Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

“How do we get to making nanomaterials that haven’t been evolved before?” asked Angela Belcher at the 2023 Mildred S. Dresselhaus Lecture at MIT on Nov. 20. “We can use elements that biology has already given us.”

The combined in-person and virtual audience of over 300 was treated to a light-up, 3D model of M13 bacteriophage, a virus that only infects bacteria, complete with a pull-out strand of DNA. Belcher used the feather-boa-like model to show how her research group modifies the M13’s genes to add new DNA and peptide sequences to template inorganic materials.

“I love controlling materials at the nanoscale using biology,” said Belcher, the James Mason Crafts Professor of Biological Engineering, materials science professor, and of the Koch Institute of Integrative Cancer Research at MIT. “We all know if you control materials at the nanoscale and you can start to tune them, then you can have all kinds of different applications.” And the opportunities are indeed vast — from building batteries, fuel cells, and solar cells to carbon sequestration and storage, environmental remediation, catalysis, and medical diagnostics and imaging.

Belcher sprinkled her talk with models and props, lined up on a table at the front of the 10-250 lecture hall, to demonstrate a wide variety of concepts and projects made possible by the intersection of biology and nanotechnology.

Energy storage and environment

“How do you go from a DNA sequence to a functioning battery?” posed Belcher. Grabbing a model of a large carbon nanotube, she explained how her group engineered a phage to pick up carbon nanotubes that would wind all the way around the virus and then fill in with different cathode or anode materials to make nanowires for battery electrodes.

How about using the M13 bacteriophage to improve the environment? Belcher referred to a project by former student Geran Zhang PhD ’19 that proved the virus can be modified for this context, too. He used the phage to template high-surface-area, carbon-based materials that can grab small molecules and break them down, Belcher said, opening a realm of possibilities from cleaning up rivers to developing chemical warfare agents to combating smog.

Belcher’s lab worked with the U.S. Army to produce protective clothing and masks made of these carbon-based virus nanofibers. “We went from five liters in our lab to a thousand liters, then 10,000 liters in the army labs where we’re able to make kilograms of the material,” Belcher said, stressing the importance of being able to test and prototype at scale.

Imaging tools and therapeutics in cancer

In the area of biomedical imaging, Belcher explained, a lot less is known in near-infrared imaging — imaging in wavelengths above 1,000 nanometers — than other imaging techniques, yet with near-infrared scientists can see much deeper inside the body. Belcher’s lab built their own systems to image at these wavelengths. The third generation of this system provides real-time, sub-millimeter optical imaging for guided surgery.

Working with Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Engineering, Belcher used carbon nanotubes to build imaging tools that find tiny tumors during surgery that doctors otherwise would not be able to see. The tool is actually a virus engineered to carry with it a fluorescent, single-walled carbon nanotube as it seeks out the tumors.

Nearing the end of her talk, Belcher presented a goal: to develop an accessible detection and diagnostic technology for ovarian cancer in five to 10 years.

“We think that we can do it,” Belcher said. She described her students’ work developing a way to scan an entire fallopian tube, as opposed to just one small portion, to find pre-cancer lesions, and talked about the team of MIT faculty, doctors, and researchers working collectively toward this goal.

“Part of the secret of life and the meaning of life is helping other people enjoy the passage of time,” said Belcher in her closing remarks. “I think that we can all do that by working to solve some of the biggest issues on the planet, including helping to diagnose and treat ovarian cancer early so people have more time to spend with their family.”

Honoring Mildred S. Dresselhaus

Belcher was the fifth speaker to deliver the Dresselhaus Lecture, an annual event organized by MIT.nano to honor the late MIT physics and electrical engineering Institute Professor Mildred Dresselhaus. The lecture features a speaker from anywhere in the world whose leadership and impact echo Dresselhaus’s life, accomplishments, and values.

“Millie was and is a huge hero of mine,” said Belcher. “Giving a lecture in Millie’s name is just the greatest honor.”

Belcher dedicated the talk to Dresselhaus, whom she described with an array of accolades — a trailblazer, a genius, an amazing mentor, teacher, and inventor. “Just knowing her was such a privilege,” she said.

Belcher also dedicated her talk to her own grandmother and mother, both of whom passed away from cancer, as well as late MIT professors Susan Lindquist and Angelika Amon, who both died of ovarian cancer.

“I’ve been so fortunate to work with just the most talented and dedicated graduate students, undergraduate students, postdocs, and researchers,” concluded Belcher. “It has been a pure joy to be in partnership with all of you to solve these very daunting problems.”

MIT researchers have used 3D printing to produce self-heating microfluidic devices, demonstrating a technique which could someday be used to rapidly create cheap, yet accurate, tools to detect a host of diseases.

Microfluidics, miniaturized machines that manipulate fluids and facilitate chemical reactions, can be used to detect disease in tiny samples of blood or fluids. At-home test kits for Covid-19, for example, incorporate a simple type of microfluidic.

But many microfluidic applications require chemical reactions that must be performed at specific temperatures. These more complex microfluidic devices, which are typically manufactured in a clean room, are outfitted with heating elements made from gold or platinum using a complicated and expensive fabrication process that is difficult to scale up.

Instead, the MIT team used multimaterial 3D printing to create self-heating microfluidic devices with built-in heating elements, through a single, inexpensive manufacturing process. They generated devices that can heat fluid to a specific temperature as it flows through microscopic channels inside the tiny machine.

Their technique is customizable, so an engineer could create a microfluidic that heats fluid to a certain temperature or given heating profile within a specific area of the device. The low-cost fabrication process requires about $2 of materials to generate a ready-to-use microfluidic.

The process could be especially useful in creating self-heating microfluidics for remote regions of developing countries where clinicians may not have access to the expensive lab equipment required for many diagnostic procedures.

“Clean rooms in particular, where you would usually make these devices, are incredibly expensive to build and to run. But we can make very capable self-heating microfluidic devices using additive manufacturing, and they can be made a lot faster and cheaper than with these traditional methods. This is really a way to democratize this technology,” says Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories (MTL) and senior author of a paper describing the fabrication technique.

He is joined on the paper by lead author Jorge Cañada Pérez-Sala, an electrical engineering and computer science graduate student. The research will be presented at the PowerMEMS Conference this month.

An insulator becomes conductive

This new fabrication process utilizes a technique called multimaterial extrusion 3D printing, in which several materials can be squirted through the printer’s many nozzles to build a device layer by layer. The process is monolithic, which means the entire device can be produced in one step on the 3D printer, without the need for any post-assembly.

To create self-heating microfluidics, the researchers used two materials — a biodegradable polymer known as polylactic acid (PLA) that is commonly used in 3D printing, and a modified version of PLA.

The modified PLA has mixed copper nanoparticles into the polymer, which converts this insulating material into an electrical conductor, Velásquez-García explains. When electrical current is fed into a resistor composed of this copper-doped PLA, energy is dissipated as heat.

“It is amazing when you think about it because the PLA material is a dielectric, but when you put in these nanoparticle impurities, it completely changes the physical properties. This is something we don’t fully understand yet, but it happens and it is repeatable,” he says.

Using a multimaterial 3D printer, the researchers fabricate a heating resistor from the copper-doped PLA and then print the microfluidic device, with microscopic channels through which fluid can flow, directly on top in one printing step. Because the components are made from the same base material, they have similar printing temperatures and are compatible.

Heat dissipated from the resistor will warm fluid flowing through the channels in the microfluidic.

In addition to the resistor and microfluidic, they use the printer to add a thin, continuous layer of PLA that is sandwiched between them. It is especially challenging to manufacture this layer because it must be thin enough so heat can transfer from the resistor to the microfluidic, but not so thin that fluid could leak into the resistor.

The resulting machine is about the size of a U.S. quarter and can be produced in a matter of minutes. Channels about 500 micrometers wide and 400 micrometers tall are threaded through the microfluidic to carry fluid and facilitate chemical reactions.

Importantly, the PLA material is translucent, so fluid in the device remains visible. Many processes rely on visualization or the use of light to infer what is happening during chemical reactions, Velásquez-García explains.

Customizable chemical reactors

The researchers used this one-step manufacturing process to generate a prototype that could heat fluid by 4 degrees Celsius as it flowed between the input and the output. This customizable technique could enable them to make devices which would heat fluids in certain patterns or along specific gradients.

“You can use these two materials to create chemical reactors that do exactly what you want. We can set up a particular heating profile while still having all the capabilities of the microfluidic,” he says.

However, one limitation comes from the fact that PLA can only be heated to about 50 degrees Celsius before it starts to degrade. Many chemical reactions, such as those used for polymerase chain reaction (PCR) tests, require temperatures of 90 degrees or higher. And to precisely control the temperature of the device, researchers would need to integrate a third material that enables temperature sensing.

In addition to tackling these limitations in future work, Velásquez-García wants to print magnets directly into the microfluidic device. These magnets could enable chemical reactions that require particles to be sorted or aligned.

At the same time, he and his colleagues are exploring the use of other materials that could reach higher temperatures. They are also studying PLA to better understand why it becomes conductive when certain impurities are added to the polymer.

“If we can understand the mechanism that is related to the electrical conductivity of PLA, that would greatly enhance the capability of these devices, but it is going to be a lot harder to solve than some other engineering problems,” he adds.

“In Japanese culture, it’s often said that beauty lies in simplicity. This sentiment is echoed by the work of Cañada and Velasquez-Garcia. Their proposed monolithically 3D-printed microfluidic systems embody simplicity and beauty, offering a wide array of potential derivations and applications that we foresee in the future,” says Norihisa Miki, a professor of mechanical engineering at Keio University in Tokyo, who was not involved with this work.

“Being able to directly print microfluidic chips with fluidic channels and electrical features at the same time opens up very exiting applications when processing biological samples, such as to amplify biomarkers or to actuate and mix liquids. Also, due to the fact that PLA degrades over time, one can even think of implantable applications where the chips dissolve and resorb over time,” adds Niclas Roxhed, an associate professor at Sweden’s KTH Royal Institute of Technology, who was not involved with this study.

This research was funded, in part, by the Empiriko Corporation and a fellowship from La Caixa Foundation.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

“How do we get to making nanomaterials that haven’t been evolved before?” asked Angela Belcher at the 2023 Mildred S. Dresselhaus Lecture at MIT on Nov. 20. “We can use elements that biology has already given us.”

The combined in-person and virtual audience of over 300 was treated to a light-up, 3D model of M13 bacteriophage, a virus that only infects bacteria, complete with a pull-out strand of DNA. Belcher used the feather-boa-like model to show how her research group modifies the M13’s genes to add new DNA and peptide sequences to template inorganic materials.

