“Kidney on a chip” could lead to safer drug dosing

From: Gabe Cherry
Michigan Engineering

University of Michigan researchers have used a “kidney on a chip” device to mimic the flow of medication through human kidneys and measure its effect on kidney cells. The new technique could lead to more precise dosing of drugs, including some potentially toxic medicines often delivered in intensive care units.

Precise dosing in intensive care units is critical, as up to two-thirds of patients in the ICU experience serious kidney injury. Medications contribute to this injury in more than 20 percent of cases, largely because many intensive care drugs are potentially dangerous to the kidneys.

Determining a safe dosage, however, can be surprisingly difficult. Today, doctors and drug developers rely mainly on animal testing to measure the toxicity of drugs and determine safe doses. But animals process medications more quickly than humans, making it difficult to interpret test results and sometimes leading researchers to underestimate toxicity.

Ryan Oliver, Post-Doctorate Researcher, demonstrates use of a special microchip that can simulate different organs and parts of the body. Photo by: Joseph XuThe new technique offers a more accurate way to test medications, closely replicating the environment inside a human kidney. It uses a microfluidic chip device to deliver a precise flow of medication across cultured kidney cells. This is believed to be the first time such a device has been used to study how a medication behaves in the body over time, called its “pharmacokinetic profile.”

“When you administer a drug, its concentration goes up quickly and it’s gradually filtered out as it flows through the kidneys,” said University of Michigan Biomedical Engineering professor Shuichi Takayama, an author on the paper. “A kidney on a chip enables us to simulate that filtering process, providing a much more accurate way to study how medications behave in the body.”

Takayama said the use of an artificial device provides the opportunity to run test after test in a controlled environment. It also enables researchers to alter the flow through the device to simulate varying levels of kidney function.

“Even the same dose of the same drug can have very different effects on the kidneys and other organs, depending on how it’s administered,” said Sejoong Kim, an associate professor at Korea’s Seoul national University Budang Hospital, former U-M researcher and author on the paper. “This device provides a uniform, inexpensive way to capture data that more accurately reflects actual human patients.”

In the study, the team tested their approach by comparing two different dosing regimens for gentamicin, an antibiotic that’s commonly used in intensive care units. They used a microfluidic device that sandwiches a thin, permeable polyester membrane and a layer of cultured kidney cells between top and bottom compartments.

Ryan Oliver, Post-Doctorate Researcher, demonstrates use of a special microchip that can simulate different organs and parts of the body. Photo by: Joseph Xu

They then pumped a gentamicin solution into the top compartment, where it gradually filtered through the cells and the membrane, simulating the flow of medication through a human kidney. One test started with a high concentration that quickly tapered off, mimicking a once-daily drug dose. The other test simulated a slow infusion of the drug, using a lower concentration that stayed constant. Takayama’s team then measured damage to the kidney cells inside the device.

They found that a once-daily dose of the medication is significantly less harmful than a continuous infusion—even though both cases ultimately delivered the same dose of medication. The results of the test could help doctors better optimize dosing regimens for gentamicin in the future. Perhaps most importantly, they showed that a kidney on a chip device can be used to study the flow of medication through human organs.

“We were able to get results that better relate to human physiology, at least in terms of dosing effects, than what’s currently possible to obtain from common animal tests,” Takayama said. “The goal for the future is to improve these devices to the point where we’re able to see exactly how a medication affects the body from moment to moment, in real time.”

Takayama said the techniques used in the study should be generalizable to a wide variety of other organs and medications, enabling researchers to gather detailed information on how medications affect the heart, liver and other organs. In addition to helping researchers fine-tune drug dosing regimens, he believes the technique could also help drug makers test drugs more efficiently, bringing new medications to market faster.

Within a few years, Takayama envisions the creation of integrated devices that can quickly test multiple medication regimens and deliver a wide variety of information on how they affect human organs. PHASIQ, an Ann Arbor-based spinoff company founded by Takayama is commercializing the biomarker readout aspect of this type of technology in conjunction with the University of Michigan Office of Technology Transfer, where Takayama serves as a Faculty Innovation Ambassador.

University of Michigan researchers used a “kidney on a chip” to mimic the flow of medication through human kidneys. This enabled them to study the dosing regimen for a common intensive care drug.

The paper, published in the journal Biofabrication, is titled “Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip.” Funding and assistance for the project was provided by the National Institutes of Health (grant number GM096040), the University of Michigan Center for Integrative Research in Critical Care (MCIRCC), the University of Michigan Biointerfaces Institute, the National Research Foundation of Korea and the Korean Association of Internal Medicine Research Grant 2015.

BME Students Triumph in Michigan Business Challenge

by Aimee Balfe, Biomedical Engineering

PreDxion: Reimagining the treatment of organ failure in the ICU

BME medical product development graduate student Walker McHugh (MSE ’17) hopes the device he’s helping bring to market will transform treatment in the intensive care unit.

Called MicroKine, the microfluidic sensor enables doctors to determine quickly and from only a drop of a patient’s blood which cytokines are causing a hyperinflammatory state that can lead to organ failure.

After working on the product and the science behind it for more than a year in the lab of his advisor, Pediatric Critical Care Professor Timothy Cornell, MD, McHugh proposed using the MBC to explore the path to commercialization.

