1 Biological systemsBiological systems … the technological point of view… the technological point of view modular and replaceable partsmodular and replaceable parts molecular motors with specific targetingmolecular motors with specific targeting durabledurable catalytic at ambient temperaturescatalytic at ambient temperatures “bottom“bottom--up” manufacturingup” manufacturing selfself--assemblyassembly genetically regenetically re--engineeredengineered mass producedmass produced examples of nanoscale actuators and pumps - modular and replaceable parts natural “components” possess a wide range highly desirable, intrinsic properties (e.g., thermostability, energy conversion, actuation, …) can be isolated and engineered for integration as structural and functional modules of nanoscale materials and systems Biological systems, ContinuedBiological systems, Continued 2 Molecular motors with specific targetingMolecular motors with specific targeting circular, linear, and antibodies DNA polymerase … linear motor; antibody … targetting youtube.com (the inner cell) complication – working in water Durable …Durable … organisms can live in hostile environmentsorganisms can live in hostile environments -- they possess proteinsthey possess proteins and other components that can withstand extreme conditionsand other components that can withstand extreme conditions secondary structuresecondary structure –– helices, sheets is a result of hydrogenhelices, sheets is a result of hydrogen bonding, a major factor in stabilitybonding, a major factor in stability contributes to the enzyme’s ability to work at high temperaturescontributes to the enzyme’s ability to work at high temperatures enzyme was cloned from a bacteria living in the thermal pools ofenzyme was cloned from a bacteria living in the thermal pools of Yellowstone National ParkYellowstone National Park many common enzymes aremany common enzymes are catalytically active at ambientcatalytically active at ambient temperaturestemperatures Taq DNA polymerase www.dnai.orgwww.dnai.org for detailsfor details 3 “Bottom“Bottom--Up” manufacturingUp” manufacturing biological systems are manufacturedbiological systems are manufactured from “bottom up,” can selffrom “bottom up,” can self--assemble,assemble, be rebe re--engineered and mass producedengineered and mass produced strategies from the nanometeric tostrategies from the nanometeric to metric scalesmetric scales Levels of information in bio systemsLevels of information in bio systems analogy withanalogy with electronic dataelectronic data storage /storage / manipulationmanipulation ROMROM RAMRAM runningrunning programprogram 4 SelfSelf--assembling ofassembling of biosystemsbiosystems … assembly of molecules without use of outside source.… assembly of molecules without use of outside source. Examples:Examples: proteins can assembly while being synthesized, some canproteins can assembly while being synthesized, some can reassemble after being denaturedreassemble after being denatured – some require help from other proteins to assemble correctly (chaperons), some undergo post-translational modifications our goal: understand, exploit, and engineer structural andour goal: understand, exploit, and engineer structural and functional biomolecules to assemble integrated nanomaterialsfunctional biomolecules to assemble integrated nanomaterials andand nanodevicesnanodevices with unique propertieswith unique properties AmphiphilicAmphiphilic moleculesmolecules selfself--assembly occurs spontaneously in nature, e.g. in cellsassembly occurs spontaneously in nature, e.g. in cells vesicles are selfvesicles are self--assembled structures withassembled structures with bilayersbilayers ofof amphiphilicamphiphilic moleculesmolecules the structures ofthe structures of cell membranescell membranes are basicallyare basically the same as vesicles, but more complicatedthe same as vesicles, but more complicated hydrophilic headhydrophilic head hydrophobic tailhydrophobic tail the simplest selfthe simplest self--assemblyassembly structure is micellestructure is micelle bilayerbilayer lipid membraneslipid membranes are typical for cellsare typical for cells micelleswater bilayer lipid membrane 5 Genetic engineering … InsulinGenetic engineering … Insulin people suffering from diabetes need to watchpeople suffering from diabetes need to watch their diet and inject insulin to control theirtheir diet and inject insulin to control their blood sugar levelsblood sugar levels insulin originally taken from pancreas of pigsinsulin originally taken from pancreas of pigs the DNA coding for human insulin wasthe DNA coding for human insulin was isolated from human cells, inserted into aisolated from human cells, inserted into a small ring of DNA