“I love controlling materials at the nanoscale using biology,” said Belcher, the James Mason Crafts Professor of Biological Engineering, materials science professor, and of the Koch Institute of Integrative Cancer Research at MIT. “We all know if you control materials at the nanoscale and you can start to tune them, then you can have all kinds of different applications.” And the opportunities are indeed vast — from building batteries, fuel cells, and solar cells to carbon sequestration and storage, environmental remediation, catalysis, and medical diagnostics and imaging.

Belcher sprinkled her talk with models and props, lined up on a table at the front of the 10-250 lecture hall, to demonstrate a wide variety of concepts and projects made possible by the intersection of biology and nanotechnology.

Energy storage and environment

“How do you go from a DNA sequence to a functioning battery?” posed Belcher. Grabbing a model of a large carbon nanotube, she explained how her group engineered a phage to pick up carbon nanotubes that would wind all the way around the virus and then fill in with different cathode or anode materials to make nanowires for battery electrodes.

How about using the M13 bacteriophage to improve the environment? Belcher referred to a project by former student Geran Zhang PhD ’19 that proved the virus can be modified for this context, too. He used the phage to template high-surface-area, carbon-based materials that can grab small molecules and break them down, Belcher said, opening a realm of possibilities from cleaning up rivers to developing chemical warfare agents to combating smog.

Belcher’s lab worked with the U.S. Army to produce protective clothing and masks made of these carbon-based virus nanofibers. “We went from five liters in our lab to a thousand liters, then 10,000 liters in the army labs where we’re able to make kilograms of the material,” Belcher said, stressing the importance of being able to test and prototype at scale.

Imaging tools and therapeutics in cancer

In the area of biomedical imaging, Belcher explained, a lot less is known in near-infrared imaging — imaging in wavelengths above 1,000 nanometers — than other imaging techniques, yet with near-infrared scientists can see much deeper inside the body. Belcher’s lab built their own systems to image at these wavelengths. The third generation of this system provides real-time, sub-millimeter optical imaging for guided surgery.

Working with Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Engineering, Belcher used carbon nanotubes to build imaging tools that find tiny tumors during surgery that doctors otherwise would not be able to see. The tool is actually a virus engineered to carry with it a fluorescent, single-walled carbon nanotube as it seeks out the tumors.

Nearing the end of her talk, Belcher presented a goal: to develop an accessible detection and diagnostic technology for ovarian cancer in five to 10 years.

“We think that we can do it,” Belcher said. She described her students’ work developing a way to scan an entire fallopian tube, as opposed to just one small portion, to find pre-cancer lesions, and talked about the team of MIT faculty, doctors, and researchers working collectively toward this goal.

“Part of the secret of life and the meaning of life is helping other people enjoy the passage of time,” said Belcher in her closing remarks. “I think that we can all do that by working to solve some of the biggest issues on the planet, including helping to diagnose and treat ovarian cancer early so people have more time to spend with their family.”

Honoring Mildred S. Dresselhaus

Belcher was the fifth speaker to deliver the Dresselhaus Lecture, an annual event organized by MIT.nano to honor the late MIT physics and electrical engineering Institute Professor Mildred Dresselhaus. The lecture features a speaker from anywhere in the world whose leadership and impact echo Dresselhaus’s life, accomplishments, and values.

“Millie was and is a huge hero of mine,” said Belcher. “Giving a lecture in Millie’s name is just the greatest honor.”

Belcher dedicated the talk to Dresselhaus, whom she described with an array of accolades — a trailblazer, a genius, an amazing mentor, teacher, and inventor. “Just knowing her was such a privilege,” she said.

Belcher also dedicated her talk to her own grandmother and mother, both of whom passed away from cancer, as well as late MIT professors Susan Lindquist and Angelika Amon, who both died of ovarian cancer.

“I’ve been so fortunate to work with just the most talented and dedicated graduate students, undergraduate students, postdocs, and researchers,” concluded Belcher. “It has been a pure joy to be in partnership with all of you to solve these very daunting problems.”

MIT researchers have used 3D printing to produce self-heating microfluidic devices, demonstrating a technique which could someday be used to rapidly create cheap, yet accurate, tools to detect a host of diseases.

Microfluidics, miniaturized machines that manipulate fluids and facilitate chemical reactions, can be used to detect disease in tiny samples of blood or fluids. At-home test kits for Covid-19, for example, incorporate a simple type of microfluidic.

But many microfluidic applications require chemical reactions that must be performed at specific temperatures. These more complex microfluidic devices, which are typically manufactured in a clean room, are outfitted with heating elements made from gold or platinum using a complicated and expensive fabrication process that is difficult to scale up.

Instead, the MIT team used multimaterial 3D printing to create self-heating microfluidic devices with built-in heating elements, through a single, inexpensive manufacturing process. They generated devices that can heat fluid to a specific temperature as it flows through microscopic channels inside the tiny machine.

Their technique is customizable, so an engineer could create a microfluidic that heats fluid to a certain temperature or given heating profile within a specific area of the device. The low-cost fabrication process requires about $2 of materials to generate a ready-to-use microfluidic.

The process could be especially useful in creating self-heating microfluidics for remote regions of developing countries where clinicians may not have access to the expensive lab equipment required for many diagnostic procedures.

“Clean rooms in particular, where you would usually make these devices, are incredibly expensive to build and to run. But we can make very capable self-heating microfluidic devices using additive manufacturing, and they can be made a lot faster and cheaper than with these traditional methods. This is really a way to democratize this technology,” says Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories (MTL) and senior author of a paper describing the fabrication technique.

He is joined on the paper by lead author Jorge Cañada Pérez-Sala, an electrical engineering and computer science graduate student. The research will be presented at the PowerMEMS Conference this month.

An insulator becomes conductive

This new fabrication process utilizes a technique called multimaterial extrusion 3D printing, in which several materials can be squirted through the printer’s many nozzles to build a device layer by layer. The process is monolithic, which means the entire device can be produced in one step on the 3D printer, without the need for any post-assembly.

To create self-heating microfluidics, the researchers used two materials — a biodegradable polymer known as polylactic acid (PLA) that is commonly used in 3D printing, and a modified version of PLA.

The modified PLA has mixed copper nanoparticles into the polymer, which converts this insulating material into an electrical conductor, Velásquez-García explains. When electrical current is fed into a resistor composed of this copper-doped PLA, energy is dissipated as heat.

“It is amazing when you think about it because the PLA material is a dielectric, but when you put in these nanoparticle impurities, it completely changes the physical properties. This is something we don’t fully understand yet, but it happens and it is repeatable,” he says.

Using a multimaterial 3D printer, the researchers fabricate a heating resistor from the copper-doped PLA and then print the microfluidic device, with microscopic channels through which fluid can flow, directly on top in one printing step. Because the components are made from the same base material, they have similar printing temperatures and are compatible.

Heat dissipated from the resistor will warm fluid flowing through the channels in the microfluidic.

In addition to the resistor and microfluidic, they use the printer to add a thin, continuous layer of PLA that is sandwiched between them. It is especially challenging to manufacture this layer because it must be thin enough so heat can transfer from the resistor to the microfluidic, but not so thin that fluid could leak into the resistor.

The resulting machine is about the size of a U.S. quarter and can be produced in a matter of minutes. Channels about 500 micrometers wide and 400 micrometers tall are threaded through the microfluidic to carry fluid and facilitate chemical reactions.

Importantly, the PLA material is translucent, so fluid in the device remains visible. Many processes rely on visualization or the use of light to infer what is happening during chemical reactions, Velásquez-García explains.

Customizable chemical reactors

The researchers used this one-step manufacturing process to generate a prototype that could heat fluid by 4 degrees Celsius as it flowed between the input and the output. This customizable technique could enable them to make devices which would heat fluids in certain patterns or along specific gradients.

“You can use these two materials to create chemical reactors that do exactly what you want. We can set up a particular heating profile while still having all the capabilities of the microfluidic,” he says.

However, one limitation comes from the fact that PLA can only be heated to about 50 degrees Celsius before it starts to degrade. Many chemical reactions, such as those used for polymerase chain reaction (PCR) tests, require temperatures of 90 degrees or higher. And to precisely control the temperature of the device, researchers would need to integrate a third material that enables temperature sensing.

In addition to tackling these limitations in future work, Velásquez-García wants to print magnets directly into the microfluidic device. These magnets could enable chemical reactions that require particles to be sorted or aligned.

At the same time, he and his colleagues are exploring the use of other materials that could reach higher temperatures. They are also studying PLA to better understand why it becomes conductive when certain impurities are added to the polymer.

“If we can understand the mechanism that is related to the electrical conductivity of PLA, that would greatly enhance the capability of these devices, but it is going to be a lot harder to solve than some other engineering problems,” he adds.

“In Japanese culture, it’s often said that beauty lies in simplicity. This sentiment is echoed by the work of Cañada and Velasquez-Garcia. Their proposed monolithically 3D-printed microfluidic systems embody simplicity and beauty, offering a wide array of potential derivations and applications that we foresee in the future,” says Norihisa Miki, a professor of mechanical engineering at Keio University in Tokyo, who was not involved with this work.

“Being able to directly print microfluidic chips with fluidic channels and electrical features at the same time opens up very exiting applications when processing biological samples, such as to amplify biomarkers or to actuate and mix liquids. Also, due to the fact that PLA degrades over time, one can even think of implantable applications where the chips dissolve and resorb over time,” adds Niclas Roxhed, an associate professor at Sweden’s KTH Royal Institute of Technology, who was not involved with this study.

This research was funded, in part, by the Empiriko Corporation and a fellowship from La Caixa Foundation.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

“How do we get to making nanomaterials that haven’t been evolved before?” asked Angela Belcher at the 2023 Mildred S. Dresselhaus Lecture at MIT on Nov. 20. “We can use elements that biology has already given us.”

The combined in-person and virtual audience of over 300 was treated to a light-up, 3D model of M13 bacteriophage, a virus that only infects bacteria, complete with a pull-out strand of DNA. Belcher used the feather-boa-like model to show how her research group modifies the M13’s genes to add new DNA and peptide sequences to template inorganic materials.

“I love controlling materials at the nanoscale using biology,” said Belcher, the James Mason Crafts Professor of Biological Engineering, materials science professor, and of the Koch Institute of Integrative Cancer Research at MIT. “We all know if you control materials at the nanoscale and you can start to tune them, then you can have all kinds of different applications.” And the opportunities are indeed vast — from building batteries, fuel cells, and solar cells to carbon sequestration and storage, environmental remediation, catalysis, and medical diagnostics and imaging.

