CA2689890C - Method of manufacturing an intracutaneous microneedle array - Google Patents

Abstract

A microneedle array is manufactured using a mold preparation procedure that begins try placing an optical mask over a layer of PMMA material, exposing the PMMA material to x-rays, then developing using a photoresist process. The remaining PMMA material is then electroplated with metal. Once the metal has reached an appropriate thickness, it is detached to become a metal mold that is used in a microembossing procedure, in which the metal mold is pressed against a heated layer of plastic material. Once the mold is pressed down to its proper distance, the plastic material is cooled until solidified, and the mold is then detached, thereby leaving behind an array of microneedles. If the microneedles are hollow, then an additional procedure is used to create through-holes all the way through the underlying substrate material using laser optical means.

Description

WO OUP/47dd PCT/U$00I16612 1VlETSOD OF MAIVUFACTURING AN
S INTRACUTANLOUS MICROPlBEbLX Ji1RRAX

TtiCIIrt1CA[. FtEtD
Thc prasatt invmtion relates gracralty to medical devices attd is particularly directed to a fluid diapensmg device and a fluid sampliag device of tbe tyW
whieh, in oao t5 embodiment pmaei<ates the stratum corneum and epidamis, but not into the dermis of stda, and in another embodiment penetntes intn the dermis so as to linterfmce with blood or otlza biologie,al fluids. The inveotion is speciSeally msclosed ae an mray of microtuedl¾a ahich piittlessly utd with miniwaJ trauma to the aidn enable fluid trans&r aitha iatb a body ss a dispzating deviee, or from the body to sampie body fluid.
BACKGROiA7D 4F TtZ IN1VRIi17oIV
Tapio*[ de]ivcsy of drugs is a vay useful method for achieving systemic or loaalized phatmacologicat effects. 7'he mm challenge in ttxttsatimaous dmg dc.hveay is provid'mg sutflcient dtug pmetraGon acrpss the Skin. The skin camsiata of muldplc layers starang with a swam cometRn layer about (for httaoaas) twemty (20) mict+ons in thicltnm (cotnpriaing dead txlls), a viable epidotmai tiss,te layer about savanty (70) micrnns in thiekaess, and a dermal tissue layor about two (2) mm in thielrAess.
The thin layer of stratum eorneum represanb a major btttier for ehemical penetration through ". The stratum ctnaeum is responable for SO"/o to 90%
ofthe skin barcier propetty, depeading upon the drog material's water solnbiHty and molxnlar weight. Tlte apidemds eomprises living tissue with a high eooxathtion of arater. Tbis Iayer pnamts a lesser barrier for draE pe,netrat4on. The dermis oontains a rich capillary netvvork close to the dermat/epidermal junation, and om a drug raec6es the decrnal depth Wa 0oR476I PCiWS00/iS672 it diffuaes rapidly to doW dwue layers (such is hair follieles, nsuscles, and intcrnal arPmsj, ar syderniea]Iy via blaod airailsdoa.
Oment topical dtuS detivay methods are based upon the use of penehmtion euhaaeipg methods, which o8a- cwse " iaitatiou, and ttw uso of ooelus vo patetm 11tat 1lydrato flle strntam eomeuin to ireduce its birnier p[opetties. Only a=ll fiutiolq of topicaw tppliod dntg ponetrstes tiaauo e>oa, with vaypooc dkiency.
Comeation methoda of bLoIogicaE fluid sampling and acn-osd drug doliveay saa wmally invaaive, That is, ahe slom le lanced in order to extract blood md measure various components when perlbrAttiag Said saaspliag, or a drug delivery proceduae is nmoaily pufomea by ifqjectioq, w)wh eas>sea psiu aud reqauvs ipOciaE fiedic8t bnving.
An sltenetrve to drug de]ivery by ntjecfion ltss beeu proposed by Hettty, McAlltrtCC, AIlen, smd Pmxmita, of Gooepa bsdUEe of TecihmoloV ('m a paper titled "Miammwlvned Needles for the Tcamdem4sE Deiivery of Drugs), in which an acray of solid microneedles is used to peaetrate Ilamagh the strsNm cocneum and into the s+isblo t5 epidcaoal layer, but nat so the decmal ]qa. ln this {Iemgia Teoh deeigq, bowevet, ft fluid is prone to loakago around Oe amy of mioroueedles, since the fluid is on the etttexioraucfsce of the stcuctuao huldi*dmmicroaaadlee.
Aapther altdrnative to dnig dolivery by injesotiaon is ditolosed in IJ.S.
Patent No.
3,964,482 (by Camsfel), im which an array of eitbdr solid or boltow microneodlas is used to peaeirade tbnuugh the shatm oornaum, itrta the epidermal ]myeC, but not to aha danmstl layex. Fluid is to be dispensed either through hotlow ndmaamdios. thmugte paY.aeable solid projections, ar saround npn-pffwmble so}id prajedions thst ame smionnded by a parmeable mataixi or un apeftaa. A rnembrane muerial is t0sed to coYmol the rato of drug relesee, and the dtug tratsfca moohanism is ab.orption. The asicrdaerdle size ie disclosad as having a dismeeer of 15 g,wge t]frough 40 paug4 (wW stwndm+d medical gauge needle dimensions), and w lepgth in the zsn$e of 5-100 microaa. The peimesble matwial may be Mad with a liquid, hydrogel, sol, 0, of tha like for traaspotting a dcug tbrough tbe proJeaions and tlgopgh ft ttraWm ooramm.
Another structure is disclosod in WO 99/00193 (by Aluea Tcxihaologios, Inc.) iu the gcam of a dmg ddivGry system, Or anatyte mpMitoriog ayseeQn, that wtes pyrSUdM-ahaped projeetione that have chtottels along their outer sarbecs. Titcac projoctiona have a lengtb in the raage of 30-50 tniemng, and providc a tnres-dermai or trans-mucous deliva,ry syitem, which een be eailtanc0d with alhasouad.
Anotha= structure, disclosed in WO 97/48440, WO 97/48441, and WO 97/48442 (by ALZA Corp.) is in the form of a devlce for enbtau:ing traasdermal agenrt delivery or samzpling. It employs a piurality of solid metsllic microbtsdes aW aaohor elemaits, etehod f+om a metal shoet, with a leQgth of 25-400 mm. WO 96/37256 (by Silicon Mierodeviccs, Inc.) disclosed anothar silieoa miaablade atruewm with blade lengtbs of 10-20mm. For enhancing eanxdamal delfvety.
Most of the otNer convendonal dcug delivery systems involve s=:t invasive needle or plurality of neocAes. An ex4mple of ihia is U.S. Patent Number 5,848,991 (by C}ross) which asos a hollow needle to pautratc tluong,iu the epidernAis and into the rirrrnis of tbe snbject's slrin whca the housing containing an eqansiWefcoaocaoflble chamber holding a reservoir of fluidie ftg is attxhed to the s1dn. Another exataple of thds is U.S. Pat$ut Number 5,250,023 (by Lee) wluelt administers Ruidia drugs using a plunlity of so6d needles that penetrate into the decmis. Thc Lee drug delivery systean ionizes the drug m help hansfer ft drng into the sian by an eleetric charge. The needles are disolospd as being within the range of 200 mtanns ihmugh 2,000 mierons.
Anothex example of a needle thst penatrstes into the dermis is provided in U.S.
5,591,139, WO 99/00I55, and U.S. 5,855,801 (by Lin) in which the needie is processed nsaig fntegnted cinmut hbrication techniques. Tbo needln am diaclosed as lta.vio,g a length in the range of 1,000 microns througb 6,000 mioroes, lhe ase of miormmedles has gM advantages in th:t intracutaneous drug delivery can bc acc.omplished witbout pain and without bleedin& As used horein, the tcrm "ntienoneodirs" refers to a plnrality of cbngated stsucturea that ase sufficicntly ]ang to paeetrate through the stratum corneaon skin layer and into the apidermal lsyet, yet are also sufficiently short to not penatrate to the dasmallayet. Of coarse, if the dead oe11s have beea aompletely or meatly ranoved $om a poaRion of stcin, tben a very minute length of microneedle aould be used to reach thc viable epidcmnal t;ssne.
Since micronecdle tWinoiagy ahows much promise for drug delivety, it would be a fitrther advantage if a microneedle spparahu could be provided to sample flnids witltin sidn tissue. P'uthecutotae, it would be a futther advanraga to pmvnde a micmnaedlc array WOOO74764 PGT/US00lI3612 in which the iadividual microneedlas wens of a hollow sttucture so as to aJiow fluids to pass from an inteiaal chamber thtougly the hoilow microneedles and into the stlan, and were of saflicient leagth to eaante that they will roaoh into the epidermis, entirely tbrough the tbatum corneum.
8t7NASARY OF 7'MC IKvEMTTON
Acoordin8ly, it is a primtrSr advautage of the presatt invention to provide a micmneodla amry in the form of a patch which can pcrform intraeutaneous drng delivery, It is anothcx advantage of the present invention to provide a micxonwdle arcay m the fortn of a patch that caa perform biological body-fluid testing and/or sampling (inclvding interetitial fluids and/or blood). it is a furtbcr advantage of the pocesettt invmtion to provide a microneedle atrsy as part of a closed-loop systetn to control dtug delivoty, bssai on faodback intwmation that anailzes body flufds, wbioh can achieve t+eat tune continuous dosing aad monitoring of body activlry. It Is yet attother advantaga of the preocnt invention to provide an elechupbonbcallylmianonoodfo-anlwncad traasdemaal dtug defivery system in ordor to aoWave Ngttrrate drttg delivery aad to aeldcvo sampliag of body fluids. It is a yet fwthet advatttaga of the paeemt inventitm to provide a method for manufacturing an array of microneedles tuing microthbricstion xcbniques, includfng stattdard se3ttlconduetor fabtication techniqurs. It is still another advantage of the preaeat imresttion to provide a motltod of matutfwtmhig an amy of mfcroneedies comprising a plaseic materiat by a"self-molding!+ method, a micrommofding metbod, a naicroembossitng method, or a microinjection method. It Is stall attother advantaga of the preeeat invention to ptvvide an atray of edged tnicroneedlea that, in one configuration are hollow and have at least one blado with a subsqotiaily sLap edge that sssiss in penetration of the stfi-tum oorneum of sYin, and in another configuration the miemneodles aro solid and huve at least ww blacic witb a sabataotiatly sharp edge to asaist in penetrating tha atratum cornatm. It ius aull a furtlser advantage of the pnmt invention to provide a miamnetxlle atray that has suffieieat separation disteme bctween the individual micrmLeedie8 so as to ensure penetration of the sCratum cornettm of ekin to achieve gmater trat9decsoal flux. It is stiil another advaatage of the pramt invention to pmvidc a aeettmd of tnatutfsctttting aa atray of microneedtes in which a metal mold is initiatFy manufaetured for use in a WO 00/74784 PCP/tlSbe/15613 muxoeinboasiag procedure, while allowing a suftioia-t sepatatioa diatance betwem iaciividuai mioroncedlas of the array, then use a proeednre for areatiag hollow chambas md tbrough-holea in the subrccnte of the microneedle azrry, It is yet motha' advantage of tLe pmeaeat invendon to provide a miaoneedte attay tlud bas saasing aqabilifiea qir~g S optisal, spoctw-opic, co]orimelric, eloctt+oehqnieal, th=al, grnviputric, and light scattering seneing meana. It is stili anot6er advwttage of the presant invention to providc a mcthod for munfacUniag im aRay of miamneedles that traee ahear forees daring a da mold'vl pmeedure to errate almp hoAow microneedtes.
Additional advwteges=nd otheranoveJ fauum oÃthe invention will be sot farth in part in the descriptiun that Mows and in pwrt will boooma spparent to tLoae dcilIeA in thc sut upon ecaminstian of the 1'ollaaring oor may be learaed witli the pracssca of 80 invention.
To aabieve the fotdEoing and othar advantages, and in weordme with one aspoct of the prasant inventim a fut embodiment of an improved rnioroneedle array is is oonstNobod of silicon and aUicon dioxide coanpounds using MEMS (i.e., Mioro-Eleot<o-Mooh=nical-Systama) tac6Mobgy and staodani miaobbrieation teahniqaes. The mioeomedle wap may bo fihaiaatai ftoma a aificm die wb{ah can be ebchod in a microfabrication paoees: oo oiate hotlow or aalid individual microneedles.
T[ie reaWting array of microaeedles can penetratn with a stnall pressure through the attatum corneum of skan (including sldn of animals, relttilee, or otlter creattua--typicaliy skia of a flVing aeganism) eo eetlwr deliver drW or to Uilitue biolog1cs1Md sampft (e.g., aamplimg iotmrstitial fluida andlor blood) through the boiiow mietoaea3lec at poe+es made th3+ougb skin via solid micronoodles. The drug reseivoir, andJor the chemical analysis compoaenta for sampling body fltrid, may be fabricated inside ft silieoa die, or an additional thiok fitm layer wm be bonded or atheravise attaehed over the sEh'oon mftftte to araate the regervoir. The delivery of drags aed sampiing of fluids can be performed by way of pasaive dffWoa (o.g., timp rakaae). matantaoaoua itljedioen, PnwMai vacamm, udtrammd, aAr electWlwrcais (a.g.. iontophocrsia). A compZete closed-loop systtoa caa be manufacturod includipg aotive elemdtta, such ae micro-machined pmnpa, heatera, and mixers, as well as passive elements such ea sensors. A smart patoh can theneby be fibrlcatod thtut samples body flnida, par6ortna ebendatry to dcoide on the appmpriate dtug WO OW74764 pCrrBS0on5612 dosage, and tben administere the comeeponding amoam of drug. Such a system can be made disposabio, including one with on oa-boeird power suipply, In a second aobodimon% an sriay of hollow (or solid) microneodlog can be conaruieted of plastic or some other type of molded or cvst material. When usirig plastic, s a micso-rnachining teehniquo is vaed to febricace the molds fior a plastic micmfonming prooess. The moMs mte detacheble md oam be ra-uaed. 8iace thiq pTOoedmm reqnisrs only a one-time investmont in the mold miero4naehining, the resulting plastio rnicroshucture should be much less expeneive tlun the use of mierofabrieetion tecWques to constiuct microneedle arram as well as being able to mmufactm plastic mkmamfle arraq+s Tnuch more quiekly and acxsnratelyr. It wiil be oadorstood thet sueb hollow niiorrtneedks may also be referred to hec+cin Aa "hollow eleraents," or "hollow projocxima,"
inaluding in tha claims. Yt wi1l alao be uddeamod Nut sudi solid micmoeedks uW sleo bo 1 9rx~e1 to haeein as "solid elemoats," or "solid projections" (or merely "lm.jeqioo"), including in the claims.
IS Molds uted In the ecmd embodietent of the preseet invetuion can eontein a mieropillar array and mict+ebole auay (or both), which we fiebricated by micro-machining methods. Such micao-machiaing met6ods may inclnda micco elecnode-disehatge machinmg to make the moWs fronm a variety of inesals, ieclading staieileaa steel.
atuminums, copper, iron, tunptm, end their alloys. The molds altarnatively caa be fabdcatod by micxofabriatioti technSques, ineluding deep reactive etching to mate silioon, eilican dioxide, a,nd silioon cerbide molds. Atto, LIGA or deep W
ptooemcs can be used to make molds andlat eloarapiatod metei molds.
The nvmufthttfng pnoee&mes fbr acaiog plaetic (or otlttr moldeWe meCemisl) acmya of miovoneedlea ir0uwle: "satf-moldiog," nmitxomoiding, microanbouing, aad m,iaroiqjec2ion techniylos. In the "stdf-motding" metbod, a pJsstic fibn (guch as a pulynw) is ptaeed an a mietnpiller eraqy the platic is tbm beamd, and piaadc dofbrmstion due to gravitational fanae causes thc plAstic film to doform and araete the microneedle atnwtiua. Using tbis procodiuo, only a single mold-half is required, Wlu,n using the micrnmoldiAg tocFnuqK a similat mitxopillat aaay is used along with a aeeoxd mold-half, whic,h is then closed over the plasdc IIlm to foim the microneedle structurc.
The miom-ernbossing method usas a singlc mold-half that contains an srray of d WO UYl74764 micrapillars and conicat cut.o ts (miCroholes) whhiab is pressod against a flat ssuface (vrhid essantim!!y acts as tLe second mold-halfJ npon which the platie film is ieitially plsxd. In the mieroipjectioa method, a meltad pfasdc aubstattcs is injecbed betwean two inicro-rnachined tnolds ffiet oontain microhole and micropilL9r atrrtys, s Of coarae, matead of moldinig a plastic matpK the 3mic[qneadlc ways of tho Pmot invcntion could alw be cvoawded of a tnetallic mate=iai by a die easting method using sosttc of Oe sarne structures as are used in the moldipg teehniques diocuaaed Above.
Sioce noetal is somewhat ata+e expensive aed mora dffwla to work witb, it ia probably not tho prefetrod matarial exaept for some very striogeat nquirements involving unusual oh nicalc or unasual appliatdon or pLecc ckeinnstances. Tbe use of chmucal anhsncas, ult:asound, or elecfria fdds may also be und to intrease tratudanal flow t1t.e whea used arith the mitanneedle anays of the parsent iavmtioa.
In the dispensing of a liquid drv& the pre4ent inveation can be effeydvcly combined with t1u application of an alectnic field between sn anode and cathode attaehed 1s to the sldn whicti eaoses a low-kvcl ciocxeic cw+ent. The present invention combines the a-icroncodle sray witlt ebcanphoretic (ag., iogwphos+esis) or electroosmotic edohancemcnt, whic6 provides tfie necxaeary means our molecules to Iravel through the thicker dermts into or fro,m the body, thereby increasing the pormeebility of both the tb*xiWn eornenan and deapen layers of atdn. While the traespoct improvement through tho stratutn comeum is mostly due to microneodie piercing, eloetriophoresis (e.g., iont+opbor+etie) providas higher trmtsport tates in epidetmis and dermis.
The ptrosent invention can thereby be used with medical davicas to dispemse drugs by alcctrophomtic/microneedle cnhamcernent, to san*e body fluids (while providing sa electcopboretieally/miczoneedle-enhanced body-tluid senenr). and a drug delivery systecn with fluid samspling foodbiek using a combinuion of thc other two devices, For example, the body-fluid sensor can ba used for a oontinuoua or periodie sampling noninvasive measurement of blood glucose level by extracting giwmse through the skin by revexse iontopltoresis, and measudng its conoartration using a biocloctrochenical sensot. The dxug deiivery portlon of this ittvention usas the nticroneodie array to provide elecxrodes t6at apply an electric potenttal between the electrodes. One of the electrodes is also filled Wp W74764 PCTJIJSlO/15612 witb an ionized den& and the ahrrged dcug taol;eowles move into the body due tn the applied electiic potcnxial.
In an atternstive embxihmwt of hobow miaattoaues, an edged micraneedle is provided that inciudas at lanst one ioogitadM blade that nms to the top surFace or tip of the miaroneedle to aid In pencRWon of the stratum comaum of tlsin. Tha blade at the tap surface pmvid,as a sbnp tip ft in.a+aises the It7r.obltvad of penetrating tba skia wFm wmiu~g into coatact tlurewith. ln a psefrrrad mode of the edgu[ hollow miaeonnedks, thert are two such longitudinal blades thet are conetiiteted on opposite smPacea at apptnxiruately a 180' angle along the eyliechicA! sida walt of the mieroneedUe. Bavb lo eW blade tu a crosraeaian tbat; whea vieaired fwn above ft mitxomodle tap.
las a pro5k that is spproximakly thW of an isoacolea triangle. 1t-e blade's edge cen run tho oWit+e kngth oftbe mimneedte fl+om its vary top smface to its 6ottoum surface where it is nomted oft ft substrato, or ft edge cm be disoontb-ued partway down tho lenplt of tha uuamneedle as 11>G miaonoodie otster surtwo appraac8es the anbatxata The ts orientadou of tbe blada in the t3ticronocdle array can be random, in which the blades of variouc iadividud microtteedlm point in t(! ditl'erent dhoGfions.
In an attexnative anbodimeat of a solid mianoneedle, a star-shaped solid microttoodle is provided bavung at ieact one btade with a TelaQively s>op edge to assist in peaetradog the stralian oorneuzn of elaA. In a prefeAed embodirqent of a bladad cr cdged 20 aiotid microne dle, a tlm pointed stsr-theped solid miaroneedle is provided In which eeoh bladc has a tinsugular etast-tection when viewed &amn the top of tlte micro eedle, and eaoh of ttaae triaaglos appt+oximatee d>at of an isa9oelea triettgle. Tbe base of each of the ieoaoeles uivon meea at a ocoer of the micaaneedle to fo[m asatdaped s<tuaun when soao frotn the top of the nxicrol-eedle. At least one hola through the substrsta 25 preferably is baatod aear Iho side sut6oea of at ieaat one pair of bladee of the soHd microneodk, and pmffecabiy a dmnugh-hole wouW be located near eaeh pair of sacb blades. In this prdmired embodiment, thete wottld be tbrea edged bladec aad tbras a4accnt ttnoueholes in the substrste for eaeh mieroneedle.
In a fittha altoZnstive embodiwatt, a porous polymer, wch as a hydrogel ar 30 solgel matrix can be impregueted with active maotaial and deposited in the inside comers boween the bladcs of tho star. This prov{des an additional delivefy meoltanism.
e WQ I[IrJ4764 PCTlIJ500ri5612 1be mictonoadle arrays of the preeamt invention ane Qignifipmt]y improvod by using a proper separation distattoe between each of the individaal microneedles. A very uaefiil range of sepatstion distances bdween miaonaedles is in tbo range of microns, and moae preferabiy in the rango of 100-200 mim+m, The outer diamcta and mica+oneedlo length is also very important, and in cmbinalion with the sepsration diatance will be anecial as to whCtfnr or not the u2ieroneedles will actually penetste the sMun comanm of sitin. For holloar eiteutw microneedles, a uteful outor diamotes taage is from 20-100 mierons, and morz preferably in the saage of20-i0 xniarons. For cincaiar micxoxaeodles that do not have sharp edges, a useful length for ase with interedtial fluids is in the rango of 50-200 micmns, and more pt+ekrabty in the range of 100-130 mimug for ase with other biological fluids, a usethl Iength is in the range of 200 microns - 3 mm, and mot+e praferably in tha iaage of 200400 microns.
For cireular hol[ow micr+oneodies having sbup edEos (such as those having t6e blades with griangular shaped edges), a useSul laigth for use with interstitlal tluids is in is the range of 50-200 microns, and more prefcrably in the rmge of 80-150 microns; for use with othaor biological tluidr, a usot4l kagth is agaia in the rwiSe of 200 miarons - 3 mnt, and more prr.farably in the xaage of 20040Q mimons. An example of a"ahsep edge" as used hetein is whetro the Bp of the blade edge exhibits a dimension at its angular ver=
that is ss netrow or narrowcr tfren 0.5 microns. For solid microneedlos having a star 2o s6aped pnofiie with sharp edges for its star-shaped blades, a useful length is in the range of 50-200 microns, aad more prstaably in the reng,e of 80-150 rniomns, while tha radina of eaeb of its blades is in the range of 10-50 znicmns, and more prefemb]y in the range of ] 0-15 miccons.
The praent invention caabe mmaunfactnred with an altcrnative methodology using 25 a mold preparation proced@e that begins by plaeing an optical mask over a Jaycr of PMMA mate:ial, then exposing the PMMA mataial tbat is not meslced to x-rays or ewther type of high enetgy radiation (e.g., neutrons, electrms), and developing that PMMA material in a photone;ist process. 'Fhe rumainitlg PMMA mataria) is then coated (e=g., bkeiiWlated) with metal, such as nickel. 'VVbou the oosting has reae6od the 30 appropriste thicknm it is detached to bocome a meral mold to create polymer or other type of moldable plsstic material. T7tis metal mold is then used in a microcmbossing WO /M4761 PCT/USOUlS612 prooedure, in which tho motat mold is plraaed against a heated Isyer of polymer or other plastie n-aDerial. Once the mold is pebesed down to its pl+oper distaaoe, the plastic or polymer material Is coolod to be solidifud, and the mold is thea detached, thereby leaving bebiW an airay of microneedies. If the mictt>iuadles ste hollow, then aitaraative procodures to create tbrnugh holes all the way tbrrough the micranoedles and its mWerlying eubstrate rnaEaial asos a methodology- suclt as, for axsa,ple. laser abiatioa, water jet cqsion. efocbrlo disoherge mscbroin& pissms atclring, and paYticle bombandmmt.
Another altemative prooa&ue to create polymer or plaatic micmneedtes is to begin with a two-Iayet laminate *ucUue of biocompatible lnaoerial. A rnetalTic mold ereated by UJ+ Pwm is thm pused down eII the way thmugh the top layer of this isminote, and paretally fnto ttse bottom lay+er m er,swe that tlte top laya is =direly panetixtr.d. This ooeurs wtu7e the lsminate mateaia) bas baen heated to its plastic, defonnablo tempetaturc.
Qace the laminatr maoerial has thet- becn cooled, tbe mold is removed and the top lsyar is dotacbed from the botoom layer Tdis top Lyar wi11 now have lwks ileat will be flufhea opecxded npon by a micomboeiug paqood.ure using a diffarent molct. This different mold creates hollow microneedlea, in which the through-holeg that notmatly need to be iatcr created ia the substrate have ahrady been crtated in advance by the firat pressing or molding procedure.
Another refineinent of the preseet iavendva is ao ereate a mit roneulle ar,ray that has senft eapaldlities. ht this souctuca, the tips or side gnooves of the miemneediea are ccated with a puticular chemical that aida in detecting a partienlar chemiosl or biological stnscturc or fluid that come into contact with the tips of the mioroneedles. A
sensing means is perfonned by tho use of optioal enpV, for example suoh as a laser ligbt aowce tbat is dit+eoted thraugh the tnwmneedle stmetiae, in which the miczoneedles thcrosclves are made of subatantially fransparalt iroateriaL Other sensing mcehanisms alsa conld be used. as discussed ixxrinbe]ow.
A further alternative msnufactuming process for hollow or solid mieroneedies is to create shear forces along tha oWtr snrfiaces of the diatal or tip poc6an of ahe hollow or 30solid nnicmnoedie dming its amlding or embossitig prooecs. '[le shear farcos are aetually errated during the de-moldiag step while the microneedle array materiai is beiag cooled.