called a plasmidsmall ring of DNA called a plasmid which was placed in production cellswhich was placed in production cells –– large quantities easily availablelarge quantities easily available this recombinant insulin can then bethis recombinant insulin can then be purified and given to diabeticspurified and given to diabetics Genetic reGenetic re--engineeringengineering sitesite--directed mutagenesis techniquedirected mutagenesis technique – Nobel prize in chemistry to Michael Smith in 1993 the information in the genetic material can be changedthe information in the genetic material can be changed -- aa synthetic DNA fragment is used as a tool for changing onesynthetic DNA fragment is used as a tool for changing one particular code word in the DNA moleculeparticular code word in the DNA molecule this reprogrammed DNA molecule can direct the synthesis of athis reprogrammed DNA molecule can direct the synthesis of a protein withprotein with an exchanged amino acid residue(s)an exchanged amino acid residue(s) 6 Protein engineeringProtein engineering protein designprotein design -- to improve the stability or modify activity ofto improve the stability or modify activity of enzymesenzymes washing processwashing process -- by specifically changing an amino acidby specifically changing an amino acid (orange) close to the catalytic region (yellow)(orange) close to the catalytic region (yellow) – the enzyme can afterwards survive the chemicals also needed to make our clothes clean – Genencor International - specifically changed amino acids in subtilisin (a fungal protein degrader), so that it would work better in the washing machine – fungi were treated with chemicals that causes changes in the their DNA code and then grown under “washing machine” conditions this resulted in a fungi providing enzymes working well underthis resulted in a fungi providing enzymes working well under those specific conditionsthose specific conditions Mass productionMass production to produce antibodies, antigen is injected into a mouseto produce antibodies, antigen is injected into a mouse immune cells (B cellsimmune cells (B cells –– lymphocytes, from spleen) become amplifiedlymphocytes, from spleen) become amplified and produce polyclonal antibodies (and produce polyclonal antibodies (AbAb) to this target antigen) to this target antigen – limited source, undefined product, animal-dependent better resultsbetter results –– monoclonal Abs.monoclonal Abs. – isolated B cells are fused with myeloma cells (an immortal cell line) – the fused cells are screened to find the ones that produce the best antibody - specific for one site on a target resultresult -- an immortal B cell line producing one type of antibodyan immortal B cell line producing one type of antibody once the fused cells stabilize, they can be culturedonce the fused cells stabilize, they can be cultured indefinitelyindefinitely 7 Current applicationsCurrent applications iinn vvitroitro bbiologicaliological sscreeningcreening – DNA, Hybridization, Detector Arrays LabLab--OnOn--AA--ChipChip – PCR, Molecular Diagnostics ddrugrug ddeliveryelivery andand ttargetingargeting – In Vivo Molecular Medicine ssensorsensors, biosensors, biosensors ssmartmart mmedicaledical ddevicesevices – dental, glucose, electric nose TTissueissue eengineeringngineering – implants, transplantation Biological screeningBiological screening a gene is “expressed” when the protein is made (thea gene is “expressed” when the protein is made (the gene is “on”)gene is “on”) – since the process of making a protein starts with the making of the mRNA, its levels allow to quantify gene expression – useful to determine function of a gene as well as finding drugs to fight a disease methodsmethods –– hybridization of a chip withhybridization of a chip with immobilisedimmobilised DNADNA probes with the sample, fluorescent evaluationprobes with the sample, fluorescent evaluation 8 Final evaluationFinal evaluation Areas of useAreas of use Agricultural BiotechnologyAgricultural Biotechnology Environmental TestingEnvironmental Testing Food TestingFood Testing Livestock DiagnosticsLivestock Diagnostics Identity TestingIdentity Testing Individualized MedicineIndividualized Medicine Human DiagnosisHuman Diagnosis Basic ResearchBasic Research ethical issues:ethical issues: • should we screen newborns before birth for conditions and diseases? • will everyone have access to screening? • what are social implications of newborn screening? 