1 / 26

BioModular Multi-Scale Systems

BioModular Multi-Scale Systems. Goal - Design, Model, Fabricate and Evaluate a universal Molecular Processing System to identify a variety of targets for Discovery, Forensics, Homeland Security and Clinical applications. Molecular Analysis. In vitro Diagnostics $2.5T healthcare

samson
Télécharger la présentation

BioModular Multi-Scale Systems

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. BioModular Multi-Scale Systems Goal - Design, Model, Fabricate and Evaluate a universal Molecular Processing System to identify a variety of targets for Discovery, Forensics, Homeland Security and Clinical applications

  2. Molecular Analysis • In vitro Diagnostics • $2.5T healthcare market, 70% of clinical decisions based on IVD • Homeland Security • Growing market • Forensics • 350,000 case backlog • $2.0B market • Types of Markers • DNA (nuclear, mt) • RNA (messenger, gene activity) • Proteins (over/under-expression) • Challenge • Each marker requires a different assay and hardware platform to analyze • The processing time is typically > 1 day, requiring highly trained operators • Highly expensive ($3,000 per test for BRCA I/II genes)

  3. IVD and Cancer • Global cancer cases:12M/yr with7.6M deaths/yr • Total cost of cancer care in US is $171B/yr with productivity losses of ~$1 trillion/yr • Current IVD market is $7B and projected to be $14B by 2013 • IVD potential has not been realized in cancer clinical care area due to; • Lack of “standardized” protocols for generating clinical data from biomarkers • Highly sophisticated equipment and expertise required to implement many existing assays MISSION: Develop a standard assay protocol and instrument platform to provide automated & low-cost target identification.

  4. 3’ 5’ G C T A C G T A C T A C C 5’ C C G A T A A A C G T T T A T G G G C 1 2 3 4 5 6 7 8 9 Base calling TGCTACGAT … Next Generation Sequencing(Sequencing-by-Synthesis, SbS) DNA(0.1-1.0 ug) Cluster growth Sample preparation Sequencing Genome Analyzer Image acquisition Cluster Station • Prep gDNA – 6 h • 5 h cluster preparation • 3 d single read run (70 bp reads) • 2b bases per day

  5. Single Molecule Sequencing Conformal Seal • 1.1 kbp dsDNA • Gap = 9 nm • Ti/Au nanoelectrodes • Fused quartz substrate • Sputter deposition of metal off-normal Chou, Nano Lett. 8(2008) 1472.

  6. To Micro-scale contacts NIL Prepared Substrate Nanowires (d = 5 – 10 nm) Proposed Technology Polymer-based Nanosensor Bioreactor V1 V2 = Enzyme V1 E Nanofluidic Via (5 – 10 nm) Nanopillar Support To Micro-scale contacts V2 E E Enzyme Tether E ssDNA E dsDNA E E Expelled Bases Nanosensor d and ∆t dAMP λ-Exonuclease Length Sensing dTMP Entropic Trap dsDNA

  7. Nucleotide ID using Nano-Scale Time-of-Flight Time I C Electrode 1 T ∆t = Flight Time Electrode 2 G A A Histogram C G Frequency ∆t ∆t ∆t ∆t T Threshold Level ∆t (time units)

  8. Nanosensor Arrays for DNA Sequencing • Does not require cloning, amplification (PCR, SDA, Cluster), gel electrophoresis or fluorescence • Shear genomic DNA (tight and controllable size distribution) • Hybridize to capture probe • Exonuclease digestion (sequencing, only 1 enzymatic reaction) • Can be done for proteins as well! (proteolytic digestion, PMF) • Can accept any sample and prepare templates for sequencing • Isolate target cells (can sequence single cells with no amplification) and SPE • Prepared via mixed-scale replication technologies with simple modification chemistries (high-scale production at low-cost) • Modular design approach • Polymers used as substrate materials for chips • Can sequence fragments to 50 kbp (or larger) • Simplifies assembly for whole genome sequencing projects • Can re-sequence selective genes for diagnostics (haplotyping) • Throughput and Cost analysis • 1,000 nanosensors per chip • 1,000 bp per second (clipping rate of exonuclease) • 8.6 x 109 per day of raw sequence information (~3-fold redundancy for Human Genome) • COST per genome – <$1,000