Belcher sprinkled her talk with models and props, lined up on a table at the front of the 10-250 lecture hall, to demonstrate a wide variety of concepts and projects made possible by the intersection of biology and nanotechnology.

Energy storage and environment

“How do you go from a DNA sequence to a functioning battery?” posed Belcher. Grabbing a model of a large carbon nanotube, she explained how her group engineered a phage to pick up carbon nanotubes that would wind all the way around the virus and then fill in with different cathode or anode materials to make nanowires for battery electrodes.

How about using the M13 bacteriophage to improve the environment? Belcher referred to a project by former student Geran Zhang PhD ’19 that proved the virus can be modified for this context, too. He used the phage to template high-surface-area, carbon-based materials that can grab small molecules and break them down, Belcher said, opening a realm of possibilities from cleaning up rivers to developing chemical warfare agents to combating smog.

Belcher’s lab worked with the U.S. Army to produce protective clothing and masks made of these carbon-based virus nanofibers. “We went from five liters in our lab to a thousand liters, then 10,000 liters in the army labs where we’re able to make kilograms of the material,” Belcher said, stressing the importance of being able to test and prototype at scale.

Imaging tools and therapeutics in cancer

In the area of biomedical imaging, Belcher explained, a lot less is known in near-infrared imaging — imaging in wavelengths above 1,000 nanometers — than other imaging techniques, yet with near-infrared scientists can see much deeper inside the body. Belcher’s lab built their own systems to image at these wavelengths. The third generation of this system provides real-time, sub-millimeter optical imaging for guided surgery.

Working with Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Engineering, Belcher used carbon nanotubes to build imaging tools that find tiny tumors during surgery that doctors otherwise would not be able to see. The tool is actually a virus engineered to carry with it a fluorescent, single-walled carbon nanotube as it seeks out the tumors.

Nearing the end of her talk, Belcher presented a goal: to develop an accessible detection and diagnostic technology for ovarian cancer in five to 10 years.

“We think that we can do it,” Belcher said. She described her students’ work developing a way to scan an entire fallopian tube, as opposed to just one small portion, to find pre-cancer lesions, and talked about the team of MIT faculty, doctors, and researchers working collectively toward this goal.

“Part of the secret of life and the meaning of life is helping other people enjoy the passage of time,” said Belcher in her closing remarks. “I think that we can all do that by working to solve some of the biggest issues on the planet, including helping to diagnose and treat ovarian cancer early so people have more time to spend with their family.”

Honoring Mildred S. Dresselhaus

Belcher was the fifth speaker to deliver the Dresselhaus Lecture, an annual event organized by MIT.nano to honor the late MIT physics and electrical engineering Institute Professor Mildred Dresselhaus. The lecture features a speaker from anywhere in the world whose leadership and impact echo Dresselhaus’s life, accomplishments, and values.

“Millie was and is a huge hero of mine,” said Belcher. “Giving a lecture in Millie’s name is just the greatest honor.”

Belcher dedicated the talk to Dresselhaus, whom she described with an array of accolades — a trailblazer, a genius, an amazing mentor, teacher, and inventor. “Just knowing her was such a privilege,” she said.

Belcher also dedicated her talk to her own grandmother and mother, both of whom passed away from cancer, as well as late MIT professors Susan Lindquist and Angelika Amon, who both died of ovarian cancer.

“I’ve been so fortunate to work with just the most talented and dedicated graduate students, undergraduate students, postdocs, and researchers,” concluded Belcher. “It has been a pure joy to be in partnership with all of you to solve these very daunting problems.”

MIT researchers have used 3D printing to produce self-heating microfluidic devices, demonstrating a technique which could someday be used to rapidly create cheap, yet accurate, tools to detect a host of diseases.

Microfluidics, miniaturized machines that manipulate fluids and facilitate chemical reactions, can be used to detect disease in tiny samples of blood or fluids. At-home test kits for Covid-19, for example, incorporate a simple type of microfluidic.

But many microfluidic applications require chemical reactions that must be performed at specific temperatures. These more complex microfluidic devices, which are typically manufactured in a clean room, are outfitted with heating elements made from gold or platinum using a complicated and expensive fabrication process that is difficult to scale up.

Instead, the MIT team used multimaterial 3D printing to create self-heating microfluidic devices with built-in heating elements, through a single, inexpensive manufacturing process. They generated devices that can heat fluid to a specific temperature as it flows through microscopic channels inside the tiny machine.

Their technique is customizable, so an engineer could create a microfluidic that heats fluid to a certain temperature or given heating profile within a specific area of the device. The low-cost fabrication process requires about $2 of materials to generate a ready-to-use microfluidic.

The process could be especially useful in creating self-heating microfluidics for remote regions of developing countries where clinicians may not have access to the expensive lab equipment required for many diagnostic procedures.

“Clean rooms in particular, where you would usually make these devices, are incredibly expensive to build and to run. But we can make very capable self-heating microfluidic devices using additive manufacturing, and they can be made a lot faster and cheaper than with these traditional methods. This is really a way to democratize this technology,” says Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories (MTL) and senior author of a paper describing the fabrication technique.

He is joined on the paper by lead author Jorge Cañada Pérez-Sala, an electrical engineering and computer science graduate student. The research will be presented at the PowerMEMS Conference this month.

An insulator becomes conductive

This new fabrication process utilizes a technique called multimaterial extrusion 3D printing, in which several materials can be squirted through the printer’s many nozzles to build a device layer by layer. The process is monolithic, which means the entire device can be produced in one step on the 3D printer, without the need for any post-assembly.

To create self-heating microfluidics, the researchers used two materials — a biodegradable polymer known as polylactic acid (PLA) that is commonly used in 3D printing, and a modified version of PLA.

The modified PLA has mixed copper nanoparticles into the polymer, which converts this insulating material into an electrical conductor, Velásquez-García explains. When electrical current is fed into a resistor composed of this copper-doped PLA, energy is dissipated as heat.

“It is amazing when you think about it because the PLA material is a dielectric, but when you put in these nanoparticle impurities, it completely changes the physical properties. This is something we don’t fully understand yet, but it happens and it is repeatable,” he says.

Using a multimaterial 3D printer, the researchers fabricate a heating resistor from the copper-doped PLA and then print the microfluidic device, with microscopic channels through which fluid can flow, directly on top in one printing step. Because the components are made from the same base material, they have similar printing temperatures and are compatible.

Heat dissipated from the resistor will warm fluid flowing through the channels in the microfluidic.

In addition to the resistor and microfluidic, they use the printer to add a thin, continuous layer of PLA that is sandwiched between them. It is especially challenging to manufacture this layer because it must be thin enough so heat can transfer from the resistor to the microfluidic, but not so thin that fluid could leak into the resistor.

The resulting machine is about the size of a U.S. quarter and can be produced in a matter of minutes. Channels about 500 micrometers wide and 400 micrometers tall are threaded through the microfluidic to carry fluid and facilitate chemical reactions.

Importantly, the PLA material is translucent, so fluid in the device remains visible. Many processes rely on visualization or the use of light to infer what is happening during chemical reactions, Velásquez-García explains.

Customizable chemical reactors

The researchers used this one-step manufacturing process to generate a prototype that could heat fluid by 4 degrees Celsius as it flowed between the input and the output. This customizable technique could enable them to make devices which would heat fluids in certain patterns or along specific gradients.

“You can use these two materials to create chemical reactors that do exactly what you want. We can set up a particular heating profile while still having all the capabilities of the microfluidic,” he says.

However, one limitation comes from the fact that PLA can only be heated to about 50 degrees Celsius before it starts to degrade. Many chemical reactions, such as those used for polymerase chain reaction (PCR) tests, require temperatures of 90 degrees or higher. And to precisely control the temperature of the device, researchers would need to integrate a third material that enables temperature sensing.

In addition to tackling these limitations in future work, Velásquez-García wants to print magnets directly into the microfluidic device. These magnets could enable chemical reactions that require particles to be sorted or aligned.

At the same time, he and his colleagues are exploring the use of other materials that could reach higher temperatures. They are also studying PLA to better understand why it becomes conductive when certain impurities are added to the polymer.

“If we can understand the mechanism that is related to the electrical conductivity of PLA, that would greatly enhance the capability of these devices, but it is going to be a lot harder to solve than some other engineering problems,” he adds.

“In Japanese culture, it’s often said that beauty lies in simplicity. This sentiment is echoed by the work of Cañada and Velasquez-Garcia. Their proposed monolithically 3D-printed microfluidic systems embody simplicity and beauty, offering a wide array of potential derivations and applications that we foresee in the future,” says Norihisa Miki, a professor of mechanical engineering at Keio University in Tokyo, who was not involved with this work.

“Being able to directly print microfluidic chips with fluidic channels and electrical features at the same time opens up very exiting applications when processing biological samples, such as to amplify biomarkers or to actuate and mix liquids. Also, due to the fact that PLA degrades over time, one can even think of implantable applications where the chips dissolve and resorb over time,” adds Niclas Roxhed, an associate professor at Sweden’s KTH Royal Institute of Technology, who was not involved with this study.

This research was funded, in part, by the Empiriko Corporation and a fellowship from La Caixa Foundation.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

“How do we get to making nanomaterials that haven’t been evolved before?” asked Angela Belcher at the 2023 Mildred S. Dresselhaus Lecture at MIT on Nov. 20. “We can use elements that biology has already given us.”

The combined in-person and virtual audience of over 300 was treated to a light-up, 3D model of M13 bacteriophage, a virus that only infects bacteria, complete with a pull-out strand of DNA. Belcher used the feather-boa-like model to show how her research group modifies the M13’s genes to add new DNA and peptide sequences to template inorganic materials.

“I love controlling materials at the nanoscale using biology,” said Belcher, the James Mason Crafts Professor of Biological Engineering, materials science professor, and of the Koch Institute of Integrative Cancer Research at MIT. “We all know if you control materials at the nanoscale and you can start to tune them, then you can have all kinds of different applications.” And the opportunities are indeed vast — from building batteries, fuel cells, and solar cells to carbon sequestration and storage, environmental remediation, catalysis, and medical diagnostics and imaging.

Belcher sprinkled her talk with models and props, lined up on a table at the front of the 10-250 lecture hall, to demonstrate a wide variety of concepts and projects made possible by the intersection of biology and nanotechnology.

Energy storage and environment

“How do you go from a DNA sequence to a functioning battery?” posed Belcher. Grabbing a model of a large carbon nanotube, she explained how her group engineered a phage to pick up carbon nanotubes that would wind all the way around the virus and then fill in with different cathode or anode materials to make nanowires for battery electrodes.