9 LabLab--onon--aa--ChipChip Basic ideaBasic idea Miniaturize fluidic systems inMiniaturize fluidic systems in the same way that electricalthe same way that electrical systems were miniaturized forsystems were miniaturized for the IC industry.the IC industry. Reduce a chemical laboratoryReduce a chemical laboratory in size so that it can be placedin size so that it can be placed on a chip.on a chip. Same or similar processes as inSame or similar processes as in macro, but different technologymacro, but different technology Active componentsActive components – Micropumps, microvalves, microsensors, micromixers, microreactors Flow driveFlow drive hydrodynamic flow Fluid flow profile • Parabolic shape • No-slip at walls eletrokinetic flow Fluid flow profile Flat front shape “Moving” walls 10 Flow controlFlow control Electrokinetic focusing Flow cytometry Gated valve LabLab--OnOn--AA--ChipChip for most laboratory tests, the sample size is in thefor most laboratory tests, the sample size is in the milliliter (ml) range, and the tests are done in a laboratorymilliliter (ml) range, and the tests are done in a laboratory lablab--onon--aa--chip:chip: – sample size can be very small – test could be possibly done at home (point-of-care) – eventually tests could even be embedded in a person PCR reactionPCR reaction – multiplication of target coppies – high sensitivity 11 PCRPCR –– temperature cyclingtemperature cycling denaturdenaturaatete dsDNAdsDNA 9393ooCC bindbind primerprimerss 3737 -- 5555ooCC prolongprolong primersprimers 7070ooCC TaqTaq polymerasepolymerase denaturdenaturaatete dsDNAdsDNA 9393ooCC repeat the cyclerepeat the cycle PCR on chipPCR on chip 12 Drug delivery and targetingDrug delivery and targeting deliverydelivery –– liposomesliposomes – microscopic fluid-filled pouches (vesicles) – could be used to release anticancer or antimicrobial compounds targetingtargeting –– specific recognitionspecific recognition – target specific cell types based on surface proteins Smart Medical DevicesSmart Medical Devices glucose sensingglucose sensing –– blood glucose metersblood glucose meters small computerized machines that “read”small computerized machines that “read” concentration of glucoseconcentration of glucose not completely comfortable …not completely comfortable … American Diabetes Association, ~21 million Americans (7% of theAmerican Diabetes Association, ~21 million Americans (7% of the population) have diabetespopulation) have diabetes annually > $132 billion in direct and indirect costsannually > $132 billion in direct and indirect costs of these 21 million, there are > 175,000 type 1, often referred to asof these 21 million, there are > 175,000 type 1, often referred to as juvenile diabetes, diabetes patients under 20 years of agejuvenile diabetes, diabetes patients under 20 years of age globally, more than 1 in every 600 children has type 1 diabetesglobally, more than 1 in every 600 children has type 1 diabetes incidence in children and adolescents is increasing by ~3 percentincidence in children and adolescents is increasing by ~3 percent annuallyannually ~ 28 percent of these patients in the US use insulin to control their~ 28 percent of these patients in the US use insulin to control their disease … need to measure glucose levelsdisease … need to measure glucose levels 13 Recent trendsRecent trends The Agamatrix Presto launched June 2008: • No coding • Comparatively inexpensive • Sample size 0.5µl • 31 March 2010 - AgaMatrix, Inc. and Sanofi-Aventis announce long-term agreement for the development, supply and commercialization of blood glucose monitoring (BGM) solutions LifeScan’s new product, One Touch Vario, incorporating technology developed by Universal Biosensors (UBI) and manufactured in Rowville, Melbourne, Australia, launched in the Netherlands in January 2010: • 0.45µl • Side-loaded sample • No Code • Results in 5 seconds • Accurate to within ±15% User interfaceUser interface 14 Link to yourLink to your smartphonesmartphone • MyGlucoHealth for Nokia owners test marketed: Within 4 weeks downloaded 40,000 times by users in 130 countries • Lifescan followed the iPhone route Automated solution …Automated solution … insulin pump controlledinsulin pump controlled by continuously operatingby continuously operating glucose sensorglucose sensor “inject” the sensor“inject” the sensor link to the data transmitterlink to the data transmitter pair with the insulin delivering pumppair with the insulin delivering pump comfortable, user independentcomfortable, user independent 15 Tissue engineeringTissue engineering implantsimplants -- in retinal diseases, photoreceptor cells are destroyedin retinal diseases, photoreceptor cells are destroyed artificial retina device transmits signals directly to the optic nerveartificial retina device transmits signals directly to the optic nerve • camera and microprocessor mounted in eyeglasses. • receiver implanted behind ear. • electrode studded array tacked to retina. • wireless battery pack worn on belt for power. The