CA2129010A1

CA2129010A1 - Improvements relating to monitoring systems

Info

Publication number: CA2129010A1
Application number: CA002129010A
Authority: CA
Inventors: Pankaj Madganlal Vadgama; Paul William Crump
Original assignee: Individual
Current assignee: Victoria University of Manchester
Priority date: 1992-02-01
Filing date: 1993-01-26
Publication date: 1993-08-05
Also published as: WO1993014693A1; US6064900A; AU3363793A; JPH07508183A; US5749832A; EP0624074A1; AU669350B2

Abstract

Method and electrode assemblies for using or installing an electrode (especially enzyme electrode) in vivo, in which a protecting medium is introduced at the installation site to suppress adverse effects on the electrode's output. The medium is preferably an isotonic solution (e.g. saline) and/or a buffer solution and/or an anti-coagulant, and may be of increased viscosity (e.g. a gel or hydrogel), and may be coated on the electrode assembly. The preferred electrode assembly is a needle within a trocar cannula, preferably with the needle tip set back to form a recess to contain gelled medium which can then be fed with liquid medium. The assembly can be made as a sterilised, sealed pack bearing calibration and/or other data relevant to its use, especially in machine-readable form.

Description

WO 93/14693 pcr/c~B93/oo163 - 1 - 212~0:~0 El ectrode .

This inventi.~n rela~es t~ i.mpr~vements reIati.ng m~nit~ring systems, and m~re parti.cu).arly t~ impr~vements relati.ng t~ systems f~r mnni.~ring vari.~us bndy parameters, and especi.a)..l.y ti.ssue parameters, in vi.v~ by use ~f e.~ectr~des.
It is kn~wn t~ use electr~des as part ~f systems f~r m~nit~ring a variety ~f parameters in bi~l~gical c~nditi~ns ~r in bi~l~gical pr~ducts ~r mat:erial.s, especially as sens~rs. An especiall.y useful f~rm ~f electr~de f~r such purpnses is in the ` mnnit~ring ~f gl.uc~se i.n bndy fJ.uids, f~r example in bl~nd ~r tissue, and t~ d~ this ei.ther with samples taken fr~m a subjec and studied i.n vitr~ ~r by use ~f the electr~de sens~r i.n vi.v~.
H~wever, th~ugh such el.ectr~des w~rk well in vi.tr~ there is a maj~r problem in i.n viv~ use whi.ch arises fr~m the time requi.red f~r the stabilisati~n ~f the el.ectr~de - i.e. the time required f~r the signals fr~m the electr~de, when placed in viv~, t~ reach a c~nditi~n in which the signals cease changing even th~ugh the env.ir~nment ar~und the e.l.ectr~de i.s n~t changing.
This time delay can be as much as several h~urs, which effectively prevents use under c~ndi.ti~ns requiring rapid depJ.~yment. A.l.s~, i.n the case ~f e).ectr~des measuring gluc~se ~r ~ther c~mpnnents inv~lving an ~xidati~n/reducti~n pr~cess, there can be a c~nsiderable depressi~n ~f the si.gnal respnnse under in vi.vn c~ndi.ti~ns, s~ that there i.s pn~r c~rrelati~n between the signals and measurements ~f the same am~unts ~r cnncentrati~ns ~f analytes under i.n viv~ and i.n vi.tr~ c~nditi.~ns.
It can be seen that such effects are n~t satisfact~ry f~r accurate use in vi.vn and can restrict severely the usefulness ~f such e.l.ectr~de,s under i.n viv~ cnnditinns despite their ~therwise valuable prnperti.es when used under i.n vitr~ cnnditi.nns.
There i.s, therefnre, a c~nsiderab.l.e need f~r s~me fnrm ~f the el.ectr~des ~r methnd nf use ~r which can ~vercnme these - disadvantages and al.l~w reliable and cnnvenient use in vivn.
35The reas~n f~r this "read-nu~" depressi~n ~f the signal fr~m the e.l.ectrnde is nnt kn~wn, but we believe i.t arises fr~m s~me barrier nr interference tn its activity which i.s set up when the 21~9010~