  9. Modular System for Complete Sample Processing and Sequencing • Process any clinical sample; blood, tissue, urine, saliva, etc. • Universal detector – process any sequence variation • Directly sequence 50 kbp fragments • Sequence one genome in <1 day • Cost for whole genome analysis <$500 Pt Wires

  10. Center Organization Council of Deans, VC of Research Director Soper Deputy Directors Rusch Podlaha-Murphy Murphy External Evaluation Team Industrial Advisory Board Administrative Assistants Scientific Advisory Board Cain Center Research Thrust Areas Un./Pre-college Ed. – Pang/Nixon ICI – TBN, Weaver TA2 Functional Materials (McCarley) TA1 Molecular Assays (MaGee) TA4 System Engineering (Murphy) TA3: Multi-Scale Molding (Kazmer)

  11. Production Methods Top => Down Bottom => Up Atoms/molecules Bulk domain Atomic structures Micro-/nano- structures Functional System: Mixed-ScaleAssemblies with Top-down & Bottom-up

  12. Lab prototypes usually rely on bottom-up techniques, which are not feasible for mass production Layers & components must be redesigned for top-downmanufacturing & assembly Issues: replication, handling, alignment, bonding, … Design forNano-Manufacturing

  13. Multi-Station Molding • Layers with different length-scale features will be produced, aligned, and assembled in a multi-station mold: • Internal alignment is grossly setby the tooling and fine-tuned by smart material actuators • Stations includetheir own heaters, actuators, &sensors toperformprocess stages

  14. UV & thermal imprint lithography is the process of choice: Provides excellent replication Relatively fast process Amenable to multi-station design Imprint, surface treatment, imprint, bond, … Processing history is vital to layer replication & end-use performance Each processing step provides initial & boundary conditions for subsequent step(s) Residual stresses & layer properties will dictate relaxation, dimensions, and consistency Multi-Layer Processing

  15. Simulation aids development of machine design, process settings, and control strategies Simulation of large area, multi-scale molding is daunting An integrated simulation can model the viscoelastic flow and thermal/structural response of multilayer nano-composites across all process stepswith a singleconstitutive model Simulation Multi-Point ImmersedBoundaryMethod(MPIBM)

  16. Researchers suggestcontinuum models areinappropriate at nano-scale This is not settled… McKenna, Science, 2005: Continuum Modeling McKenna, 2005 (27 nm PVAc) Plazek, 1980 (2 mm PVAc)

  17. Multi-domain characterization Glassy state: DMA Melt state: cone & plate rheometer New constitutive models needed Constitutive Modeling Materialmodelspans15 orders ofmagnitude:from 1 ns to 1 month WLF

  18. Multi-Scale Replication:Combinatorial Toolset

  19. Resource Capabilities – Patterning Clean room @ LSU EBL @ PSI X-ray Source @ LSU Mask Aligner@ Paul Scherrer Institute (PSI)

  20. Resource Capabilities – Molding Blow Molding @ UML Simulations @ UML Injection Molding @ LSU & UML Imprinting @ UML

  21. Fabricating Vias in Silicon Stamps at 5-25 nm 25 nm wide

  22. Multi-Scale Replication:Surface Modification • Surface chemical and mechanical modification can improve polymer flow, replication fidelity, insert life time, and part demolding • Optimization of coating chemistry, internal structure, and thickness • Different coating methods (i.e., thermal and plasma chemical vapor deposition) and materials (i.e., metal carbides and nitrides) for different mold inserts/polymer substrates • Use of polymer and organic/inorganic composite mold inserts

  23. Nanochannelsin PMMA by UVNIL

  24. Multilayer Process Testbed

  25. Homemade Machine

  26. Universal Molecular Processing System sought for in-vitro diagnostics, security, and forensics applications Moore’s law, coupled with advances in top-down nano-manufacturing will enable such devices Significant research barriers must be overcome: Bioreactors for controlled monomer generation Top down manufacturing of mixed scale features Assembly of multilayer composite systems Design methodologies for very large scale integration of mechatronics Conclusions

More Related