Cornell agreed, and McHugh teamed up with business student Caroline Landau (MBA '16) to form a company, PreDxion, based on an initial application for the device: monitoring cancer patients receiving chimeric antigen receptor T-cell (CAR-T) therapy. CAR-T uses a patient’s own immune cells which have been genetically engineered to recognize a specific protein on tumor cells. Once reintroduced into the body, these cells seek out and destroy the patient’s cancer.

Though this treatment has had promising results, a potential downside is that a patient’s immune system can overreact, producing a flood of inflammatory cytokines which can quickly lead to organ failure. MicroKine can determine in just 30 minutes which cytokines are out of the normal range, allowing doctors to prescribe the specific anti-cytokine medication that matches those elevated in the patient.

The technology has already achieved proof of concept. In late 2014, Cornell’s lab received an emergency use exemption from the FDA to use the device in a patient experiencing cytokine release syndrome in late 2014. The case was a success, and the team began envisioning a larger impact.

That’s what impelled McHugh to throw his hat into the MBC. He hoped to use its structure – the deadlines, the coaching from Zell Lurie, and partnership with a business student – to explore potential markets, walk through financial models, and flesh out a business plan.

Their work has paid off; the team won $30,000 in the MBC, which they will add to awards from The Coulter Foundation and U-M’s Michigan Translational Research and Commercialization for Life Sciences Program, to continue down the path to commercialization. One of the challenges, says McHugh, is that the product is in a new, niche area of the companion diagnostic space, so the FDA and potential drug-company partners need to assess how to approach it. Ultimately, PreDxion hopes it can structure a pharmaceutical-company partnership that could open the door to cooperative clinical trials and marketing efforts.

McHugh is hopeful that the technology will one day be a game-changer. “Things haven’t changed much over the last 25 years in terms of how we treat organ failure in the ICU,” he says. “We’re are still largely limited to supporting the failing organs.  By targeting the inflammatory processes that are actually driving that dysfunction, we hope MicroKine will bring personalized medicine to the ICU.”
Other contributors to MicroKine include Professor Katsuo Kurabayashi and postdoc Pengyu Chen.

The Michigan Business Challenge (MBC) is a campus-wide competition where student teams have the opportunity to develop a business plan, receive mentoring from the Zell Lurie Institute for Entrepreneurial Studies, and win cash prizes to develop their business.

Project MESA: Bringing safety and dignity to mobile gynecological exams

Taking fourth place in the MBC social impact category is a team from M-HEAL (Michigan Health Engineered for All Lives), the U-M student-run organization that brings biomedical engineering to global health work.

The team, which includes several BME undergraduates, used the competition to evaluate its plans to scale up work on a portable gynecological exam table for use by mobile health workers traveling to remote villages.

Evolution of Project MESA portable exam table prototypes: A (2011 original); B (2013 with stirrups), C (2014 with adjustable backrest), D (2016 with integrated backpack).

Called Project MESA, the team has been working with partner clinics and NGOs in Nicaragua since 2010 on iterative designs for the table. They hoped to use the MBC to test their assumptions about producing and distributing the table on a larger scale to make a bigger impact on healthcare delivery.

Project MESA’s business lead, Katherine Chen, says the coaching was invaluable in helping these mostly engineering students think more critically about issues such as customer preferences, pricing strategies, and business models. “Originally, we designed the product to be produced in the U.S. with the idea that it should be repairable with locally available materials,” she says. “But through customer discovery, we learned that most clinics don’t have the resources to do repairs, so we’ve decided to design the table to be more durable in the first place. In addition, we assumed that a distribution channel in Nicaragua would be hard to manage, but the MBC judges encouraged us to explore that option.”

With $1,200 in prize money from the MBC, the team returns to Nicaragua in May to, among other things, talk with local machinists and distributors; delve into how clinics make their purchasing decisions; assess potential market size; develop new partnerships; and solicit feedback on the newest iterations of the table, which better address durability, portability, aesthetics, and patient positioning.

Chen says the MBC is a great resource for BME design students. “Developing the business plan really helps you define your end goal and determine if it’s financially and logistically feasible,” she says. “It helps you gain an even stronger sense of direction for your design.”

Project MESA’s co-lead is BME student Erik Thomas; other members include: Maya Ben-Efraim, Val Coldren, Bansili Desai, Sabrina Deutsch, Samantha Fox, Hannah Heberle-Rose, Steven Houtschilt, Christina Khouri, Jaime Landsman, Lillian Lantis, Jennifer Lee, Siri Manam, Andrea Mathew, Keely Meyers, Kyle Morrison, Molly Munsell, Madhu Parigi, Monica Patel, Maddie Price, Bharathi Ramachandran, Jen Spiegel, Alejandra Vaquiro Valencia, Shreya Wadwhani, Eldy Zuniga.

Lab on a Chip

Scientists at the University of Michigan are developing microfluid devices to better develop and test human cells. Their three-dimensional cultures create environments that more closely mimics that of the human body than the traditional flat petri dish. With this research, Professor Shuichi Takayama hopes to reduce the cost of drug development and advance disease treatment by provided miniature environments that mimic parts of the human body.

ABOUT THE PROFESSOR: Shuichi Takayama is a professor of Biomedical Engineering and Macromolecular Science and Engineering at the University of Michigan. His research includes the development of microfluidics and micro/nanotechnology platforms capable of testing cells and subcellular components with combinations of mechanical, chemical, electrical, topographical, and thermal stimuli.