Future ofThe Future of NanoNano-- BiotechnologyBiotechnology diagnostic vs. therapeutic medicinediagnostic vs. therapeutic medicine why play “catchwhy play “catch--up” when you can prevent it orup” when you can prevent it or diagnose it early and fix it fast!diagnose it early and fix it fast! prevention and early diagnosis has always beenprevention and early diagnosis has always been cheaper than therapeuticscheaper than therapeutics 16 Market view …Market view … Measures of Nanotechnology’s maturationMeasures of Nanotechnology’s maturation R&D surging: global nanotech R&D $1 trillionR&D surging: global nanotech R&D $1 trillion estimated for 2015estimated for 2015 term “nano” approaches ubiquitous status in U.S.term “nano” approaches ubiquitous status in U.S. society and media (>18,000 citations in U.S. media insociety and media (>18,000 citations in U.S. media in 2005).2005). “gold rush” for nano“gold rush” for nano--patents continuespatents continues – over 4,000 U.S. patents issued to 2006 perhaps most importantly, nanotechnologyperhaps most importantly, nanotechnology commercialization is moving forward at a rapid rate…commercialization is moving forward at a rapid rate… products include paints, coatings, sporting goods,products include paints, coatings, sporting goods, sunscreens, cosmetics, personal care products, stainsunscreens, cosmetics, personal care products, stain-- resistant clothing, food and food packaging, and lightresistant clothing, food and food packaging, and light emitting diodes used in computers, cell phones, andemitting diodes used in computers, cell phones, and digital camerasdigital cameras 17 Potential applications .. pharma / chemicalsPotential applications .. pharma / chemicals pharmaceuticals and medical productspharmaceuticals and medical products – new and more effective drug compounds – nearly perfectly targeted drug delivery – diagnostics, sensors, and assays – DNA sizing and sequencing – bioelectronics – bio-warfare protection – antibacterial dressings and coatings cchemicals and basic materialshemicals and basic materials – ultra-lightweight, high-strength, precision-formed materials – nano-composite polymers for structural and electronic applications – membranes and filters for costeffective desalinization of water – thermal and optical barriers – ink jet materials – high efficiency and novel catalysts – neo-composite cements – wrinkle / stain / water resistant textiles cconsumer electronics andonsumer electronics and computingcomputing – miniaturized supercomputers – terabit non-volatile memory – pervasive computing – low voltage and high brightness displays – faster semiconductors and microprocessors eenergynergy – thin film photovoltaics for cost effective solar energy – cost competitive fuel cells for automotive applications – micro fuel cells for portable power applications – high capacity, rapid charge batteries ttools andools and mmethodsethods – scanning probe microscopy – software, simulation – directed self assembly and lithography Potential applications .. electronics / enargyPotential applications .. electronics / enargy 18 Pervasive penetration in the longPervasive penetration in the long--termterm scale … automotive examplescale … automotive example Estimation of market sizeEstimation of market size nnanotechnology related goods and servicesanotechnology related goods and services –– by 2010by 2010-- 20152015,, USD trillionsUSD trillions 19 Key drivers limiting penetrationKey drivers limiting penetration ConsiderationConsideration EffectEffect ExamplesExamples TechnologicalTechnological complexitycomplexity Integration requirements andIntegration requirements and interdependency delay penetrationinterdependency delay penetration for complementary designsfor complementary designs New chip architecturesNew chip architectures require integration withrequire integration with peripheral providersperipheral providers Product life cycleProduct life cycle Limits integration of new andLimits integration of new and improved components into systemsimproved components into systems Automobile (3Automobile (3--4 years)4 years) Aerospace (decades)Aerospace (decades) RegulatoryRegulatory limitationslimitations Rigorous regulatory approvalRigorous regulatory approval process limits adoption, successprocess limits adoption, success raterate •FDA approval•FDA approval •FAA approval•FAA approval InvestmentInvestment requirementsrequirements Creates significant switching cost,Creates significant switching cost, raising required value for innovationraising required value for innovation to penetrateto penetrate CMOS chip fabricationCMOS chip fabrication facilities (> $ 2B)facilities (> $ 2B) Market impact will take timeMarket impact will take time TimeTime