How about using the M13 bacteriophage to improve the environment? Belcher referred to a project by former student Geran Zhang PhD ’19 that proved the virus can be modified for this context, too. He used the phage to template high-surface-area, carbon-based materials that can grab small molecules and break them down, Belcher said, opening a realm of possibilities from cleaning up rivers to developing chemical warfare agents to combating smog.

Belcher’s lab worked with the U.S. Army to produce protective clothing and masks made of these carbon-based virus nanofibers. “We went from five liters in our lab to a thousand liters, then 10,000 liters in the army labs where we’re able to make kilograms of the material,” Belcher said, stressing the importance of being able to test and prototype at scale.

Imaging tools and therapeutics in cancer

In the area of biomedical imaging, Belcher explained, a lot less is known in near-infrared imaging — imaging in wavelengths above 1,000 nanometers — than other imaging techniques, yet with near-infrared scientists can see much deeper inside the body. Belcher’s lab built their own systems to image at these wavelengths. The third generation of this system provides real-time, sub-millimeter optical imaging for guided surgery.

Working with Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Engineering, Belcher used carbon nanotubes to build imaging tools that find tiny tumors during surgery that doctors otherwise would not be able to see. The tool is actually a virus engineered to carry with it a fluorescent, single-walled carbon nanotube as it seeks out the tumors.

Nearing the end of her talk, Belcher presented a goal: to develop an accessible detection and diagnostic technology for ovarian cancer in five to 10 years.

“We think that we can do it,” Belcher said. She described her students’ work developing a way to scan an entire fallopian tube, as opposed to just one small portion, to find pre-cancer lesions, and talked about the team of MIT faculty, doctors, and researchers working collectively toward this goal.

“Part of the secret of life and the meaning of life is helping other people enjoy the passage of time,” said Belcher in her closing remarks. “I think that we can all do that by working to solve some of the biggest issues on the planet, including helping to diagnose and treat ovarian cancer early so people have more time to spend with their family.”

Honoring Mildred S. Dresselhaus

Belcher was the fifth speaker to deliver the Dresselhaus Lecture, an annual event organized by MIT.nano to honor the late MIT physics and electrical engineering Institute Professor Mildred Dresselhaus. The lecture features a speaker from anywhere in the world whose leadership and impact echo Dresselhaus’s life, accomplishments, and values.

“Millie was and is a huge hero of mine,” said Belcher. “Giving a lecture in Millie’s name is just the greatest honor.”

Belcher dedicated the talk to Dresselhaus, whom she described with an array of accolades — a trailblazer, a genius, an amazing mentor, teacher, and inventor. “Just knowing her was such a privilege,” she said.

Belcher also dedicated her talk to her own grandmother and mother, both of whom passed away from cancer, as well as late MIT professors Susan Lindquist and Angelika Amon, who both died of ovarian cancer.

“I’ve been so fortunate to work with just the most talented and dedicated graduate students, undergraduate students, postdocs, and researchers,” concluded Belcher. “It has been a pure joy to be in partnership with all of you to solve these very daunting problems.”

MIT researchers have used 3D printing to produce self-heating microfluidic devices, demonstrating a technique which could someday be used to rapidly create cheap, yet accurate, tools to detect a host of diseases.

Microfluidics, miniaturized machines that manipulate fluids and facilitate chemical reactions, can be used to detect disease in tiny samples of blood or fluids. At-home test kits for Covid-19, for example, incorporate a simple type of microfluidic.

But many microfluidic applications require chemical reactions that must be performed at specific temperatures. These more complex microfluidic devices, which are typically manufactured in a clean room, are outfitted with heating elements made from gold or platinum using a complicated and expensive fabrication process that is difficult to scale up.

Instead, the MIT team used multimaterial 3D printing to create self-heating microfluidic devices with built-in heating elements, through a single, inexpensive manufacturing process. They generated devices that can heat fluid to a specific temperature as it flows through microscopic channels inside the tiny machine.

Their technique is customizable, so an engineer could create a microfluidic that heats fluid to a certain temperature or given heating profile within a specific area of the device. The low-cost fabrication process requires about $2 of materials to generate a ready-to-use microfluidic.

The process could be especially useful in creating self-heating microfluidics for remote regions of developing countries where clinicians may not have access to the expensive lab equipment required for many diagnostic procedures.

“Clean rooms in particular, where you would usually make these devices, are incredibly expensive to build and to run. But we can make very capable self-heating microfluidic devices using additive manufacturing, and they can be made a lot faster and cheaper than with these traditional methods. This is really a way to democratize this technology,” says Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories (MTL) and senior author of a paper describing the fabrication technique.

He is joined on the paper by lead author Jorge Cañada Pérez-Sala, an electrical engineering and computer science graduate student. The research will be presented at the PowerMEMS Conference this month.

An insulator becomes conductive

This new fabrication process utilizes a technique called multimaterial extrusion 3D printing, in which several materials can be squirted through the printer’s many nozzles to build a device layer by layer. The process is monolithic, which means the entire device can be produced in one step on the 3D printer, without the need for any post-assembly.

To create self-heating microfluidics, the researchers used two materials — a biodegradable polymer known as polylactic acid (PLA) that is commonly used in 3D printing, and a modified version of PLA.

The modified PLA has mixed copper nanoparticles into the polymer, which converts this insulating material into an electrical conductor, Velásquez-García explains. When electrical current is fed into a resistor composed of this copper-doped PLA, energy is dissipated as heat.

“It is amazing when you think about it because the PLA material is a dielectric, but when you put in these nanoparticle impurities, it completely changes the physical properties. This is something we don’t fully understand yet, but it happens and it is repeatable,” he says.

Using a multimaterial 3D printer, the researchers fabricate a heating resistor from the copper-doped PLA and then print the microfluidic device, with microscopic channels through which fluid can flow, directly on top in one printing step. Because the components are made from the same base material, they have similar printing temperatures and are compatible.

Heat dissipated from the resistor will warm fluid flowing through the channels in the microfluidic.

In addition to the resistor and microfluidic, they use the printer to add a thin, continuous layer of PLA that is sandwiched between them. It is especially challenging to manufacture this layer because it must be thin enough so heat can transfer from the resistor to the microfluidic, but not so thin that fluid could leak into the resistor.

The resulting machine is about the size of a U.S. quarter and can be produced in a matter of minutes. Channels about 500 micrometers wide and 400 micrometers tall are threaded through the microfluidic to carry fluid and facilitate chemical reactions.

Importantly, the PLA material is translucent, so fluid in the device remains visible. Many processes rely on visualization or the use of light to infer what is happening during chemical reactions, Velásquez-García explains.

Customizable chemical reactors

The researchers used this one-step manufacturing process to generate a prototype that could heat fluid by 4 degrees Celsius as it flowed between the input and the output. This customizable technique could enable them to make devices which would heat fluids in certain patterns or along specific gradients.

“You can use these two materials to create chemical reactors that do exactly what you want. We can set up a particular heating profile while still having all the capabilities of the microfluidic,” he says.

However, one limitation comes from the fact that PLA can only be heated to about 50 degrees Celsius before it starts to degrade. Many chemical reactions, such as those used for polymerase chain reaction (PCR) tests, require temperatures of 90 degrees or higher. And to precisely control the temperature of the device, researchers would need to integrate a third material that enables temperature sensing.

In addition to tackling these limitations in future work, Velásquez-García wants to print magnets directly into the microfluidic device. These magnets could enable chemical reactions that require particles to be sorted or aligned.

At the same time, he and his colleagues are exploring the use of other materials that could reach higher temperatures. They are also studying PLA to better understand why it becomes conductive when certain impurities are added to the polymer.

“If we can understand the mechanism that is related to the electrical conductivity of PLA, that would greatly enhance the capability of these devices, but it is going to be a lot harder to solve than some other engineering problems,” he adds.

“In Japanese culture, it’s often said that beauty lies in simplicity. This sentiment is echoed by the work of Cañada and Velasquez-Garcia. Their proposed monolithically 3D-printed microfluidic systems embody simplicity and beauty, offering a wide array of potential derivations and applications that we foresee in the future,” says Norihisa Miki, a professor of mechanical engineering at Keio University in Tokyo, who was not involved with this work.

“Being able to directly print microfluidic chips with fluidic channels and electrical features at the same time opens up very exiting applications when processing biological samples, such as to amplify biomarkers or to actuate and mix liquids. Also, due to the fact that PLA degrades over time, one can even think of implantable applications where the chips dissolve and resorb over time,” adds Niclas Roxhed, an associate professor at Sweden’s KTH Royal Institute of Technology, who was not involved with this study.

This research was funded, in part, by the Empiriko Corporation and a fellowship from La Caixa Foundation.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

“How do we get to making nanomaterials that haven’t been evolved before?” asked Angela Belcher at the 2023 Mildred S. Dresselhaus Lecture at MIT on Nov. 20. “We can use elements that biology has already given us.”

The combined in-person and virtual audience of over 300 was treated to a light-up, 3D model of M13 bacteriophage, a virus that only infects bacteria, complete with a pull-out strand of DNA. Belcher used the feather-boa-like model to show how her research group modifies the M13’s genes to add new DNA and peptide sequences to template inorganic materials.

“I love controlling materials at the nanoscale using biology,” said Belcher, the James Mason Crafts Professor of Biological Engineering, materials science professor, and of the Koch Institute of Integrative Cancer Research at MIT. “We all know if you control materials at the nanoscale and you can start to tune them, then you can have all kinds of different applications.” And the opportunities are indeed vast — from building batteries, fuel cells, and solar cells to carbon sequestration and storage, environmental remediation, catalysis, and medical diagnostics and imaging.

Belcher sprinkled her talk with models and props, lined up on a table at the front of the 10-250 lecture hall, to demonstrate a wide variety of concepts and projects made possible by the intersection of biology and nanotechnology.

Energy storage and environment

“How do you go from a DNA sequence to a functioning battery?” posed Belcher. Grabbing a model of a large carbon nanotube, she explained how her group engineered a phage to pick up carbon nanotubes that would wind all the way around the virus and then fill in with different cathode or anode materials to make nanowires for battery electrodes.

How about using the M13 bacteriophage to improve the environment? Belcher referred to a project by former student Geran Zhang PhD ’19 that proved the virus can be modified for this context, too. He used the phage to template high-surface-area, carbon-based materials that can grab small molecules and break them down, Belcher said, opening a realm of possibilities from cleaning up rivers to developing chemical warfare agents to combating smog.