Wd 00171761 PCTR3S00/15612 T'he amount of ahw can be controlled by the cool-down tamperatu% a.ttd if properly done will result in m"meedlas having-elanp edges (radur ttran mooth edges) along their upper surfues at;hcir tips.
S6l1 otlx5r advsntages of the pneseat invention will become apMwt to those $ 9ldlied in this art 6rnm the foliowing description and drawings wherein there is described and shown a profened ambodimmt of tlds invantion in one of the best modes oontemplated for carrying out ti-e inveniion. As will be realized, the immtion is capable of orher digerent embodiments, and its ecveral details arc capablc of modification in vatious, obvious aspects all without departing from ttle invention.
Accordingly, the drawings and desarlptions will be regardat as illustrative in nat3re s:nd not as resirictive.
BR[EVDESCBIriYON olrBa Diuwilvcs T1-a acconapaaqriog drawings ieicocponied in and forming a pad of the spec9fication illuslrate scverel aspects of the presenr invention, and togeticer with the is dasmipdoa and cialms setve to aocplain the pinciples of the imrcaeion. In the draarings:
Figure 1 is an ekvational view in pactisl eross-saction of a bottorn mold piovided at the imuitid step of a "sdf-mokliag" mrthod of maaufk=ring an airay of piasac mieroneedfea, as consiruetcd according to ttic principles of tha present invondom Figure 2 is an elevational viaw in partial cxcas-section of the mold of Figure 1 in a aeoond stap of tbe self-moltiing pmcedute.
Figuro 3 is aa elevatioaal view in partial etoss-seotion of the mold of Figure 1 in a tbu~d at~ of the soif-rnoldiug panoedure.
Fignrc 4 is sn olevatiauat view in partial cross-section of the mold uf Figure I in a fauth step of lhc aelf-molding ptooodpto.
Figure 5 is m alevational view in paaztial cross-seotion of the mold of Figura 1 in a fiRh step of the scif-awlding procedart~
Figure 6 is'n r,levstiotral view in crmas-section of an array of hollow micrr,needles eonstructed according to the solf-moiding pmcodus+e depicted in Fignres 1-5.
Figarc 7 is a cxos9-sectional view of a top mold-half used in a micromotding procedure. according to theprinciples offlu prosent invention.

it WO 00174764 PCl'/USaOns61:
Figuro 8 is an olevational viow of the bottom half of the mold that mates to the top mold-half of Figure 7, and which is used to fotm plastic nrtct+otteedles accor+ding to the tnicromolding pt+ocedura.
Figura 9 is an elevational view in partial cross-seation of one of the method steps in the tmuaeomolding procedm uaing tha mold halvzs of Figures 7 and 8.
Figare 10 is an elevational view in pattial eross-section of the mold of Figure 9 depicting the next step in the miemmolding proeedure.
Figure 11 is a cxoss-xcCional view of an arrsy of plasiic rniecvnoedles eonst:ucted acoording to tbe rnicromolding procedure depicted in Figures 7-10.
Fignre 12 is an elevational view in partial eross-nccion of a top mold-half and a bottom plamu surface used in ereatiag an array of molded, plastie inica+oneedles by a micmanbossing procedare, as eonstructod sacordirg to the principlas of the preaat inveation.
Figure 13 is an elevational view in partial cross-section of the mold of Figure 12 in a subsequent pmcess etep of the mieroembossing method.
Figure 14 is an elevadonal view in partial crosa-section of the mold if Figurc showing a later atep iu tb0 microembossiug proeedute.
Figure 15 is a cross-seetional view of a mioeonecdle ariay of holiow nsioroneedles cotfsnveted by the mold of Figwm 12-14.
Figure 15A is a cross-soCtional view of an aaay of anicroneedFes which are not hollow, and are constructed acconding to the mold of Figures 12-14 without the micxopillars.
Figure 16 is an elevational view in pattial cinss-sootion of a two piooo mold used in a micmiajeotion mothod of manufacturing plastic microneedies, as constructed 2s according to the prineiples of the present invention.
Figure 17 is a cross-goetional vicw of a micronoodle array of hollow n3icroneedlea consbvcacd by the mold of Figure 16.
Figme 18 is a cross-seational view of the initial semiconductor wafer that will be formed into an anca.y of nticroneedles by a microfabrication prmc.edwo, according to the principles of the presau iuvention.

WO Non'4761 FCTIDS00/id629 Figure 19 is a crosi-seorioasl view of tbe semiootrductor wa$ot of Figure 18 after a hole pattem has been establlahal, and attar a si]ioon nittide layer ]wa been deposited.
Figura 20 is a cms-soctionel view of the watb[ of Figtr,e 18 atter a photoresEst maslc operation, a deep reactive ion eLoh operation, aad aa oxidixe operation have bcon QCrfOrn]ed Figure 21 is a avse-seotionW view of tbe wafr,r of Figrue 20 ahar the silioon nitride has been rcmoved, and after a deep Yrwtive ion ctcb has created thmugh boles, tlmtreby resuitiag i,n a hollow taicroneedle.
Ffg= 22 is a patqeCdve viow of a midronmdle array on a samieonducto:
subst<ata, including a magmi6ed view of individual cylindrical mioroncodiex.
Figiue 23 is a aoss=sccdoaal view of an elecerophamtically eelasaoe! body-flaid scador, basad upon a boliow miearioedle asngr, ss oomet<ncted aooo[diug lo dte psinciples of the pcpent invs,n4on.
Figure 24 is a croaa-sectim~at view of an eleofrophomtiaally mhsooed body-fhud 1s aeuoor, based npon a svlid micxnneadle acray, am aonattuftd aocording to ffie prlnciples of the paicer.nt invaatim Figare 25 is a aou-seciand view of an etxuode, based upon a hollow nziwoateedle atmy, as eonstivctad according to thc principles ofihe present invention.
Figurc 26 is a c,rose-ucdoaal view of an eleotrode, based upon a golid baioroneedle sm, as eonshicted aocotdfiug to the prkciplas oflhe paaen[ juveatioo.
Figuro 27 is aprrspwtive view of a soosing syatem attached to a huinar, band and foz'earm, whiob ineludos aa eiec.tmphorodcally entutnood body.Huid sensor as per Figur+e 23 asid an aiwrnde at per Figons 25.
Figun 28 is a cmw-sectionad view of an electraphot+etkaIly adtenoed drug detivery system, based upon a hollow mi.omlteedle aaay, as constracted according to the principles of t&e pramaot invnation. -Figune 29 is a cnoss-sectiml view of an aieotrophoredcally mbanced dmg dalivery ayston, based upon a solid micronoaAe array, as conatraotod according to the pzincipks of the preseert iavehtion.

WOOt#-74764 !(,'T/u9lNa5612 Figvre 30 is a peespeadve view of a closed-loop ckug-clelivery system, as viewed froce the side of a patch that makeR cotttact with the skin, as cottstrqnted accoading to t11e pdnoaples of t6e praent inventian.
Fignre 31 is a perspective view of tbe olosed-loop drug-delivery systemn of Figure 30, as seen $+om the oppoalte ode ofihe patcb.
Fisare 32 is a paapecwc view of aa altmo.tire m4bodirnaat hollow microaaod1a fiaving sharp edga foi gtUter paaatration into slCin.
Figinie 33 is a top plan vlcw of the edged bollow micronaedle of Fignre 32.
Figure 34 is a peespea4ive vkw of aa alteraadve canetouctiolt for an edged hollow microneed.te as seen in Fipre 32.
Figure 35 is a perapeotive viow of an ahexnativa embodiment sotid naicmnecd1e having aar-tiuped set of daaap blades.
Figore 36 is a uip plan viow of Wo snr-siiapod wlid mive+oaeedie of Figare 35.
Figut+e 37 it; a tabie of taic[oite;edla peoetraioa- dsta fer an smay of cil+cular hollow iS mir.iot~odka ~tt a sep~on dialmoeaf30micm~oa.
Figuro 38 is a aarble of tniw+onoedie penetration data for ao aaay of cfrculau= hollow mioroneedles at a soparation distsnca of 1001nior0as.
F">g-Ve 39 ia a table of e<inngWe paeeUWam dua for an am-y ofcirouiar bollow micraaeaedies at a sepsration distancQ of 150 microns.
Figure 40 is a mble of mirroneedie penat~ation data for an alray of ciraalar hoitow miaroneedles at a sepaaation diaanoe of 200 miavne.
Figure 41 is a table ofymc+vneedie peautrattotl data for an array of clrcutar bollow roictoneedles at a mpeaatioo discmoc of Z50 laiavns.
Figure 42 is a table of taacrenoedle penettation data for an array of ciranlar holiow micraneedlee at a sopa:Rtion dishnce of 300 naict+ons.
Fig-m 43 is a table of mimoiioedle pencrration data for an aYray of edpd hollow microneedles at a separation diotance of SO a-icrons.
Figuro 44 is a table of microneedle pencftiion data for an atiay of rdged hollow miaoweedles at a sopaatio dbbm of 100 microna.
Figum 45 is a table of mimneodle poaotlatiop data for an array of edged hollow !lmcaoaeedks at a sepalation diatanee of 150 micrrma.

WO 0U174164 rCTlU600/i5612 Figure 46 is a table of microneodie ponotration data for an arrey of edgcd hollow mica+oaeediee at a aqacation distiaoc of 200 mic~mat.
Figuro 47 is a tablo of mioraneodlo penetradon datu for an array of cdged hollow microneedles at a aeparation distance of 250 microns, s Figato 48 is a table of aoicwaeedle penetcation data for ant atray of edged hollow microneedles at a sqraration distsflce of 300 mierooa.
Figure 49 is a gnph showing the eff'act of microneedle sepsration versns hansdermml tinx.
Fignre 50 is a graph showing the effieot of mlcronealle length veraus tcmnsdccmal to flux for two differmtt aaioronoedle sepatation distmroes.
Figoms 51 is a gaph showing the effect of miaroawedlee langih vecsus a rado of trwsdemnal flux votxus skin damage, for two differant miomneedle separation distauces.
Fignra 52 is a grsph showiag the effeat of Vplied prearam of a fluid versac tran.9dstmal flux for apenicularmieroateadle atray, ls F:gures 53A-S3E aro aievational views in cross-section illustrating stepa for pieparing a trwld for a miqvtnolding psmxdn:e to cmte hollaw circutar miomaeedles.
Figaces 54A-54F are alevatioasi viaws in cross-socgodn of paaceas steps for a microembo3siaE procedure to ereate hoitow nnicraneedles, as well as micromachining and 1a.ser bunwig sqeps to carate hollow chambors and thrnugh-holes in the botoQm of the 20 substtate structnrG
Figures 55M5F are elevational views in cross-seation of fuitb.er process steps for oraating holim miatoaeedlta.
Figure 56A-S6B arre a alevational views in cross-seedon of 3miaroneedle a¾tays that have seming capabilittes usittg optieal devices or chemioal coaenge.
?S Figwma S7A-57B aro side elevatioosl viaws of a da-mokling peooedure to crea0e shaap iioliow mieroneedles.

bE?ALt.ED DF$CRIt170K OF IU PRBFtRRSD EMBODrMENT
Refere,nce will now be rnule in detail to the prescat prefexred efmbodiment of the 30 ivcntioq an examplee ofwhich is illastratod in akc accompanying drawIngs, wberein like numeraEs indicate the aame eiemaots throughout the views.

