Designing Nanostructures at the Interface between Biomedical and Physical Systems: Conference Focus Group Summaries (2005)

Human functions are the most complicated systems. It is probably the greatest scientific and engineering challenge to duplicate some or all the basic human functions on a chip. The success of this work can be of tremendous societal and economic rewards. While the basic functions of a human organ are generally understood, the feasibility of fabricating nano or micro devices on a chip that supply the same biological, chemical, and electrical activities as those of a human organ has only been explored recently. Some of these examples include artificial noses, tongues, ears, retina, skin, etc. There are many more human functions that can be duplicated on a chip. Furthermore, with advancement of the nanoscience and engineering, the integration of several human functions on a chip seems to be feasible. In principle, a human chip can be prepared based on the same or completely different scientific principles from the biological reactions in the actual human organ. The following are examples of the human on a chip concept.

• Identify basic human functions in the nanoscale.

• Build a nano digestion system that converts organic materials into energy.

• Build a nano breath system that converts O₂ to CO₂ and, in the meanwhile, releases energy.

• Build a nano viewing system that detects images and transfers them into digital data.

• Build a nano smelling system that can simultaneous identify different chemicals in a low concentration, low volume gas sample.

• Build a nano listening system that can record and identify acoustic signals over a wide range of frequency.

• Build a nano sensing system that can simultaneously detect minor changes of temperature, pressure, humidity, and other environmental factors.

• Build a nano electromechanical or optomechanical system that can move with the input of light, sound, temperature, etc.

• Build a chip that contains more than one of the above functions.

1. Freedman, David, The Silicon Guinea Pig. Technology Review, June 2004. 107:62-69.

Summary written by:

Stu Hutson, Graduate Science Writing Student, Boston University

Focus group members:

• Andreas G. Andreou, Professor, Department of Electrical and Computer Engineering, Johns Hopkins University

• Raymond Dean Astumian, Professor, Department of Physics, University of Maine

• Prabhakar Bandaru, Assistant Professor, Materials Science Program, University of California, San Diego

• Maria Bellantone, Editor, Nature

• Jeff Byers, Doctor, Institute for Nanoscience, Naval Research Laboratory

• Tejal Desai, Associate Professor, Department of Biomedical Engineering, Boston University

• Gary Gilbert, Chief, Knowledge Engineering Division, US Army Medical Research and Materiel Command and Research Associate Professor, University of Pittsburgh

• Rachel S. Goldman, Associate Professor, Department of Materials Science and Engineering, University of Michigan

• Stu Hutson, Graduate Science Writing Student, Boston University

• Gyeong Hwang, Assistant Professor, Department of Chemical Engineering, University of Texas at Austin

• Donald Ingber, Judah Folkman Professor of Vascular Biology, Department of Pathology and Surgery, Harvard Medical School-Children’s Hospital

• Way Kuo, Dean of Engineering and University Distinguished Professor, College of Engineering, University of Tennessee, Knoxville

• Sean Palecek, Assistant Professor, Department of Chemical and Biological Engineering, University of Wisconsin - Madison

• Wolfgang Porod, Director, Center for NanoScience and Technology, Notre Dame University

• Michael Simpson, Distinguished Scientist and Professor, Department of Molecular-Scale Engineering, Oak Ridge National Laboratory, University of Tennessee

• Mercedes Talley, Program Director, W. M. Keck Foundation

The task was to determine how to build a “human on a chip.” The problem was that no one really knew what that meant.

Among the 17 experts gathered, amidst backgrounds ranging from materials science to vascular biology, everyone had a slightly different speculation about the intention behind the phrase.

Was it a charge to build a microfluidic system that would give quasihuman responses to drugs—a kind of biomolecular crash-test dummy intended to speed up the expensive early trial phases of drug discovery? Was it some borg-inspired desire to have human processes take place on some injectable piece of plastic—an artificial oxygen filter for asbestos-torn lungs, or emergency islet cells for diabetics? Maybe a trash digester for the colon.

