to increase the oral bioavailability of drugs by stabilizing them and retaining as much drug as possible through the passage from the mouth to the small intestine where the drugs are absorbed. Their goal is to limit the discomfort, inconvenience, and safety issues posed by injections.

The microcontainers are fabricated by nano and micro fabrication techniques, then they are filled with medicine in a way that IDUN compares to making a Toffifee chocolate. The empty polymer container is filled with medine then a polymer lid is attached to close the container (like filling a caramel shell with nougat then closing it with a chocolate lid). The lid should be pH sensitive so that the medicine is released unidirectionally into the cell wall of the small intestine, increasing the chances of absorbing the drug into the bloodstream.

The entire process is undergoing research: fabricating the polymer shell involves photolithography, embossing, and 3D printing, and the morphology of the shells is being investigated to determine which sizes and shapes best protect the drugs during their journey through the GI tract. Filling the polymer shells requires researching formulations of medicine and polymer and the filling technique involves CO₂ impregnation and punching. It is also essential to choose a material for the microcontainer lids to be sure of a controlled release into the intestinal wall.

Citations and resources:

https://idun.dtu.dk/Research/Drug

https://www.su.org/experts/anja-boisen

https://www.healthtech.dtu.dk/english/research/research-sections/section-idun

Figures:

Top: Photo of a gel capsule containing microcontainers. Each microcontainer is approximately the size of a grain of salt. https://idun.dtu.dk/

Bottom: Diagram of the microcontainer concept. The process of filling the microcontainer is compared to making a Toffifee chocolate: the microcontainer, which is 70-300 μm in height and 300 μm wide, (toffifee caramel shell) is filled with medicine (nougat and nut), then closed with a lid (chocolate lid) which dissolves and releases the medicine in one direction. https://www.youtube.com/watch?v=VLNGCW6ea6M

Slide 4: Microcontainers: testing

Science details:

The oral delivery of drugs using microcontainers is tested first in vitro (studies performed outside a living organism) then in vivo (animal studies using mice and rats). An in vitro study would be measuring how much drug is released from the microcontainers in a gastric medium (pH of 1.6) versus an intestinal medium (pH of 6.5). The in vivo experiments involve measuring the concentration of the drug in the animal’s bloodstream at different times. The results show increased bioavailability for a longer period of time when compared to the control (delivery without microcontainers). IDUN faces challenges moving forward because the human GI tract is long so the microdevices need to stay intact for longer while also using biodegradable materials so that plastics do not accumulate in the body.

Citations and resources:

https://www.su.org/experts/anja-boisen

https://www.healthtech.dtu.dk/english/research/research-sections/section-idun

https://idun.dtu.dk/Research/Drug

https://www.youtube.com/watch?v=P0Y9sqXAHo0

Figures:

Top: Photos of microcontainers of various shapes (un-filled, spherical, tubes, stars). https://www.youtube.com/watch?v=P0Y9sqXAHo0

Bottom left: Results of in vivo testing. Plasma concentration, measured in in μg/mL, of a drug is plotted against time for the microcontainers (red) and the Eudragit coated capsules used as a control (blue). In both cases, the plasma concentration peaks at <100 minutes, but the microcontainers cause a sustained plasma concentration exceeding 0.5 μg/mL lasting from 200-1400 minutes, whereas the control drops below 0.5 μg/mL after 200 minutes. https://www.youtube.com/watch?v=P0Y9sqXAHo0

Bottom right: Results of in vitro testing. Cumulative release of a model drug, in %, is plotted against time for coated and uncoated detachable microcontainers (D-MCs), where the containers are exposed to a pH of 1.65 from 0-120 minutes then a pH of 6.5 from 120-480 minutes. The coated D-MCs show a plateau until 120 minutes then a sharp increase in cumulative release of the model drug from <20% to 80% at 120 minutes. The uncoated D-MCs show a gradual cumulative release to 55% at 120 minutes then a jump from 55% to 65% at 120 minutes. https://core.ac.uk/reader/112373140

Initial Notes

https://kvinderifysik.dk/2020/12/06/professor-anja-boisen-is-awarded-the-order-of-the-dannebrog/

“her research has formed the basis for substantial innovation in how drugs are delivered to the body using nanotechnology.”
Field + benefits: “We work with micro and nano devices for sensing applications and drug delivery: two activities with great synergy. For example, our developed nanomechanical sensors can be used to characterize new drug formulations. We hope to provide new and safe solutions for oral delivery of labile drugs, such as insulin, and to facilitate better monitoring of the effect of treatment of diseases, such as cancer.”

Nano For You | SingularityU Exponential Manufacturing Thailand Summit 2019

https://www.youtube.com/watch?v=itn1CpCA8z0

2019 Thailand lecture
Zika and dengue - no cure, no vaccine, zika is sexually transmitted (might not know if carrier), Doctor takes blood, lab uses centrifuge to separate plasma and look for markers in there - but people might not have access. Bluray player has 3 laces (?), modem spins very fast. Put a nanoparticle on the disk to detect zika. Cover with biomolecules (?) that will bind to the biomarker particles, they will cluster and be visible under a blue laser (from bluray player). Their lab made a prototype 4 years ago. They sold first in Thailand, second in Malaysia (so only 4 years from prototype because the technology was repurposed). Cross-disciplines: nanobead (high tech) + old school DVD player. (for Societal Impact).
Can use similar stuff to see atoms - 1981 Binning and Surich (???).
Bottom-up manufacturing: design DNA and get it manufactured and shipped. DNA has 4 bases - make DNA that folds in any shape you want (box, circle, smiles, all in nm regime). Pour into solution and molecules assemble themselves.
Top-down manufacturing: more expensive, clean rooms.
8 examples of nano manufacturing.