Waoa74744 FcTrtJSeone612 Rdbuig now to ffia dcawinga+, Figune 1 ahwws a mold ganoraUy dasigosaed by the refemnce numeral 10 that comprises a plurality of miaropil(am incltldiDg :niccvpillara 12 and 14, that are mounted to a basa 16 having a plaoarr uppar surfatx 18.
Micropillar 12 pmf'a[ably ia cylindr3cal in shepeq and has an outer diameter dasigoated "Dl,"
whereaa micmpollar 14 (which afso pmfaably is aylindrical in ehoqse) has a diemmter deslgntod "A2." T5e centerlinas of micaopiUn 12 and 14 an sapaated by a dietaaoe "p3;
and dw vortioal6eight of mift*llara 12 aad 14 is dasigtWod by the Iatter "L1:' In a preferred configiuation, the &oerrrs DI and D2 ane ia the ranga of 1-49 micrans, more prefaeably about ten (10) micooas (i.e.,1O micmna =10 misrometers), the height L1 in tlu rmgc of 50=3000 mia+nns, whexeas the separadon diatauce D3 is in the range of 50-1000 tniaeronm, nm preftably froan 50-200 miq+om, Micmolecttodo-disc6rrgs m,ecteiniag ese be ased to fabricate the mold 10 from matats, suah aa sttia'iess tteel. alumimmm copper, ima, tnngsten, or other mata) alloys.
Mold 10 ovuld also be fabrlet-tcd from rilioan or siticoa carbide uslag htemted drauit - proeeasim orphotolitbographic prDearft F*ite 2 depicgs tbo mold 10 wd a thiq ltW of plslsk ss;ch as a polyosa film, dealgaatcd by the refdrenoe nemGral 20, which 3s plaoed on the miciepillara 12 and 14.
t4~rreby mdCing oootact at tha ti+aftcm tnnmals 22 aad 24, respectsvel.y. Onos the polymer film is placed an the micropillm. t6e polyraiar is 4aated to just above the motting tempttature of the plastie material. AsaropiIIara 12 and 14 are heated to above tha glass transition tampeiataee of dw pWtio matena1, but are pceferably held below the inelttng temparature of the platia mataial. 'Ibi: eetabiia6es a umperetat+e Vadient withitt thc plastie 5ha, xfbw which the p4Ac Mrt Is anbjeeted to nataral giavitatioaal fotces, or placed in a aankitage. Z'Wrthe[mom, an air-pre.esure gradiwt aieo c'n be establiahed aarm dw deFdrmiD,g piaelic fi'lm, by applyit-g pt+essure $om abovr, or by applyFnB a vacuum from below the filns level. 1U ovasll etrt'eet on the piaatic filnm is 69 it will nndargo a"self-molding" oparatioty by way of the gavitational force or oaturiftigal forac.
and tha air-tressore gradient can be usod to aceeleata the aelf-motd'iag proaess.
Figmm 3 depicts the mold 10 at a ftathor step in the pxocessiag of the plastFc film, shoaring the reaelt of the MpMtM gradient. This reautt is that the areas contacUng the mierapillars (at the rafa+ence numerale 22 and 24) will have a sm,allcr dcixmadm as WO OW74764 PCT/US9U0Jl9i22 ooampated to ihe i+emaitiug portiwaa of the plastk film 20 that m batwodt the pUlars 12 and 14. 'lberofore, tha poetiona 30, 32, sod 34 of the plastic matarial will undergo gt+eater defixmptioa, as viewed on Figame 3.
Figq[e 4 ckpiass the taold l0 at yet a lata step in the self-mold'mg ptocesa, s showing the leitial8bga in which the uald (inchuding iaianopitlan 12 and 14) is imted above the melting teanpeakne of ft plutic uataia120. Dusing this lattar stege of the self-moWng proccss, the p1a=flc matatd wi'ti oootiaue be meit aad to be removed km the topc of tlte pillat>e 12 a-d 14. As vkwed 'ut Figure 4, tbe ramaining p+urfions not in contaet with ediaropilWs 12 smd 14 will ooutinne to ddoam dowaward (la viawed on t0 Figmrs 4) at tbe rofa+mca aumerals 30, 32, and 34, Figue+e $ depicts the mold 10 at the Sual atage of salf-molding, which illuatrates the iket thet thc plaatie muexlal has complelely melted down and away fm ehe tops 22 and 24 of ttt4 mioropitlars 12 and A. At tlois point tlsa mold aod the plas&
maiedal art both cooled down. tlMaby foaming tha fmai shape tl,at will become the mioroncedtes.
25 T6ia finai-abape inchOw an ouda' wa1140 and 42 f,ot the micraneodie being formed by uticvopillar 12, mnd aa oatet waII at 44 aud 46 for the micronoedte being fomned at the mirropilIa 14.
Fipm 6 ilh>etmtes the crost-aootiomai sbapo of the micronoodlc wray, generaily desigaated by ttle tr,fereaoa nunfemt 60, afta it hes bean detached ltorn the mold 10. The 20 leR bmd arimaeedle 62 hss a rdatively slaup upper edge, whiCh appew as po4nts 50 and S2. Its outer wall is illnatested at 40 and 42. whiob are slopat with respeet to the veatioal, as deeWmed by the anglec "Al" aad "A2," The right haod side mic,omoedle 64 exhibits a dmilar sharp top edge, as indicated by the points 54 and S6, and also exbibits a stoped outer waIl at 44 and 46. The angle of thia ovier wall ie indiaated at the angles 25 "A3" and "A4." The prafered value of angles Al-A4 is in the range of zero (0) co fntiy-five (45) degrees. ' The iumer diamster of the left-hand mictvnoodle 62 is indicated by the distance "Dl," aad the haner diameter of the ag6t hwd microneedle 64 is indicatiod by dse diatance "D2." Thcac distances Dl and D2 are anbstantiaily the sAtnc distbmee as the diameter of 30 lpicxopillars 12 imd 14, as indieated in Fism I. FuAt7ptore, the disrmce D3 6ctwoea the centerlines of the ntiaroneedles on Figure 6 is csaemiatly the seme as the distanee D3 tf WO OO171764 PC'T/U300/f4Gt2 be;weon the mioropillars on Pigan I. The lcngth "L2" of the miormeedles on Figura 6 is somewltat less that- the length Y.l on Figure 1, aldtough this lat*th L2 ooatd theo>cfi"lly be a mWmum distanco of Ll.
It will be undemood that the plastic material (also i+efared to bereriit u the "Pply+na fdm") IDa]+ cande of my We of pownudy debamMe mattsial tb4t is capable of nndegOing a greduai defortnation as ite mtitinS point is raaiaJfod or sliglttly excaeded. Tbis "oudc ataooriai" cadd eveo be .ome type of tnerellic substaoce in a siturtim where tba mat0o m*rial wauid defvtm nt a low awugb omqwCaaum so as to not haRm the mold itsel Tlta ptefeaad nuftral is a pbtyamide enclt as nybn, alt4ou8h m,my otLer types of polymer mmtenal mainly could be naed to &dvszMW- QtMr poleetial anataiats iachide: polyesters, vinYls, polystycattes. polyrarbumta, acrylica euctt as PMNA, pi*creftmm epoaidas, phenolics, aad aarylonitriles like serylotdtrilebntadienez tyrcno (ABS). Of cwnrae, one important orittxion is thst tbe mataial which makes up the microneedies does not chemieally reect wltb skin, or with is the 8uidic substamec tl,at is being trmported luratgtt tho hollow itttaiars of the tnicroatocdle anay.
Figure 7 dcpictts a telt mold,44 gr=2ily drsigoated by the refaueace numarai 110, of a seannd esabodime t of the present invention in wbioh tl-e mmsufaalnrong metltod f+or etroadng an aary of hollow tnicmneedles is performed by a rnioromolding pr+oeedam.
The mp moJd-hslf t to indewae vwo "yoieaoholes dqt bava sloped dde wa1)s, daaigoW
by the neferenae tpRnerals 1I2 and 114 for the ktt.hsnd miemholo 113, and by the refacnee nume:als 116 aad 113 for ttu rigftt hand miemhole 117. '17te miccoholea 113 aod 117 bave a vatical ('m Fipne 7) 1 ~ i, rsfetred 1o htxeip as a ditthmce "1.11".
11fioroholes 113 sod 117 correspond bo a paer of miclnpillant 122 and 124 t>hst are patt of a bottom mold-balf, generally desigmed by the refermce mmiber 120, tud illastra6ed ia Figure S.
Refetring back to Figure 7. the sloped side walls of the miorohole 113 atie depicted by IU atgies "A1 I" and "A12 " wiW xr.spaat to the vetrical. The side walie ofmiotolwie 117 are also sloped with respect to the vartical, as itlustrated by the angies "A13" and "A14" on Figmre 7. Simee miotoftole 113 prefasblEy is in a conieal ovetaU
slmpq the smgle Al l wiIl be oqaal to the tntgle A12; similarly for microltale 117, the angle A13 will WO OOr14164 lCJYU940Jt5612 W eqaa! to the angle A14. It Is pr*fesred that aU micxnholea in the top mold-half 110 eubabit the same sqgle with respect to tbe vertietal. whA meens titat attgies AI1 and A13 at+e alsd equal to one another. A ptt"fetred vsl.ue fla angles A11 A14 is im the rmSe of zatn (0) thmtt& farty-five (4S) deg,rees, Th,e laxgec the angle 8aan tho vcrt.icsl, the S greata the trawua to ft pian tioue when a mia+cnaodle ia pressed sgainat the slon. On Figute 7, the ilhtatratfld aogle Al I is appmxitnately twalva (12) dagroea.
Rdcning now to Figvro 8, the botoam mald-Lalf 120 iOnaludea a laat 126 hsvfng a sabstemtiaify phmat top saufwa 128, upon which tbe two miempilFrrc 122 and 124 uo muunted. '1'hess radmplhta amc prefaably cylindrical in shspe, and hava a diarndar of Io Dj 1 atpd D12, respecfirely. The distance bothroen the eentmel'mes ef fltese ttucropillaa is ckaignaotd as DI3. Diametcrc D11 aod D12 pttsftably are in the naga 1-49 miaroas, more prr,ferably about 10 miaos-s. The distmca'D13" reptesonts the separation diatance bolween the conter tinss of micropiilazs 122 and 124, which prefaably is in the ranga SO-1000 raicroas, mena prctErably in the rsuge of 100-200 microns.
15 The two mold-katvas 110 and 120 can be Mricaod fmm metals uaing eaicme]ectrodeYdisobarge mechir+iag terbuiques. Aitecnativ,ely, the molds could be fbbriaatod from silicot: or silican carbide ysimg integrated aitcuit pmoeaeing or Ng"nphic On Rpm g- athin Plmc film, &menfly dmwaW by d1e refeceaoe m>taaral 20 130, is plaoed oa rap of the mkaWllaes and heAted above tha giase transition teamperaan of ahe plastio oatoW whib the pltawc met+mna1130 rats t>pon iha taps of the poll>YS at 132 and 134, thaeby causimg the p}at clic mAberlal to beeme snil'ieieat pliable or "sutr for P-uposes of permanotly deformnog tha rnateriat's s6spe. Prcfaably, the tempasiun of the plaatic mataiiel will not be mised abovo its melting tempoxattm, abhu$h it would not 25 iclu'bit the method of the pteeent lavandon for the plastic mtterial to becAme molten jnst before the next atep of Me procedtue. In Figme 9, ft top mold-half 110 is pressod downovard and begias to dofiann the plsstie film 130. Whiie a porlion of the plssga nmterial 130 temporatily residea above the micropillers at 132 add 134, ahrger amount of tfie plastic matecial is pmesod downwod direcaly by the nwld top-half 110 at 140. 142, 30 aad 144. As can bo aexm in Figu[e 9, ft two moid halves 110 and 120 ara slfgt-md eo tla the microhotea 113 aed. 117 eottespotsd axially to the micropillxra 122 and 124.

W0 00194764 PCTI[TSN/IB612 respectively, The two mold halvts now begin to operate as a single mold asscittbly, generAIIy desigueted by ft raferance nuoaaal 100, In Figuze 10, the two mold halves 110 and 120 have aomptetely closed, t6ereby syuoeaing a11 of the p[satie t eterial 130 away 8om ft tqrs of the udcrop?]lara 122 md 124. At this point, the plastie mic,aneodlea ara formed, and the mold aad the plastic materii[ are both cooted doanu.
The watl 112 tod 114 of tlso &at miccohole 113 causes a eide outer wall to bo formed out of tlbe plastie materitl ri 150 md 15Z. The eo sponding imwr wall of the miorotteedle 1$2 is depieted at 160 snd 162, wbich is cansed by the ahape of the lo microplllar 122. Sinoe tke aner wall is s]opod, et will aonvcsp with the nonar wall 160 And 162, near the top points at 170 and 172. A tianiter oew wail 154 and 156 is formod by the iw wall 116 w1118 ofmierolrok 117. TTso moerwall ofshe mQCroneedla 184 is dapieied at 164 and 166, md these mner md outer walls convarge s,csr pointe 174 md 176.
Figuna 11 illuthstes the micraneedle srray, gemenqy designated by the referewe numeea1180, atla the mold is reaaved ftm the plastic mtoerlsl 130. A lower relaiively plaaer bese namaine, as illust:ated at 140, 142, aad 144. On Figure 11, two di#oreni microneedlet at+e fa=ed at 182 mnd 184. The aqglea formed by t6e walls are ss follows:
angle Ai 1 by wa11s 150 aad 160, angle A12 by walla 162 and 152, angle A13 by Walls 154 and 164, and aogie A14 by walls 166 aod 156. The points at tlte top if the microneedles (designeled't' 170. 17Z, 174, end 176) are fairly sharp, and ihis shaipness can be adjwtad by tbo alwpe of the mold with nspeet to the asiaroLoles and micropillar oaentations.
Tbe itetar dismeeer of noc:nneedle 182 is deaigastOd by t!u dislemx D11. and t1o imm diraneter of the micronoadte 184 is designated by the distanoe D12, The distsmcc betwedt the caitaiinea of tiiem imicrqneedEQs i3 deaippe6od es D13. Tlsew disRsmces caxrapoa:d to thpsa itluatrated on Figue S.
It is pseht+od fLst ag of tLe aogles Al 1-A14 are equai lo ane wothea, and 8ut the angles fal witlmt the raage of uso (0) to forty-five (45) dagrees. The preforred atlgte wally depwds upoa thc stamS& of tbe mtoial being u,ed to ooMW 18e mierWaedles, wo ae/747a lCTN89olIddiZ

in whicb a gnater nngle (eg., angle All) provides "ter strength. However, this enguMr iticxrnee ateo ceeses Mmaei' ftmma to t6e slita.
~ lldioroneedie aaay 180 also iacludea a rela8vely flst bose shvctiue, aa indicated at the rofereQce nwrierals 140, 142, and 144. This baee swxwre la a vertical thiclmess ss s deagnated by tla dimeosieo LiS (aee Fipme 11). The micsaaeedle heighs is dftipdod by the dimeitsiatt L12 an Flgqcc 11. '1"he hcight must be safficieat to penctrate the eldn through the stratm eon== snd inba the epidermia, and apacehnod dimension Aarlmight L12 Is fn the range of 50-3000 micmns (althanglt, abttainly mic-+oneedlaa 6borter than 50 mierons in length could be constructed itt thia manner-for use with skin costnetica, for examploy. The thklmea: LIS caa be of mp- sizq howeva. the impotbwt criterioo is that it be thick enough to be mecbanically somd so as to retain tha mioronecdle amtotttre as it is used to peusttate tbe s4in.
Refex,ring yww to Figure 12, a top mold-balf 2l0 is combjaed with a plaaar bottomn mold-hslf 240 to create an eadre mold, generally designatad by thc refexaice numeral ts 200. The top mold-half 210 oDawips ao aaay of mic:aboles a-ith mictppilisns at 2e cmter of each of de microholes. For exatapW, a miot+oitole 213. bavia$ its ootucal wail at 212 and 214, is peafarably earaeenaic with a mierepillar 222, ali a microtrole 217, baving its oaadcai wali at 216 and 216, is pmfrnbly ooaceotric with a miasopillar 224.
The fabdoadon mashod used in conjmcdoa with the mold 200 is refared to henin as "mict+oanbossing" for ft reaon tkutt tLn bnmo9oa mold-half 240 is aiu*y agat or plsm eurfaco. Tbis greatly simplifies the oonson:adon af rb9s paRicular mold.
A tbin plastio film at 230 Is placed upon the top sadacc 242 of tlris bottom mold-ltaf 240. In the latrr steps, it will be aeou 11o tba Qlsalic mataria1230 is beaCed w5ile the top mold-lnlf 210 ie ptersed down againet ibe bottom mokl4alf 240.
Microhole 213 and mleropllar 2221u-vc an sngular rdationsidp as illnstrated by the aagles "A21" wnd "A22." A simitat' anpular ralatIonsbip exists for microhale 217 sud rnicropillar 224, as illushrabed by the mtgles "A23" utd "A24." 1bese aegles rxill prefersbly be in the range of zem (0) to foiy-8ve (45) dagrw from the vaticsl. As toied iferaradr4ve, 6e grieater the aogle, tbe greater the tcatqport r8te, however, aiso the gnstar irauma lu tho slrin tissue wbea used.

