Device could ‘hear’ disease through structures housing cells

WEST LAFAYETTE, Ind. — Similarly to how a picked lock gives away that someone has broken into a building, the stiffening of a structure surrounding cells in the human body can indicate that cancer is invading other tissue.

Monitoring changes to this structure, called the extracellular matrix, would give researchers another way to study the progression of disease. But detecting changes to the extracellular matrix is hard to do without damaging it.

Purdue University engineers have built a device that would allow disease specialists to load an extracellular matrix sample onto a platform and detect its stiffness through sound waves. The device is described in a study published in the journal Lab on a Chip and demonstrated in a YouTube video at https://youtu.be/hPvY0Sj0vxY.

A device uses sound waves to detect the stiffness of an extracellular matrix, a structural network that contains cells. Changes in the stiffness of this structure can indicate the spread of disease. (Purdue University photo/Kayla Wiles) Download image

“It’s the same concept as checking for damage in an airplane wing. There’s a sound wave propagating through the material and a receiver on the other side. The way that the wave propagates can indicate if there’s any damage or defect without affecting the material itself,” said Rahim Rahimi, a Purdue assistant professor of materials engineering, whose lab develops innovative materials and biomedical devices to address health care challenges.

Each tissue and organ has its own unique extracellular matrix, sort of like how buildings on a street vary in structure depending on their purpose. The extracellular matrix also comes with “landlines,” or structural and chemical cues, that support communication between individual cells housed in the matrix.

Researchers have tried stretching, compressing or applying chemicals to samples of the extracellular matrix to measure this environment. But these methods also are prone to damaging the extracellular matrix.

Rahimi’s team developed a nondestructive way to study how the extracellular matrix responds to disease, toxic substances or therapeutic drugs. The initial work for this study was performed in collaboration with the lab of Sophie Lelièvre, a professor of cancer pharmacology at Purdue, to identify how risk factors affect the extracellular matrix and increase the risk of developing breast cancer.

The device is a “lab-on-a-chip” connected to a transmitter and receiver. After pouring the extracellular matrix and the cells it contains onto the platform, the transmitter generates an ultrasonic wave that propagates through the material and then triggers the receiver. The output is an electrical signal indicating the stiffness of the extracellular matrix.

The researchers first demonstrated the device as a proof-of-concept with cancer cells contained in hydrogel, which is a material with a consistency similar to an extracellular matrix. The team now is studying the device’s effectiveness on collagen extracellular matrices.

The device could easily be scaled up to run many samples at once, Rahimi said, such as in an array. This would allow researchers to look at several different aspects of a disease simultaneously.

This research was conducted in Birck Nanotechnology Center in Purdue's Discovery Park and financially supported by the Breast Cancer Research Program, a Congressionally Directed Medical Research Program (grant W81XWH-17-1-0250).

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Writer: Kayla Wiles, 765-494-2432, wiles5@purdue.edu

Source: Rahim Rahimi, 765-494-7716, rrahimi@purdue.edu

Note to Journalists: For a copy of the paper, please contact Kayla Wiles, Purdue News Service, at wiles5@purdue.edu or 765-494-2432. B-roll and photos of the device for detecting extracellular matrix stiffness are available in a Google Drive folder at https://purdue.university/38zL5nu. A YouTube video is available at https://youtu.be/hPvY0Sj0vxY.

ABSTRACT

A lab-on-chip ultrasonic platform for real-time and nondestructive assessment of extracellular matrix stiffness

Amin Zareei, Hongjie Jiang, Shirisha Chittiboyina, Jiawei Zhou,

Beatriz Plaza Marin, Sophie A. Lelièvre, Rahim Rahimi

Purdue University, West Lafayette, IN, USA

DOI: 10.1039/C9LC00926D

Extracellular matrix (ECM) mechanical stiffness and its dynamic change is one of the main cues that directly affects the differentiation and proliferation of normal cells as well as the progression of disease processes such as fibrosis and cancer. Recent advancements in biomaterials have enabled a wide range of polymer matrices that could mimic the ECM of different tissues for a wide range of in vitro basic research and drug discovery. However, most of the technologies utilized to quantify the stiffness of such ECM are either destructive or expensive, and therefore are unsuitable for the in situ, long-term monitoring of variations in ECM stiffness for on-chip cell culture applications. This work demonstrates a novel noninvasive on-chip platform for characterization of ECM stiffness in vitro, by monitoring ultrasonic wave attenuation through the targeted material. The device is composed of a pair of millimeter scale ultrasonic transmitter and receiver transducers with the test medium placed in between them. The transmitter generates an ultrasonic wave that propagates through the material, triggers the piezoelectric receiver and generates a corresponding electrical signal. The characterization reveals a linear (r² = 0.86) decrease in the output voltage of the piezoelectric receiver with an average sensitivity of −15.86 μV kPa⁻¹ by increasing the stiffnesses of hydrogels (from 4.3 kPa to 308 kPa made with various dry-weight concentrations of agarose and gelatin). The ultrasonic stiffness sensing is also demonstrated to successfully monitor dynamic changes in a simulated in vitro tissue by gradually changing the polymerization density of an agarose gel, as a proof-of-concept towards future use for 3D cell culture and drug screening. In situ long-term ultrasonic signal stability and thermal assessment of the device demonstrates its high robust performance even after two days of continuous operation, with negligible (<0.5 °C) heating of the hydrogel in contact with the piezoelectric transducers. In vitro biocompatibility assessment of the device with mammary fibroblasts further assures that the materials used in the platform did not produce a toxic response and cells remained viable under the applied ultrasound signals in the device.