Researchers from the Massachusetts Institute of Technology (MIT) have 3D printed a novel microfluidic device that can help stimulate cancer treatments on biopsied tumour tissue. The novel microfluidic device, which is 3D printed can help clinicians to quickly test drugs on tumour tissues and aid clinicians to better examine how individual patients may respond to different therapeutics before administering a single dose.
For years, cancer treatments have relied on trial and error where patients have to undergo multiple, time-consuming and hard-to-tolerate therapies in their way to find the therapy that may work. Even though recent innovations in pharmaceutical development aid in growing artificial tumours to test drugs on specific cancer types, these models are time-consuming and take weeks to grow and fail to take into account an individual patient’s biological makeup, which greatly hampers the efficacy of the cancer treatment.
The 3D Printed Microfluidic Device
The 3D printed microfluidic device is a chip slightly larger than a quarter consisting of three cylindrical “chimneys” rising from the surface. The chambers are ports that can be used to input and drain fluids such as immunotherapy agents or immune cells, as well as remove unwanted air bubbles.
Two other key innovations on the device are the “bubble trap” and a “tumour trap.” Flowing fluids into such a device creates bubbles that can disrupt the experiment or burst, releasing air that destroys tumour tissue. As a result, to fix this, the researchers created a bubble trap – a stout “chimney” which rises from the fluid channel into a threaded port through which air escapes.
Fluid — including various media, fluorescent markers, or lymphocytes — gets injected into an inlet port adjacent to the trap. The fluid enters through the inlet port and flows past the trap, where any bubbles in the fluid rise up through the threaded port and out of the device. Fluid is then routed around a small U-turn into the tumour’s chamber, where it flows through and around the tumour fragment.
This tumour-trapping chamber sits at the intersection of the larger inlet channel and four smaller outlet channels. Tumour fragments, less than 1 millimeter across, are injected into the inlet channel via the bubble trap, which helps remove bubbles introduced when loading. As fluid flows through the device from the inlet port, the tumour is guided downstream to the tumour trap, where the fragment gets caught. The fluid continues traveling along the outlet channels, which are too small for the tumour to fit inside, and drains out of the device. A continuous flow of fluids keeps the tumour fragment in place and constantly replenishes nutrients for the cells.
Working of the 3D Printed Microfluidic Device
Biopsied tumour fragments are placed in the chamber connected to a network of channels that deliver fluids such as immunotherapy agents or immune cells to the tissue. Clinicians can then use various imaging techniques to see how the tissue responds to the drugs.
A key feature of the 3D printed microfluidic device is the new biocompatible resin — traditionally used for dental applications — that can support long-term survival of biopsied tissue when compared with. Although previous 3D printed microfluidics have held promise for drug testing, chemicals in their resin usually kill cells quickly.
The resin is in fact the heart of the device. For instance, after experimenting with numerous resins over several months, the researchers landed finally on Pro3dure GR-10, which is primarily used to make mouthguards that protect against teeth grinding.
The material is nearly as transparent as glass, has barely any surface defects, and can be printed in very high resolution. And, importantly, as the researchers determined, it does not negatively impact cell survival. For example, the researchers captured fluorescence microscopy images, which showed that their device, called a tumour analysis platform (TAP), kept more than 90 percent of the tumour tissue alive for at least 72 hours, and potentially much longer.
Potential applications of the 3D Printed Microfluidic Device
“If someone has cancer, you can take a bit of tissue in our device, and keep the tumour alive, to run multiple tests in parallel and figure out what would work best with the patient’s biological makeup. And then implement that treatment in the patient”
Speaking about the application of the device, Luis Fernando Velásquez-García, a researcher in the Microsystems Technology Laboratories and co-author of a paper describing the device, which will be published in the December issue of the Journal of Microelectromechanical Systems, said “People anywhere in the world could print our design. You can envision a future where your doctor will have a 3D printer and can print out the devices as needed.”
“If someone has cancer, you can take a bit of tissue in our device, and keep the tumour alive, to run multiple tests in parallel and figure out what would work best with the patient’s biological makeup. And then implement that treatment in the patient,” adds Velásquez-García when explaining the uses of the device.
The researchers state that as the 3D printed device is easy and cheap to fabricate, it could be rapidly implemented into clinical settings. Doctors could, for instance, print out a multiplexed device that could support multiple tumour samples in parallel, to enable modeling of the interactions between tumour fragments and many different drugs, simultaneously, for a single patient.
However, a promising application of the device lies in testing immunotherapy, a new treatment method using certain drugs to rev up a patient’s immune system to help it fight cancer. The device could help doctors better identify treatments to which an individual is likely to respond.
Explaining the use of the device in immunotherapy treatment, first author Ashley Beckwith SM ’18, a graduate researcher in Velásquez-García’s research group said, “Immunotherapy treatments have been specifically developed to target molecular markers found on the surface of cancer cells. This helps to ensure that the treatment elicits an attack on the cancer directly while limiting negative impacts on healthy tissue. However, every individual’s cancer expresses a unique array of surface molecules — as such, it can be difficult to predict who will respond to which treatment. Our device uses the actual tissue of the person, so is a perfect fit for immunotherapy.”
How the Novel 3D printed Device Differs from Traditionally Manufactured Microfluidic Devices
Microfluidics devices are traditionally manufactured via micromolding, using a rubberlike material called polydimethylsiloxane (PDMS). This technique, however, is not suitable for creating the three-dimensional network of features — such as carefully sized fluid channels — that mimic cancer treatments on living cells. As a result, the researchers turned to 3D printing to craft a fine-featured device “monolithically” — meaning printing an object all in one go, without the need to assemble separate parts.
“The traditional PDMS can’t make the structures you need for this in vitro environment that can keep tumour fragments alive for a considerable period of time,” added Roger Howe, a professor of Electrical Engineering at Stanford University, who was not involved in the research.
“That you can now make very complex fluidic chambers that will allow more realistic environments for testing out various drugs on tumours quickly, and potentially in clinical settings, is a major contribution,” added Howe.
Because of 3D printing technology, the researchers were able to make the geometries they wanted without compromising the working of the device. Explaining about how the 3D printing technology helped in creating the geometries of their choice, Velásquez-García states, “Because our device is 3-D printed, we were able to make the geometries we wanted, in the materials we wanted, to achieve the performance we wanted, instead of compromising between what was designed and what could be implemented — which typically happens when using standard microfabrication”.
“3D printing may soon become the mainstream manufacturing technique for microfluidics and other microsystems that require complex designs”, adds Velásquez-García.
In this experiment, the researchers showed they could keep a tumour fragment alive and monitor the tissue viability in real-time with fluorescent markers that make the tissue glow. As a part of their future research, researchers aim to test how the tumour fragments respond to real therapeutics.