Wo on4744 rC17i3S0an5612 MicropMar 222 prcforably hes a cyliadrical sbape with an outer diameter designtmtod at "D21;' and micropillat 224 situilariy hos a prefarred cylindrical sbape having a diamewr "D22." Dia:neterx D21 and D22 preferably are in thc renge 1-rniceona, more prefcrabiy about 10 miorons. The disteace'7?23" roprestnts the sepatution distance between the center liaes of miempiltars 222 and 224, which poefarei,ly ii in the range 50-1000 microne, more preferably in the range of 100-200 micmns, Zhe langth of the micropillaxs fiam the bottoaY nKface 228 of the top mold-lulf 210 to the cloeed end of the rnicrohoks at 21$ and 225, respactively, is designated as the length "L,21 The mi=pillan 222 and 224 are aomewhat loAger tham this lengtb L21, to . since ihey are to mate againet tho upper surface 242 of the bottom mold-half 240, and thcrefore are longer by a distance detignatod as "L25" In this manner, the nnicron,eodies will be hollow tttrougbout their ontire l,ength. The eombfnod length of dimoasions L21 and L2S prefvrably will bc approximately 150 miorons.
The motds 210 ud 240 sviU preferably be made from a rndalt in which microcieetrode.disehsrge machining ean be used to fhbricate such metallic molds.
Altematively, the molds could be Sbrieatad ficoat silicon or silicon carbide, for axample, using intogaratnd circuit pracessiqg or itthograpbic processing.
Re&ciing now to Tignre 13, afta the plastie material Is heated above its glass ttansition teropcrafiue, thercby causing the plaofc maoerial to become sufficiect pliable or "soft" for psupoaea of pe:AnauetRly defoeaing the matetial'e shapo. PreRrably, the temperature of the phatic material will not he raiaed above its meltiag canpocatare, ahhough it would not imhit:it the mdhod of the preaant imrmlqon for the plactfc mateaial to bocome moltp: just ilefore the top nwld 210 begins to be pcrss do down against the plaetic matarix1230. This top mold movanent begias to deform ffict plastic mate.rial 230 75 snoh that it begins to fi1! the micmlwiq. 8s iUustrated at 232 and 234 (for microhole 213) and at 236 and 238 (for microhola 217).
In Figure 14, the top mold-half 2l0 has now been completely closed against the bottom planar mold-t-alf 240, and the plaaac materia1230 has now eompletely filled the microholes, as iliushated at 232, 234, 23b, and 238. IU shapc of the plastic ,mataial now has a conical outer wall at 250 aod 252, and a ooavspoading cylindrioat inner wall at 260 and 262, for the le&ilmd aucrosx.e3la 282 on Figure 14. Cosrespondingly for the WO 0017476/ ~GT![i500115612 right 2wnd microneedle 284, the plaatio matatial shqie 1-as an ontex Conicat wall at 254 and 256, as well as a cylindrical inner wtttl at 264 aod 266. The conical outer walls aMd the cylindrical inner w311s bonvatgo s-t the top points 270 and 272, aad 274 and 276. TI-o bottom st~wa 228 of tha top mold-1e1f 210 caascs a baae to bo fomied in the plastic matecia1230 at the locatioaa indicated by the refarence Aunnerela 244, 246, aad 248. Oece this sbspe Las beea foUOaed, the mold aed the plastic matrrial are oooled down, and tbrn the moids am oeprrated so thot tba plasti,c npioroaeodle array is dotached bo foaM the rbw as illuadraded in Figure 15.
In Figttr,c 15, a mdcronecdie array 2$0 has been farmai ont of the plasdc material 230, which m vic+red on FiSm 15 depicts two noictronoediaa 282 an8 284. IU
lcft-und miaaneedla 282 compdm an autor oanial wall rs viewed at 250 amd 252. and a hollow interior cylindrical wall at 260 and 262. These watls oonverge at ebc top points (ais viewed on tltie 1=ignre) at 270 uid 272, and tl-e convasgenee anglc is givai as "A21" md A222" The right haad mieroneeale 284 cottpriaea an ottDer ecaical wall 254 and 256 md ts a hollow interlor cylindrica! wall 262 atid 264, These wAW converge at the top points (cm this Figuro) at 274 and 276, and the cmveugancx anale is given es "A23" and "A24."
AiWes A22-A24 an prefersbly in the range of zern (0) to fort,y-five (45) daBeeo.
Micweeeedle asrq 280 aLw includes a rolstivaly llat lae suvewre, as indicaed at the refeaenoe nume:ais 244, 2l6, and 248. 'fhis base ocrnctume bas a vectical thiekaesu as dastgnstad by the dimmolon L2S. The ttdoroneedle he& is decignatcd by the diuaamda L22. 1LC 1101gbt 1s1116t bQ ltlWCot to pl96t[x~te ft ddtl thQ0ugh the mium comutaim and into " epidermis, and hae a prefarad dimensioq for uee with interstitial fluids in dtc raa,go of 50-200 miomea (al8sougb, aa noted above, mnch ahona miaroaeedles could be conwvcted in this mammr). The heigbt L22 eould atso 6a a greater distaeco for rte .viffi oftr biological fluids, preferabty in the range of 200-3000 microns. Tha tbicinesa L25 can be of any size, however, the irioporhnt criterion is that it be thick enough to be meebaaioelly oannd so as to ret.in the aniaoneedte attqetare an it is used to penetrate the tlcm.
The insfde diameter of the hollow microneedles is illnatrated as D21 and D22, which ooocrespond to the dimnetecs of a oylindrical hollow openiag. T'be diatanee D23 wo oon47w rcr/t1S8011501 rqmvatts tite sap=ration distenee between the evaterlines of 1bo two tnicnoneeBks 282 and 284, in tbiac ssray 280.
Figtut 13A tqresents an a[ternaxive embodanalt in vv8ieb a roicrnneedle aRay 290 compdsea `solid' trn +tmeeales 292 aoc129+t- zadec tbm hoIlow miproslmdks as aecn at 282 and 284 on Fig= 15, These eolid mioroneedtes 292 and 294 aze formod by a similar mold as viewed on Figpro 12, but witb tbe miempillars 222 and 224 ratroved fmm tUis mold, Iipd a e5aage in abepc of tlu micxaholes 213 end 217. lbis aimpia cbmge allows tbe soiid miamneedles te be fatmed wtdtin conical raictolalas (not shown on Figare 12), and ixodsx= a pointed ooimicd ahapw, ae wdn'bited by die outer onnird wa11250 and 252 far uueroneedle 292, with a top pointed sttrtbee at 296.
Sionlirly, the un=needle 2941tas a eotueal otttar wat1254 aad 256, wiflt a timil:t top pomtod ar6ice at 298. 2'ba other dimealsiar,s aod featuroa of the solid tnicraneedle anrry 290 can be exactiy the :ame as thaae fwMft of the itoltow naicmneadte turay 280 of Figure 15. or the dimaaaoas mqr be diffmmt sinoe this is tor a diffaant application.
t3 T7ta holes 251, 253, 255, can be fabricated durfng the mionost'mping or micraemboang proeedure via inclusiott of apprapmte oxraptl~ra loeatad adjscent to the microholos 213 and 217 in Figure 12.
Refocrsog to Fisum 16, a mold 300 coumiets of two tr-oTd-hah-as 310 and 340.
'ibese mold4kalvea 310 aod 340 a+e vlrnutily ideotaicd in ehape, and pmbebly in a;ze. ar compaied to the mold-balvas 210 and 240 of tBo mold 200 oa frigpre 12. T6e main diffhence in Figm+e 16 is tbat tbece mold haives are to be ased in a m4etwinjeaticln proceduro in which molten plastic tneteeai is injected from the side at 330 into the opening between the mold-halvea fotmed by pte botb= aurface 328 of the top molWnlf 310 and the top aurfaee 342 Of tda bottom mold-haif 340.
n-e mokd ancpse 300 is p¾cftabh- made of a mcbWc materid by a micro-uncltining pr+acess, ahhough it could te made of a fvnicvnductar material wrlt as silieon or silicon oabide, if dcsired. On Figune 16, the plastie tttateria1330 is being ffiled from the lofRhand aida in thia view, and has ah+eady Sllod a 8rcat micoohola 313 with plastic azatariai. T71e piastic rostead is itlusttated as it is advancing. and haa trached the point at the t+e5ei+atce manaa1336. As time peoceeds, de pMo metetiii wi11 reach and fill tbe wO 0074764 PCTlI3Soa/1 S612 second mierohole 317, wiricb has a eonicat inaer wall at 316 and 318, and a corresponding mioropilEar 324.
At ihe first ianicrahole 313, the plastic matetial has filled the shape around a micropillar 322 and within t1u conicai wal{s of tlus microbole 313, to fonm a hollow cvne having an outer wall at 332 and 334. The plastio material wftl be fnleed upward uqtil it resahes a top point as scen at the reference numaale 370 and 372. The outcr conicai shape at 332 aqd 334 will eouverge wNt1 the ititerioc shape of the mieropillar 322 at an angle dpignated by the, angles "A31" tnd "A32 " Microhole 317 also exhibits a coavargiug angular sbapa at "A33" and "A34," which is tho crn-vergenco angle betwerea the conioal walis 316 and 318 and the outer cylindrical ahape of the nucropillar 324.
Thc saparation belween the avfias 328 and 342 is given by the leogth dimerosion "L35," which will becomo tho thiclrness of the ptatmfaco nmaterial that will remaia orice the mold is opened The veatical dimeasion (in Figune 16) of the microholes is given by the dueension "L310 whieh prefcr:bly rvill crente micronealios lotsg enough to penetrace as through de straNum coQneam and into the epfdenmis, but not so long as to penarate afl tba way to tho demais when used with inteTStitial tfiids. On the otlur bamd, for usc with otbcr biologicai tluids, the microneedle leagth will be grcatar, preferably in the ranga of 200.
3000 tqitxons, so as to peneuve into the daujia.
Fzgure 17 illustrstes the mfctoneedle artay, geaeraily desipeated by the rofereaae numera! 380. On Figure 17, two micronaodles are il[ustrated at 382 and 384.
Thosc micROaeedlcs have a leng,th "I32," wbich in theory should be exactly tlu aame as the dineension 131 on Figu:e 16. assamiiog the mold was properly filled with mateIsi. A
pmfenr.d distance for L32 is in the rauge of 50-200 saicrons.
The plastic material 330 ba+s a pianar base suueture, as illustrated at 344, 346, and 348. The tluclettess of this base stcuetLne is the dimmsion L 35. The mia[onrAea tl=selves exhibit a c,onieal outer wall at 350 and 352 for the left hancl microneedle 38Z, and at 354 and 356 for the right.#tand microneedtc at 384. T:aeh microneodle has a haIIow interior, as illustratod by the cylindrical surfaca 360 and 362 for microneedle 382. and 364 and 366 for mic:roaeed]e 384. Tbcse surFaixs converge to farm points (as illumated on Figure I9) at 370 and 372 for miesnneedle 382, and at 374 and 376 for miotneroocAe 384, WO OW74764 PCTlIJBdWI'S612 =
1'ho cotuveiamr.c aitglo of theeo wAlla is detlgnnted by the anglec A31-A34, and prefersbly wffl be in the raoga of zero (0}to fosty-five (4S) degteas.
Tha innc diametor of aticronoodk 382 is givcn by the ditneosion D31, aad for miemneedle 384 is given by dimetWion D32. These dimonsions prafeiably aro in the s rango 1-49, more prefarably sbrn-t 10 nicmns. The etqtttcstion distance betareea the eentar lincs af the micaonccdtes it givtn at D33, w}dah peeferabiy is in tha r4uge 50-1000 mictnna, more preferably in the range of 100-200 micmns. The height L32 ia prefatably in the rengo of 50-3010 microns and, deponding upou the coavelenoe aeg]a A31=A34, ft bottom vvFdth of the eouticel mianocteedles aill vaty dopendiag upon the exaet t9 appikation for naage. In one prefetrai eQtbodiwent tb" baatrnan dituonaiaq deaigndted by "D34" aad "D3S," vra'll be approximt* tweaty (20) microus. The vettical thidmesa at L35 will likely be made as ft aa poseibte, howevor, the buportant cniterioa is t6at it is sufiYCtently thiok to be atochraically souad to hold the mir,noneedle erray 330 together as a sh*Ie a4ruotuse during actual ae:ge. It is UIcely tbit, fDt maat piastic materhda tbat tS might be used in thia tnolding ptoeedare, the dimeuiorn i.3S will be in tbe tange of ten (10) mieroaa through two (2) mm, or greater.
Tbe anpilar te3stionahip betwocn the micavneedlea and the oorucspceding planar base stnfaoa is preferably perpeodicuiar- although in qtaot ci$bt angle of 90 de,gvm is ttot 7equu'ad. This appHes to al! mforonoeclle ambodimeats hasin deoan'bed, inoluding 20 micnaaeedla 63, 64 s-d pbmar swrfaoa 30, 37, 34 of Figune 6, microneadlea 182, 184 and plauar aurFacae 140, 142, 144 of Figum 11, nuicmneedies 282, 294 and planar sau4cea 24t, 246,248 of Fignre 15, mimmeadlas 292, 294 and plaoar aufaoes 244, 246, 248 of F"igunc 15A,, n-iex+oneodles 382,384 od pluu sarfaoea 344, 346, 348 of Figure 17, and microneedle 470 ohd plsmec suirfaoas 440,446 of Figure 21.
2S It will be umdeastood that other metboda of fotmimg plastic micmnoedles could bc ntiiiaed to ceealo hollow miaioneedles in an saay, arithout dqpudtlg ftm dbe prinvaples of the praemt imentiom it will aieo ba mderstood that vorious tyM of materials could be used for such moldiag proaedmes, indttdtiag meteII{c materiats ilua meght be oa6t using higher taanpcratui+e dies of a similar shape and size, without departing from the 30 prlnciples of tbe presatt imeutiob.

