~P.V~N:EP~-Munche~ 03 ;15- 7-93 ; 1~:59 ; ~617) 227-5541 4~8923~94465:# 4 21~ 78 .
~ h~ technlcal field o~ this in~ention i~
the t~ea~m~nt of neurological disorder~ and, in partic~'ar, t~e ~reatment of disea~e~ and disorders which may ba remedled by tr~atment with ~e~retory substAnces, ~u~h a~ ne~rotra~mitter~, neuromodulators, hormone~, ~rophi ~actor~, or growth ~ac~ors. ~11 theee ~ubstan~e~ are characterized ky the ~ac~ thoy are s~creted ~y "~ource" celi~ and produce a epeoific ch~nge in the source ce~l it~elf or in a ~'target" cell (i.e., t~ey are bio~ogically ~ctive~.
~ e~i~it~ ln secresory subatances have beon implicated i~ variou~ neurological di~ea~ ack of neu~tran~mi~t~r-media~ed 6ynaptic con~act cause~
neuropathologlcal ~ymptom~, and can al~o lead to tho ultimate de~ruction of the n~uron~ ln~ol~ed.
For example, paraly~ls a~itan~, more commonly known a~ Parkin~on~ diseae~
chara~t~îzed by a Iack of the n~urotrans~itter.
do~amine, with~n the ~rlatum of th~ brain, ~econdary to the deetruction of th~ dopamine ~ecreting cell~ of the ~bstantia nigra. A~ected eubjocte demon~trate a ~tooped po~ture, ~tiffnee~
and ~lowne~s of mo~oment, and rh~thmic tremor of imbB, ~ith dementia be~ng often encounterod in very ad~a~cod ~ag~- of tho di~a~e.
. The dlr~ct admini~tration o~ purified or I ~.ynthet~c dopamine, its p~ecur~ors, analo~ and ~ inhibit~ h~e been atudied ~or thorap~utic value - in ~c~e t.re~tmen._ ~ }?arkin~30n ' 6 di~ea~e . The~e ~ Q~ITUTE SHEET
E~P.YON:EPA-Pun~en G3 ;15- ~-93 : 18:0a; (61~) 227-5941~ 499~23~54465;~ 5 -2- 2.1~ 78 tudlee have ro~ealed ~ariou~ problem~ wlth del~ve ~ , stability, dosag~, and cytotox~city of the appl~ed co~pound~. To d~to, none of tho~e approach~ ha~ demons~rated mo,e ~an margi~al ther~De~tic ~alu~. Brain deri~ed ~rowth factor a:so ~ay hav~ pot2~tsa1 value ir, the treatment o~
2arks'r.so~'~ d~ea6e sin_e it ha~ bee~ dcmons~rated ~o ~ai~taln the ~l~bil~'ty of ~triatal ne1.;rons iJl ~Q.
Many other d'sea~e6, e~pecially neur~logical d~aorder~ appear ~o be ~a~ed in whole, or ~n part, on the abse~ce or l~ite~ avail ~ illty, to .arget c~ls or region~, of a critical blological factor.
.
In an attompt to pr~ ~ide a cantinuou-~upp~y of drug~ or other rac~or~ to :he brain and oth~ tiB~UB~ at a cor_xol~ed rate, ~lni~t~ro o~motic pun~po ha~ ~een used. Howe~er. ll~it-d , ~: 8~t~bi~ity an~ ~tabill~y O~ ~ertair~ drug~, a~ w~ll as reservo~.- limitation~, h~v re3'ricted the e~ul~a~ of thio tochnology. For exa~ple, cont~olled ~u~ta~ned~rel-~o o~ dopamine ha~ beer attempted ~y 'mpla~tlng dop~mine en~ap~ulat-d wit~n bior~or;~ microca~-ule- ~McRae-Degueurce et al.
9883 ~e.uros-i. LCtt. 2~303-30~. Ho~ev~r, controllei ~u~tained r~le~e of a drug ~rom a biore60~ bl~ polymer:rellc3 OA bulk ~ur~ace ero~ior, Cor ~xample, du~ ~o ~ar~ou~ hydrolytic vent~, incr~a~ing thc llkellhood o~ drug de~adation. ~ d r~d-ring prodictable rel~a~o toa diffic~lt.
: ~he imolantat~on of cell~ capablo of _... . . . ... .. .
con~tit1:ti~ ~ly producing an~ 6ecreting neurolo~_cally act~e factorY ha~ aiso been attemp~ed. Rece~tly, remedial ~ran~plantation o~
_ Q~:T~TI IT 5HEET
EMP.VON:EPA-~;inchen ~ :15- 7-99 ; 18:00 : (617) 22~-5~41l 4~892~4465;~ B
-3~
neurotran~mltter-~ecretlng tia~ue ha~ been accompliohed u~ing the patient~ own ti~ue so a~
not to e iclt an immun~ re~Fon~e. For example, dopa~l~e-sec~et~ng t~oue from ~he adrenal medulla - of pa~ient~ euffering fro~ Parkin~on~o disea~e ha~
been l~.plan~ed ln their atria~u~ ~ith ~cme eucce~s.