Belcher’s lab worked with the U.S. Army to produce protective clothing and masks made of these carbon-based virus nanofibers. “We went from five liters in our lab to a thousand liters, then 10,000 liters in the army labs where we’re able to make kilograms of the material,” Belcher said, stressing the importance of being able to test and prototype at scale.

Imaging tools and therapeutics in cancer

In the area of biomedical imaging, Belcher explained, a lot less is known in near-infrared imaging — imaging in wavelengths above 1,000 nanometers — than other imaging techniques, yet with near-infrared scientists can see much deeper inside the body. Belcher’s lab built their own systems to image at these wavelengths. The third generation of this system provides real-time, sub-millimeter optical imaging for guided surgery.

Working with Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Engineering, Belcher used carbon nanotubes to build imaging tools that find tiny tumors during surgery that doctors otherwise would not be able to see. The tool is actually a virus engineered to carry with it a fluorescent, single-walled carbon nanotube as it seeks out the tumors.

Nearing the end of her talk, Belcher presented a goal: to develop an accessible detection and diagnostic technology for ovarian cancer in five to 10 years.

“We think that we can do it,” Belcher said. She described her students’ work developing a way to scan an entire fallopian tube, as opposed to just one small portion, to find pre-cancer lesions, and talked about the team of MIT faculty, doctors, and researchers working collectively toward this goal.

“Part of the secret of life and the meaning of life is helping other people enjoy the passage of time,” said Belcher in her closing remarks. “I think that we can all do that by working to solve some of the biggest issues on the planet, including helping to diagnose and treat ovarian cancer early so people have more time to spend with their family.”

Honoring Mildred S. Dresselhaus

Belcher was the fifth speaker to deliver the Dresselhaus Lecture, an annual event organized by MIT.nano to honor the late MIT physics and electrical engineering Institute Professor Mildred Dresselhaus. The lecture features a speaker from anywhere in the world whose leadership and impact echo Dresselhaus’s life, accomplishments, and values.

“Millie was and is a huge hero of mine,” said Belcher. “Giving a lecture in Millie’s name is just the greatest honor.”

Belcher dedicated the talk to Dresselhaus, whom she described with an array of accolades — a trailblazer, a genius, an amazing mentor, teacher, and inventor. “Just knowing her was such a privilege,” she said.

Belcher also dedicated her talk to her own grandmother and mother, both of whom passed away from cancer, as well as late MIT professors Susan Lindquist and Angelika Amon, who both died of ovarian cancer.

“I’ve been so fortunate to work with just the most talented and dedicated graduate students, undergraduate students, postdocs, and researchers,” concluded Belcher. “It has been a pure joy to be in partnership with all of you to solve these very daunting problems.”

MIT researchers have used 3D printing to produce self-heating microfluidic devices, demonstrating a technique which could someday be used to rapidly create cheap, yet accurate, tools to detect a host of diseases.

Microfluidics, miniaturized machines that manipulate fluids and facilitate chemical reactions, can be used to detect disease in tiny samples of blood or fluids. At-home test kits for Covid-19, for example, incorporate a simple type of microfluidic.

But many microfluidic applications require chemical reactions that must be performed at specific temperatures. These more complex microfluidic devices, which are typically manufactured in a clean room, are outfitted with heating elements made from gold or platinum using a complicated and expensive fabrication process that is difficult to scale up.

Instead, the MIT team used multimaterial 3D printing to create self-heating microfluidic devices with built-in heating elements, through a single, inexpensive manufacturing process. They generated devices that can heat fluid to a specific temperature as it flows through microscopic channels inside the tiny machine.

Their technique is customizable, so an engineer could create a microfluidic that heats fluid to a certain temperature or given heating profile within a specific area of the device. The low-cost fabrication process requires about $2 of materials to generate a ready-to-use microfluidic.

The process could be especially useful in creating self-heating microfluidics for remote regions of developing countries where clinicians may not have access to the expensive lab equipment required for many diagnostic procedures.

“Clean rooms in particular, where you would usually make these devices, are incredibly expensive to build and to run. But we can make very capable self-heating microfluidic devices using additive manufacturing, and they can be made a lot faster and cheaper than with these traditional methods. This is really a way to democratize this technology,” says Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories (MTL) and senior author of a paper describing the fabrication technique.

He is joined on the paper by lead author Jorge Cañada Pérez-Sala, an electrical engineering and computer science graduate student. The research will be presented at the PowerMEMS Conference this month.

An insulator becomes conductive

This new fabrication process utilizes a technique called multimaterial extrusion 3D printing, in which several materials can be squirted through the printer’s many nozzles to build a device layer by layer. The process is monolithic, which means the entire device can be produced in one step on the 3D printer, without the need for any post-assembly.

To create self-heating microfluidics, the researchers used two materials — a biodegradable polymer known as polylactic acid (PLA) that is commonly used in 3D printing, and a modified version of PLA.

The modified PLA has mixed copper nanoparticles into the polymer, which converts this insulating material into an electrical conductor, Velásquez-García explains. When electrical current is fed into a resistor composed of this copper-doped PLA, energy is dissipated as heat.

“It is amazing when you think about it because the PLA material is a dielectric, but when you put in these nanoparticle impurities, it completely changes the physical properties. This is something we don’t fully understand yet, but it happens and it is repeatable,” he says.

Using a multimaterial 3D printer, the researchers fabricate a heating resistor from the copper-doped PLA and then print the microfluidic device, with microscopic channels through which fluid can flow, directly on top in one printing step. Because the components are made from the same base material, they have similar printing temperatures and are compatible.

Heat dissipated from the resistor will warm fluid flowing through the channels in the microfluidic.

In addition to the resistor and microfluidic, they use the printer to add a thin, continuous layer of PLA that is sandwiched between them. It is especially challenging to manufacture this layer because it must be thin enough so heat can transfer from the resistor to the microfluidic, but not so thin that fluid could leak into the resistor.

The resulting machine is about the size of a U.S. quarter and can be produced in a matter of minutes. Channels about 500 micrometers wide and 400 micrometers tall are threaded through the microfluidic to carry fluid and facilitate chemical reactions.

Importantly, the PLA material is translucent, so fluid in the device remains visible. Many processes rely on visualization or the use of light to infer what is happening during chemical reactions, Velásquez-García explains.

Customizable chemical reactors

The researchers used this one-step manufacturing process to generate a prototype that could heat fluid by 4 degrees Celsius as it flowed between the input and the output. This customizable technique could enable them to make devices which would heat fluids in certain patterns or along specific gradients.

“You can use these two materials to create chemical reactors that do exactly what you want. We can set up a particular heating profile while still having all the capabilities of the microfluidic,” he says.

However, one limitation comes from the fact that PLA can only be heated to about 50 degrees Celsius before it starts to degrade. Many chemical reactions, such as those used for polymerase chain reaction (PCR) tests, require temperatures of 90 degrees or higher. And to precisely control the temperature of the device, researchers would need to integrate a third material that enables temperature sensing.

In addition to tackling these limitations in future work, Velásquez-García wants to print magnets directly into the microfluidic device. These magnets could enable chemical reactions that require particles to be sorted or aligned.

At the same time, he and his colleagues are exploring the use of other materials that could reach higher temperatures. They are also studying PLA to better understand why it becomes conductive when certain impurities are added to the polymer.

“If we can understand the mechanism that is related to the electrical conductivity of PLA, that would greatly enhance the capability of these devices, but it is going to be a lot harder to solve than some other engineering problems,” he adds.

“In Japanese culture, it’s often said that beauty lies in simplicity. This sentiment is echoed by the work of Cañada and Velasquez-Garcia. Their proposed monolithically 3D-printed microfluidic systems embody simplicity and beauty, offering a wide array of potential derivations and applications that we foresee in the future,” says Norihisa Miki, a professor of mechanical engineering at Keio University in Tokyo, who was not involved with this work.

“Being able to directly print microfluidic chips with fluidic channels and electrical features at the same time opens up very exiting applications when processing biological samples, such as to amplify biomarkers or to actuate and mix liquids. Also, due to the fact that PLA degrades over time, one can even think of implantable applications where the chips dissolve and resorb over time,” adds Niclas Roxhed, an associate professor at Sweden’s KTH Royal Institute of Technology, who was not involved with this study.

This research was funded, in part, by the Empiriko Corporation and a fellowship from La Caixa Foundation.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

“How do we get to making nanomaterials that haven’t been evolved before?” asked Angela Belcher at the 2023 Mildred S. Dresselhaus Lecture at MIT on Nov. 20. “We can use elements that biology has already given us.”

The combined in-person and virtual audience of over 300 was treated to a light-up, 3D model of M13 bacteriophage, a virus that only infects bacteria, complete with a pull-out strand of DNA. Belcher used the feather-boa-like model to show how her research group modifies the M13’s genes to add new DNA and peptide sequences to template inorganic materials.

“I love controlling materials at the nanoscale using biology,” said Belcher, the James Mason Crafts Professor of Biological Engineering, materials science professor, and of the Koch Institute of Integrative Cancer Research at MIT. “We all know if you control materials at the nanoscale and you can start to tune them, then you can have all kinds of different applications.” And the opportunities are indeed vast — from building batteries, fuel cells, and solar cells to carbon sequestration and storage, environmental remediation, catalysis, and medical diagnostics and imaging.

Belcher sprinkled her talk with models and props, lined up on a table at the front of the 10-250 lecture hall, to demonstrate a wide variety of concepts and projects made possible by the intersection of biology and nanotechnology.

Energy storage and environment

“How do you go from a DNA sequence to a functioning battery?” posed Belcher. Grabbing a model of a large carbon nanotube, she explained how her group engineered a phage to pick up carbon nanotubes that would wind all the way around the virus and then fill in with different cathode or anode materials to make nanowires for battery electrodes.

How about using the M13 bacteriophage to improve the environment? Belcher referred to a project by former student Geran Zhang PhD ’19 that proved the virus can be modified for this context, too. He used the phage to template high-surface-area, carbon-based materials that can grab small molecules and break them down, Belcher said, opening a realm of possibilities from cleaning up rivers to developing chemical warfare agents to combating smog.

Belcher’s lab worked with the U.S. Army to produce protective clothing and masks made of these carbon-based virus nanofibers. “We went from five liters in our lab to a thousand liters, then 10,000 liters in the army labs where we’re able to make kilograms of the material,” Belcher said, stressing the importance of being able to test and prototype at scale.

Imaging tools and therapeutics in cancer

In the area of biomedical imaging, Belcher explained, a lot less is known in near-infrared imaging — imaging in wavelengths above 1,000 nanometers — than other imaging techniques, yet with near-infrared scientists can see much deeper inside the body. Belcher’s lab built their own systems to image at these wavelengths. The third generation of this system provides real-time, sub-millimeter optical imaging for guided surgery.

