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Nanotechnology In Bio Medical Applications


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Nanotechnology In Bio Medical Applications

  1. 1. M. Meyyappan NASA Ames Research Center Moffett Field, CA 94035 email: web: Nanotechnology in Bio-Medical Applications
  2. 2. Nanometer • One billionth (10 -9 ) of a meter • Hydrogen atom 0.04 nm • Proteins ~ 1-20 nm • Feature size of computer chips 90 nm (in 2005) • Diameter of human hair ~ 10 µm Nanotechnology is the creation of USEFUL/FUNCTIONAL materials, devices and systems ( of any useful size ) through control/manipulation of matter on the nanometer length scale and exploitation of novel phenomena and properties which arise because of the nanometer length scale: • Physical • Chemical • Electrical • Mechanical • Optical • Magnetic • •
  3. 3. <ul><li>Research and technology development aimed to understand and control matter at dimensions of approximately 1 - 100 nanometer – the nanoscale </li></ul><ul><li>Ability to understand, create, and use structures, devices and systems that have fundamentally new properties and functions because of their nanoscale structure </li></ul><ul><li>Ability to image, measure, model, and manipulate matter on the nanoscale to exploit those properties and functions </li></ul><ul><li>Ability to integrate those properties and functions into systems spanning from nano- to macro-scopic scales </li></ul>Corral of Fe Atoms – D. Eigler Nanoarea Electron Diffraction of DW Carbon Nanotube – Zuo, What Is Nanotechnology? Source: Clayton Teague, NNI (Definition from the NNI)
  4. 4. • Examples - Carbon Nanotubes - Proteins, DNA - Single electron transistors • Not just size reduction but phenomena intrinsic to nanoscale - Size confinement - Dominance of interfacial phenomena - Quantum mechanics • New behavior at nanoscale is not necessarily predictable from what we know at macroscales. AFM Image of DNA
  5. 5. <ul><li>Quantum size effects result in unique mechanical, electronic, photonic, and magnetic properties of nanoscale materials </li></ul><ul><li>Chemical reactivity of nanoscale materials greatly different from more macroscopic form, e.g., gold </li></ul><ul><li>Vastly increased surface area per unit mass, e.g., upwards of 1000 m 2 per gram </li></ul><ul><li>New chemical forms of common chemical elements, e.g., fullerenes, nanotubes of carbon, titanium oxide, zinc oxide, other layered compounds </li></ul>Unique Properties of Nanoscale Materials Source: Clayton Teague, NNI
  6. 6. What is Special about Nanoscale? • Atoms and molecules are generally less than a nm and we study them in chemistry. Condensed matter physics deals with solids with infinite array of bound atoms. Nanoscience deals with the in-between meso-world • Quantum chemistry does not apply (although fundamental laws hold) and the systems are not large enough for classical laws of physics • Size-dependent properties • Surface to volume ratio - A 3 nm iron particle has 50% atoms on the surface - A 10 nm particle 20% on the surface - A 30 nm particle only 5% on the surface MORE IN SECTION II
  7. 7. What is new about Nanoscience? • Many existing technologies already depend on nanoscale materials and processes - photography, catalysts are “old” examples - developed empirically decades ago • In existing technologies using nanomaterials/processes, role of nanoscale phenomena not understood until recently; serendipitous discoveries - with understanding comes opportunities for improvement • Ability to design more complex systems in the future is ahead - designer material that is hard and strong but low weight - self-healing materials
  8. 8. • Recently, there has been an explosion of research on the nanoscale behavior - Nanostructures through sub-micron self assembly creating entities from “bottom-up” instead of “top-down” - Characterization and applications - Highly sophisticated computer simulations to enhance understanding as well as create ‘designer materials’ • 1959 Feynman Lecture “There is Plenty of Room at the Bottom” provided the vision of exciting new discoveries if one could fabricate materials/devices at the atomic/molecular scale. • Emergence of instruments in the 1980s; STM, AFM providing the “eyes”, “fingers” for nanoscale manipulation, measurement… STM Image of Highly Oriented Pyrolitic Graphite