~owe-~re- thlo procedure i~ orly ue~d ln pat~ent~
le~s I har~ 50 year~ of age, ao the ~renal gland of older ~?atier.ts may no~ eonrai~ suffi~ienl dopamine-secret~n~ ce~l~. Thi~ r~trictior. l~mit~ the ueefulness of the proc~dure a~ a remedy aince the dl~ea~e mo~t often af~act~ older people.
~ ther tran~plar,taticn approaches have demonstrated that even .hough the brair. io ~nsiderad '~ pri~ leged", re~ectics~ u;timate~y OCCU~8 with both allogra~t~ and xenogra~t~. Thie p~o~l~m necee~itatee the cs-admin~tration of inununo-~u~reJ~or~, the ueo of wh~ch render~ t~esr own ~et of compl~catlons and deleteri~ side-effecto.
'. A number of re~earche-~ ha~e proposed ~he UBe oC microcap~ule~, i.e., tiny sphere~ which e~cap~ulate a ~icroecoplc droplet of a cell ~ eolution, fox ~oth thorape~ic ~plantation purposes 2 and large ~cale product~on of blological products.
y However, theso are a number of ~ rtcoming~ to t~.e microencap~u~ation approach. ~or exampl~, t~e mic~ocap~u~e~ can be extr~meiy dlfficult to handle, including ~eing ~if~icuIt to rotrie~o after i~plantation. The type~ of encapJulati~g material6 whick ~n be u~ed are conotrainod ky ~he formation proce~ to F~lym-rB whic~ can dis~ol~e ln ~iocompa~ible s~l~ent~. Furthermore, due to the limi ed di$ru~10na~ surfac~ area per unlt volume o~
l~rger ~lze ~pheres, only a limited amount of ~ e ~an be ioaded lnto a single microcap~ule.
c~ STITIJTE SHEET
E~P.V~N:EPAFMu~chen 03 :15~ 3 ; la:ol ; ~B17) 22~-5~41~ 49a9239944~5;# 7 .
An alt~rnati~e appro~ch ha~ be~n macroencap~ulation, wh~ch typically involv~8 load~n~
ce' ;o lnto holl3w fiber~ and then ~ealing th~
extr~ml~ies. In ccntr~ tc mlcrocapQules, macrocap~ule~ offer ~he a~antage of ea~y r~trie~ ility,. an impo_t~nt ~eat-~re in therapeutic i~plants, e~p~claliy ne~ra~ implants. H~we~er, the con~tru~tion of macr~capsule~ in th~ pa~t has often ~een tediou~ and labor lnter.~i~e. Mor~o~er, due to-unreLiable closure, con~er.t onal methods of mac-oencap~ulation :~a~e ~ro~lded ir.con~ ent ~e~ultJ .
Yet anoth~r approach has ~een t~a implantatlon of ~efillable de~lces havlrg ~emi~rmeable membrane~ which a~l~w diffu~ion o~
neurotran~mlt~cr from the lu~i~al ~lde of the me~~ane into tho s~rrounding tl~ue. For exampl~, ~R ~aten~ Appl~catlon GB a 13C 916 di8close~ a dial~eio pr~be, primar~ly intended for in~estion in biologlcal ~i~Jue ~ncluding brain tl~ue, whlch mp-iJeB a d~ aly~is mombrane, and duc~- for ~u~ 'ng per~u~ion fluid to th~ mer~rane. Th-dlalysio menbran~ uch a pro~e i~ 6urrou~ded by a rlgid otruccur~ which su~port~ the r~mbrane ln contact ~lth the ~urra~d~ng t~cue. In ~notl~r ple, Int~rnational Publi~at~on woso~Is637 dieclo~s~ n~rologlc~l th~rapy device~ compri~lng a rctrievabl~ and r~fil~able ~ourc~ of neurQtran~mitt~r-~ecr~t~ng ~ ncaFoulated within a o~m~permeablo mombrane whic~ allows di~fu~on o~ the n-u~otr~n~mitter, and further incl~de~ ~ ~ource of growth ~ac~or ~n cloee prox~mlty to th- neurotran~mitter-~ocreting cel~.
`.
There exist~ a need for imprcve~ t~eraple~
for t~e tr~atment of neurological disorder~ in goneral, and i~ ~articular, a need for therapy , ~ c~T~rl ITE~-S H E E T
E~P.V~N:~PA-~unch~n ~3 ;15- ~-93 ; 18:~1 ; (611~ 227-5941~ 49B9239944B5;# 5 '~111978 do~lce~ which can augment or ~~plac~ the functions o~ dy~functional aroa~ of ~he br~i~ or oth~r organ~
witho~t cau~ing exce-~lve trauma. More ~ecifical~y, there exl~t~ a ~eed for a method o_ providi~g actlve, neuroactl~e factor to a localized region of the ner~ou~ ~y~te~ of a subject, the correc~ ~o~age of which w~ll bo con~titutiv~ly d~livered over ~im~.
Acccrdingly, it i~ an obj~ct of the preser.
~nvention to prov~de a me~hod ~or treatlng auch nourological di~order~ by d~li~ary of an implan~ablc, r~newable neurologlcal therapy device u~eful for the ~u~tained ar.d cont~olled del ~ory of bio~ogicaliy active factor~ to a ~ubj~ct. More ~art;cl~arly, to pro~ide a method ~ncluding a ronewable de~ice which can dellver biologicaliy active ~CtosJ to a ~ocali2~d region ln the brai~ of a ~ ~ject.