Catalysis (see STM image). Particle is only active at edges - can design more efficient things.
Cleaning. Lotus flower is nanotextured at different levels - prevents it from getting dirty, water rolls off taking away dirt (self-cleaning). Replicate the features (polymers - super hydrophobic surfaces).
Make colors without chemicals and pigments. “Structural blue of morpho butterfly” has nanotextured wings - distance corresponds to blue light wavelength. Could use tech to color plastics without pigments.
Cooking. Cooking over open fire can lead to diseases from inhaling particles. Can have a solar cooker: polymer foil concentrates sunlight to a mural and onto a cooking plate. (People send in pics of dishes). Conventional and Fresnel lens.
Printed electronics. Can print conducting/semiconducting materials. Can use a normal printer with conducting inks. Made by mixing nanoconducting stuff into ink (?). Examples from Joseph Wang - socks that generate energy from sweat. Can monitor stuff in sweat. Could print a solar cell on a hat. Could print bandaids on skin.
Want top-down nanomaterials to interface with biology.

Spermbot is a microrobot that helps non-swimmers.
Seeing in the dark. Mice saw in the dark for 10 weeks, put nanoparticles in their eyes via droplets, enabled “opconversion” (?) to convert to the visible region of light. Effect lasted 10 weeks. Low harm.

First Fresnel lens was installed in a lighthouse in 1823. First one in a clean environment in 1998 (?), then … make km of polymer foils, solar cookers with inside nanostructures.
Can do a DIY atomic force microscope to look at nm structures using a pickup head from a DVD player as … head.
Today: lots of oil-based chemical production. But now you can use bacteria.

NanoSeminar: Micro/Nano Engineering and Drug Delivery (2022 Webinar)

https://www.youtube.com/watch?v=P0Y9sqXAHo0

Someone talks until around 11:00. I skipped a bunch of it.

Classical diagnostics vs. point-of-care diagnostics (former is expensive, needs to be trained, equipment, time-consuming vs. rapid results, easy to use, deliverable=small device, affordable, etc.).
Materials in point-of-care: paper-based biosensing (mainly). Compatible with printed stuff, lateral flow, smart phones, etc.
Nanomaterials should help increase sensitivity.

A lot of their sensors can both administer and sense drugs. I think.
They want to implement top-down, and translate to practical applications.
DTU (?)

She started in nanomechanical sensors?
Stability, diagnostics, cell (?) delivery.
Want to characterize new drugs at early stage
Micromechanical thermal analysis. Karl indirectly measures temperature changes on the string → minute changes in phases
2nd story = diagnostics from 1 drop of blood and detecting a thing, from >6 years ago. The example is the spinning centrifugation on the disk with a drop of blood, disk is coated with nanobeads (?), blue laser from blue-ray player. Now they’re a Copenhagen-based company that manufactures these things (but did she take part in the research or no???). They work with Zika, dengue, and antibodies.
Methotrexate (MTX) used in high doses to treat children with leukemia.
300 micrometer sized devices for oral drug delivery - this is an alternative to injections. (Eg. injections or vaccines - these can degrade in oral form, or can go into solutions (what), might not go into bloodstream). They don’t want to re-formulate, they want to put into microcontainers.

Things come out at cell wall so drugs can get through (ideally).
Benefits: control of size and shape, control when and where to release, can fill with a lot of drug, only comes out in one direction which reduces wasted drug, sometimes loading into amorphous containers stabilizes drugs.
They started with small simple ones, now more complex.
Can inject liquids, loaded in powder drug… films… somehow only inside without wasting it. Can spray pH (?) sensitive polymers on top.
Measure by UV absorption.
In vivo experiments: (animal testing - rats). They have a control which is the same but no microcontainers. From blood sampling: both have the same peak, but microcontainers deliver for a prolonged period of time.
Currently they work with delivering probiotics, antibiotics, insulin, vaccine, and do local gut sampling.
Challenges: animals have shorter GI tracts so things move faster, they’re trying to make devices that stay for longer, need biodegradable materials so plastics don’t pile up in the body, they tried 3D printing small devices

Slides Plan (4-5 slides)

IDUNN sensor

How do centrifuges work?
Detecting Zika, dengue with blue-ray device. “Bottom-down”. Took only 4 years to manufacture from the prototype because they’re built from existing technology.
Nano-related concepts: surface enhanced Raman scattering (SERS), IR absorption spectroscopy in combination with so called microelectromechanical systems (MEMS) (e.g. nano- or micro-strings or membranes) for evaluation of properties of pharmaceutical

IDUNN drug (maybe not in this order)

Principles of microcontainers
Explain IDUNN drug: micrometer-sized containers for oral drug delivery. Things come out at the cell wall so drugs can get through (ideally).