  9. 9. Some 'Nano' Definitions • Cluster - A collection of units (atoms or reactive molecules) of up to about 50 units • Colloids - A stable liquid phase containing particles in the 1-1000 nm range. A colloid particle is one such 1-1000 nm particle. • Nanoparticle - A solid particle in the 1-100 nm range that could be noncrystalline, an aggregate of crystallites or a single crystallite • Nanocrystal - A solid particle that is a single crystal in the nanometer range
  10. 10. Percentage of Surface Atoms Source: Nanoscale Materials in Chemistry, Ed. K.J. Klabunde, Wiley, 2001
  11. 11. Surface to Bulk Atom Ratio • Spherical iron nanocrystals • J. Phys. Chem. 1996, Vol. 100, p. 12142
  12. 12. Nanoscale = High Ratio of Surface Area to Vol. For example, 5 cubic centimeters – about 1.7 cm per side – of material divided 24 times will produce 1 nanometer cubes and spread in a single layer could cover a football field Repeat 24 times Source: Clayton Teague, NNI
  13. 13. Size Dependence of Properties • In materials where strong chemical bonding is present, delocalization of valence electrons can be extensive. The extent of delocalization can vary with the size of the system. • Structure also changes with size. • The above two changes can lead to different physical and chemical properties, depending on size - Optical properties - Bandgap - Melting point - Specific heat - Surface reactivity - - • Even when such nanoparticles are consolidated into macroscale solids, new properties of bulk materials are possible. - Example: enhanced plasticity
  14. 14. Some More Size-Dependent Properties • For semiconductors such as ZnO, CdS, and Si, the bandgap changes with size - Bandgap is the energy needed to promote an electron from the valence band to the conduction band - When the bandgaps lie in the visible spectrum, a change in bandgap with size means a change in color • For magnetic materials such as Fe, Co, Ni, Fe 3 O 4 , etc., magnetic properties are size dependent - The ‘coercive force’ (or magnetic memory) needed to reverse an internal magnetic field within the particle is size dependent - The strength of a particle’s internal magnetic field can be size dependent
  15. 15. Color • In a classical sense, color is caused by the partial absorption of light by electrons in matter, resulting in the visibility of the complementary part of the light • On most smooth metal surfaces, light is totally reflected by the high density of electrons no color, just a mirror-like appearance. • Small particles absorb, leading to some color. This is a size dependent property. Example : Gold, which readily forms nanoparticles but not easily oxidized, exhibits different colors depending on particle size. - Gold colloids have been used to color glasses since early days of glass making. Ruby-glass contains finely dispersed gold-colloids. - Silver and copper also give attractive colors
  16. 16. Specific Heat • C = ∆Q/m∆T; the amount of heat ∆Q required to raise the temperature by ∆T of a sample of mass m • J/kg ·K or cal/g ·K; 1 calorie is the heat needed to raise the temp. of 1 g of water by 1 degree. • Specific heat of polycrystalline materials given by Dulong-Petit law - C of solids at room temp. (in J/kg ·k) differ widely from one to another; but the molar values (in J/moles ·k) are nearly the same, approaching 26 J/mol ·K; C v = 3 Rg/M where M is molecular weight • C v of nanocrystalline materials are higher than their bulk counterparts. Example: - Pd: 48%  from 25 to 37 J/mol.K at 250 K for 6 nm crystalline - Cu: 8.3%  from 24 to 26 J/mol.K at 250 K for 8 nm - Ru: 22%  from 23 to 28 J/mol.K at 250 K for 6 nm
  17. 17. The melting point of gold particles decreases dramatically as the particle size gets below 5 nm Source: Nanoscale Materials in Chemistry, Wiley, 2001 Melting Point
  18. 18. • Start from an energy balance; assume the change in internal energy (∆U) and change in entropy per unit mass during melting are independent of temperature ∆  = Deviation of melting point from the bulk value T o = Bulk melting point  = Surface tension coefficient for a liquid-solid interface  = Particle density r = Particle radius L = Latent heat of fusion Melting Point Dependence on Particle Size: Analytical Derivation
  19. 19. Melting Point Dependence on Particle Size • Lowering of the melting point is proportional to 1/r •  can be as large as couple of hundred degrees when the particle size gets below 10 nm! • Most of the time,  the surface tension coefficient is unknown; by measuring the melting point as a function of radius,  can be estimated. • Note: For nanoparticles embedded in a matrix, melting point may be lower or higher, depending on the strength of the interaction between the particle and matrix.