~ t l- anoth-r ob~ect to ~ro~ide an implantable d~ico that contain~ and prot~ct~
biologically actl~e ~actor~ theroln ~rom i3 ~
degrada ion ~uck tbat it i~ deliv~red to tho subiect in an act~e form. Y~t a~other ob~ect of th~
pre-~nt in~tion i~ to pro~id~ an ~mplantable dov~co whlch can dollver an:amou~t~of biologic~lly acti:ve factor~ roJponeive to 1~ Y~Y~ e~v~ronm~nt~l noed~. A f~rth r obj-ct 1- to prov~do an lmpla~table, protective c~ll culture d~vlce ~hich 1 r-tr_e~ble, and who~e con~ent~ ar renowablo with new and/or additional ~o~r~o of biologi~ally actlve actors.
~ efillable immunoi-olatory thorapy d-vice~
are di~clo~-d for tke local and controlled delivery S U B S TIT U T E S H E E T
E~P.VON:EPA-Munch~n 03 ;15- 7-~3 ~ 02 ; ~617) 227-5941~ 43~23~944~5;~ ~
of a biologically actlve factor to th~ brain o~ a patient. The de~ce~ gon-rally includ~ a c~ll chamn~r adapted for in~uJlon wlt~ b~ological~y active fac~or~, or ~ that ~ecr~te ~uch factor~.
The :ell cha~ber inc;ude~ a eemlpermeable ~urface acros~ which th acti~e factor~ mo~e for d~livory to the brair.. Tk2 device~ alJo include moan~ $or introd~clng 6uch coll~ or factor~ to the cell chambe~s, a mean~ for acco~ing tho cell chamver and rene~in~ t~e _el 1~ or factor~, and a ~tructural ~upport for ~upporting the coll chamber during implantation in the bra~' n and r~movable apart fro~
the cell cham~er following impla~tation.
Tn on- e~bodl~e~t of tho in~ention, the ~oll ch~m~er i9 con~tructed a~ a U-~haped tube having port~ for _il i.~g, flu-hing, and/os refilling the cell ~u~pon~on. The ~ort~ may be tho ~me or di~ferent Fort~, and c~n be ~aled to pre~ent introduction of extran~ou~ mater~al into the o-ll chamber.
!
Th~ ~upport ~tructur~ ~ ~ be, for example a m~r.drel, for pro~lding struc~ral ~u~port to th cel~ c ~ ar durl~g ~urgical in~-rtion in tho brain.
ma mandr~l m~y be, for oxam~l~, a ~olld centar~oard mandrel adapt~d to flt w~th a~l ~up~rt the wall~ of a cell chomb~ ~uch a~ a ~-~haped tube.
Alt-rnatively, the ~ndrel ~ay:b~ a ~el~ctiv ly collap~ible mandrcl that can be remo~d o~c- t~e c~ll cha~ber le pooitionad in the br~ln. Th~
ollap~lble mandrel ~y lnclud~ one or mora fla~g~-or tab~ whic~ functlon to #ec~r- the mandrel to t~e cel~ chamber durlng in~ertion.
. ~n ~no~her embodimont o~ the mandrel u~ed ln con~unc~lo~ with a U-qha~ed cell chamber, a aolid centerboard mandrel _~ initlally po~itioned withln IR ~;T~TIIT r C~ r E~P.VON:EP~T~unche~ 0~ .15- 7-93 ; 18:32 ; (Bl7~ 227-5541~ 49a923994465;#10 the ~- ~hape of th~ coll -ham~er, and a ~ ta~tially r~ gia ~hieid eloment i~ po~itioned ov~r t~o mandr~l and cell cha~er. The e2~tire a~sembly i8 then posit.ionsd wlthir. ~he ~rai~, and bo~ ~he ;nandrei - and the shleld may be ~emcved. The ~hield may include tab ~l~ment~ which inte_f_t with a~ aperture in the ~lid mandr~i to er~ble tkese two element~ to be remo~-ed fro~ the brai~ ~ub~tan-ially eimultaneou31y, lea~i~g .he cell cha~ber ir.
po~ition.
Ir. yet another e~bodiment of the in~ntive device, the device may be a coaxial double lumen t~b~ a~e~bly. In ~hat embodiment, the cell chamber i~ coextrud~d wi~h a polymer cas~ng ~olution to I for~. an ~n~ap~ul.ated cell chamber. The cell chamber I ~ay then be a concentrir lumer chamber havln~ ports connected to an i.~ner and ~n outer lu~e~ for ~illisg, flu~h~.g, and/or refilling.
: :
The b~ ologically actlve fa~tox-~ecr~ting cell may include any cell which ic known, or hao been engineered to produc~ ne~ropept de~, ro~hic ~: factors, or n~u~otran~mit~ ero~ or agcnie~50, ~i72 precuroo--, active analoge, ~r activo frag~:~ ntJ
thereof. For xu~l-, c~omaff~n cello o~ the ~: adrenal m~dul~a, mbryonic r~ntral meoenc-phali~
~:~ t~-~ue, ~nd ~ariou~ neurobla~ic coll lln~ such a~
P~12 fur.ction ~o ~upply dop~mins, and thex:e~or~, are preferro~ for irworporatio~ lnto the dovico. In me a~pac'c~ cf th in~ren~ion, the ~11 ic alloApecific (l.a., cells ~ro~r~ ano~her of tha ~ame specie~ a~ the ~ oct in . ' .