It could be a call to put human sensory systems on a chip. Artificial eyes, ears, nose, tongue, and skin combined together to make the ultimate

pseudo human probe. Then again, it’s our mind that’s really what makes us human, isn’t it? Maybe this should be some sort of preliminary mock neural network.

For all I knew, “human on a chip” suggested a recipe for soylent green guacamole.

After a day’s discussion, the issue came down to realizing that this was, after all, a nanotechnology conference. The secret of the group’s purpose was buried in the implicit fact that, at some point, nanotechnology and the workings of human cellular biology are going to have to merge in a complex and meaningful way. And, scientists today aren’t exactly sure how these two technologies are going to interface.

This uncertainty arises because nanotechnology works on a scale where many biological functions at the cellular and sub-cellular level are controlled by weak, non covalent interactions, such as electrostatic, van der Waals forces, hydrogen bonds, and metal coordination chemistry. When you push molecules together, you change their chemical activities. And when you change their activities, you change their physical conformation; it’s just occurring on a very, very small scale. While researchers can make pretty good guesses at how fairly simple and uniform nanostructures behave at this level, the complex mosaics of the human body, like the hierarchical assemblies of proteins that make up our cells and tissues, are still outside current understanding.

So, the group devised a way to set up a scheme that would enable a very fundamental meeting between nanotechnology and the human body, while at the same time allowing researchers to find out more about those biological complexities that they don’t understand. They reworked their group’s title into “Design Principles of Living Systems,” at the cell level, and designed a device called a multiplexed dynamic force spectroscopy array.

Inside a human cell, the workings of a single protein—how the long chain of peptides kinks or untangles in order to hide or expose active links—isn’t solely dictated by regulatory enzymes or chemical triggers in the environment. The protein is also being tugged, stretched, and scrunched by the surrounding intracellular and extracellular matrix that gives cells their shape. These physical forces radically skew how a protein reacts to chemical and enzymatic cues, and cell function results from this form of interplay between mechanics and chemistry.

The basic schematic of the array looks a bit like an underwater clothesline. The protein to be studied is strung like a tangled cable between two,

20-nm-thick. These can be Carbon, Nickel, Platinum, or Polypyrrole/Gold composite nanowires. Using subtle electric pulses or weak magnetic fields, those two nanowires can be sheared outward, creating a tug-of-war stress on the protein, or pulled inward, bunching the protein up.

Researchers could then use an imaging technique, such as fluorescence resonance energy transfer (FRET) or fluorescence recovery after photobleaching (FRAP), to observe how this protein responds to different enzymatic and chemical cues while under this stress. For more advanced studies, more proteins could be added to the same nanowires or to nearby sets of nanowires to see how the proteins react.

Donald Ingber of Harvard Medical School, who was chosen to act as spokesperson for the group, suggested that a good first object of study would be fibronectin, a relatively well-understood glycoprotein responsible for binding cell membranes to the extracellular matrix that holds multiple cells together. From there, more complex proteins could be observed.

Eventually computer models could be designed around these observations, allowing researchers to more accurately model reactions that cells would have to different stimuli. Being able to individually scrutinize proteins in a mechanically relevant context would also help drug developers pin down what enzymatic and protein pathways are really being affected by potential medical treatments.

The array could also become a finely tuned biosensor. Proteins could be engineered to open different active binding sites under different shear forces, so that modulating the forces would cause the proteins to react if certain molecules targeted to those sights (possibly chemical weapons or illegal drugs) were present in the surrounding solution.

The plan for the array, however, is far from realistic at this point. The optical methods of observing the individual chemical events and protein structure aren’t sensitive enough to observe individual changes in proteins as they happen. Not to mention that there is no method accurate enough to place individual proteins between the wires and reliably attach the ends.

“On top of the technical problems, there is the simple fact that this is also the exact type of research that is not going to get funded through your typical channels,” Ingber said. It’s too rooted in “maybes” and too far removed from application. But, it might be a good idea to keep in mind for ten years from now…if anyone asks you to design a human on a chip.

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