  20. 20. • For metals, conductivity is based on their band structure. If the conduction band is only partially occupied by electrons, they can move in all directions without resistance (provided there is a perfect metallic crystal lattice). They are not scattered by the regular building blocks, due to the wave character of the electrons. v = electron speed  o = dielectric constant in vacuum  , mean time between collisions, is  / v • For Cu, v = 1.6 x 10 6 m/s at room temp.;  = 43 nm,  = 2.7 x 10 -14 s Electrical Conductivity
  21. 21. • Scattering mechanisms (1) By lattice defects (foreign atoms, vacancies, interstitial positions, grain boundaries, dislocations, stacking disorders) (2) Scattering at thermal vibration of the lattice (phonons) • Item (1) is more or less independent of temperature while item #2 is independent of lattice defects, but dependent on temperature. • Electric current collective motion of electrons; in a bulk metal, Ohm’s law: V = RI • Band structure begins to change when metal particles become small. Discrete energy levels begin to dominate, and Ohm’s law is no longer valid. Electrical Conductivity (continued)
  22. 22. • If a bulk metal is made thinner and thinner, until the electrons can move only in two dimensions (instead of 3), then it is “2D quantum confinement.” • Next level is ‘quantum wire • Ultimately ‘quantum dot’ Source: Nanoscale Materials in Chemistry, Wiley, 2001 3D 2D 1D 0D
  23. 23. Adsorption: Some Background • Adsorption is like absorption except the adsorbed material is held near the surface rather than inside • In bulk solids, all molecules are surrounded by and bound to neighboring atoms and the forces are in balance. Surface atoms are bound only on one side, leaving unbalanced atomic and molecular forces on the surface. These forces attract gases and molecules  Van der Waals force,  physical adsorption or physisorption • At high temperatures, unbalanced surface forces may be satisfied by electron sharing or valence bonding with gas atoms  chemical adsorption or chemisorption - Basis for heterogeneous catalysis (key to production of fertilizers, pharmaceuticals, synthetic fibers, solvents, surfactants, gasoline, other fuels, automobile catalytic converters…) - High specific surface area (area per unit mass)
  24. 24. Fine Particle Technology • Frequently encountered powders: - Cement, fertilizer, face powder, table salt, sugar, detergents, coffee creamer, baking soda… • Some products in which powder incorporation is not obvious - Paint, tooth paste, lipstick, mascara, chewing gum, magnetic recording media, slick magazine covers, floor coverings, automobile tires… • For most applications, there is an optimum particle size - Taste of peanut butter is affected by particle size - Extremely fine amorphous silica is added to control the ketchup flow - Medical tablets dissolve in our system at a rate controlled by particle size - Pigment size controls the saturation and brilliance of paints - Effectiveness of odor removers is controlled by the surface area of adsorbents. From: Analytical methods in Fine Particle Technology, Webb and Orr
  25. 25. Fine Particle Technology (continued) • Adding certain inorganic clays to rubber dramatically improves the lifetime and wear-characteristics of tires. Why ? The nanoscale clay particles bind to the ends of the polymer molecules - which you can think of as molecular strings - and prevent them from unraveling.
  26. 26. Carbon Nanotube CNT is a tubular form of carbon with diameter as small as 1 nm. Length: few nm to microns. CNT is configurationally equivalent to a single or mutliple two dimensional graphene sheet(s) rolled into a tube (single wall vs. multiwalled). CNT exhibits extraordinary mechanical properties: Young’s modulus over 1 Tera Pascal, as stiff as diamond, and tensile strength ~ 200 GPa. CNT can be metallic or semiconducting, depending on (m-n)/3 is an integer (metallic) or not (semiconductor). See textbook on Carbon Nanotubes: Science and Applications, M. Meyyappan, CRC Press, 2004.