WO ODfJ4764 pCT/o5o0/15612 It wiD be furttter tutderatood that vatiatioas m dimensions and angnlar reLtdonshipa oould bo utey'zed to coasttuct an artxy of bollow microneadles, withot-t depaatiag 6rom the prinaiplas of thc prasat-t invension. It will be sti11 Curther underatood that the atvular relationship between the miCromedles and their planar basc surface need not be precisely petpandieular (although dAt configuration is pteferred), but could have some variatioa without departing from the pcinciples of the praseut invanion;
the micmneadlea ai&o ueed not bc exactly parallel with one anothet, even though thst con5guration is prcfemed.
Yt will be yet finrtlier mtdaseood t6at other ttdcronee>3ie sltapes oould be usod th.n 1o a cylindzical shape, if desired, without dopsztu-g fnora the principles of the ptrsent invention. For example, the shtpo for ]soilow micc+aneedles cortt[d presaribe a eirclo, ellipse, square, ttiangk, orescoat or other arewRe pNL, or some otiier goometrlc structure for oither the inner oponing or the outar porimeter. Furthermore, the iaaer opeafng's shape conld be diffmmt from the outor periznetw'a abape, Moreover. it will be tandaatood that, witb only simple modiffaacions to the molds, an array ofsolid miomneedies oould be fabrieaiod using tbe molding te"ques deacribed htxtiA, without depat4ng finm tlze pirlnciplas of tbc preseut invmtion. The autat abape for such solid mricronaedtes coald preaan'be a cirelc, elfipse, squam trlangle, crescent or othcr ae coate patlt, a sqr or other jagged paimoter, or some other goometric sttnaw%
Referring now to Figure 18, a procedure for forming dry etchad microneedies will be desen'bed using an axatnple of tnierofabtication (e.g., se condiaclor fabrication) teehmiques. Starting with : s(ngla cryetai silicon wafor at rofa+enoe au:nera1400, it is pnefatrod to use a double sida poiish wafex and to grow an oxide layer on the entirt outer swfooe. In Figure 18, a cros-wetion of this wafer appeara as a aubstraho 410, a top oxida layer 412, and a bottom oxide layer 414. Any simgle cryetal silicon wafcr will suffec, ahbough it is prefemed to use a crystel stiuotttte 10b-type wafer, for nasoo,s that will be explained below. A 110-typo wafer eouW be used, howevrr, it would csnate different ailgks at eattain e.tchin,g steps.
To create the snuctoue depid.ed in Figure 19, certain pwom steps must first be performed, as desoribed beiow. TLe first step is a partern oxide step which is performed on the top side only to remove much of the top oxide layer 412. The pattern nard will WO OOR4764 BC'PRlS8O/15612 craa0e uaultiple anmutac regioma eamprking two concenlrle e;ralas eaah, of which the crosa-section vall appear as tha recemgies 416 and 418 on Figrae 19. In pezspeodve, these annu[ttr-sttttpod features wiII have the appeaeAnce aa illustratad on the perspeCdve view of l:igvre 22 at the refetmmnce ntttttetyls 416 and 418. These utnular oxide pattems s are the iuitiat stagea of tt-e sttay locations of the mukiple micxoneedWa triat wili be fozoned on ttds substrate 410.
The next stap is to deposit a iqya of silioon nitride using a low presautu vapor deposition step, wliiob will form a silim nittid.a layar on both the top and bottaau stufaoes of the auietrate 410. This appeus as the uppauo>t tayar 420 and the battpimmost layet 422 1md 424. If vifi be wvdastood thnt the battoanmost layar 422 aad 424 is one oontinuoua layer at ft step, slthougb it is not ilhtsoraned as snch on Fip;une 19, tbnce a later ft otohes out a portion of thc bottom side of the dvbstrsto betwaen ttu 3ny= 422 and4Z4.
Nemt u0 the ptooese is a patWn bottcan procsxim'e in vvbich a aquare hole is 1s pactesned bener8t the aunulus 416, 418, which is aa dizectly t+issble on Figttro 19. 11tia aquste Im1ee placed'tsy tha pstletn bottom procaedfue are now uaed in a KOH
etahing etqs that is apE-liod to the bottom side anly of the substrate 410. This KoI;I
etclft ft ar.+pdas awbWow alang tlye boetom of aha arbstcato es viewed aivag We aurlives 432, 430, and 434 oa Fipre 19. This window interrupts tho oxide layer 414 along ft bottom of sub>dtate 410, and divid.es it (on Figtme 19) into two aepwo 413 tutd 415.
This wittdorv (or hola) also inteuvpts tbo siliaon nitrida layar htto two segMents (on Figure 19) 422 and 424.
7he slope angle of the etahed window atong swQsa:e 432 ant1434 is $4.7 dagreea, due to the ptelbtted 100-type siliooa material. Iftype-i10 siifoom matmisi was esed, Sen this slope wouid be 90 degrees. TBat would be fine, Itawever, ctystdhne siIiaon 100-type meteTid is ir,ss eapensive than silicon 110 typo matedaL Afixa tlta bOH time etsLing step has been compidod, the silioon wsfer will hxve tho appearAtice as depiotod in Fipre 19.
'fhe next flaltrieatlon opaation is to perform a pattent top nitride pnor,ediue tuing a photoresist mAak. Thia removes the entire upper silicon nitride layar 420 exoept when the photortsist mask was located, which hapr,eats to be digned with the upper oxide zt WO 00I7471Mrt PCTNSGa/]5612 aanulus at 416 and 418. ?he rentainiag npper sI1ICOn nitride is indicated at the refsa+eaoe numerel 426 on Fig= 20, altbougb at this stage in tho fabriaetion procedure, the upper surface will stifl bo a plinar wrfice at ft levrl of the oxida lsyer 416 and 418, soroea ft entire horizomal dimension of Figare 20.
The neet fatuication atep is to parfonen a deep rzac.tive ion etch (DRIE) operetioA
on the top surfacx of the subetrate 410, which will atah away a tdatively dacp portion of the upper sabstrabc exnept at locetiona whare the siiioon nittide ltyer still remaine, i.e., at 426. In this DRIB ptrocotlnM ft is pmfeaed to romQve approximately 50=70 miaans of material. Atter that has occumed, the ranaish4g photonaiat mask matedal is removed.
This now expodea the top silicon nitrido laya 426.
The next fabrication etep is to oxidize all of the bsre sflicon that is now exposed along the outRx surfaccs, Thia wt71 fnrm a layer of silicon dicrside at ]ocaations on Figune 20, such as st 440, 442, 444, 446, 452, 450, and 454. Tbe oater silicon nitride taye:s d 426, 423, and 425 are not oxidiz.ad. Thc outer silicon nitride layers 423 and 425 are t5 essentially the sama stnwtuns as iayers 422 and 424 on Figocie 19, although the siliaon dioxlde laycLS 452 and 454 are now fotmed above theeo "pads" 423 and 425. It is pa~eferred that this oxidation be a mituimal amount, juet enwugh ft a futnre DRIE asaslring ps+ooedtue, and that the oziclized thicimess be approximately 5,000 AngsiroioQs. At this point in the tabrication piviced-u+e, the silicon aafar has the appearance of t4tat depioted in Figure 20.
The next step in ft fabrication proceduto is to remove the silioon nitride lW
on the top, which will remove the layer at 426 as serai om Figure 20. Tbis will expose a ciectilu region in the very center of the aeunelus saoh that ptue 6ilicon is now the outermost material on tho top stdc of the wafer, pAm that has occun+od, a deep reactive ion etch operation is perEbmned to eraute a through-hole at the rofemence mmwa1460 on Figure 21. After this step has been per6otmcd, there wtll be pune slliean exposed as the inonr wali of the thtottgh-hole 460. The,orfore, the ax,xt atap is to oxidiae the eatire wafer, which w0! place a thin cylinddcal slteli of silioon dioxide around the inaar diarneter of tbraegh-hok 460, and this oxidized layer is viewed on Figure 21 at 462 and 464.
After these ste}u bave been perForniod, a micmnacdle 465 is the resutt, having an outer diameter at "D41," aad an inner diameter tkough-hole at "A42." It is preferrod that WOM74764 lCT/f,16aWi5612 the inrner distnetar D42 bave a distanoe in thc tange of $-!0 micmm. The beight of the micrutoodla is given at tile di mdoa "L41," which has a prefaned dimemioa in the rstigo of 50-200 mimm. On Pigare 21, the substrote 410 ht19 beea divided into halves at 410A end 410D. In addition, the bottom o>dde Ieyer 450 tu ban ditridtd in haivcs at S 450A and 4508.
The bottom oMmber fozmed by dea slopeal surbces 432 and 454. in catabiastion with the horizontal atufaces 450A and 4508, aot as a smell, roaeesed storsge taak or ohamber genessily indlcated by ft sofaanae numerA 470. 'ftsis chamber 470 cen be usad to stame a iinid snch >ts insWin, $9 is to be dispeneed timoagb the aylindrical opening 460 to in the hollow roiareneodle 465. At the eeAlo of Fipm 21, ft chamber ia not very large in ovemtt pbyaical volmate, aed it aamsll)r would be preft to interounnat all ofsucfi ch.mbers for ach of t6e microneedlts in the ovaall array so that a comman fluid sonmo em>td be asal m dispwaso fitrid lo eich of U-ere chqnbarc 470. Fmtbarmom ahare map ba a need to dispeese a physically much latg,er volume of fluid, and it aiso may be deairabie 1S to provide a pesssaro 9ource, sttah as a ptaup. In auch situadons, it mey be profareble to bs'vo an extmnel storage tedc tlut is in comtounicition with en~c~ch of the fluid clwnbers 470 on tlte wafer that it used to maloe up the Attay of microneedlex, sar2- as microneedie 465.
Figtm 22 depicts an atmy of miet+oaeexllea on substrute 410, sod. ai4o illurtratoa a 20 msgnifieQ view of aom of 8xtso m=cwedies 46S. Each miemaeesile 465 axhibits a a]-littdtical attaQe in the vertiosl 6kxfiae, and hrs an oater diamoUar D41, an anmulor shaped uhper utrfaoa at 416 aod 418, and a thaangb,bole at 460. Faolt of the micronetdles 465 extods ow from the plsntr atfaCe 440'of the substr4te 410.
As can be eeon in Ngue 22, subote 410 cm eitlur be made mudt Iwer in 25 height so as to have a very large internsl volume for hnlft a fluid substmnce, or the snbatrate itsolf could he maurded onto a different matefal ttw hws some type of f[uidic opettiog that is in ocasamiadea with the obeIDbera 470 of tlta individpal micranaedies 46S.
It aill be umdastood thst ot#w samiooaductot substances bestdes silicout could be 30 usad for the faisr9cation of the aacay of mieronoodlea depicted on Figsm 22, without departing from the principlee of ft Feeent invattion. Fetrthermace, tha miamoodks wo aenrrsi rcrRTSee11961=
conld be aoated with matecials Bach xs s(lieon crrbide to impwt addi6ooal sbeagth.
Moreovpr, otber rnieroneedle thApex could be usied thaa a eylindrieal shape with an amular top surtaee, and in saey the bp sar6ce of eub misamaedks could be aloped to mreate adatpar edge, If dcsired, without depa;thlg fnotn tlm priociples of the paant s imna,oon, It witl aiso be uadei'atood dw tbe pl+ferred dimenaions dcussed hareiaabove an oniy prefetred, and atq+ mierotieedle length or diamotar dw is appnopriate for a partioukc chanicsl flnidic commpound aad ft apateWa sibn atnptwra conld be used vvitboat departing'liorn the prinafples of the preaent itrvendoa As diecussed above, for ase witb interstitial body lhdds ft is prekned dutt the microaoedle petxttate ftous6 the stratum corneum into the epidertnis, but not pcnettalc into the dana9s itaelf. This otems that onh miravneedles would typicaIly be no longec than two hutxlred (200) nticmas, thongTs they must typioaEly be at Ieaat fiity (50) sqicrm in letgtI. Sowova, for use with other biological fluids, a useful length is in the ranga of 200 mioroes - 3 mm, and tnona pmafsrabiy in tbe range of 200-400 mmierooss. Of comae, if eososeac appffeatiow we~e desired, then dw microaeedle could be much shortar in length, even as abort as aw (I) miavn. Fiaally, it will be. undaretood that aay sizs or sbape of fluid-holding chamber oould be wsed 'm a dtutdclivery sy-ata% wbich wip be fuctber discussed bc[einbelow. In addition, for a body-titiid aotn,pling systsm4 a fhtid-holditte obamber would sko pneferahly be In ootneannicatioo with ft tlnmgh bola 460 of ewh of the raiamnaodlee 465.
Figure 23 depiots an oleatrophorttiaelly enbaiurod body-luid sensor that is based upC-n a hollow mie,raoeedle atray, genarall,y desigasted by the [afextoce anmGrai $00.
Sansor 500 inalndes a plemlity of micromeedles 530. which sre esah holbw, havhtg a vartical opeairtg tlCOuglmuk aa iodicAad at 532. A flaid chmmber 510 is in ootumtmioation with tlte hallow poitions 532 of the array of inicxoneedles 530. Of course, other fluid driving mechaaisms could be used as wa auah as passive diffusion {e g, time Wldlie), itlataOtapaOni ItVecUAA, pCei/OtC, v*Caypl, or ultiisoud.
Fluid chamber S 10 is oonarocuctod of a bottom (in Fignro 23) plaaar surfaca whioh hss opanipp that am aiiW with tba mkodeedies 530-a left vera;cal wall S14, and a right veurtioal walt 516. The top (or oeiling) of t6e fluid dnmber S10 is made up of $1 WO @0174764 PCT/U9YOJI5612 a planar mataial which is divided into individual ebatco6es. Tba middle eisctrode 525 is part of tha fkuid saaaor, and makes it poaeible to mesanm a aurrcaat or voltape arithin the &id cbamber S10. Bioetrodes 520 aad S22 aee electrically eoqmeotCA to om aoodta (aad am be of a 1ingla sti'+actune, rach as an aama]ar ring) so ea to act aa iho olectraAorccia s oloctrodes (i.e., as either an anode or a catlwde) that facilitm the oraneport of fluid *zolgh the holbw mioraneedks 530 S+om the *n into the fluid ollomber 510.
11t.c heigAt of Qte ftoid chamber e0aaha+e is deagoated es "LS4," svbich coauld be alty tiasonablo dimanaion that is Iwge anough to hold a soTwfent volumc of fluid for a petticular applic.ativn. Of oouxaa, if desiznct, the Snid c)tatraber 510 could be comm*A to zo a mtich larger e:temal reaarvoir (aot slwvrn), and a pump could evGn bo asod if pfeesure or vaaoxua is desired for a puticuiar applioation.
TIu Iryer 540 mpsoalte the atradan oomema, the layer S42 mpmanta the viable epideamis, and the IntgeBt layer $44 represents the darlnia, wbia6 conta'sas nerves and capillaries.
1S 71m applicatiooa of microneedleo S30 into the stratum corneam 540 and epidcnnnic 542 deem.9es the eleeMcal retistmice of tha etmiuat oornetun by a 6ctor of apwommtely fifty (50). The apQtied voltage. thaefora durins aiactrophorasis (e.gq iontophoresis) or deetroostnoais am be gteatly reduced, teaeby resuiting in low power aonaumptIon and improved safoty. laatophoresia provides the nocossery means for 20 amleonles to ttavel 11uough the thicker demis into or n+om the body. The oombiaation of the micraneedlea and the eleettie geld tlo is appiiad botwua the electrodca 520 and 522 (acting as an anode, for oxample) and a remotely placed olect;+ode (e.g., oleokode assambly 505. viewod um Figarc 25, and acL'n,g ae a cathode, for example) pmvidas for aa inc~aso in petoaeability for both the strwtmn corncum and the deeper layars of skin.
25 Wbilc the transpozt impt+ovamaat In atratum comoem is mostly due to microneedle pierciag me ele*~s paovides hiz'hw tlamwoit atea in the spidmis and deania.
Tliis fs not only true for smalI aized moleau]w, but ako for the larger aad moc+e complex usefal molecaks.
The body-ituid eampliog saaor S00 om be ascd ft a eoiftinaous n0n-iavasive 30 maaaiuesuait of blood glucose Ieve1, for axmnple. Glucose is extraat,ed thraudh the skin by reverse iottbopi-orzaia, and its aoaceatr4ttop is than cbamctmizod by a Wo e8P14964 PCiYUS90f1563x bioelevtroahemioal sansor. Tho senaor cotaiprbes tl-e chamber 510 t6at is SiIIad with hydrogot and gincoaa oxiclase and the elacteode 525, The glmcosa molerulea ara a+oved froa, the body by the flow of sodium and chloride tons caused by the applied eleetric potentitl. The doUxtion of the glucose ooncxntration in the bydrogel pad i4 perl+otmed by the bioekcerochmical semsor.
An altemative anboditnent S50 is depicxed in Figure 24, ln which the mniannoedies S80 ere solid, ratber dw holtow. A fluid-filled chember 50 is provided and also ceanprises hydcogal ffllcd with glucose oxidase. The chamber 560 is made of a botoom wail 562 that 1'saa openon:ga proximal to the individmd tnicronoedles 580, in which these opeaiqgs are dealgnwtod by dw edEeeooe mmnefal M. C>tiambe' 560 aba inoludes side.valls 564 mnd. 566, as we118s electeodeo $70, S72, and 575.
The electrode 575 is oonstneW a: pd of the ~nieal srAaw:
eleca+odes 370 sood S72 ut u the eleolmptioretic eleatrodes, actiiag dther as an aaod.e or cafhodb to sd up an electric cucramt tlu+augh the sldn whioh flows to a remoaelydaehcd 1s (to the alovt) eleotrode (Gg., eaeemode mnmbly SS5. viewed oa F'igun 26).
As In dw sensor 500 of Figurc 23, thc aansport rate of fluids is eAhaneed by ~not only ttu piereing effocc of the microneedles 580, but alao dw etecttic finld induciag a cornatt tbrongh the skin. In ihe gluovse smnpling tctempley gluaosa is atlractcd ioto tbe chmaaber 560, aad its ooncentretion is measurod by dw bioalecOrochemicaE
seneor.
The heigbt of the fltdd e6amber dmcLwe is desiputed ts "LSS," whiah coutd be any nopsoaable dimqnsion tltat is large enough to hold a suffieient volume of flaid tbr a particular applicadon. Of come, if desired, tbe fluid atmmbet 560 could be ooanected to a inuch largar cxtaual resetvoir (not siwwm), aad a pwnp could evice be ueed if proesare or vaouum is desirod far a particulw application.
Pigm 25 depm m demoplioretie eleeorode asombly that is besed man a hollow mioraueedle acray, Baoerally dod8aatai by the refaence numerpi 505.
Electgg3e assanbty $0 inalpdrs a plurality of auici+onoodles S31, eaoh being boliow and haviag a vertical opening tlsrongboat, aa indir,atad at 533. A flvid aZaember 511 is in aommu9cation with ehe hollow portions 533 of the atray ofnaicxoneodles 531.
Fluid chamber 511 is caastructed of a bottomQ plsrar =mfaae 513- whioh has apeninge tbat are aligaed with the microneedles 3 31--a leR vertical wall 515, and a right Wo eer74764 RCYlC)$00113612 vertica) wall S 17. 71e top (or oeitiagj of ;Quid ehamber 511 is madt of a plmlar qlectrode materid 526. Tha electrode 526 ii* to be electrically aonnaaed to a low-murent vaoltege source (not ahowm on Fipne 25), eizher tbrougv a aubslrate pathway (sach ao a integratod circuit trace or a printed eircuit 1'uil path) or a wire (also not shown on Figure 25).
The height of the flaid clumber 511 is givca by the dimension "J 52," wbieh can be of amY practical9izo to hoid a suffid-eru amwuat of hydrogel, for exanmple, to aid in tha conduction uf cutrwtt while actiag as the olcattode. In electnode assembly 505, the fluid within chaiaber 511 proferably would not be eioctrically charged As aen ba saen in Figtuc 25, the hollow znicroneadles 531 penetrate the atratum cornenm 540 and into the viable epidermis 542. The mianaoedleg 531 pzeferably wilI
not be aufficicntly loug to penetrate all the way to the dermii 544.
An afteinative eanbodimeat SSS is depicted in Figure 26, in which the micsuneodtea 581 etn sdid, rather thm bollow. A fluid chamba 561 is provided and preferabiy is filled with hydroget (which is not eleetrieapy cha=ged). Chamber 561 is l5 made of a bottom wall 563 *at has openings pmximal to the individual micrvneedies 581, in which thase openinga are desigaated by the referenee nuztteta1586.
Chamber 561 also ineludes side walir S6S and 567, as well as a top (or ceiling) clooti+ode 576. The elecbode 576 may Act aa a cadtode, for exampl.e, in a situation wLere electrode assembly S5S is being used in con,jtmotion with a body-fluid sensor, snch as sensor assembly S50 viewed on Figure 24, in wh[ch its electtodes 570 and 572 may act, for exampla, as ao anode. The height "L57" of fluid chamber 561 could be aay reasonable diamerwion tltat is large enough to hold a safSoient volume of tha hydrogel to eoheace the fluid flow via the ,clcchia fleld between the respective anode and cathode of the aystem.
Figure 27 itlpshates a portion of a human acm and hand 590, along with a drug dnlivary electrode aatetnbly 500 and a saoond eteetrode as9embly 505. Both cl4ctrodes are attachod to the aldn of the buman user, via tWr micmn.eedtes, such as the hollow micK,needlea 530 (viewed on Fignre 23) and the hollow mieroneedles 531 (viewed on Figure 25).
Since an electrical vohage is applied betwoen the taro elecaocte essemblies and 505, it is prof'fened to uae a low caarent power supply, genaralIy desigastad by tbc t+eferseca mimeral 596, that is coimoeted to esch of the electrodes via a wire 592 or a wire WO I0/74784 PC?lUSoN15612 594, mspectively. It will be uaderstood that ny typa of physical electnica]
circuit eould be s{sod to ptavide the eledcicat cooductors and powe supply neceasuy to set up an appaopnatie dectrical poteetial, without dcpatting timrn the primcipks of the preseat invention. In fact, the eleclrode assemblics and wirin& along with an sasociatad power supply, aould all be containcd on a single apparatus within a substrate, such as that viewed on Figiams 30 and 31 herein, or by uee ofptiitited cireuit boaNs.
FWmte 28 depicta an elocta+aphoratically enhanood fhudie dtug dalivery apparattts tbatt is based upon a h,ollow microneedle atray, geaerally 3esigosted by the refet+ence mmmml 60Q. ]hug.delivery apparatus 600 ineiudes a phmlity of microneedles 630, whieh are eacb hollow, having a vptioal opa-iag throughout, as itodicaLed at 632. A fluid ehamber 610 is in com:nuniratioan with t}us hoIlow portinms 632 of tbe aaay of micrrrneedles 630.
'p']uid cbamber 610 is cobstsucted of a bottom (in Fignne 28) plaaar s-xtfaae which has openmgs that ore allgnad with the microneedles 630--a leit vottioai wall 614, t5 and a right vaRieal wall 616. The top (or ceil'mg) of tbc IIuid cianber 610 is mada eq, of a plsnar matexisi 620 that aots as aa eleetrode. T3leetrodc 620 is pact of the drug delivery appsratua, and makes it po sb!e to induce a cunent flow through fluid chamber 610.
Bketrodes 620 and 622 are conmectod so as to act as tho dec:eropltotecic electmdcs (i.e., as ti(har an anode or a cathode) that fecilitate the transport of fluid thraugh the hollow miaroneodlea 630 ftom the fluid cbamber 610 into the slcin.
The height of tlre Qsid ehamba sernettma is drsigoated as L60," which could be any t+eamable dimension that is ]arg+c cmough to hold a safficient vohmie of flvid for a patticular drug dclivery applicetion. Of courae, if desired, tho fluid charnber 5 10 could be conieeted to a much largcr ectempl raaervoir (not si,own), and a pump could even be usett ifpteseuna or vacuum is desired for a patioWar applicatien.
The layer 540 represmts tho`sttalum eorneum, the layer 542 represettts the viable epidaamis, and the largest iayer S44 repreaenta the daonis, wlkh eontai,ne netves and capillaticB.
The application of microneedlea 630 into the stratum corneum 540 and epidermis 542 dcmmes tbe elec.trical resistance of the 9uat<un oonaum by a factor of apprazinoatoly fifty (50). The applied voltmge, theefore, during eleatrophoresis (e.g., WOOOt/74764 PC?NSOW1361x lemtophOCCsfs) ese be gttatly irodueed, thaoby resuiting in low power consurnpdon snd impmved sefsty. Iontophm3is pmvides the t-cocssary me= ft ploloowea to travol thraugb the thicker dermis into or from the body. The oombination of ihe microneed}es and the elcchic SeIQ tHtt is applicd between t1x electrodee 620 tmd 622 (aetfng as Anodes, for exampie), and anothe+r electrode (e.g., elacwode assembly 505, acting as a cathodo) tlut is attacW elsewhere on the skin of the nser, provides for an inarease in pecmanbility for both the atratum comeum and thc deepac layers of akin. VHhile the t:anspoxi impmvemmt in stratum ooomettnt is moetly due to micraneedle piereing, the elcetrap}ms+esis provides bioa' transpott rates in the qgdemis and detmia.
T4is is not only hne for amall aized molecules, but also for the lasger and more eomplat usalLt moleculea.
The drug dolivay epparatus 600 can be usrad for a coniinnous iton-invaaive medicet device that caa oontinuously delfver a fluidic drug tbrough the sloai and into the body. For example, iusulm couid bc deliverext to the blood smam via the micronoedles 531, dvougll the stratum contettm 540 and tpidermis 542, and also into the dernlis 544 whene the ismlin would be absorbed into the cepillaries (not ahawn).
An alternativo embodimeat 650 is depicted in Fignre 29, in which the micxoneedles 680 are solid, nthcr thaa hollow. A flnid-SDed chsmber 660 is provided and al o co ios hydrogcl. Chambaar 660 is madc of a botowm wall 662 that has openings ptnximsl to the individual micmwodies 680, in which thase openiap,s arc desigtutted by Ibe refenmue nalsle=at 685. Chambec 660 also includ.es side walia 664 and 666, as weII as alactrodea 670, 672, and 67s.
The eleeirvde 67S is oonstructed as part of the bioeIectroohtmaicai sanaor.
The eleotrodes 670 and 672 act as the aloetrophooetic Clecnndes, actiag aither as the anode or cethode to set up aa eleetric aurrant throuo the skin, in conjtmction with anotha electzode assmnbly (snch sg aiectnade asxmbly 655, vieroved en Figme 26) ptaced elsewherc on the user's don.
As in the drug defivery app,natns 600 of Figuns 28, the traaspod taba of fluids is diltanced by aot only the piereaig eilbet of the microneedles 680, but also the electaic field inducing a euireat througb the sk-n. In tiie insnlin dispeesing example, insulin is WO OV14764 PG17ii88YriS612 npeDod fram the chamber 660, and theraforz, flowe out tbrongb opaninga 685 proximal to micarancedles 680, tbm iob tbe asei"t stdn.
The ttesight of tiw flaid ehambar aemetun is de6igoated as 'E,65," which could be aay reaseoabla dQaension that is larga enough to hold a eufficieat volusna of fluid for a patticdar apptication. Of con¾ea, if dodt+ed, the fluM ohambar 660 could be oonnectod to a mueh largea extemat raaetvoir (n ot ahown), and a ptuap ca~d even be need if preasm or vacswm is desired for a parcicular application.
Figura 30 dapiotg a closed-Ioop dn,g-delivety system gjarsity dedpowd by the rekwu nguteCal 700. Zbit clased-loop syeGem. 700 utehudss a pav of elv*og>wcEic pak generally designated by the referenoa numoratt 500 and 505, which aaeb iuctade an anry of micronoadlcs for Aoid samp>aeg. Pad 500 eoanpdsoa : aensat atoembly (aa dcacaUd handoabove with respod eo F"*m 23), and pad 509 ooaepciser an ekctrale asaotnbly (as dsatss'bed hmiabovc with reapeot eo Figpre 25).
Claeed-bop syatefn 700 alao includet a pair of eloowphoreic p.da, gencralty designated by ffie nrfteooe mtmernls 600 an8 605, tltiat each iuulude an a:tsy of mieroneedles for dcug delivery. Pad 600 c,oapprisee s cimg delivery a,pparatus (ss deaalbod >etvinabove vvith respect to Figure 24 4md pad 50 omopricaa aa alectrode assambly (as d.emmibed lasreieabove wlth t+espoct te FUtae 25). Of cxnac, eloctropharalic pads having solid micrormdies could inoad be used, auch that pads 500 and 600 (with hollow miantbeod[ac) ooidd be roplarW by pads 530 aad 650 (with solid auiccas,eedlta), and pad 505 (with hollow miexomeadles) eaild be stiplaoed by a pad s55 (with aoTid atio~+onead]os).
Pads 50p md 600 an movnbod to a sabctrate 71% whicla cso be made of eMa a solid or a somewhat fiexlble maoaial. Witldn sabstrame 710 prelbrably residet a ieseavoir 712 (withtn the subelrate 710) that ]iotde the ftuid which is to ba dlspensed tWaugh che mimoeadlee of pads 600. Raservoir 712 conid be made yp of iodividoal "amali"
chtmboas, such as a iarge wmber of riwmbm 610 that are comnecoed to a soiuoe of 1luidic drug.
it wiII be understood dtat the reaalvoir 712 prefdably is cmpletely contauoed within aubstiM710, and oaatiot be aeoa 5vm this view of Figuce 31. As sa altxrnative, however, a fluid ch nei (such as a flexible tube at 730) could be connected into subsaata vvo oonailcl eCTfUS99n5622 710 and, by use of a pump (not shown). fptther qmtities of the fluid could be provided and diapenaed ihrougb; the m"oaoedlea of pads 600, using fluidic pressure.
FIgtme 31 illustratn the oppoaite side ofthe cloaal`loop sysftn 700. A
contooilar 720 is mounted tu the uppa sutfkce Ctn tda view) of substrate 710. Cartroller preferably comprises a type of miarochip tLat oontains a cantrat pmces,aing unit that can pGdo:m nnnteric calcuLtions and logical opoations. A nrniaopeoecseor that exeeutes softwm instrnctioas In a saquea>bia! (or in a pmatlelj tttamner would be suf6ciaut. A
mioroeoneroller hftgmtcd cincwit would also euffiee, or an ASIC that eontains a micmprDcessor cinanit.
AdjacGut to controller 720 is an eloctrophat+aric power anppiy with a battery, tha cotnbiztation being gaierutly desigaated by the re5crence maneral 722. In addition, a visua! indicator osa be ptaced on the surfaca of the subatrate, as at 730.
This viawl indicator could give a dircct reading of the quantity of interest, sach as glnaoae eoeaentrstion, or same other body-fluid parameta. The visaal indieator pncferably cotn)risos a liquid otyatal display that is capable of displaying alpbaniuneric chara4tern, including aumbore.
While a pwpping syetem that croatee fluid pressure oould bo used for dispcneing a fluid.ie drug into a body thtougb hollow mieronoodtec, such as emplacod on pads 600, in sr,any instances it is prefecned to uae a,n eloat:ophorosis method to enhanee the delivay of the drags thsough the micrronoedlea. As discussed 6ercinebove, applicadon of Ynicroaeedles can deerease tba electrical resistanae of tho stratm corneum by a faotor of fifty (SO), and so the voltago necestmy to facilitatc clectrophoresis can be greatly reduced, iaqzroving safety and requiting mucb less power consumption. By use of the ekctrophorasia, tho moloculea makiug up the Anfd drug will travel tlnou.gh the tlricker dcrmia ittLO or from the body, ond the wmbinedoa of both transport-eahaacing mcthods provides an iner+oase in parmeabilityf'or both the straWm eomaam and the doeper layecs of the sldu. The lydnsport improvement in tbo so'atum coasetm- is mostly due to micronoodle picrcing, although the electrop6orasis provides hdgher transport raus in the cpidarmia and derntis, The closod-loop drug-delivery system and iInid-9empift syatatn 700 caa be usod for cantinuous noninvasive mea surmetit of blood glucose level by extracting, via revexae WO 00/74764 PGTIi1500/1Si12 iontopboroais, glucose tluongh the sldn snd measuring its c=centration by the bioeloct,rochemical soaeor (such as tlte eensor coastrucced of the hydnogel chamber S1U
and seesor elecetvde 525, along with tht con>rollat 720). The hydrogel pads conWning mict+oneodics (i.e., pads 500) eahmot the naverae iontophox+esls to move glucose s raolecnles $rotn tha body by the flow of aodium aod dilocitte ioos, wbich are eaus i by tbe applied elestrie potentitil via rdootrodes 520 and 522. Onee the glaodse connattration is measured within ihe hydrogol pads 500, the pmw atnouat of insulin, for examplc, can be dispenaed Iluvugh the other pair of pads 60p that malGe up part of tbe closod-loop trystem 700.
As discussed hereinaboveõ drug delivery is performed by applying an alectric Pa~~g betwmn two mieroneodlo aeray elocbvdes. One of the elxemdes is filled with an ionized drug (such as iasulin), and the c,barged drug naolecules move into the body due [o the ekctrio potential. Contmllar 720 wi}1 detemmine bow mueh of a drug is to be diapansed ttsrougb the micxonoaue array 600 at any periicular tim% thenaby mairing Iho ts closed-loop system 700 a"smart" drugldelivay syasm.
7'his smarc drug-dalivvry system can be used as an artificiai pancxeas for diabetas patie,ats, ss a portable harraoncAerapy device, as a pot#ablo system for cmtiauous out-pat9c.nt clemotheixpy, as a site=specific analgedc patch, as a tannporary and/or rate-conttoilodaiootine petoh, or for many ot5or types of dtugs. Such syatcma could be made as a dispostblo design, or as a re6llable dosigo.
It will be andafttood that the tlosocb-loop system 700 can be used in macty applications, including as a paiNess wd convaaient tnansdamal drag-ddivary system for contlnuous sad conamlled outpatient tltetapies, a painless and eemvonient body-fluid sampling cystem for oontirntotu and pmogrtmmed optpatieat body-fluid monitormg, as a 2S high-rate truisdeemal drug delivery system, or aa a high-acc raey transdertnal body-fluid sampling syatem, bione spasifically, tbo closed-loop systetn 700 of the prasemt invention caa be used as a portable Mgh-accur=y painloss sensor for outpatieot blavd glucoso-tevol morritorin& as a portable system for oontinuans or rato controllal outpsticat chemotherapy, as a temporary and rate cantnolled nicotine patch, as a sits=speci6c eont:vllod analgesie patch, as an eatarnally attaahed artificial pana+oes, as axteraaily attacixd ardficial cndncrine glands, ss tamparature.coutno(led fever-reducing patches, as WO IIOf74761 PC'P/t78G9ltS6I2 heart r-ate-coHtroIled nittoglyoecln higbmQe tranademnwl patches, as tetnporanly conttoilcd bounonal lugh-rate t:anedermal I-atohae, as erectila dystimction treatrnent high-rate trauedennd poleltee, end as a cantiauoqi aor.unte blood.aaaiyais syrtam.
Another use of tbe otose&loap sysoem 700 of tLe peaeot imaudo la t+o fio ea s potpibte dnW
dalivay tystcra ft outpartiant delivery of tbw fotlawkg druga ttxE thetmpcutia agents, for example:
aentsal Darvnus syatern thmapy asgrxtcr, payelao cnergirang dntgs, txaunqailizers, auidconvuleents, tnmcla rataxents and eatti-pafooeoa sgmtts, amokh* cassmon agents.
analgetics, mttipytetice and enti-inflamraatory agaats, antispaa<nodioa and anfiulm agettts, Ynkimirtubials, fntiuulariis, eytnpathomimett'ie patches, aatiparaastic agente, aeoplaetic agdtls, nlgritiont2 ageats, auod vitaaodas, It will be uaderecood dmt.ruiota tnttarials othor than mose disclosed haoimbove cn be used for oonstracting ft closed-loop syatem 700, and for aanaucEfog individttal body-fluid etmaplin somre and indivlduwl dmg dekiray syate+oms. Stxdt otbcr analeciala could include dimmnd, bio-eo~'bla 1ttClats, oatatnics, polymecsõ and polymer eampositea, including PYRBXV. It will yet be tiuther undatstood " ft elecimteot+etieally/miaroneedle-enbanQOd transdatnal method of trufltport of the pxssant tnvonSon c:att alsa be cambamd with ultmsoaad and elaetropottMion, in oalnr to tuobiave Ligharate dta,g delivery mto individual oella.
ft will Also be undataod ilut ihe leqgth of tlye ittdividuAl miaroneedles ie by tkt the most important dima~sion with regatd to l+novidiqg a psmm imd bloodias dtnt dispoasing eye0an, or a paYniese and bloodku body-fluids s npftg systin 004 tbc opposita di[xtion of flaid flow. While the dimensions discvaead luc+einabove ire prafcmd, md the rangoa diacusted pte aomtal for human afcin, it will ftrtber be undantood that dx mieromeodle ueays of the pnsaat inventian can be usad on fldn of my ethe.r farm of lfviclg (or even dead) creatures or oxgeoigne, and tho prefamd dimensioas may be qtute dilratmt at cotapared to tbose aamc dimaosions for uso with htuaan sldn, all withaut depmrtiug 6om tbe pimtaples of thepretM iavmticn.
It yet will ba wederatood that t1c dnmicah and mtthaiala wed in the molda and dies can be quita diffirmt t6en thosa dimwad lteninsbove, without departing ftom die principles of the praeent ittventiou. Further, it will ba tmderstood that ft chemicals used in achmg and layariue opa'atioau of toicrofabrication disctruW above ooukl be quft WO 4674764 pl; t'/USOd/1Sf12 diffarait than thosa diseussed hereinabovq without depating fmm thc priaciples of the pesrxtt invemtion.
Figure 32 illuwtratas auother altemative embodlmeat of a hollow micmneedle, gepaatly designstod by the tefereaee numeral 600. The main body of the nnicnoaeedle s 800 has a generAUy cylindrical shape, as indicatad by its oater surface at 802. A generatiy circulsr opemng creates a hole at 806 thnough which fluids can ppss. The cylindrical slupo is prefcrabl.y maintained throughout thc length of ntic=oneedlc 800, so tbat its bWom profile wouid also raaiutmin a gar-cratiy citcalw shape, as depicted at 810. Of couzsc, minar variancea in this shape coald be utlliud without depnting fram tho principles of the presart invation, such as an eiliptical abape for its arosFSection (rathGr ahan a circular shape), for examppie.
The gene=al cyfindrical shape is preferably maintsined aloo at thc top posaon, as scan by thn outa wa]l at 808. The tap snrfiaa at 804 wM Itavc the frnm of a pair of ooncentric circics. in sitnations wtrere the opening 806 is oircular. The bottom portion at t9 810 of mienaneedte 800 is abuttad to a bose olemcnt baving a generally plansr sttrfacx at 805. In a pxefetred mode of conetenction, microneedlc 80U aad the surfacc 805 would be of a unitary eonsdruction, 4.e., it would be fotmod fi+om a single piorx of materiaL This single piccx of matorial would prefaably be a molded plastic or like wataisl, or a cast metal or like mater3el. Of course, composite tnatorWa oauld also be udClzul.
One prianary advantage of the shape of micmnocdle 800 is that it bas a pair of sharp edged projections at 820 atu1830 that aid the penehation of the outer surface (i.c., atratum cornewn) of the stdn, ttrotr.by requiring less ftroc to be applied wb-ea acing an axray of such usicroneedles 800. Each ed od pxajeation or blede 820, 830 has a cross-seetional 6hapc that is gevmrally triangular when viewed from the top of microncodla 800 23 (see Figure 33). The exact shapa of the triangle will depend upon the sarengtb requiremcnta of cach of the blades 820, 830, the materiai uced to eanehvat miammedle 800, end the atnount of sldn danage thst is allowable in a particular uaago application.
The prefar4d cross-secdonal shapo is tbat of an isosceles triangle having a basc angle in abe isnge betweea I and 45 . Of cotnse, a rounded contour cantid be used bnat+md of sasight waUs for the blade sudaces, without departing fincn thc principles of !ha presait invanti~.