electr~de is pu~ direct~y int~ c~ntac~ wi.th c~mpact bi~l~gl.c~l tissues when i.t is intr~duced int~ a b~di.ly envir~nment.
we have n~w f~und that these disadvantages can be ~verc~me by intr~ducing a l.i.qui.d medi.um int~ the si.te i.n vivn at which the electr~de is t~ be used, s~ that the li.quid medi.um intr~duced can pr~duce an c~mpati.ble envir~nment f~r the electr~de. This may be as a prel.ude t~ the b~di.ly fl.uids making c~ntact with the electr~de, but may be at any c~nvenient m~ment bef~re, during ~r after such c~ntact.
Thus acc~rding t~ ~ur inventi~n we pr~vide a meth~d f~r using ~r i.nstalling an eJ.ectr~de in place in viv~ which cQmprises the-step ~f pr~vidi.ng, at the site ~f intr~ducti~n ~f the said electr~de, a pr~tecting medium which, with~ut injuring the bi~l~gica.l env.i.r~mnent, suppresses the adverse depressive effect ~n the electr~de's ~utput induced by the h~stile bi~l~gical envir~mnent when it has n~t been m~dified by the pr~tecting medium. This pr~tecting medium may then be m~dified ~r replaced by an aque~us surr~unding medi.um which all~ws the electr~de t~
bec~me exp~sed t~ the b~di.ly bi~chemical changes ~f the surr~undi.ng envir~nment whi.ch i.s t~ be l~nit~red.
This pr~ecti.ng medi.um i.s f~und helpful by ~verc~mi.ng the fact ~hat ~i.ssues themseIves can present an envj.r~nmen~ l~w in water and high in pr~tein and el.as~i.c c~nnective _issue macr~molecules (c~llagen, eLasti.n, g).yc~pr~teins~ and als~
surface-active pr~tei.ns which tend t~ f~ul eLectr~de surfaces.
All ~f these dist~rt the n~rmal "aque~us s~luti.~n" cnnditi~ns used t~ calibrate the sens~r in vi.tr~. The pr~tecting medi.um is intended t~ pr~vide a pr~tecting ~r less h~stile envi.r~nment in which the e.l.ectr~de can functi~n.
It is b~e1.ieved that thi.s pr~tecti.ng medium may act in ~ne ~r _ m~re ways, 'th~ugh they are n~t fully underst~nd. The pr~tecti~n may be mechanical, chemica ~r bi~-physical, ~r any c~mbinaci~n ~f ~ne ~r m~re ~f these. In i.ts simplest f~rm, it pr~tecis the surface ~f the electr~de s~ that it makes minimal c~ntact with any medium which pr~duces adverse effects ~n the elec-r~de's perf~rmance bef~re i.~ makes c~ntact wich the medium in viv~ i- is t~ m~nit~r. The "adverse effects" may be, f~r example, WO 93/14693 PCT/GB93/~0163 _ 3 _ 2 1 2 3 0 1 0 .
c~mpressi~n by tissue which may squeeze a necessary aque~us film ~n the electr~de surface (~r i-ts membrane), ~r the devel~pments ~f an air space ar~und the electr~de -- f~r example in blQQd, b~ne ~r cartilage, but especial].y in subcutane~us tissue which physically prevent~s c~ntact with the tissue t~ be m~nit~red.
Chemically, it may be the effect ~f air ~r ~xygen, which may act adversely by its action ~n the electr~de. Thus, for example, air ~r ~xygen (~r even nitr~gen) may f~rm a layer whi.ch physically impedes access ~f the medi.um t~ be m~nitored, ~r it may affect the pr~cesses by which the electrode ~perates, ~r it may even interfere with the medium to be m~nit~red so as to block its access t~ the electrode, f~r example by leading to dehydration by evaporati~n at the membranes.
An additi~nal pr~blem can be that a high concentrati~n Qf bl~d c~mp~nents l.eads to l~cal. c~agulati~n and thereby f~nms a "skin" ~r barrier ~f relati.vely impermeab~e material which then hinders the access of the material t~ be m~nitored tQ the electr~de surface. This will be made w~rse if the material ~cQagu.l.um) is itsel.f then in c~ntact with a surr~unding layer ~f air and then t~tally ~r partially dehydrates t~ form a denser Qr less permeable barri.er.