  27. 27. CNT Properties • The strongest and most flexible molecular material because of C-C covalent bonding and seamless hexagonal network architecture • Young’s modulus of over 1 TPa vs 70 GPa for Aluminum, 700 GPa for C-fiber - strength to weight ratio 500 time > for Al; similar improvements over steel and titanium; one order of magnitude improvement over graphite/epoxy • Maximum strain 10%; much higher than any material • Thermal conductivity ~ 3000 W/mK in the axial direction with small values in the radial direction See for videos of bending, compression, etc., of CNTs
  28. 28. • Electrical conductivity higher than copper • Can be metallic or semiconducting depending on chirality - ‘tunable’ bandgap - electronic properties can be tailored through application of external magnetic field, application of mechanical deformation… • Very high current carrying capacity (10 7 - 10 9 A/cm 2 ) • Excellent field emitter; high aspect ratio and small tip radius of curvature are ideal for field emission • Other chemical groups can be attached to the tip or sidewall (called ‘functionalization’) CNT Properties (cont.)
  29. 29. CNT Applications Sensors, Bio, NEMS • CNT based microscopy: AFM, STM… • Nanotube sensors: bio, chemical… • Molecular gears, motors, actuators • Batteries (Li storage), Fuel Cells, H 2 storage • Nanoscale reactors, ion channels • Biomedical - Nanoelectrodes for implantation - Lab on a chip - DNA sequencing through AFM imaging - Artificial muscles - Vision chip for macular degeneration, retinal cell transplantation Electronics • CNT quantum wire interconnects • Diodes and transistors for computing • Data Storage • Capacitors • Field emitters for instrumentation • Flat panel displays Challenges Challenges • Control of diameter, chirality • Doping, contacts • Novel architectures (not CMOS based!) • Development of inexpensive manufacturing processes • Controlled growth • Functionalization with probe molecules, robustness • Integration, signal processing • Fabrication techniques
  30. 30. Carbon Nanotubes: Some Examples SWNT MWNT Tower Close view of MWNT Tower MWNT Structures Courtesy: Alan Cassell
  31. 31. • Certain applications such as nanoelectrodes, biosensors would ideally require individual, freestanding, vertical (as opposed to towers or spaghetti-like) nanostructures • The high electric field within the sheath near the substrate in a plasma reactor helps to grow such vertical structures • dc, rf, microwave, inductive plasmas (with a biased substrate) have been used in PECVD of such nanostructures Plasma Reactor for CNT Growth Cassell et al., Nanotechnology, 15 (1), 2004
  32. 32. Biosensor
  33. 33. CNT Based Biosensors • High specificity • Direct, fast response • High sensitivity • Single molecule and cell signal capture and detection • Probe molecules for a given target can be attached to CNT tips for biosensor development • Electrochemical approach: requires nanoelectrode development using PECVD grown vertical nanotubes • The signal can be amplified with metal ion mediator oxidation catalyzed by Guanine. Courtesy: Jun Li 3+ 2+ e 3+ 2+
  34. 34. • CNT tips are at the scale close to molecules • Dramatically reduced background noise Traditional Macro- or Micro- Electrode Nanoelectrode Array Nanoscale electrodes create a dramatic improvement in signal detection over traditional electrodes Electrode • Scale difference between macro-/micro- electrodes and molecules is tremendous • Background noise on electrode surface is therefore significant • Significant amount of target molecules required • Multiple electrodes results in magnified signal and desired redundance for statistical reliability. • Can be combined with other electrocatalytic mechanism for magnified signals. Nano- Electrode Insulator Nanoelectrode for Sensors Source: Jun Li
  35. 35. Functionalization of DNA Cy3 image Cy5 image C. Nguyen et al, NanoLett., 2002, Vol. 2, p. 1079.
  36. 36. Electrochemical Detection of DNA Hybridization - by AC Voltammetry 1 st , 2 nd , and 3 rd scan in AC voltammetry 1 st – 2 nd scan: mainly DNA signal 2 nd – 3 rd scan: Background 1st 2 nd and 3rd #1-#2 #2-#3 Lower CNT Density  Lower Detection Limit J. Li, H.T. Ng, A. Cassell, W. Fan, H. Chen, J. Koehne, J. Han, M. Meyyappan, NanoLetters, 2003, Vol. 3, p. 597.