frameframe (years)(years) 00 -- 33 33 -- 77 7+7+ SystemsSystems -- NonNon--volatile memoryvolatile memory Biomimetic materials,Biomimetic materials, BioelectronicsBioelectronics Nanowire memoryNanowire memory and logicand logic StructuresStructures andand ddevicesevices DisplaysDisplays Sensors, diagnostics,Sensors, diagnostics, assaysassays / F/ Fuel cellsuel cells // SolarSolar cellscells Novel therapeuticsNovel therapeutics throughthrough functionalizedfunctionalized ddendrimers,endrimers, nanotubes,nanotubes, otherother nanoparticles fornanoparticles for targetedtargeted drug therapydrug therapy PassivePassive // materialsmaterials NanoparticlesNanoparticles // BulkBulk compositescomposites // CoatingsCoatings // CatalystsCatalysts // ToolsTools High performanceHigh performance nanocomposites,nanocomposites, ceramics, metalsceramics, metals ?? regulatory complexity and product life cycles technologicalcomplexity 20 Why nanoWhy nano--biobio--tech is differenttech is different players will “own” the innovations onplayers will “own” the innovations on multiple levels:multiple levels: – patent protected (IP ownership) – require proprietary know-how significantly lower barriers tosignificantly lower barriers to market entry for mostmarket entry for most applications thanapplications than e.g.e.g. biotechbiotech oopportunities for near term revenue will allow bothpportunities for near term revenue will allow both attackers and incumbents to develop robustattackers and incumbents to develop robust “bootstrap” models“bootstrap” models concentrated in university andconcentrated in university and academic / centralacademic / central labslabs ssecure strategicecure strategic assets and maintainassets and maintaineded options foroptions for growthgrowth nnonon--traditionaltraditional competitorscompetitors may emergemay emerge Asses relevance of each platformAsses relevance of each platform 21 Personal care productsPersonal care products Friends of the Earth:Friends of the Earth: Nanomaterials, Sunscreens and CosmeticsNanomaterials, Sunscreens and Cosmetics ReportReport largest single category (125 products) is health and fitnesslargest single category (125 products) is health and fitness (including sunscreens, cosmetics, and other personal care(including sunscreens, cosmetics, and other personal care products)products) at least 116 cosmetics, sunscreens, and personal care productsat least 116 cosmetics, sunscreens, and personal care products containing nanomaterials commercially availablecontaining nanomaterials commercially available NanoNano--silver consumer productssilver consumer products brooms, food storage, refrigerators, air filters,brooms, food storage, refrigerators, air filters, drywall, paint, medical coatings, sports clothes,drywall, paint, medical coatings, sports clothes, washing machinewashing machine Samsung’sSamsung’s Silvercare WasherSilvercare Washer Shaper Image’sShaper Image’s Fresher Longer Miracle FoodFresher Longer Miracle Food storagestorage 22 The time for action is nowThe time for action is now materials engineered or manufactured to the nanomaterials engineered or manufactured to the nano-- scale exhibit different fundamental physical, biological,scale exhibit different fundamental physical, biological, and chemical propertiesand chemical properties – quantum physics effects – exponentially increased surface area these new properties (“nanothese new properties (“nano--ness”) create unique andness”) create unique and unpredictable human health and environmental risksunpredictable human health and environmental risks – increased surface area creates increased reactivity and enhanced intrinsic toxicity – size creates unprecedented mobility to human body and environment Human health risksHuman health risks enhanced toxicity: some nanoparticles shown to cause DNAenhanced toxicity: some nanoparticles shown to cause DNA mutation, structural damage to mitochondria and even cell death inmutation, structural damage to mitochondria and even cell death in laboratory studies.laboratory studies. – Nanoparticles of titanium dioxide and zinc oxide (cosmetics and sunscreens) photoactive in studies, producing free radicals and causing DNA damage – Carbon fullerenes (Carbon60): Adverse impacts on aquatic species and low levels have been found to cause damage to human liver cells unprecedented mobility:unprecedented mobility: – due to size, nanoparticles more easily taken up by the human body and can cross biological membranes, cells, tissues and organs more efficiently than larger particles – once in the blood stream, nanomaterials can be transported around the body and can be taken up by organs and tissues including the brain, heart, liver, kidneys, spleen, bone marrow and nervous system. – entry