A preferred methQd f~r pr~vi.di.ng the required envirQnment is t~ maintain adjacent t~ the e.ectr~de surface a z~ne c~ntaining a pr~tecting medium, whi.ch may be ~ne ~r m~re of the f~llQwing:-(a) an isQt~nic s~ uti.~n, substantially is~t~nic with the in ViVQmedium t~ be mnnit~red (f~r example having mOsm ~f 275-295);
(b) a buffer s~luti~n, c~mpatible with the in viv~ medium t~ be mnnit~red, t~ av~i.d large pH changes whi.ch in turn may affect the el.ectr~de signal size; and/Qr (c) an anti~ c~aguJ.ant, which serves t~ reduce the chances ~f c~agulati~n ~ver the surface ~f the electr~de Qr any part ~f j.ts structure (e.g. ~ver its membrane).
The is~t~nic s~l.uti~n (a) may be a simple aque~us saline (s~dium chJ.~ride) s~luti~n, ~r i.t may c~ntain additives. Such additives may be any c~nventi~nal phanmaceutically acceptable additives c~mpatib~e with saJ.ine s~luti~ns and useful fQr - m~difying ~r i~pr~ving them, f~r example to preserve ~r sterilise ~ 0 _ 4 _ them. Simpl.e examples inc ude p~tassi.um i~n, lactate (as i.n Hartmann's S~luti.~n) and bi.carb~nate. Further examples i.nclude agents t~ reduce inflammati~n (e.g. c~r_is~l), analgesics ~r ~ther agents t~ reduce pain (e.g. procainamide), agents which render tissues m~re permeable t~ liquids or electrolytes (e.g.
hyaluronidase) and s~ can "~pen up tight ti.ssues" t~ pr~vide freer permeabi.li.ty, agents t~ reduce bacterial gr~wth (e.g.
antibioti.cs), and mi.xtures ~r c~mbinati~ns there~f.
Other c~mp~nents which may be used, i.n s~luti~n ~r suspensi.~n, i.ncl.ude c~mp~unds (f~r example perflu~rocarb~ns and/~r l.ipi.ds) whi.ch diss~lve ~xygen and s~ can serve as reservoirs f~r ~xygen t~ prevent ~xygen starvation and/~r the ~xygen and/~r c~-fact~rs necessary f~r the functi~ning ~f an oxidase-based enzyme electr~de; anti.-~xidants, surfactants and ~5 many ~thers, pr~vi.ded always that they are pharmaceutically acceptable and d~ n~t - by their nature ~r their c~ncentrati~n -cause any unacceptable, undesirable ~r adverse effect.
Any "active" c~mp~nents used ti.e. those in~ended t~ pr~duce effects, and especiall.y effects ~ther than as cQmp~nents (a), (b) ~r (c) abnve] may if desi.red be in any c~nvenient ~r c~nventi~nal f~rm, for example a "sl~w-rel.ease" ~r ~ther f~rm which can reduce re-abs~rpti~n by the circulati.~n. An example ~f such a "sl~w release" f~rm i.s that ~f ].ip~s~mes encl~si.ng the relevant active ingredient ~r ingredients.
The buffer s~luti.~n may c~ntain any pharmaceuti.cally acceptable buffering c~mp~nents but especially may be based ~n ph~sphates i.n kn~wn manner (e.g. a mi.xture ~f m~n~-s~dium and di~
s~dium ph~sphates) and ai.med at pr~duci.ng ~r maintaining a pH ~f ab~ut 7.0 t~ 7.8.
Prefer~.y, h~wever, an is~t~nic buffer s~luti~n i.s used.
When an anti-c~agulant i.s used this may be a natural pr~duct -(f~r example heparin, hirudi.ne, pr~staglandin) ~r a syntheti.c pr~duct (f~r exampJ.e ethy.l.enediamine tetracetic acid -- c~mm~nl.y referred t~ as "EDTA" -- ~r an anal~gue ~r. derivative there~f;
such camp~unds may be c~nvenientl.y referred t~ as carb~xylated amine c~mp~unds). ~li.x~ures ~f such materials may be used i.f deoired.

