The telltale heart

Somewhere, Dr. Frankenstein must be jealous. A research institute in Boston is replicating major human organs on microfluidic devices and linking them in a complex, biomimetic system. Rather than being run out of town by villagers with torches and pitchforks, The Wyss Institute for Biologically Inspired Engineering at Harvard University is getting grants and working with pharmaceutical companies on proof-of-concept studies.

The Wyss Institute’s lung-on-a-chip combines microfabrication techniques with modern tissue engineering and living human cells to mimic whole organ functions.

Last year, the institute debuted its lung-on-a-chip, a microfluidic device that can help test experimental drugs. That device has spawned Wyss devices that mimic other organs, such as the kidney, intestine and heart. The devices are based on technology developed by Wyss Institute Founding Director Donald E. Ingber, M.D., Ph.D., and Wyss Technology Development Fellow Dan Dongeun Huh. In this MICROmanufacturing interview, Dr. Ingber discusses the future of these devices and how they are manufactured.

MICRO: What are the key technologies involved in these microfluidic devices?

Ingber: The Wyss Institute Biomimetic Microsystems platform focuses on development of microdevices that recapitulate human-organ-level functions to perform drug screening and toxicology studies. They may also serve as therapeutic and diagnostic devices. The lung-on-a-chip was our proof-of-principle for drug screening and toxicology. The chip has a microfluidic channel split horizontally by a thin, porous and flexible, 10µm-thick PDMS (polydimethylsiloxane) membrane coated with matrix proteins that normally hold cells and tissues together in our organs. We put human airway epithelial cells on top of the clear membrane and flow air over it. Human capillary blood vessel cells are placed on the bottom, and we flow a culture medium, sometimes containing human white blood cells, to mimic blood. This central chamber is also lined on either side by empty microchannels created with a PDMS erosion technique. We then apply cyclic suction to the side channels of the flexible PDMS device, which causes the cell layers adherent to the membrane to stretch and then relax, as they do when you breathe. We can mimic the entire inflammatory lung response by putting pathogens (bacteria) on the airflow side of the device, and we can carry out real-time, high-resolution microscopic analysis because of the high clarity of the PDMS. You can actually see white blood cells migrating across the cell layers and the membrane, and then engulfing the pathogens in the air space.

MICRO: What is the next step?

Ingber: We are working with pharmaceutical companies to develop disease models for conditions such as pulmonary edema, asthma and COPD (chronic obstructive pulmonary disease). We’re also developing other organ systems, such as a kidney-on-a-chip that experiences flow similar to that seen within the urine-forming ducts of the kidney, and a gut-on-a-chip, or intestine, that undergoes peristaltic-like motion and has intestinal bacteria growing in it. We recently received an FDA grant to link the lung-on-a-chip to a beating-heart-on-a-chip, developed by Kit Parker at the Wyss Institute, to test the cardiotoxicity of aerosol-based drugs. That’s important, because cardiotoxicity causes the failure of more than 30 percent of all drugs, regardless of target. The idea is eventually to link all these devices to create a human-on-a-chip.

MICRO: How might these microfluidic devices work as therapeutic devices?

Ingber: We are developing a spleen-on-a-chip as a blood-cleansing device to treat patients with sepsis. The process begins by taking blood from a patient who has sepsis, which occurs when the blood is infected with a pathogen. The blood passes through the chip, which uses magnetic nanoparticles coated with natural blood protein, or opsonin, that bind with various types of living microbes, including many gram-negative and gram-positive bacteria, fungi, viruses and parasites. Magnetic field gradients pull the bound pathogen out of the blood into isotonic saline and the cleansed blood is returned to the patient. We are also developing a diagnostic device that can tell what the bug is within 1 hour after a blood sample is taken. The results have been exciting, and we’ve recently received a $12 million grant from DARPA (Defense Advanced Research Projects Agency) to advance the sepsis therapeutic device.

MICRO: Would the goal of a human-body-on-a-chip system be to eliminate animal and human tests or to supplement them?

Ingber: The near-term goal is to supplement that process, but the hope would be to replace certain animal models during the drug-development process. Today, drugs have to undergo costly animal tests that take years and often do not predict what will happen in humans.

MICRO: Where are these devices in the commercialization process?

Ingber: We’re developing partnerships with pharmaceutical companies based on small-scale proof-of-principle studies. We are also working on development of more robust manufacturing techniques, establishing design specs and exploring system integration and automation.

MICRO: How are these devices being manufactured?

Ingber: Manufacturing has been done by students and fellows in the lab, but we have just started to outsource that process to increase the robustness of the cell culture and quality system. Our first 50 lung-on-a-chip modules made by a commercial manufacturer should be delivered in October.

MICRO: What do you see as the key breakthroughs in microfluidics at the Wyss Institute in coming years?

Ingber: We see more cross development of microfluidics for far-ranging applications in both medical and non-medical areas. For example, another group at Wyss is working on increasing window insulation efficiency. We noted that penguins can stay warm at the South Pole using microcapillary flow to warm their skin, so we are working with the insulation group on using microfluidic microcapillary flow inside windows to increase insulation efficiency. It’s a totally out-there concept, but because Wyss research is so broad, we constantly find synergies across platforms. µ

Contact information for the Wyss Institute: Telephone: (617) 432-7732. E-Mail: [email]info@wyss.harvard.edu[/email]. Web: http://wyss.harvard.edu.