Working with Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Engineering, Belcher used carbon nanotubes to build imaging tools that find tiny tumors during surgery that doctors otherwise would not be able to see. The tool is actually a virus engineered to carry with it a fluorescent, single-walled carbon nanotube as it seeks out the tumors.

Nearing the end of her talk, Belcher presented a goal: to develop an accessible detection and diagnostic technology for ovarian cancer in five to 10 years.

“We think that we can do it,” Belcher said. She described her students’ work developing a way to scan an entire fallopian tube, as opposed to just one small portion, to find pre-cancer lesions, and talked about the team of MIT faculty, doctors, and researchers working collectively toward this goal.

“Part of the secret of life and the meaning of life is helping other people enjoy the passage of time,” said Belcher in her closing remarks. “I think that we can all do that by working to solve some of the biggest issues on the planet, including helping to diagnose and treat ovarian cancer early so people have more time to spend with their family.”

Honoring Mildred S. Dresselhaus

Belcher was the fifth speaker to deliver the Dresselhaus Lecture, an annual event organized by MIT.nano to honor the late MIT physics and electrical engineering Institute Professor Mildred Dresselhaus. The lecture features a speaker from anywhere in the world whose leadership and impact echo Dresselhaus’s life, accomplishments, and values.

“Millie was and is a huge hero of mine,” said Belcher. “Giving a lecture in Millie’s name is just the greatest honor.”

Belcher dedicated the talk to Dresselhaus, whom she described with an array of accolades — a trailblazer, a genius, an amazing mentor, teacher, and inventor. “Just knowing her was such a privilege,” she said.

Belcher also dedicated her talk to her own grandmother and mother, both of whom passed away from cancer, as well as late MIT professors Susan Lindquist and Angelika Amon, who both died of ovarian cancer.

“I’ve been so fortunate to work with just the most talented and dedicated graduate students, undergraduate students, postdocs, and researchers,” concluded Belcher. “It has been a pure joy to be in partnership with all of you to solve these very daunting problems.”

MIT researchers have used 3D printing to produce self-heating microfluidic devices, demonstrating a technique which could someday be used to rapidly create cheap, yet accurate, tools to detect a host of diseases.

Microfluidics, miniaturized machines that manipulate fluids and facilitate chemical reactions, can be used to detect disease in tiny samples of blood or fluids. At-home test kits for Covid-19, for example, incorporate a simple type of microfluidic.

But many microfluidic applications require chemical reactions that must be performed at specific temperatures. These more complex microfluidic devices, which are typically manufactured in a clean room, are outfitted with heating elements made from gold or platinum using a complicated and expensive fabrication process that is difficult to scale up.

Instead, the MIT team used multimaterial 3D printing to create self-heating microfluidic devices with built-in heating elements, through a single, inexpensive manufacturing process. They generated devices that can heat fluid to a specific temperature as it flows through microscopic channels inside the tiny machine.

Their technique is customizable, so an engineer could create a microfluidic that heats fluid to a certain temperature or given heating profile within a specific area of the device. The low-cost fabrication process requires about $2 of materials to generate a ready-to-use microfluidic.

The process could be especially useful in creating self-heating microfluidics for remote regions of developing countries where clinicians may not have access to the expensive lab equipment required for many diagnostic procedures.

“Clean rooms in particular, where you would usually make these devices, are incredibly expensive to build and to run. But we can make very capable self-heating microfluidic devices using additive manufacturing, and they can be made a lot faster and cheaper than with these traditional methods. This is really a way to democratize this technology,” says Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories (MTL) and senior author of a paper describing the fabrication technique.

He is joined on the paper by lead author Jorge Cañada Pérez-Sala, an electrical engineering and computer science graduate student. The research will be presented at the PowerMEMS Conference this month.

An insulator becomes conductive

This new fabrication process utilizes a technique called multimaterial extrusion 3D printing, in which several materials can be squirted through the printer’s many nozzles to build a device layer by layer. The process is monolithic, which means the entire device can be produced in one step on the 3D printer, without the need for any post-assembly.

To create self-heating microfluidics, the researchers used two materials — a biodegradable polymer known as polylactic acid (PLA) that is commonly used in 3D printing, and a modified version of PLA.

The modified PLA has mixed copper nanoparticles into the polymer, which converts this insulating material into an electrical conductor, Velásquez-García explains. When electrical current is fed into a resistor composed of this copper-doped PLA, energy is dissipated as heat.

“It is amazing when you think about it because the PLA material is a dielectric, but when you put in these nanoparticle impurities, it completely changes the physical properties. This is something we don’t fully understand yet, but it happens and it is repeatable,” he says.

Using a multimaterial 3D printer, the researchers fabricate a heating resistor from the copper-doped PLA and then print the microfluidic device, with microscopic channels through which fluid can flow, directly on top in one printing step. Because the components are made from the same base material, they have similar printing temperatures and are compatible.

Heat dissipated from the resistor will warm fluid flowing through the channels in the microfluidic.

In addition to the resistor and microfluidic, they use the printer to add a thin, continuous layer of PLA that is sandwiched between them. It is especially challenging to manufacture this layer because it must be thin enough so heat can transfer from the resistor to the microfluidic, but not so thin that fluid could leak into the resistor.

The resulting machine is about the size of a U.S. quarter and can be produced in a matter of minutes. Channels about 500 micrometers wide and 400 micrometers tall are threaded through the microfluidic to carry fluid and facilitate chemical reactions.

Importantly, the PLA material is translucent, so fluid in the device remains visible. Many processes rely on visualization or the use of light to infer what is happening during chemical reactions, Velásquez-García explains.

Customizable chemical reactors

The researchers used this one-step manufacturing process to generate a prototype that could heat fluid by 4 degrees Celsius as it flowed between the input and the output. This customizable technique could enable them to make devices which would heat fluids in certain patterns or along specific gradients.

“You can use these two materials to create chemical reactors that do exactly what you want. We can set up a particular heating profile while still having all the capabilities of the microfluidic,” he says.

However, one limitation comes from the fact that PLA can only be heated to about 50 degrees Celsius before it starts to degrade. Many chemical reactions, such as those used for polymerase chain reaction (PCR) tests, require temperatures of 90 degrees or higher. And to precisely control the temperature of the device, researchers would need to integrate a third material that enables temperature sensing.

In addition to tackling these limitations in future work, Velásquez-García wants to print magnets directly into the microfluidic device. These magnets could enable chemical reactions that require particles to be sorted or aligned.

At the same time, he and his colleagues are exploring the use of other materials that could reach higher temperatures. They are also studying PLA to better understand why it becomes conductive when certain impurities are added to the polymer.

“If we can understand the mechanism that is related to the electrical conductivity of PLA, that would greatly enhance the capability of these devices, but it is going to be a lot harder to solve than some other engineering problems,” he adds.

“In Japanese culture, it’s often said that beauty lies in simplicity. This sentiment is echoed by the work of Cañada and Velasquez-Garcia. Their proposed monolithically 3D-printed microfluidic systems embody simplicity and beauty, offering a wide array of potential derivations and applications that we foresee in the future,” says Norihisa Miki, a professor of mechanical engineering at Keio University in Tokyo, who was not involved with this work.

“Being able to directly print microfluidic chips with fluidic channels and electrical features at the same time opens up very exiting applications when processing biological samples, such as to amplify biomarkers or to actuate and mix liquids. Also, due to the fact that PLA degrades over time, one can even think of implantable applications where the chips dissolve and resorb over time,” adds Niclas Roxhed, an associate professor at Sweden’s KTH Royal Institute of Technology, who was not involved with this study.

This research was funded, in part, by the Empiriko Corporation and a fellowship from La Caixa Foundation.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

“How do we get to making nanomaterials that haven’t been evolved before?” asked Angela Belcher at the 2023 Mildred S. Dresselhaus Lecture at MIT on Nov. 20. “We can use elements that biology has already given us.”

The combined in-person and virtual audience of over 300 was treated to a light-up, 3D model of M13 bacteriophage, a virus that only infects bacteria, complete with a pull-out strand of DNA. Belcher used the feather-boa-like model to show how her research group modifies the M13’s genes to add new DNA and peptide sequences to template inorganic materials.

“I love controlling materials at the nanoscale using biology,” said Belcher, the James Mason Crafts Professor of Biological Engineering, materials science professor, and of the Koch Institute of Integrative Cancer Research at MIT. “We all know if you control materials at the nanoscale and you can start to tune them, then you can have all kinds of different applications.” And the opportunities are indeed vast — from building batteries, fuel cells, and solar cells to carbon sequestration and storage, environmental remediation, catalysis, and medical diagnostics and imaging.

Belcher sprinkled her talk with models and props, lined up on a table at the front of the 10-250 lecture hall, to demonstrate a wide variety of concepts and projects made possible by the intersection of biology and nanotechnology.

Energy storage and environment

“How do you go from a DNA sequence to a functioning battery?” posed Belcher. Grabbing a model of a large carbon nanotube, she explained how her group engineered a phage to pick up carbon nanotubes that would wind all the way around the virus and then fill in with different cathode or anode materials to make nanowires for battery electrodes.

How about using the M13 bacteriophage to improve the environment? Belcher referred to a project by former student Geran Zhang PhD ’19 that proved the virus can be modified for this context, too. He used the phage to template high-surface-area, carbon-based materials that can grab small molecules and break them down, Belcher said, opening a realm of possibilities from cleaning up rivers to developing chemical warfare agents to combating smog.

Belcher’s lab worked with the U.S. Army to produce protective clothing and masks made of these carbon-based virus nanofibers. “We went from five liters in our lab to a thousand liters, then 10,000 liters in the army labs where we’re able to make kilograms of the material,” Belcher said, stressing the importance of being able to test and prototype at scale.

Imaging tools and therapeutics in cancer

In the area of biomedical imaging, Belcher explained, a lot less is known in near-infrared imaging — imaging in wavelengths above 1,000 nanometers — than other imaging techniques, yet with near-infrared scientists can see much deeper inside the body. Belcher’s lab built their own systems to image at these wavelengths. The third generation of this system provides real-time, sub-millimeter optical imaging for guided surgery.

Working with Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Engineering, Belcher used carbon nanotubes to build imaging tools that find tiny tumors during surgery that doctors otherwise would not be able to see. The tool is actually a virus engineered to carry with it a fluorescent, single-walled carbon nanotube as it seeks out the tumors.