WQ flOt/4164 h'CIY[tS4f/16612 IU iiluatrated blade 820 hae an upper gonarslly ttiAr-galw surface at 822, and onc of its sidc walls is tipresantod by the lilanAt surfl+ce at 824, as sean on Figut+e 32. A
sirailar pianar wali is on the opposite side at 836 (sx Pigure 33), and the Jnnctioan of these two planar watis 824, 826 formt a geaocally sbsrp odge, as depicted at the refaenoo s munerni 828.
The second pnnerastop or blade 830 ie similwdy formed of two geae,rally planar side wNis at 834 and 836 (see Figuta 33), which also join at a gmteaally aharp edge at 838. The uppar snsface of the blade 830 is depictod at 832 as baving a geaerally tdangttlw shapo, in the illaatrated esabodittsmt.
It will be understood that either less or more than two shazpened bfadc projectiows eould be utilized in the mieenneedlo 800 of Figqre 32 without depardng fium the principles of the preseat invetuion, aitbough the two blades 820 and 830 ate an optimal design.
As illus~tated on Ftigirre 33, the innet diamater of the opeWng 806 is depictcd at the re6mcc oamera1842, and thc oata diamew of the mimneedIe 800 is depiated at the refer+ence n,umerai 840. The sizc of the outer diameter of micronoedk 8110 is very inopoatant as to its peaetradng oapabiilties into the eldn, whmeas tbe inner dianneter 842 is of iessar ia~ce in ttut rcgad. However, the itsner diametar 842 must be large mough to cssily pass the desired nwlacules of the fluid to be passad themduough.
Figure 34 ilIastrnoas a similar hollow mics+oneedle, gmexlly desi$aWd by the refes+onea ntmneca1850. This aitamative ombodimpat mic,t+onoodle 850 also iaciudes two longitudinai blede etnccduu at 870 and 880, spd also is of a genesally eylindrical shape throtighout most of its iagth fivm its base elasuat's bottom surface at 855 to its top surfaoo at W. Tbe opening at 856 is also generally circular in sitvatioas whcare the mxx+oneedle 850 is of cylindrioai slVe. Of eourse, the overall otae: shape of tfie micnoneadie 850 and the isnum shape of the opening 856 could be somawbat nou-oircular (suah as an elfipse) without depar6.og Smm the prinaipk4 of the present invention.
In Figure 34, miero-eedlee 850 oould be eoestnusted of a molded plastic or a cast metat materid, but in this patianlar represaatation the mieroneedle 850 is conawctod using semiconductor fabrication teohniquts. The 8tst blade 870 has a gaterally plwtar side watl at 874, add in o4njuncqon with a similar sidc wall not sb,own oa Figure 34, WO YW74764 pc`r/tJ8oWi5622 fomas a ganeratly shap edge at 878. 'lU Cmss-seetion pro8lc of this blade sttucti= 810 is seen at 872, as baving a generally iso"es trimegalar shape, althougb more rowMed side walls muid bc atilized without departing fiuoan the prisiciples of the preaau invsntioa.
On Figare 34, tlaE shatp edge 878 does nat oontinue aal the way to the bottom aurface 855 of the ada,otteedle base suucture,lwt in:tead contiaur,a down to a point where tbc blade eauctmre discantimus, as illasbrated at 862. 'fhis could be utiliaed to ene te a grester yield of microneedlo sbxctum using samieonductor fibrication teohniqtus, or could be utilized to epeate ashuctmc IaatdAg gcaater mechanical atrmgth near the bottom ann (e.g., at tbe side wal] area 864) of the adcroneedle 850. When usixtg this type of sbape for the steactwa of micraneaile 850, the oater diameter of the microneedle baa the form ahown at 860 as it joins the planar bottom surface 855. This s6ape at 860 could be generaily atmi-circular, but also could be of a larger diameter to provide goeaoer mechatsicttl atr+cngth ttiars the outer diatncoar naar the top surfaoe 854 of rrnicronoodle M.
T'be aeoocd blade 880 6as a similar top protle at 882, and a similaa sharp edge at 888. 'i'he sidc wall stiuedm neer the bottoao of tbe secood bledc 880 ia not viewable in Figtue 34, bttt am be iuferred flom thc ehape of tha bottom aideavall at 864.
Other vniat+oaoa In shape of tbe micraaealk struetuoec depicted ia Pigures 32 and 34 could be ntileud witLout dqirrtiag firoaa ibe prltxiplea of the prcsent invention. The primary goele Are to create mealaioally sound st.zactiu+es that can panetrate the atratam corneum of bwnan sirin (or otlur type of amimal or evcm plant skin), and the ahap loagitudinal blade structtm are a great irnprovesneat over sach hoIlow mimneedies that do not have these side bladas, enltaneing penetration ofdYugs ahmugh the aldn.
it will be understood that the miamne,edte struoUaes dCpicted in Figurea 32 and 34 oould be constracted of any rnaterials and by any tygo of faWcation techniques, without departing froa: the principlas of tbe prueni iaveattion.
Anotbcr variation in the hollow microneedles depicted on Figures 32 atut 34 would be to have a top sarface tbat ls not genaalky tlat, but inatead has a arouate or parebolie top swrface as secn lbm one of the sides of *e miaroaeedle soructurc. 77ii8 type of atnwhere cvuld either be machined, or could be gencrated during de molding, as illustrated in Figm 57A and 57B, discOStod heranbelow.
An oitemative solid mic[oneodle ahepc is depicted in Figores 35 and 36, in which the solid microneodie is generally staralwped in profik, As viewed $om its top surface (sx Figure 36), the solid microneedle 900 is e generauy f1>me-pointed star shape, haviug thtea lottgitudiasl bledos at 910, 920, and 930. The top aurfece of each of tltese star-shaped blades is depicted at 914, 924, aud 934, and as oan be sopt from FYg=
35 tmd 36, a major portion of tluaa top surfaooa is godmalfy triacgulor in abrpe. The praferrod shapt is that of an isosceles triangle, in whiob the bato angle of tltis triangle is in the range of 2-45. Of cownsa, ft snuilier this be.so angle, ihe smatlm ft amount of skin dsauege done when the ttuvroneedle 900 is inserted ittto the stratum cearneum, Farh blade 910, 920, and 930 bat a ptur of gmenlly plasw side wa11s at 912, 913, ta 922, 923, 932, and 933 (aNttoagb theso side walls could be somewhat curved in conoour, if deaivad). '17-eae side walla convage to fonn a generally sitsop point at 918, 928, and 938, tsspeetively. In the illustrated embodimeat of Figu¾v 35, mipvneedle 900 oantintus this star-shaped profile fiimn its top qurfacea at 914, 924, and. 934 down to its bottom odges at 916, 926, and 936, wlia+e the micromeodk sf<upur+o joins its top planar base ts atruotu:e at 905. Of coorse, ft very ttpper sLdko we most key as far as tnalan,g a peaotratian into the skin through the strxtnm eorm=n, and tlto precise shape of tho blWes 910, 920, and 930 may somewhat vsury along the longitadinal length of miarancedle 900 wichaat deperting from the principles of the par,eent invaatton. The mqor benefit of this shapo is its satall crops-sectional araa allowing easy insartion Into ft skin, yet a lxrge 20 azuhce attia providing high rstas of active pertetration through the sidn.
Sinoe microneedle 900 is volid, for fiquid to be dispeased ittpv the sicin or to be seMled from the sldn, a sot of openings is pmvided in the base deutmt or substrate at 908. It is prcforred thxt a singie opesting be looated along each pair of pmjections or blades, as illustrated an Figere 36, in which an opening 940, 942, and 944 is provided 25 betweea thc biades 910-920, 920-930, and 930-910, mspectivaly. Of cauree, different sized bolas and diff'erent hole looadons, as well as diffcnnt mtmbers of holes for t2at matter, coold be milized with the solid bti<xoneadle 900, without depstting from the prineiples oftlus proseart invention.
Miomnecdlo 900 coald be conettttctod of virtuaily any ntatcciai that is 30 biooompatible with human stan (or otlmr animal or plant akin). This iactudes molded plastic or cast metal, or perhaps a silicon or siliaon-dioudo shtzntoe that is manufaraured 'aV0 O01T4764 PC7YUSOW156a2 uefng zomioondactor and plastic fabdcation tachuiqaw. Tho ovp mufaoe at 914, 924, and 934 ts lllu9tratad as being gcnerally plsnar, although this could be changed easily enougb to cause tho mid.portlons of tho saicroneedle 900 to be somewhat lower than the points of the ttrce blades at their top edges 918, 928, and 938. Such a conshuction would have a s sinailur side appearance to the hollow rnicroneedle 1420 dcpicted on Figure 57B.
It will be vnderstood that more or less tlun tbree biadea could be constructed to cre$ta a soHd microneodle sach as that of miemneedle 900, without departing from the principlea of the proseat inveaition. Even a single blade design could be used, having either one or two sharp edges. While the three-bladed solid miaroneodle 900 is of a opdmat dtt9ign, certainly a four-bladed desip could also be mamnfactarAd and used, and provide genemIly good resalts. In a four-baded det,ign, it would be prefasr+cd that esoh pair of blades bave a comesponding through-hole in the subsiraft benesah the botscun poitioon of the solid microeeedle, al*vglt eueh holes am not nboeaaarily zcquired betweea eecb prir of bls,dm The siae of each of tbe thmugh.hokc aneh as bolcs 940,, 94Z. lad 944 i5 is up to the dasigner, although its iancr diameter should be suPFiciently largo to a]low usefw molecule: to psas therothR+augh.
Another veay i,mportant xtidbute of atrsyt of mictweedles is the separation distance betwoea eaeh of the mitaonuliles with regard to their placement on the subsqate or bass sttucau+e. On one hand, the more micconeadlcs per given area of a snbsbate, the graater the ampunt of "travsdecmat flux" (or transdetnial flow) of a fluid that wi11 be transported tluough the raiaraneedles (i.a., in the cue of hoilow microneedles). On tbe other hand, it has been dotecmined that the cl.oscr the apacing of mierazteedles, tiu less Re1y thst the micmneedles will aauaily pceetrate the atratnm ooRnenra layer of skin daa to the clasticity chatRCtesistics arnd meehmieal aftngth of skia. Ther+e{rnre, a dichotomy exiats tlut indieataa the separation between mieronoedles is critical for a usefed dewice.
1'igures 37-42 provide tebufas dab iDusftatiqg tho egecta of miteioneedle loagtb, micrroneedle outer di,meter. and micnaneadle seperation for cimlpr hollow miotoneedles, such as dosa depieted in Figure 15, Figure 22, and Figures 25 aad 28. As relaoad hareinabove, the micronxdks iuuslmtcd in these 8gut+es we hollow, having intaaal cylindrrical openinga, but are not edged or eharliased with realwat to having any typo of blade structune along their ouoer surfaees or tips. fitttherioore, the tabuLar data of Figures WO UW74764 pCr/CIS~Wlsi12 37-42 are with respect to microneedloi that am srraa,ged in a hexagonat aenfiguration.
All dimeaaions on these Fig= 37-42 are in microns (i.e., miorometera). F.aeh chart shows ten rows that repreaemt various tpic:roneedie lengths in the range of 30=300 micmos, aad ten columns sborving mfcanneedie outer diaweters in the range of mictons. Eaeh chact is for a differtnt seperadon distance, startutg with 50 miarons, and tbca increinenting by 50 miarons to the 1'uuT cbart of Figure 42 that shows a separation of 300 micmns.
Iha table eotries of "Y" roprosmt a siuaeban wha+e the micronaedle pepdrate:
the sldn. A table enhy of "n" repnxts a oonSpuaacan wlasno the wiondneedk will tiot penetrate sld<t. Finally, the "diamond" shipe repromro a trble owry im whicb the miaroneedIe will poasibly penetrate the akin, bowcver, it is not certain tbat penetration wili ocCta.
F,aoh table oontaips a dsalad Iipo (such as linc 1002 on Figune 37) that roughly indicates that table entries bolow the Iino w01 likely pmetrate the " wheneas table emtties above the Iine will liFely not penetrste the slda. Theae lincs rqresara approximations to a certain eztant, and a tolaance of at Iesst plus or miaas 10% should be aoasiderod when ut9li:ing this data. la some arcutn9teoces the toleraace should be morc Wke plus or zainus 20'ti.
On the variouc charte, the lines are indioated at 1002 for Figure 37, 1004 for Figure 38, 1006 for Figure 39, 1008 for Figure 40, 10Ia for Figure 41, and 1012 for Figaxe 42. Each of thesq lines aan be spproximately de8ned by an eqttation, in which the variables ate mictvneedk kngth mpmded by "L," amd tha ooter diuneter rspresented by the variablo "D." For thcsc oqnaxlons, Al! dimensions are in mierons. In Fygure 37, the equation is: L= 9D + 120; fiar Figore 38, the eqnation is: L= 5D + 50; for Figme 39, Ihe equation it: L = 2.77D + 72.3: for Figuce 40, the eqwttion is: L= 1.S4D +
59.2; for Figure 41, the equation is: L m 0.856D + 124; and for Figure 42, the equation is: L 0.47D + 133.