, ~ . .
,,~
, ~ IR ~;TIT U T E S H E E T
WO g3/00128 . ~ ".!' i~ ,` PCT/US92~053 which it is to be implanted) or xenospecific (i.e., cells from another of a different species).
The encapsulated cells, or cells contained 5 in the cell chamber of the invention, include neurosecretory cells that secrete biologically active factors such as gamma aminobutyric acid, serotonin, acetylcholine, norepinephrine, endorphins, enkephalins, dopamine, and precursors, agonists, 10 active analogs, and active fragments thereof. The cells may also secrete a dopamine precursor, such as L-dopa, or a dopamine agonist, such as bromocriptine. Other factors, and cells secretin~
such factors, may be used in practicing the present 15 invention.
The term ~biologically active factors~ used herein includes neurotransmitters such as gamma aminobutyric acid, serotonin, acetylcholine, 20 epinephrine, norepinephrine, ~luatmic acid. The term also includes fibroblast growth factors and dopamine. The term further includes precursors, agonists, active analo~s, and active fragments of these neurotransmitters (e.g. dopamine precursor 25 L-aopa and dopamine agonist bromocriptine). Cells that~secrete peptiae~factors such as peptide ~neurotransmitters, growth factors, trophic factors ;- anq~or hormones may also be useful. These include:
insulin, Factor YIII, trophic factors such as 30 erythropoeitin and growth hormones, biological response modifiers such as lymphokines and cytokines, enzymes, and antibodies from antibody-secreting cells, neuropeptides such as enkephalins, dynorphins, Substance P, and endorphins, as well as factors such ... ...
WOg3~00128 ~9~ 7 8 PCT~US92/05389 as nerve growth factor (NGF), brain-derived neutrophic factor (BDNF), neurotrophin-3 (NT-3), an array of fibroblast growth factors, and an array neurotrophic factor.
The cell chamber may also include a hydrophobic matris, such as an ethylene vinyl acetate copolymer, or a hydrophilic matri~ such as a hydrogel. The cell chambers may be post-production 10 coated or treated with an impermeable outer coatinq, such as a polyurethane, ethylene vinyl acetate, silicon, or alginate covering part of the cell chamber.
The invention will ne~t be described in connection with certain illustrated embodimen~s.
However, it should be clear that various modificaticns, additions, and subtractions can be made without departing from the spirit or scope of 20 the invention. For esample, the present inven~ion should not be read to require, or be limited to, a particular device shape, material, neurotransmitter, growth factor, or cell line described by way of esample or illustration.
;
~CTIU59Z /05389 ~111978 P~QIUS 1 4 AUG 1992 Brief DescriPtion of the Drawinas - The invention itself can be more fully understood from the following description when read S together with the accompanying drawings in which:
FIG. 1 is a graphic representation of a single plate mount embodying multiples of the system of the present invention;
FIGS. 2A - 2D are side elevation views of cell encapsulation vehicles used in practicing the present invention;
FIG. 3 is a perspective viPw of a vehicle embodying the centerboard mandrel embodiment of the invention;
.
FIG. 4A is a cross-sectional side view of a 20 vehicle embodying the collapsible mandrel of the invention; and FIGS. 4B and 4C are top and bottom cross-sectional views of the Yehicle of FIG. 4A, respectively;
"
FIG. 5 is an orthogonal side view in ~rosg-section of the vehicle of FIG. 4A;
FIG. 6 is a perspective view of a vehicle . . .
embodying the present invention; -; 30 FIG. 7 is a series of perspective views of a vehicle embodying the present invention, which al80 .~ integrates protective shields about the tip of the implant during surgical placement, which shields are 35 retractable prior to centerboard removal;
~, , j, . i .
~ . . _ . _ . ... .
2 1 1 1 9 7 8 PC~IUS9;~ S38~
ROIUS 1 4 ~llG 1992 FIG. 8A is a cross-sectio~al side view of another vehicle embodying the present invention; and~
FIG. 8B is a top cross-sectional view of the vehicle of FIG. 8A.
FIG. 9 is an orthogonal side view in cross-section of the vehicle of FIG 8A;
FIGS. lOA - lOD are a series of 10 longit~dinal-section views cf a camming shield embodiment of the invention, the series illustrating operation of the shield;
~IG. llA is a cross-sectional side view of a 15 double lumen vehicle used in practicing the present invention; and FIGS llB and llC are top and bottom cross-sectional views of the vehicle of FIG. llA, respectively;
FIG. 12 is a longitudinal-section view of a double lumen embodiment of a vehicle cf the present invention, also showing a means for filling/flushing using an applied nozzle;
FIG. 13 is a perspective ~iew of another embo~iment of a vehicle embod~ing the invention; and ~IG. 14 is a longitudinal-section view of the vehicle of FIG. 13.
Li~e reference characters in the respective ~igures indicate corresponding parts.
; .
, E~P.YON:EPA-M~ncn9n C3 :15- 7-3a : 19:03 ; (617) Z2~-5941~ 49~23994465;~11 -12- 211197~
Refillable immunoi~olatory neurological therapy de~ic~ aro di4closed ~or tho con~t~tuti~
and co~trolled delivory o~ blological y activ~
factors to a t~r~et treat~ent ~lto of a pat'e~t ~uff~rlng ~rom a n~urologlcal daficie~cy or dy~function.
