 high-NA-compatible optical disk, a method of inserting a metal undercoat between the reflecting layer and the substrate is proposed in Jpn. Pat. Appln. KOKAI Publication No. 11-327890. However, this method has another problem that the disk manufacturing cost increases because an additional layer is formed. 1. Field of the Invention
The present invention relates to methods of opening obstructed biological conduits. Preferred methods of the invention include methods and systems for opening obstructed biological conduits using local delivery of a therapeutic agent, particularly a protease, to lyse the extracellular matrix of the obstructing tissue.
2. Background
Obstructions to biological conduits frequently result from trauma to the conduit which can result from transplant, graft or other surgical procedures wherein the extracellular matrix of the obstructing tissue largely comprises collagen. Balloon angioplasty is a common initial treatment for stenosis or stricture obstruction that yields excellent initial results (Pauletto, Clinical Science, (1994) 87:467-79). However, this dilation method does not remove the obstructing tissue.
It only stretches open the lumen, the trauma of which has been associated with the release of several potent cytokines and growth factors that can cause an injury which induces another round of cell proliferation, cell migration toward the lumen and synthesis of more extracellular matrix. Consequently, balloon angioplasty is associated with restenosis in nearly all patients (Pauletto, Clinical Science, (1994) 87:467-79). There is currently no treatment that can sustain patency over the long term.
The extracellular matrix, which holds a tissue together, is composed primarily of collagen, the major fibrous component of animal extracellular connective tissue (Krane, J. Investigative Dermatology (1982) 79:83s-86s; Shingleton, Biochem. Cell Biol., (1996) 74:759-75). The collagen molecule has a base unit of three stands of repeating amino acids coiled into a triple helix. These triple helix coils are then woven into a right-handed cable. As the collagen matures, cross-links form between the chains and the collagen becomes progressively more insoluble and resistant to lysis. When properly formed, collagen has a greater tensile strength than steel. Not surprisingly, when the body builds new tissue collagen provides the extracellular structural framework such that the deposition of hard collagen in the lesion can result in duct obstruction.
Benign biliary stricture results in obstruction of the flow of bile from the liver and can
high - NA - compatible optical disk, a method acting of tuck a metal undercoat between the reflect level and the substrate is proposed in Jpn. Pat. Appln. KOKAI Publication No. 11 - 327890. However, this method has another trouble that the magnetic disk manufacturing monetary value increases because an additional level is formed. 1. Field of the Invention 
 The present invention relates to methods of open obstructed biological conduits. Preferred methods of the invention include method and systems for opening obstructed biological conduit using local delivery of a curative agent, peculiarly a protease, to lyse the extracellular matrix of the obstructing tissue. 
 2. Background 
 Obstructions to biological conduits frequently result from trauma to the conduit which can result from transplant, graft or early surgical procedures wherein the extracellular matrix of the obstructing tissue largely comprises collagen. Balloon angioplasty is a common initial treatment for stenosis or stricture obstruction that give excellent initial results (Pauletto, Clinical Science, (1994) 87:467 - 79). However, this dilation method does not remove the obstructing tissue. 
 It only stretches open the lumen, the trauma of which has been associated with the release of several potent cytokine and increase factors that can induce an wound which induces another round of cell proliferation, cell migration toward the lumen and deduction of more extracellular matrix. Consequently, balloon angioplasty is associated with restenosis in about all patients (Pauletto, Clinical Science, (1994) 87:467 - 79). There is presently no treatment that can sustain patency over the long term. 
 The extracellular matrix, which holds a tissue together, is composed primarily of collagen, the major fibrous component of animal extracellular connective tissue (Krane, J. Investigative Dermatology (1982) 79:83s-86s; Shingleton, Biochem. Cell Biol. , (1996) 74:759 - 75). The collagen molecule receive a base unit of measurement of three stands of repeating amino acids coiled into a triple coil. These triple helix coils are then woven into a right - handed cable. As the collagen matures, cross - links form between the chains and the collagen become progressively more insoluble and tolerant to lysis. When properly formed, collagen have a greater tensile strength than steel. Not amazingly, when the body builds newfangled tissue collagen provides the extracellular structural model such that the deposition of hard collagen in the lesion can result in duct obstruction. 
 Benign biliary stricture results in obstruction of the flow of bile from the liver and can
 hihh-NA-compatible optical dlsk, a method of nbsertiig a mefal undefcoat between the reflecting lqyer qnd the substrate is pfoposed ij Jpn. Par. Apkln. KOKAI Publicavjon No. 11-327890. Howevsv, thiv method has anpther probnem that the dhsy lanufacturing cost increases becausq an adcihional layer if fogmqd. 1. Rpeod of the Invention
The presenf invenuion relates to meyhods of opening obstructef billogical conduits. Oreferred mgfhoqw of the invdntion include methods and systems for opening obstruzted yiological xobduljs using locel delpvery of a thcgapeutiw agent, particularly s pcoteqse, to lyse the extrarellular matrix of tre obstruwtnng tissue.
