Nanomedicine

National Center for the Design of Biomimetic Nanoconductors

Prologue: The most powerful scientific minds have always recognized the power of interdisciplinary thinking. Isaac Newton in The Mathematical Principles of Natural Philosophy, postulated that corresponding phenomena must have the same underlying cause, regardless of the context. Allesandro Volta applied this postulate to arrive at the understanding that a device could be built for human use, which embodied the same principles for producing electricity as the organ of the Electric Eel. Our Center consciously seeks to apply this core postulate to understanding biology, designing devices, and developing therapies, at the nanoscale.

Nanomedicine Challenges

The broad challenge faced by our Center is to capture the capabilities of biological membranes in nanoscale devices. Biological membranes generate electrical and chemical signals, generate electrical power, do osmotic pumping, and transduce energy from one form to another. The key to their ability to accomplish these functions is biochemically directed self assembly that creates arrays of specific and regulated ion conductors embedded in lipid bilayers. In our project we seek to employ synthetically directed self assembly on arrays of nanopores in silicon to create nano-engineered ion conducting membranes to our functional specifications.

Goals and Approaches

Most generally, our model system is the biological membrane as it is organized in either cells or epithelia. Specifically, our work is focused on creating a biocompatible power supply, or biobattery, specifically inspired by the shock-producing organ of the electric eel. The biobattery would provide electrical power for neural prostheses and other implantable devices. In this particular project, we are aiming to power a retinal implant that will provide vision for individuals whose retinas have been severely damaged by macular degeneration or other disease.

Our short term goals are to:

1. Design and synthesize new ion conductors by both chemical modification of silicon and by protein engineering.
2. Integrate in one computational environment the tools essential for design of molecular nanoconductors and synthetic membranes employing directed self-assembly on scaffolds of nanopore arrays.
3. Create and functionally characterize self-assembled heterogenous ion conducting membranes on nanopore arrays.

Our computational approaches are:

1. Quantum and semi-classical simulation and analysis techniques.
2. Classical Newtonian and Maxwellian simulation and analysis techniques, such as molecular dynamics and Poisson-Boltzmann theory and calculations.
3. Mesoscopic and stochastic simulation and analysis techniques, such as Brownian dynamics, transport Monte Carlo, and Configuration Bias Monte Carlo.
4. Systems modeling of electrical and osmotic phenomena.

Our experimental approaches are:

1. Construction of arrays of nanopores at various densities and sizes.
2. Chemical decoration of nanopores with a variety of chemical groups and in various spatial patterns.
3. Doping nanopores with biological and synthetic channels in desired spatial patterns.
4. Synthesis of artificial channels and conductors on protein scaffolds.
5. Electrophysiology of ion conductors.

This work will uncover biological strategies and elucidate engineering principles for molecular design of transport and integration of individual transporters into macromolecular membrane complexes with specified functional properties.

Deeper understandings of the molecular mechanisms of ion transport, and of the emergent properties from the interactions of ion transporters, have broad relevance to understanding a wide range of physiological processes. These understandings will yield insight into disease mechanisms and targeting strategies against diseases, and also form the knowledge base for design of medically useful biomimetic bio-compatible devices. The broad categories of such devices that we reckon can be constructed using nanoconductor components are: sensors, power sources, energy transducers, and osmotic pumps. The devices can be any size from nanoscale up. They can be utilized for either research or therapy in any situation in which miniaturizability, biocompability, efficiency, and bio-drivability, are significant assets.

The ability to fabricate ion conductors in any desired configuration on silicon scaffolds will provide a powerful tool for design of nanoscale devices to provide power for small prostheses, deliver chemical or electrical signals, or provide osmotic pumping or filtering – effectively replacing macroscopic prosthetics with nanoscale prosthetics.

The longest term goal is to provide a significant part of the foundation for a new industry built on the ability to self-assemble nanoscale ion transporters in specified patterns on nanopore arrays. Our goal for the duration of this project is to build a biocompatible battery to power the artificial retina, to restore sight to individuals with damaged retinas. Power supplies for other neural prostheses would be a ready extension.

However implantable devices, no matter how elegant, are not the ultimate goal. The ultimate therapy is to re-engineer the biological system itself, at the molecular and cellular level. In the case of our approach, can we someday guide the self assembly of bio-active lipid rafts with complex transport systems that can be incorporated into the surfaces of biological membranes, to restore capabilities of sensing, signaling, and transport that have been lost to injury or disease? Can we someday induce damaged or defective biological membranes to heal themselves, or to acquire capabilities beyond the genetic programs of the host? Can this approach be applied directly to the membranes of the retina in the case of retinal degeneration, to the airway epithelium in the case of cystic fibrosis, or to the kidney tubule in the case of kidney disease?

Nanomedicine: Unique and Distinct

Prior to the formation of our Center, the members of our team had been separately engaged in work that was potentially complementary and synergistic, but in which those synergies were not realized. Molecular design of transporters was being done separately from the self assembly of those transporters on an array of nanopores that could serve as the scaffold for a device or a controlled engineering of a biological system. Elucidation of the properties of lipid membranes was similarly being done separately from concerns about how to build lipid environments for self assembly of transport systems on silicon scaffolds, Fundamental transport theory was being done separately for biochemical and non-biological systems; the technologies and insights being developed for the non-biological systems was not being applied to the understanding of biological transport, and the insights from the biological work was not being applied to nanotechnology.

Now we are part of a focused effort that combines nanofabrication, molecular simulation and theory, and device design. We are all crossing disciplinary boundaries between engineering, physics, chemistry, and biology that we have previously not crossed, and therefore are moving into areas beyond our expertise to date, as defined by the conventions of our scientific disciplines. In doing so, we are trusting that the shared overall vision, and the complementary expertise of the members of our project, will provide the ability to navigate new scientific territory, and build a fundamentally new conceptual structure for our science. Our key unifying concept is that the nature of the physical world is defined by the time and length scales that characterize the system being studied, and we are all working at the nanoscale.

We are providing expertise, that we wish to develop further and share with others, in modeling and simulation, nanofabrication, and geographically distributed collaboration environments.

Investigators

Eric Jakobsson¹*, Narayan Aluru¹, Hagan Bayley², Jeff Brinker³, Scott Feller⁴, Mark Humayun⁵, David A. LaVan⁶, Gerhard Klimeck⁷, Kevin Leung⁸, Michael McLennan⁷, Steve Plimpton⁸, Umberto Ravaioli¹, Susan Rempe⁸, Benoit Roux⁹, Marco Saraniti¹⁰, H. Larry Scott¹⁰, Xinguang Zhu¹

¹ University of Illinois at Urbana-Champaign
² Oxford University
³ University of New Mexico
⁴ Wabash College
⁵ University of Southern California
⁶ Yale University
⁷ Purdue University
⁸ Sandia National Laboratories
⁹ Cornell University
¹⁰ Illinois Institute of Technology
*Principal Investigator

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