biomems for future drug discovery needs -...

a report by

D r s A r j u n S e l v a k uma r , 1 Y u h -M i n C h i a n g , 1 S imon S im s 2 and

J am i e W i b b e nmey e r 2

1. Applied MEMS, Inc. and 2. Xeotron Corporation

I n t r o d u c t i o n

Billions of dollars are spent finding ‘blockbuster’drugs by pharmaceutical companies. Due to thepotential riches that can be earned from theseblockbusters in the global healthcare market,pharmaceutical companies are increasing the dollarsspent each year on research and development(R&D). About US$400–800 million and 10 years isspent by each of these companies to bring a drug tomarket for which only one out of five lead drugcompounds make it to final clinical use.1 Hence,there is tremendous pressure within these companiesto ensure an improved ‘success rate’, reduced cycletime and lower R&D costs.

Towards this end, there is a drive towardstechnologies that support miniaturisation and highthroughput, which enable faster drug targetdiscovery and drug development. Miniaturisationallows numerous experiments to be carried out usingsmaller quantities of expensive reagents and testsamples. High-throughput screening and massiveparallelism increase the speed at which numerouscombinations of experiments yield the blockbusterdrug compounds.

B i oMEMS f o r D r u g D i s c o v e r y

Using Micro Electro Mechanical Systems (MEMS)fabrication technology, it is possible to makestructures with micron-sized features that enablemechanical, electrical, thermal or chemicalfunctionality using substrate materials such as silicon,glass or plastics. Moreover, since it is an offshoot ofmicroelectronic fabrication technology, it isfundamentally suited towards precisely controlled,mass manufacturing. When applied within thepharmaceutical, life sciences and healthcareapplication fields, components made using thistechnology are commonly referred to as ‘bioMEMS’

devices. These devices often take the form ofmicroarray chips, microfluidic chips, lab-on-a-chip,or µTAS (micro Total Analysis System), drugdelivery components and enable miniaturisedinstruments on chips the size of a few millimetres onedge to 1mm in thickness. They can performanalytical, synthetic, amplification and detectionprocedures requiring only a tiny volume of chemicalsand in a fraction of the time of conventionalinstrumentation. These components are often anintegration of electrical, fluidic and optical elementswithin the bioMEMS instrument.

In the past two years, the doubling of bioMEMSpatent applications is mainly attributed to newmarkets for proven drug discovery technology. Thewidespread use of bioMEMS devices has quicklybeen accepted by pharmaceutical companies as a rapidand accurate solution for screening for compoundsand thereby increasing the speed of development ofnew therapeutic pharmaceuticals.2 Apart from higherspeed, advantages of using bioMEMS devices includelower cost of reduced use of reagents and labour,greater control and modularity.3

BioMEMS devices also create new applicationswithin these arenas and accelerate the rapid growthof these markets. BioMEMS devices have beenapplied to a variety of steps in the drug discoverypathway. From the areas of genomics to proteomics,many laboratory instruments can be miniaturisedonto a bioMEMS chip. This is yet another advantageof MEMS technology since it can effectivelyintegrate multiple functional blocks together,allowing quick and inexpensive performance ofcomplex multistep analytical protocols, whichtraditionally require a host of different machines.Finally, the mass manufacturability of MEMStechnology permits low per-unit-cost componentswith very accurate and repeatable dimensionalcontrol that are vital for effective sample mixing and

BioMEMS for Future Drug Di scover y Needs

B U S I N E S S B R I E F I N G : F U T U R E D R U G D I S C O V E R Y 2 0 0 4

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Technology & Services

1. Norman L Sussman and James H Kelly, “Saving Time and Money in Drug Discovery – A Pre-emptive Approach,”Business Briefings: Future Drug Discovery 2003, London: Business Briefings Ltd, June 2003, pp 46–49.

2. Ed White, “The Rise and Rise of Biochip Patenting - An Engineering Perspective”, 2003 Thomson Derwent,http://thomsonderwent.com

3. M Lesney, “The Microfluidic Milieu”, Modern Drug Discovery, September 2002, pp. 37–41.

separation. The lower unit costs permit single-usedisposable devices, thereby preventing the risksassociated with cross-contamination from reuse.

In the field of drug discovery, key bioMEMS devicesare microarrays, microfluidic chips, and microcapillary electrophoresis (CE) chips. The microarraymarketplace is growing rapidly and these devices arebeing used widely. Microarray technology allows bothminiaturisation and high-throughput processing forapplications such as drug discovery, gene expression,genotyping, mutation screening, gene synthesis andproteomics. Intriguing results are beginning to emergefrom the use of DNA microarrays to classify subtypesof cancer and to guide treatment decisions. Once theyare optimised further for classifying disease,determining the most appropriate treatments, theirmarket potential could be significant.