  37. 37. 30 dies on a 4” Si wafer <ul><li>Potential applications: </li></ul><ul><li>Lab-on-a-chip applications </li></ul><ul><li>Early cancer detection </li></ul><ul><li>Infectious disease detection </li></ul><ul><li>Environmental monitoring </li></ul><ul><li>Pathogen detection </li></ul>Fabrication of Genechip 200  m 300  m
  38. 38. <ul><li>Chen, G.Y., Thundat, T. Wachter, E. A., Warmack, R. A., “Adsorption-induced surface stress and its effects on resonance frequency of microcantilevers,” J. Appl. Phys 77 , pp. 3618-3622 (1995). </li></ul><ul><li>Ratierri, R. et al ., “ Sensing of biological substances based on the bending of microfabricated cantilevers,” Sensors and Actuators B 61 , 213-217 (1999). </li></ul><ul><li>Fritz, J. et al. “Translating Biomolecular Recognition into Nanomechanics,” Science 288 , 316-318 (2000). </li></ul><ul><li>Wu, G. et al. “Origin of nanomechanical cantilever motion generated from biomolecular interactions,” PNAS 98 (4), 1560-1564 (2001). </li></ul>Courtesy: Prof. A. Majumdar, U.C. Berkeley Detecting Biomolecular Interactions Using Molecular Nanomechanics Target Molecule
  39. 39. Wu, G. et al. “Origin of nanomechanical cantilever motion generated from biomolecular interactions,” PNAS 98(4), 1560-1564 (2001). Immobilization of Single-Stranded DNA on Cantilever Courtesy: Prof. A. Majumdar, U.C. Berkeley Thiolated ssDNA 5’-HS ATCCGCATTACGTCAATC TAGGCGTAATGCAGTTAG-5’ (Complementary Strand) Au Self-Assembly of ssDNA PB = Sodium Phosphate Buffer Solution - - - - - - - - + + + + + + +
  40. 40. Wu, G. et al. “Origin of nanomechanical cantilever motion generated from biomolecular interactions,” PNAS 98(4), 1560-1564 (2001). Courtesy: Prof. A. Majumdar, U.C. Berkeley Hybridization Experiments Probe ssDNA Target ssDNA
  41. 41. PSA Wu, G. et al ., “Bioassay of Prostate Specific Antigen (PSA) Using Microcantilevers,” Nature Biotechnology (Sept., 2001) HSA: Human Serum Albumin HP: Human Plasminogen fPSA: free PSA cPSA: complex PSA Courtesy: Prof. A. Majumdar, U.C. Berkeley Prostate Specific Antigen (PSA) Detection
  42. 42. DNA Sequencing Using Nanopores Goal: Very rapid gene sequencing
  43. 43. (~2nm diameter) G. Church, D. Branton , J. Golovchenko , Harvard D. Deamer , UC Santa Cruz  -hemolysin pore Axial View Side View DNA Sequencing with Nanopores The Concept (very first, natural pore) - Nanopore in membrane - DNA in buffer - Voltage clamp - Measure current
  44. 44. Open nanopore DNA translocation event Nanopore Ion Conductance • When there is no DNA translocation, there is a background ionic current • When DNA goes through the pore, there is a drop in the background signal • The goal is to correlate the extent and duration of the drop in the signal to the individual nucleotides Source: Viktor Stolc
  45. 45. <ul><li>After a decade of using protein pores, efforts are underway in many groups to develop synthetic pores (such as in Si 3 N 4 ) </li></ul><ul><li>• Interaction with single nuclotides </li></ul><ul><ul><li>- ~20 nucleotides in  HL simultaneously </li></ul></ul><ul><li>• Slower translocation </li></ul><ul><ul><li>- 1-5  s /nucleotide in  HL </li></ul></ul><ul><li>• Resistance to extreme conditions </li></ul><ul><ul><li>- Temperature </li></ul></ul><ul><ul><li>- pH </li></ul></ul><ul><ul><li>- Voltage </li></ul></ul><ul><ul><li>•  - hemolysin is toxic and hard to work with </li></ul></ul>Potential Advantages of Solid-State vs. Protein Nanopores
  46. 46. Nanopore Dimensions Determined by DNA Structure Source: Viktor Stolc
  47. 47. <ul><li>Voltage-clamp amplifier designed to measure pA level currents </li></ul><ul><li>Fast (up to 1GHz) data acquisition </li></ul><ul><li>Software for automatic blocking event detection and recording </li></ul>DNA Sequencing Experiments AgCl AgCl Voltage Clamp Amplifier nanopore chip KCl KCl Data Acquisition
  48. 48. Spontaneous Blocking Events with Synthetic Nanopores
  49. 49. A A G G G G C C Status of Nanopore based DNA Sequencing G G A A A A G C C T T Present Future