Nearing the end of her talk, Belcher presented a goal: to develop an accessible detection and diagnostic technology for ovarian cancer in five to 10 years.

“We think that we can do it,” Belcher said. She described her students’ work developing a way to scan an entire fallopian tube, as opposed to just one small portion, to find pre-cancer lesions, and talked about the team of MIT faculty, doctors, and researchers working collectively toward this goal.

“Part of the secret of life and the meaning of life is helping other people enjoy the passage of time,” said Belcher in her closing remarks. “I think that we can all do that by working to solve some of the biggest issues on the planet, including helping to diagnose and treat ovarian cancer early so people have more time to spend with their family.”

Honoring Mildred S. Dresselhaus

Belcher was the fifth speaker to deliver the Dresselhaus Lecture, an annual event organized by MIT.nano to honor the late MIT physics and electrical engineering Institute Professor Mildred Dresselhaus. The lecture features a speaker from anywhere in the world whose leadership and impact echo Dresselhaus’s life, accomplishments, and values.

“Millie was and is a huge hero of mine,” said Belcher. “Giving a lecture in Millie’s name is just the greatest honor.”

Belcher dedicated the talk to Dresselhaus, whom she described with an array of accolades — a trailblazer, a genius, an amazing mentor, teacher, and inventor. “Just knowing her was such a privilege,” she said.

Belcher also dedicated her talk to her own grandmother and mother, both of whom passed away from cancer, as well as late MIT professors Susan Lindquist and Angelika Amon, who both died of ovarian cancer.

“I’ve been so fortunate to work with just the most talented and dedicated graduate students, undergraduate students, postdocs, and researchers,” concluded Belcher. “It has been a pure joy to be in partnership with all of you to solve these very daunting problems.”

MIT researchers have used 3D printing to produce self-heating microfluidic devices, demonstrating a technique which could someday be used to rapidly create cheap, yet accurate, tools to detect a host of diseases.

Microfluidics, miniaturized machines that manipulate fluids and facilitate chemical reactions, can be used to detect disease in tiny samples of blood or fluids. At-home test kits for Covid-19, for example, incorporate a simple type of microfluidic.

But many microfluidic applications require chemical reactions that must be performed at specific temperatures. These more complex microfluidic devices, which are typically manufactured in a clean room, are outfitted with heating elements made from gold or platinum using a complicated and expensive fabrication process that is difficult to scale up.

Instead, the MIT team used multimaterial 3D printing to create self-heating microfluidic devices with built-in heating elements, through a single, inexpensive manufacturing process. They generated devices that can heat fluid to a specific temperature as it flows through microscopic channels inside the tiny machine.

Their technique is customizable, so an engineer could create a microfluidic that heats fluid to a certain temperature or given heating profile within a specific area of the device. The low-cost fabrication process requires about $2 of materials to generate a ready-to-use microfluidic.

The process could be especially useful in creating self-heating microfluidics for remote regions of developing countries where clinicians may not have access to the expensive lab equipment required for many diagnostic procedures.

“Clean rooms in particular, where you would usually make these devices, are incredibly expensive to build and to run. But we can make very capable self-heating microfluidic devices using additive manufacturing, and they can be made a lot faster and cheaper than with these traditional methods. This is really a way to democratize this technology,” says Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories (MTL) and senior author of a paper describing the fabrication technique.

He is joined on the paper by lead author Jorge Cañada Pérez-Sala, an electrical engineering and computer science graduate student. The research will be presented at the PowerMEMS Conference this month.

An insulator becomes conductive

This new fabrication process utilizes a technique called multimaterial extrusion 3D printing, in which several materials can be squirted through the printer’s many nozzles to build a device layer by layer. The process is monolithic, which means the entire device can be produced in one step on the 3D printer, without the need for any post-assembly.

To create self-heating microfluidics, the researchers used two materials — a biodegradable polymer known as polylactic acid (PLA) that is commonly used in 3D printing, and a modified version of PLA.

The modified PLA has mixed copper nanoparticles into the polymer, which converts this insulating material into an electrical conductor, Velásquez-García explains. When electrical current is fed into a resistor composed of this copper-doped PLA, energy is dissipated as heat.

“It is amazing when you think about it because the PLA material is a dielectric, but when you put in these nanoparticle impurities, it completely changes the physical properties. This is something we don’t fully understand yet, but it happens and it is repeatable,” he says.

Using a multimaterial 3D printer, the researchers fabricate a heating resistor from the copper-doped PLA and then print the microfluidic device, with microscopic channels through which fluid can flow, directly on top in one printing step. Because the components are made from the same base material, they have similar printing temperatures and are compatible.

Heat dissipated from the resistor will warm fluid flowing through the channels in the microfluidic.

In addition to the resistor and microfluidic, they use the printer to add a thin, continuous layer of PLA that is sandwiched between them. It is especially challenging to manufacture this layer because it must be thin enough so heat can transfer from the resistor to the microfluidic, but not so thin that fluid could leak into the resistor.

The resulting machine is about the size of a U.S. quarter and can be produced in a matter of minutes. Channels about 500 micrometers wide and 400 micrometers tall are threaded through the microfluidic to carry fluid and facilitate chemical reactions.

Importantly, the PLA material is translucent, so fluid in the device remains visible. Many processes rely on visualization or the use of light to infer what is happening during chemical reactions, Velásquez-García explains.

Customizable chemical reactors

The researchers used this one-step manufacturing process to generate a prototype that could heat fluid by 4 degrees Celsius as it flowed between the input and the output. This customizable technique could enable them to make devices which would heat fluids in certain patterns or along specific gradients.

“You can use these two materials to create chemical reactors that do exactly what you want. We can set up a particular heating profile while still having all the capabilities of the microfluidic,” he says.

However, one limitation comes from the fact that PLA can only be heated to about 50 degrees Celsius before it starts to degrade. Many chemical reactions, such as those used for polymerase chain reaction (PCR) tests, require temperatures of 90 degrees or higher. And to precisely control the temperature of the device, researchers would need to integrate a third material that enables temperature sensing.

In addition to tackling these limitations in future work, Velásquez-García wants to print magnets directly into the microfluidic device. These magnets could enable chemical reactions that require particles to be sorted or aligned.

At the same time, he and his colleagues are exploring the use of other materials that could reach higher temperatures. They are also studying PLA to better understand why it becomes conductive when certain impurities are added to the polymer.

“If we can understand the mechanism that is related to the electrical conductivity of PLA, that would greatly enhance the capability of these devices, but it is going to be a lot harder to solve than some other engineering problems,” he adds.

“In Japanese culture, it’s often said that beauty lies in simplicity. This sentiment is echoed by the work of Cañada and Velasquez-Garcia. Their proposed monolithically 3D-printed microfluidic systems embody simplicity and beauty, offering a wide array of potential derivations and applications that we foresee in the future,” says Norihisa Miki, a professor of mechanical engineering at Keio University in Tokyo, who was not involved with this work.

“Being able to directly print microfluidic chips with fluidic channels and electrical features at the same time opens up very exiting applications when processing biological samples, such as to amplify biomarkers or to actuate and mix liquids. Also, due to the fact that PLA degrades over time, one can even think of implantable applications where the chips dissolve and resorb over time,” adds Niclas Roxhed, an associate professor at Sweden’s KTH Royal Institute of Technology, who was not involved with this study.

This research was funded, in part, by the Empiriko Corporation and a fellowship from La Caixa Foundation.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before it is quickly broken down. Many companies have created blood tests that can pick out this tumor DNA, potentially helping doctors diagnose or monitor cancer or choose a treatment.

The amount of tumor DNA circulating at any given time, however, is extremely small, so it has been challenging to develop tests sensitive enough to pick up that tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now come up with a way to significantly boost that signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

The researchers developed two different types of injectable molecules that they call “priming agents,” which can transiently interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a study of mice, they showed that these agents could boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10 percent to above 75 percent.

This approach could enable not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It could also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood draw, and it makes things visible that previously wouldn’t have been. The implication is that we should be able to give everybody who’s doing liquid biopsies, for any purpose, more molecules to work with,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard and Viktor Adalsteinsson, director of the Gerstner Center for Cancer Diagnostics at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoc Shervin Tabrizi, and Broad Institute scientist Kan Xiong are the lead authors of the paper, which appears today in Science.

Better biopsies

Liquid biopsies, which enable detection of small quantities of DNA in blood samples, are now used in many cancer patients to identify mutations that could help guide treatment. With greater sensitivity, however, these tests could become useful for far more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on developing new sequencing technologies to use after the blood is drawn.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Adalsteinsson, and their trainees came up with the idea of trying to increase the amount of DNA in a patient’s bloodstream before the sample is taken.

“A tumor is always creating new cell-free DNA, and that’s the signal that we’re attempting to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the tube of blood,” Love says. “Where this work intercedes is thinking about how to inject something beforehand that would help boost or enhance the amount of signal that is available to collect in the same small sample.”

The body uses two primary strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down DNA that they encounter, while immune cells known as macrophages take up cell-free DNA as blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are well-established biopharmaceutical modalities, and they’re safe in a number of different disease contexts, including cancer and autoimmune treatments,” Love says. “The idea was, could we use this kind of antibody to help shield the DNA temporarily from degradation by the nucleases that are in circulation? And by doing so, we shift the balance to where the tumor is generating DNA slightly faster than is being degraded, increasing the concentration in a blood draw.”

The other priming agent they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a well-known tendency to eat up synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver were probably taking this up just like they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract those immune cells and leave the circulating DNA alone so that it could be at a higher concentration,” Bhatia says.

Earlier tumor detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after the cells were transplanted, the researchers showed that these priming agents could boost the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

Once the blood sample is taken, it can be run through the same kinds of sequencing tests now used on liquid biopsy samples. These tests can pick out tumor DNA, including specific sequences used to determine the type of tumor and potentially what kinds of treatments would work best.

Early detection of cancer is another promising application for these priming agents. The researchers found that when mice were given the nanoparticle priming agent before blood was drawn, it allowed them to detect circulating tumor DNA in blood of 75 percent of the mice with low cancer burden, while none were detectable without this boost.

“One of the greatest hurdles for cancer liquid biopsy testing has been the scarcity of circulating tumor DNA in a blood sample,” Adalsteinsson says. “It’s thus been encouraging to see the magnitude of the effect we’ve been able to achieve so far and to envision what impact this could have for patients.”

After either of the priming agents are injected, it takes an hour or two for the DNA levels to increase in the bloodstream, and then they return to normal within about 24 hours.