through inhalation or ingestion; jury still out on ease of skin penetration 23 A new class of manufacturedA new class of manufactured nonnon--biodegradable pollutantsbiodegradable pollutants pathways:pathways: during manufacturing, transport, use, or disposalduring manufacturing, transport, use, or disposal (e.g., nano(e.g., nano--cosmetics or other nanocosmetics or other nano--personal care products:personal care products: washed off in the shower and join water waste streams.)washed off in the shower and join water waste streams.) environmental impacts:environmental impacts: – mobility - ability to persist; reach places larger particles cannot; move with great speed through aquifers and soils; settle slower. – transportation - large and active surface for absorbing smaller contaminants that could “hitch a ride” over long distances – reactivity - interactions with substances present in the soil could lead to toxic compounds – durability and bioaccumulation - nano-aluminum and stunted plant growth; nano-silver and microorganisms management challenges: detection and removal?management challenges: detection and removal? – New protocols and cost-effective technologies for measuring, monitoring, and controlling nanomaterials are required New nanoNew nano--specific toxicity testingspecific toxicity testing paradigms are requiredparadigms are required European Commission’s Scientific Committee onEuropean Commission’s Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR):Emerging and Newly Identified Health Risks (SCENIHR): – “Experts are of the unanimous opinion that the adverse effects of nanoparticles cannot be predicted (or derived) from the known toxicity of material of macroscopic size, which obey the laws of classical physics.” U.K. Royal Society and Royal Academy of Engineering:U.K. Royal Society and Royal Academy of Engineering: – “Substances made using nanotechnology should be considered new chemicals and undergo extra safety checks before they hit the market to ensure they do not pose a threat to human health.” Food and Drug Administration agency in USAFood and Drug Administration agency in USA – believed that the existing battery of pharmacotoxicity tests is probably adequate for most nanotechnology products that we regulate. Particle size is not the issue. – publics strongly agains 24 Petition Focus: NanoPetition Focus: Nano--sunscreenssunscreens sunscreens are classified by FDA as human drugs and should besunscreens are classified by FDA as human drugs and should be subject to rigorous presubject to rigorous pre--market regulationmarket regulation red flags regarding free radical creation and DNA damage;red flags regarding free radical creation and DNA damage; unanswered questions about skin penetration.unanswered questions about skin penetration. despite their unique dangers and patented differences, FDA currentlydespite their unique dangers and patented differences, FDA currently considers nanoconsiders nano--sunscreens equivalent to bulk material sunscreens.sunscreens equivalent to bulk material sunscreens. petition calls for nanopetition calls for nano--sunscreen recall until manufacturers submitsunscreen recall until manufacturers submit and FDA reviews preand FDA reviews pre--marketing testing data proving the drugs’ safetymarketing testing data proving the drugs’ safety and efficacy.and efficacy. requirements:requirements: – comprehensive nanomaterial-specific regulations – new paradigms of nano-specific toxicity testing – clasification of nanomaterials as new substances – mandatory nanomaterial product and ingredient labeling – compliance with the National Environmental Policy Act (NEPA) What should be doneWhat should be done learn from the pastlearn from the past: regulatory agencies must act: regulatory agencies must act quickly if they hope to avoid repeating the mistakesquickly if they hope to avoid repeating the mistakes of past regulatory failures of “wonder” materials orof past regulatory failures of “wonder” materials or technologies (e.g., asbestos, CFCs, DDT, PCBs)technologies (e.g., asbestos, CFCs, DDT, PCBs) adequae regulationadequae regulation: a regulatory framework is: a regulatory framework is needed that protects workers, the general public andneeded that protects workers, the general public and the environment from the impacts of nanomaterialsthe environment from the impacts of nanomaterials throughout their lifecyclethroughout their lifecycle much more robust EHS studymuch more robust EHS study: adequate, publicly: adequate, publicly available, independent, peeravailable, independent, peer--reviewed safety studiesreviewed safety studies on the environmental and health impacts ofon the environmental and health impacts of nanomaterialsnanomaterials