Microfluidic devices fabricated using MEMS offernumerous application potential such as high-throughput drug screening, clinical diagnostics andgenetic analysis. Passive elements such as enclosedchannels, conduits, nozzles and reservoirs can befabricated using micromachined substrates such assilicon and glass, which are then bonded together.Active elements such as valves and pumps can also befabricated using the same processing steps, thusintegrating an entire microfluidic system. Whendealing with small volumes, an enclosed microfluidicsystem offers the benefit of a variety of processingoptions such as sorting, mixing and separation of tinysample volumes as well as containing evaporationlosses that are significant when dealing with microlitreand nanolitre volumes. These microfluidic structurescan be integrated with electrodes to form capillaryelectrophoretic systems for rapid assay development.

MEMS F o u nd r i e s

The entry barrier to manufacture the bioMEMSdevice for healthcare and pharmaceuticalapplications, however, is high. Moreover,biomedical companies usually do not have captiveMEMS fabrication capabilities since the bioMEMSdevice is typically just one of many components thatneed to be integrated into their final productoffering. As a result, a significant portion of thesebiomedical companies are strategically partneredwith a MEMS foundry facility for the developmentand manufacturing of their mission-criticalbioMEMS devices.

Most biochips with microfluidic structures arefabricated with bulk micromachining technologyusing wet and dry etching techniques to provide amore robust fabrication method with higher

structure flexibility but with a lower cost structurethan most high-aspect ratio micromachiningtechnologies. Applied MEMS has core competenciesin bulk micro-machining and robust wafer/waferbonding technologies. Some popular materials usedfor bioMEMS devices are silicon and glass. Siliconserves as a multipurpose substrate that can be micro-machined and can house microfluidic features as wellas integrated conductors that enable electrodes, bondpads, etc.4 Moreover, it can be subjected to surfacetreatments to enable biocompatibility or to possessappropriate surface chemistry properties. Glass orpyrex have the advantages of being highly suitabletop caps that are transparent, easily machined usingMEMS, laser ablation or ultrasonic drilling and alsobiocompatible. Glass, being an electrical insulatingmaterial, facilitates having electrically conductivelayers deposited and patterned on it. Through the useof these materials, microarrays, microfluidics,microfluidic CE chips and micro biomedical toolssuch as nozzles and needles can be fabricated.

C a s e S t u d y – X e o Ch i p ®

Taking advantage of Applied MEMS demonstratedfoundry capabilities, Xeotron has partnered withApplied MEMS to create its proprietary in situsynthesised DNA oligonucleotide (oligo) microarraytechnology for a broad range of applications. Thecore of this technology is an in situ parallelcombinatorial synthesis within the three-dimensional(3-D) nanochambers of microfluidic chips(Xeochip®) and involving photo-generated reactionchemistry and digital photolithography. This enablesan extremely flexible, cost-effective and yet highlyindustrialised process.

The XeoChip® is fabricated at Applied MEMS usingMEMS bulk micromachining technologies (seeFigures 1 and 2). Channels connecting the synthesischambers are 56µm in diameter and have beenetched into the silicon with a cover glass bondedonto the upper surface, creating 8,064 individual, 3-D reaction chambers. Each chamber is connectedin parallel by fluid distribution channels, allowingparallel reagent flow to all reaction sites. The DNAsynthesis in the chambers utilises a photo-reactiveprocess where a digital micro-mirror device is usedto shine light on specific individual reactionchambers at the appropriate time. This technologyallows the production of high-quality customoligonucleotide microarrays with quick turnaroundand low cost. These microarrays are typically used ingene expression experiments where ribonucleic acid(RNA) levels from up to 8,000 genes can bemonitored, in parallel. The XeoChips® are used withexisting commercial detection equipment,


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4. Kurt Petersen, “Silicon as a Mechanical Material,” IEEE Proceedings, 70 (1982) 5, pp. 420–457.


dramatically lowering entry costs and allowinggreater access to more researchers.

Each chamber is an isolated site for chemicalsynthesis or bioassays. This microenvironmentsignificantly enhances rates of intermolecularinteractions, such as hybridisation. The microfluidicflow through the XeoChip® is pressure driven andcontrolled by a programmable solvent manifold.