:

WO 93/14693 ~ 1 2 9 0 1 0 PCr/GB93/~)0163 -- 5 -- .. .

An especially useful class ~f c~mp~nent is a material whi.ch can raise the visc~si.ty ~f the li.quid, either by simply increasin~ the visc~si.ty ~r by fnnmi.ng a gel nr hydrngel. These assist in retai.ning ~r l~cali.sing the added pr~tective medium and by increasing the abi.lity tn maintain a sufficiently aquenus medi.um adjacent t~ the e).ectr~de (e.g. by attracting water by nsmnsis) sn as tn faci.li.tate its functinning cnnsistently.
Higher viscnsity leads t~ a viscnus snluti~n which can be held in a stabl.e manner arnund the el.ectrnde; this can assist the liqui.d medium t~ remain lncalised where it i.s required, i.e. mainly near t~ the eJ.ectr~de surface, and reduce surface f~uling. Indeed, it is useful t~ use these (especially the hydr~gels) t~ c~at the surface nf the electr~des (the active electrnde surface itself, nr any membrane surface ar~und it, enclnsing nr surr~unding it.
It is a].sn advantagenus f~r such gels tn be adherent, i.e.
able tn f~rm an adherent J.ayer ~n the surface nf the electrnde ~r a part nf the eJ.ectr~de assembly (e.g. nn a surrnunding membrane).
Such visc~sity-enhancing c~mp~nents may be mnn~mers (e.g.
glycern]., mannit~l) nr s~nl.uble macr~mnJ.ecules ~r pnlymers, ~f natural nr syntheti.c nature (e.g. pnlyvi.nyl al.cnhnl, pnly-HEMA
[pnly-hydrnxyethyl-methacrylate], albumi.n, dextran, gelatin, he~astarch) ~r mi.xtures there~f. Indeed, they may be any materi.aJ.s which can fnrm nr cnnsti.tute n~n-t~xic gels ~r hydrngels.
One f~rm ~f the present i.nventi.nn which can be especially useful is a c~mbi.nati.~n ~f a hydr~phi.lic gel and a supply ~f liquid medi.um (e.g. isnt~nic snlutinn) t~ the gel layer. This supp.l.y nf snl.utinn may be c~ntinunus nr disc~ntinunus, as may be f~und mnst apprnpriate f~r the parti.cular circumstances nf use.
This assists in maintaini.ng li~uid in a layer arnund the electrnde.
Exampl.es nf electr~des which may be used include mnst ~f the cnnven~i~nal e.l.ectr~des and e.l.ectrnde systems, f~r example:-(a) any nf the metal.s (in the f~rm ~f the element ~r a cnmpnund)used fnr the study nf el.ectrnchemically active species (e.g.
silver, pl.atinum, nr any nther base metals which are~useful W093/14693 PCTtCB93/00163 212~010 - 6 -f~r the study ~f ac~ive species, f~r example asc~rba~e, paracetamnl, e~c.), membrane-c~vered electr~des using such metals and membranes ~f such materials as i~n-exchange p~lymers ~r materials ~f c~ntr~lled p~r~sity. These i.nclude S materials such as the pnlyether sulph~ne (PES), p~lyvinyl chl~ride (PVC) and c~mmercially avai.lable pr~ducts such as Nafi~n: these can be used in c~njuncti~n wi.th neur~-transmi.t~ers (e.g. n~radrena.l.i.n, d~pami.ne) (b) ~xidase-based enzyme electr~des, i.n which the ~xi.disable species may be f~r example gluc~se, lactate, etc.~
(c) de-hydr~genase-based enzyme electr~des (F~r these, the liquid supp.ly t~ them may be a s~urce ~f the~c~-fact~r (reagent) t~
facilitate the functi~ning ~f the electr~de):
(d) ~xygen electrhdes: these are similar t~ the enzyme electr~des lS but can be ~perated at higher v~ltages, e.g. appr~xLmately 0.6v against a Ag/AgCl reference electr~de.
The medium may be app.ied in a variety ~f ways, and ~ne very c*nveniçnt way is t~ intr~duce it int~ the site in which the electr~de is t~ be used but bef~re the electr~de is inserted in ~20 place. Such i.ntrhductj.~n may be by c~nventi~nal means, such as - ~injecti.~n ~r infusi~n. This can be achieved using c~nventi~nal equipmen~, f~r exampl.e hyp~dermic needles and the like, especially as these can be used t~ intr~duce a c~ntrolled v~lume ~f the medi.um.
An al.ternative meth~d i.s t~ insert the electr~de and the medi.um t~gether (e.g. si.muJ.tane~usly) s~ that the electr~de surface is n~t expnsed t~ deleteri~us materials, f~r example air ~r ~xygen. This can be d~ne by:-(a) inserti.~n ~f a tr~car cannu.1.a f~ wed by the pr~tective medium and then the electr~de;
(b) using à pair ~f needles (especially a c~ncentric pair ~f need.l.es), ~f whi.ch ~ne need].e (preferably the central ~ne ~f a c~ncentric pai.r) is an electr~de and the ~ther is adapted to pr~vide a supply ~f the pr~tecting medium ar~und the electr~de as it i.s inserted. (The pr~tecting medium (e.g.
buffer s~.l.uti~n) can then be trickled fr~m a supply reserv~ir ~r can reach the needle ti.p by capillarity.