Figures 43-U provide frathor tabular deta, this timo for edged or "shup"
hoIlow miaraneedles, such as tlwae depicted in Figures 32-34. Zhesa edged rr+icrouecdles are also oircular or cylitldrioal in overail sfiapo, but, as descnbed above, include two longitadinsl blades with a ra>atively eharp edgo to aid in pcnetratiag the srtatwn earneum WO COf14764 Pt:T/090o/1S6i2 of die sJdn. As will be seen as compaitd to the tables of Figutts 37-42, ponetrating aldn is more eWly accouiplished using the edged microneedles. As notad hereinabove, an "adged" micronoalle is one in which its tip bas a radius less thsa or oqual to 0.5 microw.
AB before, a table antty of "Y" indicates that a pmctration oxura, a table antry of "n" indiotttcs tW a penetcation does not oa;ar, ard a table euby of a dia,mond-shapod symbol intliades tbat a petsettation of the sldn may ooeur, but is not de6taite. A dashed line is dmwn on Figures 4348 to indieato the hldgiood that emariea above tlie dashed lins will not saaceed in pautrating the sidn. while entrica below tho line will be succcssful in such patttratim The Iines ate indicated by the re&reuee numerals 1022 for Figwre 43, 1024 for Fig+ns 44, 1026 for Figure 45,1028 for Figure 46, 1030 for Figure 47, ,ad 1032 for Figure 48.
Similnr equations for these linas can be doterrained from this data, where agaira the variable L is equal to the micronoedle length and the variablc J) is equal to the outer diameter of the mictooeelle. In Figuro 43, tbe spproximste e4uation ia; L= 9D
+ W. in Fipm 44, the cquz&a is: L~ 51); in Figure 45, the oquatiott is: L= 2.77D +
115; in Figure 46, the equation ir. Y. =1.54D + S6; in Figame 47, t4e equa6on is: L=
0.$56D +
64.4; aod in F'igara 4$, the oquatian is: L= 0.47D + 96.5.
It can be tasily seen from the tabulated data of Figurea 37-48 thtu the greater the sepm'atiol+ between mim+onoedlea, the more likely that the sk3n wiU be penetrated at any given length of nsicanneedlc. If ra]shvely small mecrotseodiea having an outer diameter of twenty aiice+ons aro desired fbr use in a mieroneadle amry, than tha tabular data indioates that t6e microneedle should be at leas! 100 microns in )engW, and oither 2S0 ar 300 microns sepatatiodo diataaca (see Figures 41 aad 42). On the other hand, the same 20 nricaon outer diameter micnooaocUes that incfide adgcs (as per Figaa 32) wip iikaly penettate thc slan at a neodie length of at leaat 60 nlicrons and a separatian of 150 or 200 microns. This is an obvious improvement in microneodle density per imit area of the substratc upon which the microneodle arrty is mowited, thereby allowing a dramslic inc,rease in tha amount of mataial delivered or extracted thraugh tho skin.
MicroneedIe density is an important factor in dispeusng fluids or sampting fluids through the stcatam comcvm of the skin. This is clearly indicated in the graph of Figure 49, in wbich the X-axis represeats microneedle sepsoratiion ia miarans, and tbc Y-axis WO AOI/14764 PCl/U800/15612 rcprosors the traasdannal Qux of an active fluid such as a niacinamide solution, in units of micrograms pa squre centimotec pa 24 hoare of time.
The baso or refea+atxx line of Figure 49 is raptr,seoted by the "iataat slcin"
line 1044, wbich is in wmoe the usstodesmal flux rate of nomal skin wfflxoat any miaromeedtes, in tbe above unite of five (5) microgrcams pa squaz+s eeniimetec pa 24 houcs time. 77ds base lint 1044 is slso indieaeed as being "1X" times a notniitel tt^ansdanne3 flux rate. If the stcatun+ aorna~m layer of human elott is ramovoti, then the traasdenral flax ratc is ine+dnod by a fACtor of tsrenty-fnw (24), and is repremtal by the line 1042, which indicates spgnoxaanately one.huadred twenty (120) miorogratns per square eentimaDer per 24 hours of tran9de:mat flux flow rate. This line is also refated to as "24X" on Figure 49.
If micscnte.vdks are used, the flow rate is vatiable, as per tM curve (or more acou:ately, tbe segpepted Wse) at 1040, which at 100 rnicrons of separation provides a 46 times (or 4M flow rate as comparod to the intact akin Row rate of 1X. This Row rate ristsually deotnasas as the microncodle separation imcnases, since tbe density of nsict+ooeedles is proportionate to the sqwa:+e root of separatio~n distance.
For examplo, at a micronoedle separatioa of 400 microna, the trandeimal flux rue is wYly 5 times (5X) the 8ovr rate of imaat akim (at 17C).
Figure 49 as$nmes dnt the microneedla langeha are aal$c.iently loag and have a setffioient ehape to penctrate the skin at tho separacions Iisted atoog the 7C
axis.
Othorwisc, the transdennal flux rates will be sigaificaatly :educad. However, any tuicaoneedle usage that doett not satually pcnetrate the stratmn cotawm will likely ctrate a cetain amowtt of butmtts and breaks in the skln, wt=ich wiII grovide a c,aatainlttar+ma in the transdermal flux rate. For example, if ibe ntiaroneudle snsy is provided brving miaroneedles of 410 ralcroaa in outer diasnew atfd 50 microns in tength, it is not h'lceiy that microneedle penetrac(on wi[1 eeotu in very nuay places at virtuaAy any separation.
However, thens wiil still bo enough indetns and brsaks in the slcin to prnvide a four times (i.e., 4X) inccesse in the transdennal flux of a drug or solution such as ttiaeinamide in water. To eohieve the r+esaJts of Figim 49, the mieronc.cdld length was 100 microns and its outer diameter wos 20 miccnau. It can be seen fivm Fignre 49 that a micmneedle separation of around 170.17$ mitx+ons will provide nesults that azo equal to the removai of WO ee/747id I+GTlU8A0113612 ft atratnm ootneum layea ofaldn.
Utilizing a passive difxiuion model of human skin and miaroneedle shuctares, the kventars also psvvide the chut of Figura 50. The X-exis of Figure S0 saFteseats the.
micmmedle leegah in micrana, while the Y exia re}wmnts the transdecmai flux of an S aetive solution, in mimgrams par aquere caotitaeter per 24 houts time pexiod Tho cwvos on ft Saph ire depieDod with reepect to a 5% niaabamide solution 9a water.
The knm ctuve at 1052 repmo5omts a micrcmeedle aasy in w4dch ft neadlea hava a 200 micron sepaotion in a hexxegotte] pattem. The upper curve at 1050 regc+eaeats a n3ieteneodle seesy ia widoh d-e mixaneedlaa hsve a 100 miaaot separation io a ha7pnd ta pattern. Very usoful tianaderartal flux ratos caa be povided witb mfamneedk atrays having a sepQation of 200 miatons at a needle kngth of 100-110 miowd, and an outer dimetar of 20 nniorans` It caa be seoa froan Figure 46 thei this range of miorooeedle lagtbc and oufer dianetas tiea witbin a smpll tolaanoe of the lina 1028 that indicates whc~t-cr or aot miaoneedle penettgtion wi71 oocnr in sk9n. Tbis table of data on Figate 46 15 represents adged hoJivw miGronoodtcs, as despn'bed above.
Figura 51 provides mothar masure of usage for miCS'oaaedlee. The X-wris reproseuts mia=oneedte laigtlt in ulieroas, while the Y axis is a ratio of transdezalal flux using a sotiqion of niftiomide in waater venias alan daoup Yrban umg the aucroneedle anay. A nommal figure of ttsnsdennal tMx vasus aldn damage is provi4ed at the value 20 of one (1) sIong ft Y-axis. The upper curvc at 1060 depicts Hle tatio when nkronaedles have a 200 micron soparation. The lower Cwve 1062 ehorws a siaiilar mfcronecdle array having enly a 1oo t*ron sepmmdoa. Whi1v the tranadct7nsl thut will typicaUy be mueh greaW wl,em the miavtaeedle separatim is snudler, also ft alda deaanw wiU be gmater.
As ctnn be seem 6om tbe aarres 1060 $ad 1062, oaoe t6o ttuiarooeedle tmgth exce,ds 100 25 microns, the ttransderrtul flux veisvs aidn damago ratio tends to incmsc ratiia sllmply.
Tbe mieroneeale pmer dWnmsw was 20 miauns for the datr ofFiguce 51.
Figure 52 ia another gtaph rowamting inibxmati,on regaaling passive diffiaion of fluids using mioroneedles as oompoW to ft use of miaroneedies mdmr pnssace to increase the traagdanal flow. The X-axis -is in nnits of ptaaWre, gs per squarv 30 oeadmeter.1'tte Y-axis is tbo tremdeamal flux of m ac.tive soluttotl in miarogrnms per aquaw ccntimeter per 24 hours timc pariod, and ft values of this c6a:t aro for a 5%
4' VYO 00V74764 PC'4'/US00115612 solution of nisciaamide. In addition, tbe results of this chs[t werv podueed nsing nmimneedles of 100 microns lenpth, 201picxoats onter diameter, and a aeparntion of 200 ~niceams.
For iataot skin, the lowest horizontal line at 1076 9adicates a relativoly low trsasdaosal IInx of tha aohstion to the slcin. if the strstum oosneun of the akin is ranoved, tlnis oriasdermel f= g-atly inaeases bo the l+igisa ioduotal line at 1072.
Anotber borizontal line at 1074 indic.aae the b=ensdennal tlwt rete tWag nmicrpneedks under paaive diffision.
If paasx, is applied, thea tire flow rate ohangea as tbo pmmrsre ehapgCS. This is ittdir,atad by the eloped litte 1070. As ean be aeett, if the preastuv ic fncsessod by tbt+ee oiders of magaitude, thm tfu tlow rato of the b=sdarmal Qux also inateases by sppeoximmely tbtee osdenc oftm>gdibA.-Based npozt the above infannaeion, it is pcofared that the outer dismoter of eircular micmoedles (without "aatp edgcs) be in the rmwgc of 20-100 micions, more 1s profwably about 20-50 inictnos. In additian, lt is pre&arned tbat the heigbt (or lamgtb) of the miaivnoodles for use with intastltie) ffuida be in the range of 50-200 micaons, mara pretaably about 100-I54 miorops; for use with otha biologitd tluids, tha prefamd langtls is in the rmge of 200 mimm - 3 mm, md more poeftrably in dte ramgo of 400 e,iorons. Finally, it is pmferred tYmt the sapsration betweea mictoneedles in thc uray bt: in the ru>ga of 100-300 miorom nwra prehraMy abont 100-200 miomae. Of otwrea, dlmensioas otusidc the above-listcd lttnges will still be somewhat usefni, even for n>{tiemeedk ldfgths and ev,p-azation distoeas as small es 50 microns, or as largo as 1000 maiuwuc.
For koHow circular mieroneedles having edges (e.g., see mioroneedle 8fl0 in pigwm 321 it is prefealcd that the oater dLamotar ba In the iwge of 20-100 miorons. and mare psefeubly In de range of 20-SUmir,mas. For esa with iotamdtial &aids: the kngth will prefembly be in the tange of 50-200 microns, mme prefersbly in the rangc of 8t?-1S4 microna; for uee with vthw biolo,gical fluids, the length will pnaferably be in the range of 200 mianons - 3 rtmk and trmn prelbrably in the ra4ge of 20"t10 mitxoas.
F3nelly, the aeparation will preferably be In the range of 100-300 mierons, more peef+erably in the mge of 100-200 rnicrous.
~

WOOUtT47N PCT/USoeff8612 For solid microneedles of the atar-slmped desipa depicted on Figures 35 and 36, it is pioferrod that the radius of oae of the apake4 or edgod blsdes (e.g., blade 910j, as indieated by tiu radius 950 on Figure 36, be preferably in Oe range of 10-50 microns, and more ptr.ferably in the raage of 10=15 mic.ranis. ne iength of the solid microsteedles will s praferably faA in the rartgo of 50-200 miavna for nse with intecatitiet fluatds, at-d marc prefraably in the range of 80-150 iniarotis; for use with otixe biologicai fluids, tl-e Imgth will preferably be in tha xange of 200 microns - 3 mm, aud mdre prafcrably in the raage of 200-400 microaa, '17te soparaxion disqmee vvill prefrrabiy faII in tbe raW
of 100-300 micr=6 and more preferably in the range of 100-200 micxons.
Fignctis 53A-53E lIlustrate the steps for pnpar,ir,g a mold to make hollow mka+aneedies, according to the prinoiples of the prewt inveotion. The first step is depicted in Figcuo 53A, in which a substrate 1100 is provided with a top layor of positivo photosesist material at 1102. T'he substrata can ba spin coated, or an adhesive oan be used to attach the photoresiat 1102 to tbe iaubstrato 1 iOD. The sabsti<ate can consist of siiicon, IS silieon-dioaide, plastic, metal, or other aaitabte compounds. The photon:siat mataial wiU
praferably comvrlso poly(methylmetldCrylatc), aiso known as "PMMA," although othcr saitable conpomxts canld be used, such ,u poiyouymethyieua (POM)-polyaikoosulfoac (PAS), polymetixacrytimide (P11Q, aad poly(taetide-co-glycolide) (PLG).
In Figure S3B, a mask at 1104 iv placed ovw the photoresiat iaycr 1102, and elecpomagnetie caeygy is d'uected ibrough thc mask froap a light aome, in which the light ersergy moves in the direcGon as indieatod at 1106 on Figure 53a. The mask 1004 prehrably is made of gold matal, and in this in3tmwe, the r.lecrnmagnetic energy comprises x-rays.. It wili be tmderatood that many ditl'erear-t typea of phototesist procedptrs or the like could ba used without depariing from the principles of tha pcesent invenrian, and for exarogle, high enesgy nuclear ps=tictes might be subadtuttd for decUumapwde eneW in some prooeLss.
Figwe 53C representa aa expose and develop step, in which a chemioal eompoued is used to etch away the portions of the PMMA materlai that werc not protoeted by the mask 1104 in the prior Mep at Figure 538. On Figure 53C, the threo-dimensiouoa]
rnicroneedk ahapes begine to beooma appmnk A pais of hollow micmneedle orma are iIlustratod ia Figure S3C at I I 10 and 1120, In cross-sootion, the micrancalle forin I I 10 wo a/74764 tcrlOWtfa5632 sbows a fxnet wall at 1112, a aeooW aali at 1114r aod a ltollow ma or Lale at 1116.
Simiierly, the xn3oroneedle form 1120 co.tpprisoa a Srst wall at 1122, a second wall at 1124, end bollow aiea or lwle at 1126.
Both microneedle farma 1110 and 1120 will be of tho appopdwA imgth anud ower dianneter to pmduce :aiaonoedlo amrys a4 recommended hea+eioabove. The sepsration between mia+oneodlai is dapiotad by the dimeasion 110S, md thin also will pretrably be of a diatance as reoommended henioabovG
Figure 53D is a step where tlne microneedle fenns ae electropiatod with metal.
In tha prefcnrod embodifieut, this metttl at li30 will aomprise nictel. As a~a optFonal i n t e r m e d i a t e a t c p , t h e s u b s t r a t e.1100 and s a i c ro n a a l l c f o a n a a t 1 i 12, 1114, 1122, and 1124 (which in combination camprise two eircular or cylindricol miaronoedle fosrne) can be cletnically comd to aid in laoer tr,leaee befese tlne C1eGc+opleting takas glaca.
After do nielcel electcoplelasg has achleved the sppropciate thiolatess, the step of detaching ft mctal form takes place in the 9tep i!!aftW on Figtre 53E.
A"rtvetse ,s codopr' mold arin now exist, as gaureNy dapiatcd by the retiaeooe mmteral 1130.
Instead of a hollow scea or hole, a cyWxlhicat pt+ojacdon tarv appm at 1132 atrd 1134 in the metal mcdd. SiatilvZy, inateed of oylindrioal or neociy cylindeieal ptojaetiooe at 1112.
1114, atid 1122, 1124 (a eeea aon Figua 33C and S9D), thara ae nmv liolbw eylindrioal sbepea fotmecl at 1140-1142, snd 1144-1146, wWch represW the areas where the ,mimmoft oylind" walia will form.
Pignres 54A-54C dqrict *e stepa of microemboating to fesrn molded microaeedles that are hollow, as comeocuated accordiug to the pniaciples of the present n-vant,ion. The metal miavaeedla mold at 1130 is attaehed to a moveable pm ram 1152, to form a tacuchnre that will be Lnpreised againat a polyma or otber plaatia material. 'Flus ruovoable sItuctn is iadicated by 'the refaanca numarnl 1150.
The polymer or othaor typG ofplssdc matcrial at 1160 is pitsod on the surface of a heated phtta 1154. The asscmueadie mitet9al preforabty wiH oomprim a biocompauble polymer aiatcdtl, althoagh otber matecials could be used iaclading polyeerbor4 or even PMMA.
1'he beatad p1aQe 1154 pravida suCicient thennsl eaarU to rausa ahe ktnparatuane of the biocomEsatible polymer matemial at 1160 until it becomes tvadily deFonnsabla. ln ottter words, the palyaer,r makrial is plue3 into its =plasric" stage by raising its WO 00174764 BCT/[TS00/15612 lemperature substanially to its elastic worldng toraperatua+a. The moveable pross aesembly 1150 is now pressed down tow.rd the heated plate 1154 aod ag,aiust the biocosnpatible polymcr ntaterul 1160. It is prefemod to aaooMlish ihis taak within a vaatum to presatvc the biocompatibilityr and sterilization chaactaisties of the fqhm cnicroneedias.
A cool-down etagc is next, as dcpieted by ahe final wsult in Figwe 54B. The heateti plate 1154 now becomes a cooling plate, and the biocempatible polymer material is cooled to the point where it becomee solid arul will not readt'ly deform.
The ntovoable presa ram assembly 1150 is now raisad, thotoby leaving bebind a microneedle atray to having a substrate at 1162. Yn the illustrated embodime.nt of Figwn 54$, tker+e are two hollow mieroooedlcs at 1170 And 1180, not yet haviqg tluvugh-h,oles in the subsncate 1162. T6e micmnee+dle at 1170 is depicted in aross-seet;on as having a fmst wall 1172 and a second wall 1174, which are generally cylb3drieal in ahape. These waifs surround a hollow area or hole at 1176. Similarly, mioroneedlo 1180 s6ows a cxoss-sadoa of a pair t5 ofwalls at 1182 and 1194, containing a oylindrical hollow area at 1186.
Afle.r the cool=down stage, the microneedle atruy is zemoved from the plite 1154, thmreby IeaviaB behind ttu sttuenne as illustrated at FWue 54C. The taicraneodle acparation is indicated at the dimaniion 1165. T6is dimenaian is equal to the dimenaion 1105 depicted on Figura 53C.
20 It wiA be undastood #tat other types of plastic farming p:vicesses oaa be usod than etnbossing. In fact, virtually ail types of molding or mict+omolding proeeseea can be utilized. Emboasing is one subsct of these typea of moldings, and injectloa moMing is a second subset, vVhioh was desaribed hcrainabove for other mioranealle shalua.
The abovo etracture depicted in Figure 54C could be used as the "&al" product 25 for catain uses with sicin. This atruoture consists of substrate 1162 and two hollow rnicroneediea 1170 and 1180, ia which the hollow cavities 1176 and 1] 86 eacb forrn a small cnp-iiice volume that does not prohvde ootnpletely through tha nbstrate 1162. This structm could be used for dmg delivery by fiili g the cup-like lwIIow cavities 1176 and 1186 with a drug active that can slowly kaeh out into biologieal systans.
30 Figures 54D-S4F illastrate varfous mvthods of kxmiag ahaQnbens beneath the micmneedle array, and for.miag through-holes. In Piguze 54D, a hollow chamber at 1190 WO 00174764 tCTRl590t15612 is formed on @te opposite sidc of tHe subatrate, thereby for,rntiug a mietoncedle 8nay stractme 1192 that cantaina bollow mimneadles 1170 and 1180, and a cltamber that can hold aome type ef ltaid, Tldo ehamber can be ibzmed by micromaRacldaing, or pedaps by an oxygen plaama ctchmg process. Other methodotogies conld be used without depwting from the pripaiples of the pmsent invention.
ru Figut+t: 346õ a laser light:ourea is nsed to Saidt the "drillneg" pmess to msko through-holes that are concentric or otherwise aattercd along the hoAow miamaeedles 1170 aad 1180. On Figure 54E, a laeer Gght soaroo is usad to buYn away some of the atl6sthate mateeiai along the l'mes at 1194 xnd 1196. The final eemlt is s6avvn at FiZure 54F, in which a tinal ncicroneedlc anry 1198 is iilnstrated sitowiag thrnugh-1loles frons the chmnber 1190 to tba top of tla; mics+onoedles, in which thc rnieronoadle opening 1176 atfd 1186 are aligned qridl ft lsa light burned boles at 1 I95 and 1197, respectively.
Figqtrs 3SA 55F illttstrate an alternative meihodology for oonatnioting holiow plistic microneedias. Starting with a iaminate material at 1200 and a biccompatibie polynaar at 120Z, ttbese materials are joined alang a plaaar euafte at the Iioc 1204 an Figure SSA. This joitting cen be perfoltaod by an tdhesive piqoess, or other temporary moobanical mems.
A saold 1210 is now pmvided, wbich preWrably vvill be made of a ntetaWo or otlier suitable material. 1n Figure 55B, the biocompatible polymers are pleoed an a beatod p1aLe 1212. and ft mold 1210 is placed upon a moveable pt+ess t'am. After tho lnald has been pxesfod imo the biaoonapmlit-le polymers, tho nm press is retewved aad the tnaterial is eooled, thaxeby wriving at a n:ucture iltustrtted in FSgure SSC in which holes 1224, 1226, and 1228 are fotmad all the way tltrongh tbe upper laM now de,signated az 1220.
1"hese holes also continue put-waQ+ iuoo the lowex layer at 12Z2.
The laminate moutlal3 that were eatller gluod together are now detached ftm one another. Tbis now provi8os a him atruetttre 1220 that has ihe thirough-holez 1224,122fi, and 1228, and is allustrated in Figtae SSD. Tbis film laya 1220 is ttow pkced upoa a haated plato 1230. A mold ahuctore 1280 is now provided and wili ba preesed against fikn layer 1220 after the Slm lalrcr 12201ve been hated to its pla9tic atage.
On Figure SsE, the cylindrical projectiono 1282,1284, and 1286 are u9od to create the tl+rou,gh-holes fur theea boik-w mioroneedleo.