These microfluidic chips provide several attractivebenefits for use as biological microarrays:

• flexibility – different sets of DNA sequences canbe easily synthesised;

• controllable temperature and flow conditions;• readable by most commercial detection instruments;• easy-to-handle because molecules are inside the

chip, not on the surface;• small inner volume, less than 6µl per chip; and• highly efficient molecular contacting environment.

P r o b e S y n t h e s i s W i t h i n t h e X e o C h i p ®

Each XeoChip® or microarray consists of 63 x 128features (reaction chambers). The fluidic channelswithin the chip have been designed for optimal, evenflow of reagents throughout each feature of the array.Xeotron uses its patented photogenerated reagent(PGR) during oligonucleotide synthesis withstandard phosphoramide chemistry in conjunctionwith a maskless, digital micro-mirror device (DMD)projector (see Figure 3) to effectively synthesise anyDNA sequence at any feature on any chip. Thecombination of microfluidic chip, PGR chemistryand DMD projector enables a highly flexible chipplatform with robust performance and goodreproducibility. Coupling efficiencies in excess of98% allow the synthesis of oligos up to 100 bases inlength in a few hours.

U s e o f X e o C h i p s ®

The microfluidic chip is inserted into a chip holderfor use in Xeotron’s microfluidic hybridisationstation. The hybridisation station allows multiplechips to be hybridised and washed at the same time.For typical expression analyses, arrays are hybridisedto Cy3 and Cy5 fluorescently labelled cDNA orcRNA. Following hybridisation, the chip holder canbe transferred to a microarray scanner for fluorescentimage capture (see Figure 4).

Figure 4 presents an example of a XeoChip® usedin differential gene expression of brain versusskeletal muscle samples. This XeoChip® contains254 oligos representing cancer-related genes in 30replicates throughout the chip. Use of the chipyields uniform spot intensities (see enlarged image,

Figure 4) and a well-differentiated gene expressionpattern of the two tissue samples. Red featuresindicate over-expression of that gene in muscle,and green, in brain, while yellow indicatesapproximately equal expression. The circularfeatures are readily analysed with mostcommercially available image analysis software, togain an estimation of gene expression levelsbetween two biological samples.

As demonstrated with the Xeotron application, themicrofluidic MEMs chip provides an ideal mediumfor manufacture and use of tools to study changes ingene expression levels. This is just one of manyapplications that can make use of DNA biochips.Similarly, synthetic peptides may also be synthesisedwithin these chips. The bioMEMS XeoChips® areinvaluable tools for use in the expanding the fields ofgenomics and proteomics.


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Figure 1: Xeochip® composed of micro-machined silicon and glass layers

bonded to each other.

Figure 2: 8,000 feature XeoChip® with distribution

channels connected to the reaction chamber

features of the array.

App l i e d B i oMEMS T e c h n o l o g y P l a t f o rm

Due to increasing cash-conservation and time-to-market pressures of today’s global economy, manybiomedical companies are requiring their foundrypartners to offer solutions that significantly reduceboth the cost and time of bioMEMS device R&Dcycles and that lower the perceived entry barrier tousing MEMS technology.5 In order to address theseconcerns, Applied MEMS, Inc. introduced a familyof bioMEMS technology platforms (known as

Applied BioMEMS™) based on standardisedfabrication processes that reduce the costs and cycletimes of proof of concept, product prototyping andvolume production phases of bioMEMS devicecommercialisation. Unlike integrated circuitelectronic chips, MEMS devices are inherently 3-Din structure and encompass multiple physical andenergy domains. This often necessitates a custom andnon-standard process to be developed for eachapplication need. Therefore, our standardisedApplied BioMEMS™ technology platforms aretargeted on very specific and prominent productfamilies of bioMEMS devices for healthcare andpharmaceutical applications.

In order to address the most prevalent bioMEMSdevice applications, our initial Applied BioMEMS™technology platforms are divided into four families:

• MicroArray family is formed on a single siliconwafer as the platform for sample screening, sampleidentification and similar spotted array applications.

• MicroFluidic family for lab-on-chip, microreactor,DNA/protein chips and similar applications. Themicrofluidic chambers, channels and ports areformed on a single silicon wafer, which is bondedto a glass capping wafer.


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Figure 3: A digital micro-mirror projector is used to direct light to specific features on the array, forming

acid in the presence of PGR.

5. H Goldberg, D Chang, A Selvakumar, and Y-M (Johnson) Chiang, “Applied BioMEMSTM Technology Platforms – AFoundry Methodology for Reducing the Commercialization Pathway for BioMEMS Devices”, COMS 2003 Digest, 7–11September 2003.

