Engineers at Stanford University and at Georgia Institute of Technology have created a small, autonomous device with a stretchable/flexible sensor that can be adhered to the skin of cancer-bearing mice to measure the changing size of tumors. The team claims that the noninvasive, battery-operated FAST (Flexible Autonomous Sensor measuring Tumors) device is sensitive to 10 micrometers and can send results to a smartphone app wirelessly, in real time.
In their published paper in Science Advances, the team described tests in in vivo mouse cancer models, which demonstrated that the sensor could discern differences in tumor volume dynamics between animals treated using an active drug, and vehicle-treated animals, within just hours of the start of therapy.
The researchers maintain that the FAST device represents a completely new, rapid, inexpensive, hands-free, and accurate way to test the efficacy of cancer drugs in preclinical models. They also said that the sensor has a number of advantages when compared with other common tumor measurement tools such as calipers, implantable pressure sensors, and imaging. And on a broader scale, they suggest, the sensor could potentially point to new directions in cancer treatment.
Alex Abramson, PhD, is first author of the researchers’ report, and carried out the work while a postdoc in the lab of corresponding author Zhenan Bao, PhD, at Stanford School of Engineering. Abramson is now assistant professor of chemical and biomolecular engineering at Georgia Institute of Technology.
Abramson explained to GEN, “We are excited about the prospects of fully automating the drug screening process in vivo. This will hopefully allow for many more drugs to be tested in this manner than previously possible before, and it will enable the collection of vast in vivo datasets for cancer drug candidates. Furthermore, we hope that our sensor will elucidate new patterns in drug pharmacodynamics in vivo that happen at a time scale that could not be measured previously. This sensor will provide rapid feedback on short-term tumor regression, and this data can be correlated to drug effects on long-term tumor regression.”
Abramson, Bao, and colleagues described their developments in a paper titled, “A flexible electronic strain sensor for the real-time monitoring of tumor regression.”
Each year researchers test thousands of potential cancer drugs on mice with subcutaneous tumors. Few drugs make it to human patients, and the process for finding new therapies is slow, partly because some technologies for measuring tumor regression resulting from drug treatment can require weeks to read out a response. “Researchers typically read out in vivo models by comparing tumor volume regression between multiple replicates of treated and untreated controls,” the authors explained.
“In some cases, the tumors under observation must be measured by hand with calipers,” noted Abramson. However, the use of metal pincer-like calipers to measure soft tissues is not ideal, and radiological approaches cannot deliver the sort of continuous data needed for real-time assessment. The scientists further commented in their paper, “… inherent biological variations combined with low-resolution measurement tools and small sample sizes make determining drug efficacy in vivo a difficult, labor-intensive task. Accurately determining treatment response is critical to clinical translation, and tools automating in vivo tumor regression measurements could facilitate this process by gathering high-resolution continuous datasets in larger animal cohorts.”
Advances in data quality and reduced manual tasks could thus lead to more accurate experimental results, they noted, and enable the development of methods for automated, high-throughput in vivo drug testing. “We noticed that the current methods for tracking tumor regression were costly, burdensome, and only took snapshots rather than continuous measurements of tumor volume changes. With this sensor, we wanted to fully automate the process of tumor regression measurements,” Abramson commented to GEN.
The FAST sensor has been developed as a commercially scalable, wearable electronic strain sensor that the developers showed could continuously monitor micrometer-scale changes in volume of subcutaneously implanted tumors at the minute time scale. This is in contrast with caliper and bioluminescence measurements, which can require weeks-long observation periods for read-out changes in tumor size. Composed of a flexible and stretchable skin-like polymer that includes an embedded layer of gold circuitry, the sensor is connected to a small electronic backpack designed by former postdocs and co-authors Yasser Khan, PhD, and Naoji Matsuhisa, PhD. The device measures the strain on the membrane—how much it stretches or shrinks—and transmits that data to a smartphone.
For the sensor itself, we developed a strain sensor that didn’t put any additional stress on the tumor environment and was also sensitive down to cell-level resolution,” Abramson explained further to GEN. “A soft SEBS (styrene-ethylene-butylene-styrene) substrate combined with an ultra-thin layer of conductive gold allowed us to achieve those characteristics.”
Using the FAST backpack, potential therapies that are linked to tumor size regression can quickly and confidently be fast-tracked for further study, or excluded as ineffective. In their reported tests in two live mice subcutaneous tumor models, the researchers demonstrated that the sensor’s high resolution in both time and space allowed it to discern initial treatment efficacy within just five hours after therapy was initiated. The sensor could also read out continuously for >24 hours on a single battery charge.
The team said that the new device demonstrates at least three significant advances. First, it provides continuous monitoring, as the sensor is physically connected to the mouse and remains in place over the entire experimental period. Second, the flexible sensor enshrouds the tumor and is, therefore, able to measure shape changes that are difficult to discern using other methods. And a third benefit is that FAST is both autonomous and noninvasive. It is connected to the skin—not unlike a band-aid—battery-operated, and connected wirelessly. The mouse is free to move unencumbered by the device or wires, and scientists do not need to actively handle the mice following sensor placement. FAST packs are also reusable, cost just $60 or so to assemble, and can be attached to the mouse in minutes.
The breakthrough is in FAST’s flexible electronic material. Coated on top of the skin-like polymer is a layer of gold, which, when stretched, develops small cracks that change the electrical conductivity of the material. Stretch the material and the number of cracks increases, causing the electronic resistance in the sensor to increase as well. When the material contracts, the cracks come back into contact and conductivity improves.
Both Abramson and co-author Naoji Matsuhisa, PhD, an associate professor at the University of Tokyo, characterized how these crack propagation and exponential changes in conductivity can be mathematically equated with changes in dimension and volume.
The researchers also had to consider whether the sensor itself might compromise measurements by applying undue pressure to the tumor, effectively squeezing it. To circumvent that risk they carefully matched the mechanical properties of the flexible material to the skin, to make the sensor as pliant and as supple as real skin.
“It is a deceptively simple design,” Abramson said, “but these inherent advantages should be very interesting to the pharmaceutical and oncological communities. FAST could significantly expedite, automate, and lower the cost of the process of screening cancer therapies.”
He added: “This sensor can currently be produced in any lab around the world for ~$60 based on the procedures we outline in our paper. We hope that scientists will begin using our sensors immediately in experiments that utilize subcutaneously implanted tumors … We are still working to create an implantable version of our sensor that would be required to measure many of the tumors found in the body that are not on or near the skin … One of the big challenges that we are working on for the implantable sensor is developing a standardized surgical procedure to perform the implantation. Additionally, we are working to miniaturize the electronic components to make the implantable version of the sensor less invasive.”
The team stressed that the sensor is “designed specifically for preclinical drug screening trials, and any efforts to translate the sensor to humans should consider the surgical impact associated with placing the sensor at a given tumor location.” Noting other potential limitations of the technology, the authors nevertheless concluded, “Regardless of these limitations, this sensor’s ability to continuously, autonomously, and accurately record tumor volume regression suggests that this method could supplant current tumor regression measurement techniques used during in vivo preclinical trials, unlocking new avenues for high-throughput in vivo drug discovery screenings and basic cancer research that takes advantage of the sensor’s time-dependent datasets.”
The technology could also feasibly provide new insights that could improve existing drug treatment regimens, Abramson suggested. “By exploring short-term drug pharmacodynamics in vivo, we hope to provide insight into dosing schedules that lead to more rapid tumor regression.”