Library Design and High Throughput Screening. The design of Combinatorial libraries and the development of high throughput screening methods are core objectives of the ICD. Combinatorial methods pervade and unify our research activities with a common set of experimental tools. Instrumentation breakthroughs are crucial to the success of CombiSci . The ICD will advance library fabrication; rapid, high sensitivity readout methods; and high throughput screening. Library design and high throughput screening concepts embrace fundamental scientific issues as diverse as metal deposition, polymer synthesis, molecular evolution strategies, liquid/gas phase transport, and micro-analytical detection schemes. Many activities support efforts in each materials thrust and thus represent a unifying theme.

Library Design. The research thrusts require a range of library synthesis strategies and fundamental advances in library design. We have fabricated complex arrays and gradients by spatial deposition techniques via liquid handling robots, automated spotting systems, field-assisted precursor delivery, vapor deposition, and micromachined/microfluidic systems. Split-and-pool synthesis, molecular evolution, and chemical amplification strategies are also used. We have developed multi-reactor and micromachined systems to interrogate complex systems in which the Combinatorial search space includes reagent composition, concentration, temperature or pressure.

Gel transfer deposition method. (A) Optical image of gradient deposition. (B) Compisition map of PtxRuy catalyst gradient.

Spatial Deposition of Surface Gradients (Hillier, Schrader, Yeung): One of our innovations in advanced library design is field-assisted gradient deposition. This approach markedly extends the range of array formats and densities constructed using liquid synthesis by exploiting electric and concentration fields to control deposition rates. For example, a surface composition gradient can be created by diffusion-based concentration profiles followed by electrochemical or photochemical deposition. The image to the left depicts a binary gradient of a PtxRuy catalyst created by gel transfer deposition. Similarly, dense gradient arrays of polymers, self-assembled monolayers, and functionalized surfaces with continuous composition profiles or spatial micropatterning can be constructed. Gas-phase gradient deposition of metals, oxides, and organic films can be achieved using thermal evaporation or sputtering through moving shutters or masks.

Multi-Reactor/Microfabricated Systems (Porter, Olsen, Hillier): Microfabricated fluidic systems also serve as library synthesis tools or as complex multi-reactor systems. Expertise at the Keck Laboratory will be used for the construction of diverse micromachined and microfluidic systems. The image to the right shows shows a typical microfluidic system that will serve as a preparation tool for ultra-high resolution gradients or rapid detection platforms. We have also developed femtoliter volume multi-well reactor systems for library synthesis.

Other library design activities include: synthesis via molecular evolution in homogeneous catalysts and biorecognition agents; gradient deposition of polymer films; and chemical printing of complex structures on solid surfaces.

a) Optical image of chip-scale flow-focusing system. b) Fluorescent image of flow system demonstrating leadrodynamic focusing.

High Throughput Screening. Innovative high throughput screening is a second inter-woven activity in our program. Our significant expertise in analytical chemistry, scanning probe microscopy (SPM), and nanopositioning allows us to develop and exploit a range of innovative screening tools. Current activities include:

1. SPM for nanoscale surface measurements and in situ reactivity mapping,
2. massively parallel multiplexed analytical detection methods,
3. microfluidic array sensors, and 4) in situ surface plasmon resonance and ellipsometry imaging.

SPM (Porter, Hillier, Narasimhan, Sundararajan, Salapaka, Tsukruk, Zou): We have considerable experience applying SPM for spatially localized characterization of surfaces and interfaces, including in situ measurements of reactivity, mechanical properties, evolving surface topography, surface forces, adhesion, friction nanolithography, and thermal mapping on a variety of surfaces in dry and liquid environments. Recent developments with scanning electrochemical and scanning mass spectrometry techniques provide methods to interrogate reactive and catalytic systems and to perform high throughput screening studies. We use SPM-based screening methods to monitor mechanical properties in polymer systems and to measure subtle interactions between modified probes and functionalized surfaces. Commercial SPM nanopositioners use piezoelectric actuators that suffer from nonlinearities (e.g., hysteresis and creep) and limit travel ranges. To address these shortcomings, we have designed robust broadband nanopositioners by using novel control strategies (closed loop transfer functions and modified integral and double integral structures of commercial controllers) for the precise and rapid positioning of probe tips.

Scanning probe microscopy model.