Wd Q6f14764 pCT/i1S00/~3612 In an alternative configuration, the oylindriost pqjeetions 1282, 1284, and can be somewhat sbortened so tbat they rast agaIDSt the pLwar top snrface of the hcated plata 1730, i.e., along the horizotttal (osi Figtae 551=) 6ne 1235. The heated plata 123Q in tliis altanative confipxaGon, would be sabatatttiedly tkt along its top surface at, 1235, s mch tha tho opmiaga 1232,1234, and 1236 would be filled.
f-fkr tbe pceesiog ptnceas tw eCpaied aud the mataial 1220 is eaoled (by 1bft 1230) to the poiet ahace it beaomes aolidi04 the mold 1280 is ramoved and a new sttvcbm at 1240 it fbtu+ed and xcmoved from ft plate 1230. This is illustratod in Figure 5SF. Tfiis naw straefiste 1240 rcptr,seots a tni,eeoaoedle auay baving ahc+oe hollow cylindrical micronoeclles at 1242, 1252, and 1262. '1'ltese mit7+onoodles bava hollnw throug6rholaa as illuatiratod at 1244,1254, mfd 171K rtepeolively.
Another aee fa' the miaoneedlw of the ptrscnt invartion is to include a seosittg capabiSity by some type of optioal macs wilh a plastic t;ficroneedle array suuctan that is consaweal of a subdantislly ttsurepaent trtateaal. This could be WA with both hollow t s and solid mia+otsoecRas, altitough it is ptdttrod tlW solid adceanoedlos be used to prevent contautiaation of the 4g+ltt sotm meeftactisra ihat is beiug ertilisad tar this saos+ng capability. In Figorn 56, a micxoncedle uray *uctnre 1300 is dapiatcd as having a attbstrale 1302, tnd &ee miaonaxlla at 1310,1320, sod 1330. '11u ttppac atm of theaa mic:vneedies near tfieQ tip9 am eoated with a c6pnica! maileriai W+et aida in dctadiag a cheaaioal or othet biological proeess. Thi,e cLemical coating ia indicated on the t8reo mioronocciles at 1312,1372, and 1332.
Onca the micronGOdle array 1300 bas bee plaeed into the slcieE, a light sottroa is wod to proride elwkoraagnetie enagy in ft direcdon indicated by the arrov+e 1350. Yt is paefau+ed that the light sowo be sotqe type of 1aw satmx, ao that tbe alaoa+omsgaatic enetgy is collimated. The cheemcat oosding at 1312,1322. and 1332 will be of a type that will aither chauge ootor or rfmge its Lght passing chatsoudsiics when n2 oontact with tha tatget tlnid or biological materiats. In this methodology, tiu laser light that is refleabed back taward tlrc vptica! ancrgy arnmroa rvill eidtar be neducxd 'un inbettsity, as oomparod to before any chetniee] cbwges were noted at the ends of the tnicroneedles, or 3o ariil lmve a ooior variBioa.
Another nse for this eon6guration is to provide optical emetgy diaxtly ipto Wtl i10f14761 PCTN9o0/15613 portions of skitt tbat can be direetly affbated or elimulated by cettain froqucaaies of light.
1n this iastanae, the laaar light may d'aeedy provide eittxs opticai or t6ernmal enmu Into airin tiqsup, or could provide a neftdalogy fnr tratafar+ng such eneegy into unwie tissue at cartain locstiotu in w suimat body.
s Altematively, the seosore can be inzcgeed with the mlauneedle array by laytring tlie :alivr components on the fsce of the device contsinmg the pmmcutions tlutt w311 perfbrate the skin. Ono or more layars can be nsed depending upon the complexity of the dateocion proom. 3itaple canduativity measamnents for mallrtes liloC aodiaan ioas esn be rtlaUe witb only one conduaive iayar of a bioc,omprn'ble metarid, awch as the teyer 1312 on FFiguce 56A, a a layar 1372 on Figmre S6H.
Mare complex analysea (a.g, gluoose) ae seco,tn;riiehal by using several layera of senmg rnaterials. To pqwe an eazyme e?.eotnodQ, a biooompatiMe prepolymer doped with an enzyme, an enzyme modiiied with a polymerizrble group, or an enzyme modified wrth a p+oap that caut be tedmed or adsprbed 4o dto eLeoRooonduotive surface is coated on ts top of the etcobieally eonducti" poly sor and is polytaerizal using a euriag agaot or aa eaorgy soume suoh as light, at beat as necessary. This is iltnatcatod in Figo=
50 where tht eo fng oon9titr-ta aa anzyme layec tlut is depdated at 1374. The elactrically coadactiva layer is depicted at 1372. A siQgIe ruiemeedle sbnctune 1370 is iUwttaEed in Pigure 568 as a longituW{as1 alaenent peptrnding fman a subauate 1360, hawetw, it will be radeestood tlw snaty aucb iongituditul elemmt: caa be oonstiiusted on t1u rub~rate 1360 to onte a micronoodla uray (dmilu to, ag., fhe microneedles 1310, 1320, and 1330 on Figure 56A).
'17ta asayme i'ilm cxu ai6o be ooaood with addiaond layrxs of bioommpwbla pwiymass (as depicted at 1376) that oam be arnployed to proteot the sonsor oomponwfie from leaachfn& reections with biological enities, or to zeglate the aeaess of wsiytes to tlte eaxyme layer. As dcpicted in FigarA 56% the electrically conductive layer 1372, eazyme layer 1374, aad "rop" polymer layer 1376 me dapopited on vhhmRy t3ro entire sttrface of tho micraneedle srmy, except far an porttoa at the wi of the eubslrate stmetuace, as gerwaliy depieUod by tho tefemm manaW 1365. 'i he side waUs of a rnicmnoodle attay aomprtsmg mpltipte tniC=eedle devices mch aa the mietoneedlc strtushtte 1370 are not oompktely costod with the enzyme layer 1374 or secand polymer WO00/74764 rCT/US00t1f56I1 layer 1376, boeaase those arexs will be used for eleetsicxl cortaet with an eleclrochemical analyais circnit Tben;forn, only the decfttily eanduative hyes 1372 is depoeitod &ottghout the upper surfrce of tbe subatrate 1360, ittaluding Hu pestions near the left (on Figutre 568) hand end, at the numaral 1365.
S 7'hesa senaor ooe4meat kyets 13y2, 1374, 1376 can be dspceited on mictoneedles (c.g., msr.taneedlt 1370) by dipping the miaraneodle davicas in the appaapQiste chr,unicad reWuta. spitr-coating tea]miqms, electro dcpoaitiam, starapiag, depoeision of dry powde[s, nd dmil~ procasus Icnovrn by 6osc sldMt in the art.
The left-end ppitipn noer 1365 is preferably masiced cbuing the deposition proaedarau for the tn eazyme hyer or seooW polymat layer, t5crcby teaviag expesed the aleotrlaNy cend,ufive layar 1372 intbisragi0n.
The first cpnduative layer 1372 deposited on tho miarOneedies can consist of nsmy availoble meteria{a; meWt an prafemed md kWnde: Aa, Qr. 71, Fy Ag, Cu.
Condactive polymer miztwa such aa 7,7.8,84etcaoyanoquWaodinaethme with tetrathiatttlvWeae or N-ls methyIpheoaxanium c8n aLto be used. Ftntbernwre, conductivo polymas such as Poly~me, Poly0iophm4 polyperaphanyiane. aed polypltenylena vinylene and polyaailiae can be nscd.
The enzyme coating can be aalrepped in aay one of tnc thllowiqg polpmers or copoiyiaer mixtuns in tba aecoad layer at 1374: g,iatarddebyde, poly(ettrykne Btycol) 20 dictycddy ether erad polyl(1-vipylimidazole) osraiUm (4,4'dimo@tyl bipr3-idiae)zClJ, POIy N-a!'1PY~ Pay [(vinyl pyridine) Os(blPycidw},Ci], aycloded;n polyaiata, and gel8tia.
The vua' bio=petiblo prat'ecaon layer at 1376 aan include: silicflnos, fuauioatad-aWyleue pwpy[caa, nafiomo, ceflabse, PO+(vinD-fiYrici:w) aodaic, azbidbas.
2s pollnuethanes, voxies, fluarocsnbons, acrylics, parylem and polybmides.
Aaot)aer asa for this twnfigmnlioa is to provido elec6.fea1 onecgy direetly iato pOrdoaut of slan tlu+t can be diroctly aft'ected or stimalated by a small ela'trical aumati 1n this instance, the electric.ity is oondaeied via the condw,tive lqyer 1372. If it is desirable /o provide eiearical =rrat diroctly at the tipa of the mianneedlas, theu the cnzym layer 30 1374 and pnotoctive polymtr layor 1376 can be elvpiaated frant the manufwtnft piacass, leaving only the ala.uieplly conducpve layer 1372 coveriAg the entire substtato s~

WO 1e174744 PC9YiJSoa/15622 1360 and mia:oacedle stntchn at 1370. Ia tbis m9noex, electrical energy may be directly ptovIded into sldrt tissue, or could u[timatoly be tcrosfuied into muscle tissue at certain looations in an tmitnal body.
Figures S7A and 57B iIItuwe a reSttemEUt of the entlbossing procass that was earlier dexsibed in rdation to Figwos 54A S4C. In Figurts S7A, the tbieronecdle substrate at 1400 has baon defonaed by a menl (or other type of matacial) mold at 1410.
A single holfow ttucronetdlo sbntcturs is being foimed in Fignro 57A, as indkated by the cmes-seedon cylindtical vrall at 1402 and 1404. As the subwate mt-taia11400 is cooled.
:bmw favr.es ue gedesatod daieg t1,e do-molding procedure whkoh occurs a-lteti ti>a mold 1410 is ranovel from the upper surtboe of the substrste 1400. 'theae sbear foc+xs wi11 mainly occux along the ittaa surFaoes of tka walls 1402 and 1404, which ibdicate the ianer diarnctar of rio lollok mimneodie twr its tip.
The amount of shar Srnxs oen be controltod by tho cool-down tetaposatura and tioning as to whca the tuold 1410 is raleased. If the shear f+ot+CC is maQnteined at a iS odba" maotuda. tlte fiarl structure will not ltave a per,6ootly flat wfacc along dte top of thC mimaedtG but instad will l+ave a sl" sitltilv to tbat of the micraaeodla 1420 depicted in FSgut+e 579. Ytt this icietonredlc 1420, the upper mfisee of the micronoedte has ahacp points at 1422 wd 1424. snd a rather arewre shape along two of its semi-circular edges at 1426. '1'his sbape also cm be pmtbol'+c or elliptical ia natttro, and the imparttmt acpeat of t*a sltep is to provide sbatM edga at the potnts 1422 md 1424.
Ilsis is aa albemativo methodology for focntang hollow ctrcutar miemineedtes that can mot+e casily patptra#e the sCramn coraeunn of atcf.a, and mBy not nquixa the edged bladcs of flte ntimnneodk atsvopm dapiorad in Opm 32.
'fhe sbr-tdtiapod solid mimaoedle ettaatm+es can also be craded u0eg s molding proeess siq lar to that depictod in Figurdd 53A-53E, and S4A.54C. Of cousee, the solid tnicramerdles wili not requite tluougb-holes tbat at+e in alignmmt with the center of raob mioroncodle, bed wriri inmad tequu+e t6rough-boles in the aubatri0e ms,oe[ial at iocatiqns that ae substentiilly pmxitnal to tbe pair of blade shucnues aear the top surfaoc of the wbttrate.
lt will be nnde=stood tLa all typca of ntold+ng or casting pnmccdusos oottld be utilized ia co0uactiou with the present invention, so long as theat mold'utg procedures Wd CQr14764 PCrN8wn563I
oen be utilized to creaaps tho rery suuill stmctures roQuirod by the mieroaoedlee of the prmmt iave.ntion. Fu*AnnoM aomieonductor S6ticatioae 6ocLniqnes caa be asod to ci+eate the sbwctaceo iIInstratad on Figures 32-36, using paoceaeea that were de='bad bereaoebore 9n roi6ronco to Irigores 18 ZZ. Cxrbiniy Sudd nses'voirs can be eonmtictad s fcr use with the imiaroeeedle stnwdna of Figures 32-36, imd furtbamore vaeiout mWwds of use cm be utifized with tlusa microncadle sttaatonsõ aaoh se elootrapboresec or uihmuod.
Ila formgo'smg deeaipdm of a prefcmd oanbodioaent of ft invuttion has berm prr,seated for puaposes of Musksion and deseription. It Is t-ot intendol to be exhausdve or to Gmit the inveafiwj to the pmcise form disclosed. Obvious modi5catdotu or vairindomt ete paldble in ligbt of the ebw4a teeah9ngs. 'Cln: embodomaie was c!ro an md desc.riibed in order to bsst illaatrata tba primoiples of 8-e invention and its practieat appliaition ta tbercby e,u6te one of ordlnaty slritl hn t6e art tn boat nttiiza the imrantian in various anbodimaots aad with vaaoue raodi6cwtiont as are swited to the pardcutar use 1S oontiahplated, It is intsndnd that the tcope of the invention be defined by the chims sippended hetato.

Claims (6)

1. A method for preparing a mold for manufacturing a microneedle array, characterized by the steps of: providing a photoresist material, in contact with a temporary substrate; placing a mask layer upon said photoresist material, said mask layer having a predetermined pattern, at least a portion of said mask layer comprising a material that prevents high energy radiation from passing therethrough;
exposing said combination photoresist material/mask layer to high energy radiation;
removing said mask layer, and chemically developing exposed portions of said photo-resist material, thereby removing portions of the photoresist material and leaving behind a pattern of said photoresist material that represents a three-dimensional structure emulating a plurality of microneedles that are to be later formed;
electroplating said patterned photoresist material with a metallic substance; and detaching said metallic substance from said patterned photoresist material, said metallic substance thereby forming a microneedle array mold.

2. The method as recited in claim 1, wherein said photoresist material comprises polymethylmethacrylate (PMMA); or wherein said mask layer comprises gold; or wherein said electroplating metallic substrate comprises nickel.

3. The method as recited in claim 1, including the step of chemically coating said patterned photoresist material before the step of electroplating to aid in later detachment of the metallic substance from the patterned photoresist material.

4. The method as recited in claim 1, including the step of a microembossing procedure, comprising: placing a plastic material upon a temperature-controlled surface and, by use of said temperature-controlled surface, heating said plastic material to substantially its elastic working temperature, said plastic material having a first substantially planar surface touching said temperature-controlled surface and a second substantially planar surface on its opposite side;
pressing said microneedle array mold against the second substantially planar surface of said plastic material, thereby forming a three-dimensional pattern comprising a microneedle array in said plastic material; by use of said temperature-controlled surface, cooling said patterned plastic material below its deformable temperature; and de-molding, by removing said microneedle array mold from contact with said patterned plastic material, thereby leaving behind a plastic microneedle array.

5. The method as recited in claim 1, including the step of providing a vacuum during the molding process; or including the step of forming a fluid-holding chamber on the second substantially planar surface side of said patterned microneedle array.

6. The method according to claim 4, wherein the plastic material comprises a biocompatible polymer.