  50. 50. Dendrimers: What are They? • Tree-like polymers, branching out from a central core and subdividing into hierarchical branching units - Not more that 15 nm in size, Mol. Wt very high - Very dense surface surrounding a relatively hollow core (vs. the linear structure in traditional polymers) • Dendrimers consist of series of chemical shells built on a small core molecule - Surface may consist of acids or amines  means to attach functional groups  control/modify properties - Each shell is called a generation (G0, G1, G2….) - Branch density increases with each generation - Contains cavities and channels  can be used to trap guest molecules for various applications. Courtesy of:
  51. 51. • Desired features of effective drug delivery - Targeted delivery, controlled release (either timed or in response to an external signal) • Desirable characteristics of dendrimers - Uniform size - Water Solubility - Modifiable surface functionality - Availability of internal cavity - Control of molecular weight - Control of the surface and internal structure • Number of different drugs can be encapsulated in dendrimers and injected into the body for delivery - Incorporating sensors would allow release of drugs where needed • Gene Therapy - Current problem is getting enough genes into enough cells to make a difference. Using viruses for this triggers immune reactions. Dendrimers provide an alternative without triggering immune response • Cancer Therapy • Antimicrobial and Antiviral Agents Applications for Dendrimers: Biomedical/Pharmaceutical
  52. 52. Nanomaterials in Drug Delivery • Dissolution kinetics may be the rate limiting step in the absorption process for many drugs - Decreasing the particle size increases surface area and the dissolution kinetics. • Liposomes are normally used as carrier for hydrophilic drugs. Typical difficulties: physical instability, low activity, drug leakage - Alternative: water-soluble polymer based nanoparticles. These are more site-specific and exhibit better controlled-release characteristics. - To overcome toxicity issues, solid lipid nanospheres as carrier systems have been reported * . This is a lipid that is solidified and stabilized by a surfactant. Advantages: physical stability Disadvantage: low drug loading (25%) * S.A. Wissing et al., Adv. Drug. Del. Rev. 56, p. 1257 (2004).
  53. 53. Quantum Dots: What are They? • Synthetic “droplets” containing anything from a single electron to thousands of atoms but behave like a single huge atom. • Size: nanometers to microns • These are nanocrystals with extraordinary optical properties - The light emitted can be tuned to desired wavelength by altering the particle size - QDs absorb light and quickly re-emit but in a different color - Colors from blue to IR • Common QDs: CdS, CdSe, PbS, PbSe, PbTd, CuCl… • Manufacturing - Wet chemistry - Template synthesis (zeolites, alumina template)
  54. 54. ® Absorption Radiationless decay Fluorescence Valence Band Band gap Small Molecules Qdots Semiconductors Conduction Band Source: Bala Manian, Quantum Dot Corp. Qdots Have a Unique Electronic Structure ® Energy levels
  55. 55. Source: Bala Manian, Quantum Dot Corp. Size Dependence 'Particle in a box' 2.2 nm CdSe 5.0 nm CdSe E g ~ 1/L 2 L L
  56. 56. Quantum dots change color with size because additional energy is required to “confine” the semiconductor excitation to a smaller volume. Ordinary light excites all color quantum dots. ( Any light source “bluer” than the dot of interest works.) Source: Bala Manian, Quantum Dot Corp. Optical Properties of Nanocrystals
  57. 57. Material band-gap determines the emission range; particle size tunes the emission within the range Nanocrystal quantum yields are as high as 80% Narrow, symmetric emission spectra minimize overlap of adjacent colors Source: Bala Manian, Quantum Dot Corp. Size- and Material-Dependent Optical Properties
  58. 58. Applications • LEDs, solar cells, solid state lighting • Biomedical - Bioindicators - Lateral flow assays - DNA/gene identification, gene chips - Cancer diagnostics • Biological Labeling Agent Organic Dye Quantum Dot • Broad output spectrum • Sharper spectrum • Fades quickly ~ 100 ps • 5-40 ns • Unstable • Stable output over time • One dye excited at a time • Multicolor imaging, multiple dyes excited simultaneously