~ enerally, the in~entive d~ice include~ a cell chamDer for ir.fu~io~ of c~ which eecrete biolcgicaliy active ~actoro. The cham~or ha~ at ;~aot ~ne ~e~ipermeable ~urface acrose which biologically a~tlve ~actor~ secr-t~d by the c~118 can ~e deli~ered to the ~urro~nding ti~uo, such a~ the b ain. The device also includes means for lntroduci~g cello to the chamber, and ~eana for renowing ~he cello contained 'n the chamber.
:
¦ FIG. l illuatrat-a ~e~eral d-vlce~ ~0 a'tach~d to a plate mount 12 po~i~ioned abo~e tha ln~ertion Jl~eD 14 of a patient~o ~kull ~u~t prior to J ~ ~eli~e ~ to a tr-~t~ont ~it~. In cne ~or~ of the inv-ntion, and a~ ~ho~n in FIG. 1, th~ de~ic~ lO may : ~e g~reral:ly U-~hap-d. Howev~r, a~ J~8t ~hown in IGS.-2~ - 2D,- t~e~d~vic~G ~ay~hav~ dlffer~;nt configur~t~on~ whil~ porf~rming:~ub~tant~ally the ~am~ fun¢tlon.
FI5. 2A illus~ratee a d~vlco lOa havi~g a - col~ chAm~er 20 th~t l~ U-~hapad to lncrea-~ the D~ curfaco area and ha~i~g a port 22 ~or re~illing ~ne ;- cell c~a~ber 20. FI~. 2B lllu~t:ra~e~ a U-shaped cell chamb-~r 20 sl~.ila~ So that of ~T~. 2A, lncluding a ' ~: :
E~P.V~N:EPA-~,uncn~n 03 ;15- 7-~3; 18:03; (~'7) 227-5941~ 498~23954465:#12 .
~111978 manlfold 24 to protcct ~he cell cham~er ~0 during lnsertl~n. FIG, 2C illu~trate~ a doublet lumen dovice lOc tha~ lnclude~ an outer ' umen c~ll chamber 20 for carrylng the bio' ogically actt ~re factor~, and a se~:~nd ir~er umen fcr flllshing tke cell chamb~r cel ls . FI5 . 2d ~ llustrat~ a 9-' ngle tube l~d h~vl ng an inner c~ll c'ra~er 20 containing the neur~actl~re factor~ d an ou~er protecti~ve coat~ng 26 whic:h ~erves to encace at ~ea~ parL of the cell cham~er.
The r~ f the de~r~ ce lOd ie permcelectl~ e to enable tran~port of th- f a~:or~ out of tho i:~n~r c811 -hamb~r 20. Similarly, a~ described belcw, FIG. 14 lliuctrate~ a membrane implant device 120 compri~ing a cell chamber encapsulated in a emi-permea~le or po~eiet~tl~re ~nem~rane, as da~cribed above,w~h an attached tether 3 ~ . ~he mem~rane permits dlf fusion ~f th~ s~eur;~active factor~ from the cell c:h~mber to th~ traatm~nt ~ite once the device llO i~ pocitloned.
~he ~pecific embodim~nt~ are di6cus-~d ln furth~r dotalI b-low.
' Re_err~ng to F~G. 3, a ~tandard U-~h~ped -e'l chambor 20, of th typo ~bown ~n FIG. 2A, ~b~nt the~ce~tcr ~u~portlv ~trut 25,:may be ~ltted wlth a center~oard-ty~e ma~arel 24 having ~ide elot~ 3a :: ada~t-d~to receiv the c~ll ch~mber ao. Sir.co each devic- 10 of the i~vention ia~doJlgnod to b- mounted to tho patlent~c ~kull, a cap 3~ 1~ attached to the top end portion~ o~ the ~-shaped c~l~ cham~er 20 ~ccu-e th chap~ o the cna~ber 20. The cap 34 incIud - th~ port 22 u~ed for re~ ing the cell ch~mber colu~lon.
The mandrel 24 of FIS. 3 i~ d~ ned to ~uppor~ ~he ~ ~aped cell chamber 20 durlng lmplantation throl~gh the ~n~er~ion site 12 and to the ~ :
~j i ~: c~ IR~:;'rl'rl ITE SHEET
wos3/00~ r~ 4~ Pcr/uss2/0s3ss treatment site in the patient. The mandrel 24 is designed to slidably fit through an insertion port 36 in the cap 34 prior to delivery of the device lOb to the brain. The mandrel 24 includes a solid center 5 plate 18 which is substantially rigid to provide~
support to the circumferential cell chamber 20. The mandrel 24 further includes a top portion 16 which may act as a stop point during insertion through the insertion port 36.
Because the human brain can move within the cranium, there is strain caused between an implant fised to the skull and the movable brain tissue.
Thus, the mandrel 24 is generally removed after 15 placement of the cell chamber 20 to facilitate flesibility of the chamber 20 once it is positioned.
The chamber 20 is generally manufactured from a flesible material to allow the structure to compensate for such movement of the cranium, to which 20 the chamber 20 is attached, relative to the brain, into which the chamber 20 is inserted.