Figure 4. Image from a XeoChip® hybridised with

human brain cDNA (Cy3 labelled) and skeletal

muscle cDNA (Cy5 labelled).


• ElectroMicroFluidic family for electrophoresis,chemical sensing and similar applications. Themicrofluidic channels and ports are formed on asingle silicon wafer, which is bonded to a glasscapping wafer that contains integrated electrodes.

• 3-D MicroFluidic family for complex 3-Dmicrofluidics (drug delivery), micropumps,microvalve and similar applications. There aretwo independent levels of microfluidic chambers,channels and ports that are formed on two bondedsilicon wafers, which are bonded to a top glasscapping wafer.

The MicroArray and MicroFluidic platforms haverecently been introduced and the resultingdemonstrator chips are shown in Figure 5. TheElectroMicroFluidic and 3-D MicroFluidic platformswill be introduced later in 2004.

Each of the technology platform families is based on astandardised fabrication process utilising silicon andglass and results in a device that is compatible withoptical read-out techniques. There are user designguidelines for each of the technology platforms thatprovide the foundry customer with maximumflexibility in customising the chip for their application,while simultaneously reducing costs and cycle time byat least 30% through the use of standardised processes.This procedure is user-friendly, requiring the foundrycustomer to only provide the chip-level artwork alongwith a few user-defined design inputs (as per Tables 1and 2). This methodology supports the entirebioMEMS device commercialisation process fromproof of concept through low-volume prototyping tohigh-volume production.

One obvious disadvantage of a standardised technologyplatform approach is that it cannot address all possiblebioMEMS devices for healthcare, life science andpharmaceutical applications. In this situation, wherethe foundry customer requires additional functionalityor features, they would commit to customised waferfabrication runs that include the necessarydesign/process development cycles. For some of thesecustomised fabrication run situations, AppliedBioMEMS™ technology platforms can be used asstepping-stone foundations that help minimise theamount of customised design/process developmentcycles required to develop the bioMEMS device.

Con c l u s i o n

MEMS technology is ideally poised for theminiaturisation of devices and components usedroutinely in instrumentation for drug discovery anddevelopment as well as other life sciences applications.The implementation of these bioMEMS devicesenables low-volume usage of expensive reagents,

high-throughput parallelisation and integration ofmany different components onto one instrument at afraction of the cost of conventional systems. AppliedMEMS recognises the needs and requirements of thefield of drug discovery and can provide partnershipswith pharmaceutical and bio-component companiesto develop and take to production customisedbioMEMS solutions. This was exemplified by thedevelopment of the bioMEMS XeoChip® developedand produced for Xeotron Corporation. Moreover,Applied MEMS also offers standardised technology


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Figure 5: The standardised technology platforms – Micro Array, MicroFluidic

and ElectroMicroFluidic demonstrator chips.

Table 1: General Design Guidelines for MicroArray Demonstrator Chips

Single chip size >5mm x 5mm and <20mm x 20mm

Well width an geometry Customer specified

Well depth Choice of 50, 100, or 150µm

Well mask undercut ~1µm per 100µm

Well sidewall angle 90º ± 2º for geometries less than 100µm wide

Min. dimension between structures ≥ 50µm

Table 2: General Design Guidelines for MicroFluidic Demonstrator Chips

Single chip size 5mm x 5mm and < 20mm x 20mm

Trench mask undercut ~1µm per 100µm

Trench sidewall angle 90º ± 2º for geometries less than 100µm wide

Min. dimension between structures ≥ 50µm

Port geometry Square only

Port size 1,000µm x 1,000µm

Min. dimension between ports > 2mm

Option: post-structure geometry Customer specified

Channel trench width and geometry Customer specified

Channel trench depth Choice of 50, 100, or 150µm

Chamber trench width and geometry Customer specified

Chamber trench depth Choice of 50, 100, or 150mm

platforms that help lower the entry barriers into thisarena specifically through the MicroArray,MicroFluidic, ElectroMicroFluidic, and 3-DMicroFluidic Platform technologies. The use ofeither of these bioMEMs solution pathways withMEMS foundries such as Applied MEMS helppharmaceutical companies to lower drug discoveryand development costs, achieve lower per-unit cost,offer a high degree of manufacturing control, alongwith miniaturisation and high-throughput processing.These aspects lead to lower overall costs, reducedcycle times and faster time to market. ■


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Contact Information

Applied MEMS, Inc.

12200 Parc Crest Drive

Stafford, Texas 77477

United States

Tel: +1 281 879 2012

Fax: +1 281 879 2009

e-Mail: [email protected]

http://www.appliedmems.com

biomems for future drug discovery needs -...

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