:;

(c) using an electr~de which i.s c~ated with a pr~tecting meài.um which i.s i.n a f~rm whi.ch i.s sufficiently stable and durable mechanically t~ remain i.n pl.ace t~ pr~tect the electr~de surface during the stage ~f it S intr~ducti~n int~ the i.n viv~
site and thereafter either be dissipated ~r displaced by the ~ bndily fluids t~ be mnnit~red;
(d) using a cannula c~ntain~ng the pr~tecting medium and intr~ducing thi.s unti.1. i.ts exit ti.p i.s at the desired si.te fQr the e1.ectr~de and then intr~ducing the el.ectr~de thr~ugh the cannula and the pr~tecti.ng medium therei.n s~ that i.t reaches the desired site f~r use.
In these f~rms (c) and (d), the pr~tecting medium may be in the form ~f a visc~us fluid ~r a gel, Qr the like, and especially a hydr~philic gel. Such a f~rm ~f pr~tecting medium sh~uld be ~f sufficient visc~si.ty ~r strength tQ be able t~ remain in place during the critical stage ~f intrQducti~n i.n the subject.
One f~rm ~f electrQde f~r this purp~se may have the pr~tecting medium ~n the el.ectr~de surface as a membrane ~r impregnated in a membrane.
An~ther fQrm ~f c~nstructi~n which ~ffers c~nsidera~le advantages is a need].e wi.th a recessed tip, within which the el.ectr~de i.s l~cated wi.thi.n the ti.p but set back fr~m the ~pen tip ~f the needle, and the pr~tecting medium is fed t~ the recess in the tip. This all~ws the pr~tecti.ng medium t~ be fed int~ the recess at the tip, thus i.nterp~sing itself between the electr~de and the tissue int~ which the needl.e is i.nserted.
A m~dificati~n ~f this f~rm ~f c~nstructi~n is that in which the recess at the tj.p ~f the need.1e c~ntai.ns a ge.l ~r hydr~gel, which has the abili.ty t~ remain i.n pQsiti~n there with~ut fl~wing ~ut, as a ~.iquid wQuld d~. This facilitates the maintenance ~f the desirèd pr~tecti.ng envirQnment and retenti~n ~f the pr~tecting medium with the mini.mum need t~ replenish this. The gel may be i~pregnated with the appr~priate liquid medium bef~re the needle/el.ectr~de is inserted int~ the tissue which it is desired t~ m~ni.t~r. If desired, the efficiency can be impr~ved ~r safeguarded by making pr~vi.si~n f~r a supp1.y ~f the pr~tecti~n medium (liquid) t~ be fed i~, i.ntermittently ~r c~ntinu~usly, as 212~11) 8 -may be f~und necessary nr desirabl.e t~ mai.ntai.n the electr~de in g~d w~rki.ng cnndi.ti.nn and stabl.e. The gel may be any ~f thnse materi.als i.ndicated and discussed abnve in c~nnecti~n with ~he mndes fnr increasi.ng the viscnsi.ty nf the prntecting medium.