Various polymers and polymer blends can be used to manufacture the cell chamber 20 of the 5' 25 devices of the invention. Polymeric membranes ~ forming the cell chambers may include polyacrylates iy ~ (including acryli;c copo~lymers),~polyvinylidenes, polyvinyl chloride copolymers, polyurethanes, polystyrenes, polyamides, cellulose acetates, i 30 cellulose nitrates, polysulfones, polyphosphazeres, 3 polyethylene osides, polyacrylonitriles, as well as derivatives, copolymers, and mistures thereof.
" " , ~ , . .
., WOg3/001~ PCT/US92/05389 -l5~111978 The solvents used in conjunction with the above-identified polymers in forming the cell chambers 20 will depend upon the particular polymer chosen for the membrane material. 8uitable solvents 5 include a wide variety of organic æolvents, ~uch as alcohols and ketones generally, as well as dimethylsulfo~ide (DMS0), dimethylacetamide (DMA), and dimethylformimide ~DMF). In general, water-miscible organic solvents are preferred.
The polymeric solution, or ~dope~, can also include various additives, including surfactants to enhance the formation of porous channels, as well as antiosidants to sequester osides that are formed 15 during the coagulation process. Esemplary surfactants include Triton-X 100 available from Sigma Chemical Corp., and Pluronics P65, P32, and P18.
~; E~emplary anti-o~idants include vitamin C (ascorbic acid) and vitamin E. In addition, anti-inflammatory 20 agents, angiogenic factors, and cell growth factors can also be~incorporated into the polymeric membrane to reduce immune response or to stimulate cell culture, respectively. Esemplary anti-inflammatory agents include corticoids such as cortisone and ACTH, 25 desamethasone, cortisol, interleukin-l and its receptors and agonists, an antibodies to TGF, to - interleukin-l, and-to interferon-gamma~ Esemplary angiogenic factorsl`include fibroblast growth factor and nerve growth factor. Alternatively, these 30 materials can be added to the devices after ,- manufacture or formation by a post-coating or spraying process. For e~ample, the devices can be immersed in a solution containing an anti-inflammatory agent, an angiogenic factor, or a 35 growth factor.
W093/00128 PCT/US92/OS~
211197 8 -16- .~'~
Post-coating procedures can also be used to provide a protective barrier against immunogens and the like. For esample, after formation, the cell chambers can be coated (e.g., by immersion, spraying 5 or applying a flowing fluid during e~trusion, if applicable) with a surface protecting material, such as polyehtylene oside or polypropylene oside to inhibit protein interactions with the e~posed cell chambers. Other protective coatings include silicon, 10 and hydrogels such as alginates.
Various cell types can be encapsulated for use with the present invention. Multi-compartment cell vehicles are particularly useful for the 15 constitutive delivery of neurotransmitters, such as dopamine, which is secreted by cells of the adrenal medulla, embryonic ventral mesencephalic tissue and neuroblastic cell lines. PC12 cells.(an immortalized cell line derived from a rat pheocromocytoma) are : . 20 particularly preferred in some applications because .. ofitheir ability to secrete large amounts of aopamine and other active factors over long periods of time.
Other neurotransmitters include gamma aminobutyric I acid (GABA), serotonin, acetylcholine, noradrenaline, ¦: 25 peptide neutrotransmitters, and other compounds . necessary for normal nerve functions.. A number of cell..;:lines..are known or can.be.isolated which secrete these neurotransmitters...Cells can also be employed which:synthesize and secrete agonists, analogs, 30 derivatives or fraqments of.neurotransmit;ters which are-~active, including, for e~ample, cells which . secrete bromocriptine, a dopamine agonist,~and cells which secrete ~-dopa, a dopamine precursor-..
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211ig78 In other embodiments of the invention, the encapsulated cells can be chosen for their secretion of hormones, cytokines, growth fac~ors, trophic factors, angiogenesis factors, antibodies, blood 5 coagulation factors, lymphokines, enzymes, and other therapeutic agents. Other biologically active factors may include neurotransmitters, peptides, and trophic factors. Esemplary biologically active peptides include enkephalins, endorphins, dynorphin, 10 and Substance P. E~emplary factors include nerve growth factor (NGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), an array of fibroblast growth factors, and ciliary 15 neurotrophic factor.
The aqueous cell suspensions in the cell chambers 20 can further include various additives to protect the cells during the estrusion process or to 20 stimulate their growth subsequently. Such additives may include, for e~ample, a nutrient medium or growth factors which are incorporated into the agueous suspension, as well as an anchorage substrate material to enhance cell attachment. The anchorage ; 25 substrate material can be a proteinaceous material, such as collagen, laminin, or polyamino acids.
Alternatively, the cell suspension or the polymeric solution (or both) can include a foaming agent or a - blowing agent which can distort the inner surface of 30 the polymeric coating to increase the anchorage surface area of the tubular interior.
In the U-shaped cell chamber 20 embodiment of the inventive devices, additional flesibility and ~, $ ~ ";
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1 g ~ 8 PC~IUS92 ~053 strength can be applied to the portion of the cell chamber 20 of the device which estends from the surface of the brain to the filling ports 22 by dipping that portion in a potting solution such as 5 polyurethane.