“The ability to get peak activity of these agents within a couple of hours, followed by their rapid clearance, means that someone could go into a doctor’s office, receive an agent like this, and then give their blood for the test itself, all within one visit,” Love says. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers have launched a company called Amplifyer Bio that plans to further develop the technology, in hopes of advancing to clinical trials.

“A tube of blood is a much more accessible diagnostic than colonoscopy screening or even mammography,” Bhatia says. “Ultimately, if these tools really are predictive, then we should be able to get many more patients into the system who could benefit from cancer interception or better therapy.”

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation, and the Bridge Project, a partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center.

“How do we get to making nanomaterials that haven’t been evolved before?” asked Angela Belcher at the 2023 Mildred S. Dresselhaus Lecture at MIT on Nov. 20. “We can use elements that biology has already given us.”

The combined in-person and virtual audience of over 300 was treated to a light-up, 3D model of M13 bacteriophage, a virus that only infects bacteria, complete with a pull-out strand of DNA. Belcher used the feather-boa-like model to show how her research group modifies the M13’s genes to add new DNA and peptide sequences to template inorganic materials.

“I love controlling materials at the nanoscale using biology,” said Belcher, the James Mason Crafts Professor of Biological Engineering, materials science professor, and of the Koch Institute of Integrative Cancer Research at MIT. “We all know if you control materials at the nanoscale and you can start to tune them, then you can have all kinds of different applications.” And the opportunities are indeed vast — from building batteries, fuel cells, and solar cells to carbon sequestration and storage, environmental remediation, catalysis, and medical diagnostics and imaging.

Belcher sprinkled her talk with models and props, lined up on a table at the front of the 10-250 lecture hall, to demonstrate a wide variety of concepts and projects made possible by the intersection of biology and nanotechnology.

Energy storage and environment

“How do you go from a DNA sequence to a functioning battery?” posed Belcher. Grabbing a model of a large carbon nanotube, she explained how her group engineered a phage to pick up carbon nanotubes that would wind all the way around the virus and then fill in with different cathode or anode materials to make nanowires for battery electrodes.

How about using the M13 bacteriophage to improve the environment? Belcher referred to a project by former student Geran Zhang PhD ’19 that proved the virus can be modified for this context, too. He used the phage to template high-surface-area, carbon-based materials that can grab small molecules and break them down, Belcher said, opening a realm of possibilities from cleaning up rivers to developing chemical warfare agents to combating smog.

Belcher’s lab worked with the U.S. Army to produce protective clothing and masks made of these carbon-based virus nanofibers. “We went from five liters in our lab to a thousand liters, then 10,000 liters in the army labs where we’re able to make kilograms of the material,” Belcher said, stressing the importance of being able to test and prototype at scale.

Imaging tools and therapeutics in cancer

In the area of biomedical imaging, Belcher explained, a lot less is known in near-infrared imaging — imaging in wavelengths above 1,000 nanometers — than other imaging techniques, yet with near-infrared scientists can see much deeper inside the body. Belcher’s lab built their own systems to image at these wavelengths. The third generation of this system provides real-time, sub-millimeter optical imaging for guided surgery.

Working with Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Engineering, Belcher used carbon nanotubes to build imaging tools that find tiny tumors during surgery that doctors otherwise would not be able to see. The tool is actually a virus engineered to carry with it a fluorescent, single-walled carbon nanotube as it seeks out the tumors.

Nearing the end of her talk, Belcher presented a goal: to develop an accessible detection and diagnostic technology for ovarian cancer in five to 10 years.

“We think that we can do it,” Belcher said. She described her students’ work developing a way to scan an entire fallopian tube, as opposed to just one small portion, to find pre-cancer lesions, and talked about the team of MIT faculty, doctors, and researchers working collectively toward this goal.

“Part of the secret of life and the meaning of life is helping other people enjoy the passage of time,” said Belcher in her closing remarks. “I think that we can all do that by working to solve some of the biggest issues on the planet, including helping to diagnose and treat ovarian cancer early so people have more time to spend with their family.”

Honoring Mildred S. Dresselhaus

Belcher was the fifth speaker to deliver the Dresselhaus Lecture, an annual event organized by MIT.nano to honor the late MIT physics and electrical engineering Institute Professor Mildred Dresselhaus. The lecture features a speaker from anywhere in the world whose leadership and impact echo Dresselhaus’s life, accomplishments, and values.

“Millie was and is a huge hero of mine,” said Belcher. “Giving a lecture in Millie’s name is just the greatest honor.”

Belcher dedicated the talk to Dresselhaus, whom she described with an array of accolades — a trailblazer, a genius, an amazing mentor, teacher, and inventor. “Just knowing her was such a privilege,” she said.

Belcher also dedicated her talk to her own grandmother and mother, both of whom passed away from cancer, as well as late MIT professors Susan Lindquist and Angelika Amon, who both died of ovarian cancer.

“I’ve been so fortunate to work with just the most talented and dedicated graduate students, undergraduate students, postdocs, and researchers,” concluded Belcher. “It has been a pure joy to be in partnership with all of you to solve these very daunting problems.”

MIT researchers have used 3D printing to produce self-heating microfluidic devices, demonstrating a technique which could someday be used to rapidly create cheap, yet accurate, tools to detect a host of diseases.

Microfluidics, miniaturized machines that manipulate fluids and facilitate chemical reactions, can be used to detect disease in tiny samples of blood or fluids. At-home test kits for Covid-19, for example, incorporate a simple type of microfluidic.

But many microfluidic applications require chemical reactions that must be performed at specific temperatures. These more complex microfluidic devices, which are typically manufactured in a clean room, are outfitted with heating elements made from gold or platinum using a complicated and expensive fabrication process that is difficult to scale up.

Instead, the MIT team used multimaterial 3D printing to create self-heating microfluidic devices with built-in heating elements, through a single, inexpensive manufacturing process. They generated devices that can heat fluid to a specific temperature as it flows through microscopic channels inside the tiny machine.

Their technique is customizable, so an engineer could create a microfluidic that heats fluid to a certain temperature or given heating profile within a specific area of the device. The low-cost fabrication process requires about $2 of materials to generate a ready-to-use microfluidic.

The process could be especially useful in creating self-heating microfluidics for remote regions of developing countries where clinicians may not have access to the expensive lab equipment required for many diagnostic procedures.

“Clean rooms in particular, where you would usually make these devices, are incredibly expensive to build and to run. But we can make very capable self-heating microfluidic devices using additive manufacturing, and they can be made a lot faster and cheaper than with these traditional methods. This is really a way to democratize this technology,” says Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories (MTL) and senior author of a paper describing the fabrication technique.

He is joined on the paper by lead author Jorge Cañada Pérez-Sala, an electrical engineering and computer science graduate student. The research will be presented at the PowerMEMS Conference this month.

An insulator becomes conductive

This new fabrication process utilizes a technique called multimaterial extrusion 3D printing, in which several materials can be squirted through the printer’s many nozzles to build a device layer by layer. The process is monolithic, which means the entire device can be produced in one step on the 3D printer, without the need for any post-assembly.

To create self-heating microfluidics, the researchers used two materials — a biodegradable polymer known as polylactic acid (PLA) that is commonly used in 3D printing, and a modified version of PLA.

The modified PLA has mixed copper nanoparticles into the polymer, which converts this insulating material into an electrical conductor, Velásquez-García explains. When electrical current is fed into a resistor composed of this copper-doped PLA, energy is dissipated as heat.

“It is amazing when you think about it because the PLA material is a dielectric, but when you put in these nanoparticle impurities, it completely changes the physical properties. This is something we don’t fully understand yet, but it happens and it is repeatable,” he says.

Using a multimaterial 3D printer, the researchers fabricate a heating resistor from the copper-doped PLA and then print the microfluidic device, with microscopic channels through which fluid can flow, directly on top in one printing step. Because the components are made from the same base material, they have similar printing temperatures and are compatible.

Heat dissipated from the resistor will warm fluid flowing through the channels in the microfluidic.

In addition to the resistor and microfluidic, they use the printer to add a thin, continuous layer of PLA that is sandwiched between them. It is especially challenging to manufacture this layer because it must be thin enough so heat can transfer from the resistor to the microfluidic, but not so thin that fluid could leak into the resistor.

The resulting machine is about the size of a U.S. quarter and can be produced in a matter of minutes. Channels about 500 micrometers wide and 400 micrometers tall are threaded through the microfluidic to carry fluid and facilitate chemical reactions.

Importantly, the PLA material is translucent, so fluid in the device remains visible. Many processes rely on visualization or the use of light to infer what is happening during chemical reactions, Velásquez-García explains.

Customizable chemical reactors

The researchers used this one-step manufacturing process to generate a prototype that could heat fluid by 4 degrees Celsius as it flowed between the input and the output. This customizable technique could enable them to make devices which would heat fluids in certain patterns or along specific gradients.

“You can use these two materials to create chemical reactors that do exactly what you want. We can set up a particular heating profile while still having all the capabilities of the microfluidic,” he says.

However, one limitation comes from the fact that PLA can only be heated to about 50 degrees Celsius before it starts to degrade. Many chemical reactions, such as those used for polymerase chain reaction (PCR) tests, require temperatures of 90 degrees or higher. And to precisely control the temperature of the device, researchers would need to integrate a third material that enables temperature sensing.

In addition to tackling these limitations in future work, Velásquez-García wants to print magnets directly into the microfluidic device. These magnets could enable chemical reactions that require particles to be sorted or aligned.

At the same time, he and his colleagues are exploring the use of other materials that could reach higher temperatures. They are also studying PLA to better understand why it becomes conductive when certain impurities are added to the polymer.

“If we can understand the mechanism that is related to the electrical conductivity of PLA, that would greatly enhance the capability of these devices, but it is going to be a lot harder to solve than some other engineering problems,” he adds.

“In Japanese culture, it’s often said that beauty lies in simplicity. This sentiment is echoed by the work of Cañada and Velasquez-Garcia. Their proposed monolithically 3D-printed microfluidic systems embody simplicity and beauty, offering a wide array of potential derivations and applications that we foresee in the future,” says Norihisa Miki, a professor of mechanical engineering at Keio University in Tokyo, who was not involved with this work.

“Being able to directly print microfluidic chips with fluidic channels and electrical features at the same time opens up very exiting applications when processing biological samples, such as to amplify biomarkers or to actuate and mix liquids. Also, due to the fact that PLA degrades over time, one can even think of implantable applications where the chips dissolve and resorb over time,” adds Niclas Roxhed, an associate professor at Sweden’s KTH Royal Institute of Technology, who was not involved with this study.

This research was funded, in part, by the Empiriko Corporation and a fellowship from La Caixa Foundation.