The supply ~f prntecting medi.um (liquid) tn the gel shnuld be kept at a sufficient level. tn maintain the activity and the reliabili.ty ~f the el.ectrnde i.n use, while ensuring that the supply dnes n~t becnme excessive and risk causing any detrimental.
effects tn the surrnunding ti.ssue, fnr example by "fl~nding" it with injected medium nr disturbing the tissue tn such an extent that the signal nutput fr~m the el.ectrnde is debased because i.t is made mnre rem~te fr~m the tissue which is being m~nit~red.
Examples nf s~.~.utinn v~lumes and c~mpnsitinns which may be used include (but nnly fnr exemplifi.catinn and nnt limitatinn):-15 ta) Isntnnic strength, mOsm nf 275 - 295.
(b) Temperature nf 21 - 37 degrees C.
(c) ~ydrngel. l~ayer thickness, apprnximate.~y 1-100 ~m.
(d) Recessed tip dimensinns: 0.02-2mm diameter x 0.2-5mm depth.
(e) V~].ume nf liquid intrnduced with the inserti~n nf the needle/el.ectrnde: up t~ abnut 0.2 ml initi.ally. Larger nr small.er vnl.urnes may be used i.f desired, and the vnlume chnsen wil). depend upnn such fact~rs as the nverall distributi.~n in the tissue. Thus 0.2 ml may suffi.ce t~ hydrate the electr~de tip (the gel. znne) ~r 0.5 ml may in additi.~n hydrate a large "fi.eld" ~r znne arnund the el.ectrnde/needle tip and prnvi.de better prntectinn.
(f) prnpnrti~ns nf c~mp~nents: apprnxi~nating tn the ranges ~f each natural. cnmpnnent as fnund in blnnd plasma (see "Cli.nical Chemistry," by N.B. Tietz, fnr fuller details).
30 The ele,ctrndes may be made as very smal.. l. items, especially in need.l.e fhrm tn facil.itate i.nserti.nn i.ntn the site nf use. In cnnsequence, they may be made smal.l en~ugh t~ reach practically any site. A).sn, they can be made with such a simple cnnstructinn -that they may be treaced as dispnsab.le after use.
Accnrding tn nur inventi.~n we alsn pr~vide a nnvel and advantagenus way fnr stnring and se.l.ling the el.ectr~des. This relies upnn fi.rst maki.ng the el.ectrnde i.n a fnrm~which is clean :