The inventive device 10 includes a plug 38 which is placed over the cap 34, or fits integral with the cap 34 to cover the filling ports 22 and 10 insertion port 36. The plug 38 may be manufactured from silicone, or any material capable of being formed into the desired configuration. The principle function of such as plug 38 is to keep contaminants out of the ports 22, 36 when the device 10 is in 15 position within a patient.
, An alternative embodiment of a manifold 24 used in supporting ~he cell chamber 20 in a device of the present invention is shown in FIGS. 4A-4C and 5 20 which present side and end views of device lOb, respectively. In that illustrated embodiment, the mandrel 24 îs collapsible to accommodate for insertion of the mandrel 24 in the U-shaped portion of the device lOb'. As illustrated, the cap 34 i~
25 adapted to fit with the plate mount 12. The mandrel ~ 24 includes a top portion 16 to stop the mandrel :.J; while it is inserted through the insertion port 36.
, . , The illustrated mandrel 24 of FIGS. 4A-4C
-~ 30 further includes a collapæible center portion 42 having side portions 44 which move toward each other ~ during movement through the port 36, and which espand ; away from each other once they are within the U-shaped portion of the cell chamber 20.
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WO g3/00128 - PCr/USg2/05389 "'' t~?4~ 7~y8~
As best shown in FIG. 5, the mandrel 24 may further include flanges 46 that estend from the side portions 44. The flanges 46 are designed to prevent the mandrel 24 from lifting out from between the 5 U-shaped cell chamber 20 during insertion of the device lOb' into the patient's brain. This is achieved by positioning the flanges 46 near the base of the cap 34 so that once the flanges 46 pass entirely through the insertion port 36 and below the 10 cap 34, they form a wed~e beneath the cap 34; The entire mandrel 24 may be removed by lifting the cap 34 along with the mandrel 24 once the cell chamber 20 is in the desired position.
In using the devices 10 of the present invention, it is desirable to refill or replace the contents of the cell chamber 20. As shown in FIG. 6, this can be achieved by means of a tube sleeve 50.
Following removal of the mandrel 24, the sleeve 50 20 may be inserted into the cap 34 of the device lOb'.
The sleeve 50 may include one or more fill tubes 52, each fill tube 52 positioned to align with the fill ports 22 of the device lOb'. The sleeve may further include a flange 54 adapted to interfit with the 25 insertion port 36, which is also used to insert the mandrel 24. - -~
` The sleeve 50 may be manufactured from anysuitable, ma~eable material which may be formed into 30 the desired shape. Since the sleeve S0 does not come '~ in direct contact with the patient, there is no specific reguirement that it be biocompatible`
~- although the sleeve 50 would typically be sterilized before use. Further, since it is a conduit for the .~ .
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21119 7 8 PG~0~ 2 ~Q~i3~3~
''' tubes 52 carrying biological material, there is no special requirement for it to be compatible with the transported biological material, e.g., biologically active factors.
~` 5 An alternati~e embodiment of the inventive device is shown in FIG. 7. In that illustrated ~: device lOb'', the mandrel 24 includes two separate portions: a center mandrel 60, similar to the 10 centerboard mandrel of FIG. 3; and, a shield 62. The ~- center mandrel 60 is held in place within the shield . , 62 by tabs 66 on one or both legs 64. When the center mandrel 60 is placed between legs 64, the tabs , 66 snap into the tab aperture 68 on the center 15 mandrel. In the illustrated embodiment, the center . mandrel 60 further includes a ridge 58 on its . bottom-most portion adapted to receive the bottom radius of the cell çhamber 20.
s -; 20 In practice~ and as shown in FI~S. 8A-8B and FIG. 9, the center mandrel 60 slides through the insertion port.36 until the bottom ridge 58 is fitted ~ within and receives the bottom radius of the cell .~ chamber 20. Flanges 70 on the center mandrel snap ~.~; 25 under the cap 34. Nest, the shield 62 is inserted Y within the insertion port 36, its legs 64 sliding ; along the walls 61 of the center mandrel. Thus, the ; . legs 64 of the shield ~over the walls 61. The legs '5~A 64 are generally slightly longer than the length of 30 the center mandrel walls 61 to enable the shield 62 to estend around the entire cell chamber 20 and . mandrel 60. The tip portion 72` o~ each leg 64 may be , adapted to form a closure upon positioning of the shield 62, the legs 64 being slightly outwardly 35 fle~ible to ~ 1 .~, SlJBsTlT(JTF~ FT
P~llUS92 ~0538~
~011JS1 4 ~UG 1992 -permit the legs to form a gap when being moved into position over the cell chamber 20, yet close once in position.
As shown in FIGS. 10A - 10D, removal of the center mandrel 60, along with the shield 62 is illustrated. Once the cell chamber (not shown) is positioned, with the inserted center mandrel 60~and overlying shield 62, shown in FIG. 10A, the entire 10 mandrel assembly may ~e removed. Pulling up on the cap 34 causes the shield 62 to cam open against the center mandrel by its tabs 66. The legs 64 slightly outwardly fles open to enable them to open around the bottom of the center mandrel wall 70 (shown in FIG.
15 10B). Next, the shield 62 is retracted, and ths tabs 66 engage the center mandrel 60. The tabs 66 inserted in the aperture 68 may ~e sufficient, or an additional ridge (74 of FIG. 7) on the center mandrel walls may be included to catch the ends of the legs 20 64 as they move upward ~ut of the insertion port 36.