W O 93/14693 PC~r/~B93/00163 ~1290~0 - 9 -and stable, f~r example by bei.ng packed in a pr~tecti.ng medi.um as described ab~ve, and then seal.ing i.t in a sterlli.sed package and marki.ng the package wi.th detai.ls requisite f~r its use.
~Such pr~cedures and detai.ls may include calibrati~n. This may be d~ne very c~nvenientl.y in a central facility, f~r example at the manufacturing site ~r the distributi~n/st~rage site. Then the data ~f the cal.ibrati~n may be put up~n the package in any manner whi.ch is useful. f~r c~nvenient and/~r speedy use by the clinician. F~r example, the relevant data can be in c~ded f~rm, especiall.y a machine-readab~e f~rm (f~r example a bar c~de ~r a magnetically rec~rded f~rmat) s~ that the user can, by means ~f a c~nventi~nal "reading" device, "read" the enc~ded data int~ the user equipment s~ that the ass~ciated instrumentati~n equipment can assimilate the data and aut~matically make any adjustments which may be required t~ ensure that the read-~ut can be accurate with~ut the need f~r further c~rrecti~n bef~re it can be fit f~r being rec~rded.
The present inventi~n has the advantage that the depressi~n ~f the electr~de ~utput readings can be br~ught int~ cl~se match with th~se ~btained .i.n in vitr~ use. This makes the use ~f the electr~des much m~re c~nveni.ent and c~nsistent, as we].l as all~wing the use i.n vi.v~ ~f electr~des which hithert~ have really been ~f real. pract.i.cal value ~nl.y i.n vi.tr~.
The i.nventi~n has the advantage ~f ~verc~ming the pr~blems arising fr~m the fact that tissue is n~t very fluid and has a l~w water c~ntent (pr~blems whi.ch make it difficult f~r diffusi~n ~f an analyte t~ the electr~de), and the intr~ducti~n ~f aque~us medi.a i.nt~ ti.ssue i.n the manner described can "~pen up" tight tissue envi.r~nment and impr~ve diffusi~n and als~ st~p turgid tissue fr~m ti.ghtly c~mpressing the electr~de surface. Further, l.~ca].~y a~Sdéd c~mp~nents can reduce the bi~chemical effects leading t~ c~agulati~n ~f any bl~nd fr~m br~ken capillaries, and ~perate by ~ther mechani.sms t~ maintai.n water ~r el.ectr~lyte ar~und the electr~de f~r a l.~nger peri~d and thereby extend the peri~d ~f ~perabi..l.i.ty ~f the el.ectr~de. The i.nventi~n a)s~
pr~vides a c~nduit which a.l.J.~ws f~r a m~re c~nvenient and valuabl.e cal.ibrati~n ~f the electr~de in viv~ ~r i.n si.tu.

Claims

CLAIMS:

1. A method for using or installing an electrode in place in vivo which comprises the step of providing, at the site of introduction of the said electrode, a protecting medium which, without injuring the biological environment, suppresses the adverse depressive effect on the electrode's output induced by the hostile biological environment when it has not been modified by the protecting medium.

2. A method as claimed in Claim 1 wherein the protecting medium is then modified or replaced by an aqueous surrounding medium which allows the electrode to become exposed to the bodily biochemical changes of the surrounding environment which is to be monitored.

3. A method as claimed in Claim 1 or Claim 2 wherein the protecting medium or aqueous surrounding medium which allows the electrode to become exposed to the bodily biochemical changes of the surrounding environment which is to be monitored, is one or more of the following:-(a) an isotonic solution, substantially isotonic with the in vivo medium to be monitored;
(b) a buffer solution, compatible with the in vivo medium to be monitored, to avoid large pH changes which in turn may affect the electrode signal size; and/or (c) an anti-coagulant, which serves to reduce the chances of coagulation over the surface of the electrode or any part of its structure (e.g. over its membrane).

4. A method as claimed in Claim 3 wherein the isotonic solution (a) is an aqueous saline (sodium chloride) solution, optionally containing one or more additives.

5. A method as claimed in Claim 3 wherein the buffer solution (b) is based on phosphates and is aimed at producing or maintaining a pH of about 7.0 to 7.8.

6. A method as claimed in any of Claims 1 to 5 wherein the protecting medium or aqueous surrounding medium is an isotonic buffer solution.

7. A method as claimed in any of Claims 1 to 6 wherein the protecting medium or aqueous surrounding medium contains one or more components which dissolve oxygen and so can serve as reservoirs for oxygen to prevent oxygen starvation and/or the oxygen and/or co-factors necessary for the functioning of an oxidase-based enzyme electrode.

8. A method as claimed in any of Claims 1 to 7 wherein the protecting medium or aqueous surrounding medium contains an "active" component in a "slow-release" or other form (for example a liposome enclosing the relevant active ingredient or ingredients) which can reduce re-absorption by the circulation.

9. A method as claimed in any of Claims 1 to 8 wherein the protecting medium or aqueous surrounding medium contains contains a material which can raise the viscosity of the liquid, either by simply increasing the viscosity or by forming a gel or hydrogel.

10. A method as claimed in any of Claims 1 to 9 wherein the protecting medium or aqueous surrounding medium is used to coat the surface of the electrodes (i.e. the active electrode surface itself, or any membrane surface around it, enclosing or surrounding it), preferably in an adherent manner.