This is shown in FIG. 10C. Finally, as shown in FIG.
10D, the center mandrel 60 and shield 62 are removed. The tabs 66 pull th center mandrel 60 out of the cap 34 through the insertion port 36.
, 25 The shield 62 may be made from stainless steel, plastic, or other material capable of being , sterilized. Alternatively, the shield and the center 3 mandrel may be manufactured from biocompatible or 30 bioinert material generally commercially available.
In an alternative embodiment, as shown in 3 FIGS. llA-llC, the device 10c includes both an inner ~ flushing duct 82 and outer cell chamber tubes 84, s ~1 ~s :
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2 1 1 1 g 7 1~tlus9Z/0s389 R011JS 1 ~ AUG 1992 -22- ~111978 both of which are ~iocompatible for.cell viability.
The outer tube 84 may be prepared using hollow fiber~
estrusion technology, generally known to those skilled in the art. The inner duct 82 can be of any 5 appropriate material manufactured by any appropriate method. Inner tube centering is accomplished thrugh placement of inter-fitting cap 34 and tip 88 portions at either end of the device lOc.
Specifically, referring to FIGS. llA-llC, the coasial device lOc includes a cap 34 and cell chamber 20 similar to the other embodiments described in detail above. Along the center asis A-A that runs parallel to the cell chamber walls 82 is a flushing 15 duct 84 for carrying and flushing eshausted or used solution. The ~ottom portion cf the duct is open to a vessèl 86 wherein eshausted cell solution is routed up through the flushing duct and out of the device.
The,~bodiment of FIGS. llA-llC includes a tip portio ~ ~ The tip 88 includes vessel 86, and serves the 3~itional function of assisting in aligning the cell chamber walls 82 with respect to the center flushing duct 84 during construction of 25 the device lOc.
c In practice, refilling solution is introduced into the cell chamber walls 82 through the refilling ports 22. The solution flows through the 30 cell chamber 20 and into the vessel 86 at the tip of the device. Old solution, such as depleted cell ~ suspension solution, is forced out of the chamber 20 i and up through the center flushing duct 84, where it ' is espelled through the espulsion port 23.
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WO93/00128 PCT/USg2lO5389 '11~78 As best shown in FIG. 12, a fill~flush tube 90 may be adapted to fit with the tube ~leeve 50. In operation, when the device 10c is in position within the patient, a plug 38 covers the ports. In the S illustrated embodiment, the tube sleeve 50 is '' threaded on the outer surface to secure it into position either in a plate mount or directly to the skull. The-tube sleeve 50 may also have a threaded inner surface for securing a plug 38 having 10 complementary threads, as shown in FIG. 12.
Thus, when it is desirable to flush or refill the cell chambers, the plug 38 is removed and a fill/flush tube 90 is secured into the tube sleeve 15 50. The end of the fill/flush tube to be inserted within the tube sleeve may be threaded to accommodate the threads on the inner surface of the tube sleeve.
Other methods of securing the fill/flush tube within the sleeve may be used. The fill/flush tube 90 20 includes a fill duct 92 through which replenishing solution, such as new cell solution or culture medium, flows. The tu~e 90 further includes one or more fill ports 96 which align with the filling ports 22 of the device 10c to enable passage of fluid 25 therethrouqh. The fill~flush tube 90 further includes~a flush duct 94 which, in one embodiment, is ~along:~the~central'asis of tube 90. The flush duct inclu'des-'a flush port'98'which aligns with the insertion port 36 of the'device 10c.
: As shown in FIG. 12, the device 10c may ,, : further include center tube support fins 100 which 1 stabilize the position of the fill~flush tube 50 when ', it is positioned at the ports of the device 10c.
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WO93/~l~ PCr/US~2/05~9 ~i -24-'~11.1978 Other methods and devices for securing and stabilizing the fill/flush tube 50 may be used, and are known in the art. For instance, the refill/flush capabilities of the current invention al~o allow the 5 introduction oE therapeutic medicaments or other`
biologically active factors prior to the cell chambers without removal of the chambers contents.
In yet another embodiment of the present 10 invention, shown in FIG. 13, the device 10d may include a filter basket 110 with a delivery sheath 112. The filter basket 110 is manufactured from a biocompatible micro-filter material generally commercially available. It may be ~ealed at the 15 pro~imal end, and attached to an upper portion 114.
Due to the problem of movement between the skull and the brain, discussed in further detail above, it is desirable that the upper ~ection 114 be flesible to accommodate such mo~ement. The upper portion 114 may 20 be topped with a retaining screw 116, or other securinq device.
As shown in FIG. 14, the filter basket 110 may be adapted to contain a membrane implant device 25 120 which enables constant, controlled flow of biologically active factors from the inner cell chamber, out into the desired treatment~site. The implant device 120 may be a tethered cell chamber, as described above, or other device for containin~
30 biologically active factors. The illustrated device is replenishable by removing the retaining screw 116, or other plug or cap, and lifting the membrane implant device 120 or other cell chamber, out of the filter basket 110.
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W093/00128~ 5~ 9 7 8 The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiment~ are therefore to be considered in all S respects as illustrative and not restrictive, the scope of the invention being indicated by the ippended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are 10 therefore intended to be embraced therein.
What is claimed is:
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