11. A method as claimed in any of Claims 1 to 10 wherein there is used a combination of a hydrophilic gel and a supply of liquid medium (e.g. isotonic solution) to the gel layer, which assists in maintaining liquid in a layer around the electrode.

12. A method as claimed in any of Claims 1 to 11 wherein the electrode is a metal electrode (e.g. silver or platinum), a membrane-covered electrode, an oxidase-based enzyme electrodes, a de-hydrogenase-based enzyme electrode or an oxygen electrodes.

13. A method as claimed in any of Claims 1 to 12 wherein the medium is introduced into the site in which the electrode is to be used but before the electrode is inserted in place, for example by injection or infusion.

14. A method as claimed in any of Claims 1 to 13 wherein the electrode and the medium are inserted together so that the electrode surface is not exposed to deleterious materials, for example air or oxygen.

15. A method as claimed in Claim 14 which comprises insertion of a trocar cannula followed by the protective medium and then the electrode.

16. A method as claimed in Claim 14 which comprises using a pair of needles (especially a concentric pair of needles), of which one needle (preferably the central one of a concentric pair) is an electrode and the other is adapted to provide a supply of the protecting medium around the electrode as it is inserted.

17. A method as claimed in Claim 14 which comprises using an electrode which is coated with a protecting medium which is in a form which is sufficiently stable and durable mechanically to remain in place to protect the electrode surface during the stage of its introduction into the in vivo site and thereafter either be dissipated or displaced by the bodily fluids to be monitored.

18. A method as claimed in Claim 14 which comprises using a cannula containing the protecting medium and introducing this until its exit tip is at the desired site for the electrode and then introducing the electrode through the cannula and the protecting medium therein so that it reaches the desired site for use.

19. A method as claimed in any of Claims 17 or 18 wherein the protecting medium may be in the form of a viscous fluid or a gel, or the like, and especially a hydrophilic gel, preferably of sufficient viscosity or strength to be able to remain in place during the critical stage of introduction in the subject.

20. A method as claimed in any of Claims 1 to 19 wherein the electrode used has the protecting medium on the electrode surface as a membrane or impregnated in a membrane.

21. An electrode assembly comprising a protecting medium as defined in any of Claims 1 to 20 on the electrode surface as a membrane or impregnated in a membrane.

22. An electrode assembly as claimed in Claim 21 comprising a needle with a recessed tip, within which the electrode is located within the tip but set back from the open tip of the needle, and the protecting medium is fed to the recess in the tip.

23. An electrode assembly as claimed in Claim 21 or 22 wherein the recess at the tip of the needle contains a gel or hydrogel.

24. An electrode assembly as claimed in Claim 23 wherein the gel or hydrogel is impregnated with the appropriate liquid medium before the needle/electrode is inserted into the tissue which it is desired to monitor.

25. An electrode assembly as claimed in Claim 23 or 24 wherein provision is made for a supply of the protection medium (liquid) to be fed in, intermittently or continuously, as may be found necessary or desirable to maintain the electrode in good working condition and stable.

26. An electrode assembly as claimed in any of Claims 21 to 25 in which the electrode, preferably first made in a form which is clean and stable, is packed in a protecting medium as described in any of the preceding claims and sealed in a sterilised package, optionally with the marking of the package with details requisite for its use.

27. An electrode assembly as claimed in any of Claims 21 to 26 in which the electrode is calibrated, and preferably data of this calibration is put upon the package, for example in coded form.

28. An electrode assembly as claimed in Claim 27 in which the calibration data is on the package in a machine-readable form, for example a bar code or a magnetically recorded format, so that the user can, by means of a conventional "reading" device, "read" the encoded data into the user equipment so that the associated instrumentation equipment can assimilate the data and so allow automatically make any adjustments which may be required to ensure that the read-out can be accurate can be made, automatically or otherwise, without the need for further correction before it can be fit for being recorded.

29. A method for using or installing an electrode in place in vivo, substantially as described.

30. An electrode assembly useful for a method as claimed in any of Claims 1 to 20 and 29, substantially as described.