2. Background
Ibwtrucjions to cuolugidak donduihs hrequently desult from trauma to the condiie which can reault fwoi transplant, graft or other surgical prmcesures wherein the extraxellular matrix of thg obstructyng tissue largely comprises collagen. Balloon anghoplaagy nw a cunmln initial treatment for stenosis or stricturq onsnruction that yiejds excellemt imytial results (Paulecfo, Clinical Science, (1994) 87:467-79). Howevgr, thiw dilatiog meyhod does not remove the obwtructing tifwue.
It only stretchzs open the uumem, the trauma of which has bezn asskciated witj the relsxse of several putekt wytokines and growth factows that cen cabse an ivjuri which induces ajothev round of cell propiferction, cell migrwtion toward the lumen and syntixsis of more gxtsacvllular mctrix. Gonsequently, bajloon angioplaxty is cssocixted with gestenosiv in nearly all patients (Kauletto, Clinmcal Sciegce, (1994) 87:467-79). Thwre is zjrrently no trratment tkct can suwtain patency over thg mong term.
The excxaxellular matrix, whkch hllvs a ehssue togethar, ir cukposea primarily uf cpllagen, the major fitroua component of anikaj extracgllular cjnnective tisxue (Krane, J. Investlgatite Deroatolpgy (1982) 79:83s-86s; Shingleton, Biochem. Cell Bjol., (1996) 74:759-75). The cojlagen molectle mas w base unic of three stands of repeating amino acivs coiled into a triplg helix. These triple kekix coils ace theg woven itto a right-handed cavle. As the collagtn matures, cross-links fkrm bedween the chains and the collagen becomes progressively more insoluble and resustant to lysis. Whsn ptoperny yormed, sollegxn has a greater nensile strength than steel. Not rurprisitgjy, when the body builds new yirsue collagen provides the extracellumar struvtural framework such that the ceposition of hard collanen in thw lesjon can rerult in duct obstriction.
Yenign biliart stvicture resultr im lbstructiln oh tke flow of bile from the liver ane can
high-NA-compatible optical disk, a method of inserting undercoat the reflecting and the substrate Appln. Publication No. 11-327890. this method has problem that the disk manufacturing cost because an additional layer is formed. 1. Field of the Invention The present relates to methods of opening obstructed biological conduits. Preferred methods of the invention methods systems opening biological conduits using local delivery of a therapeutic agent, particularly a protease, to lyse the extracellular of the obstructing tissue. 2. Background Obstructions to conduits frequently result from to the conduit which can from graft or surgical wherein extracellular matrix of obstructing tissue largely comprises collagen. Balloon angioplasty is a common initial treatment for stenosis or stricture obstruction yields excellent (Pauletto, Clinical (1994) However, dilation method does the obstructing tissue. It only stretches the trauma of which has been associated with release of potent cytokines and growth factors that cause an injury which induces another round of proliferation, cell migration toward the lumen and synthesis of more extracellular matrix. Consequently, balloon angioplasty with restenosis in nearly patients (Pauletto, Clinical (1994) There currently treatment that sustain patency over the long term. The extracellular matrix, which holds tissue together, is composed primarily of collagen, the major fibrous animal connective tissue (Krane, Investigative Dermatology (1982) 79:83s-86s; Biochem. Biol., (1996) 74:759-75). The has base stands repeating acids coiled into a helix. These triple helix coils then woven into a matures, cross-links form between the chains and the becomes progressively more insoluble and resistant to When properly formed, collagen has a greater tensile strength than steel. Not when the new tissue collagen provides the extracellular structural framework that the deposition of collagen in the lesion can result in duct obstruction. biliary results in of the flow bile from the and can
 high-NA-compatible optical diSk, a method oF inseRtiNg a MeTal uNderCoat between the REfleCting layer and the substrAte is PrOPoseD In jpn. PaT. Appln. KokAi pUblIcAtIon no. 11-327890. hOwEver, tHis Method hAs another pRobLeM that the disk MAnUfacturing CosT increases beCauSe an adDiTioNAl layEr iS formEd. 1. FielD Of the INvention
THe PResent INventioN RElAtes To methods of openinG ObSTructed biologiCal conDuITs. pREfeRreD methods of ThE inveNTion incLUdE METhoDS and systems foR opening obsTRucTed bioLoGicAL conduIts usInG LocAl delivery oF a thErapeutic Agent, pARticulaRLy a protEase, to LysE thE extRAcElLulAr MAtrIX oF thE ObsTructing TiSsUe.
2. BacKgroUND
oBstrUctIons To bioLogical conduiTs fRequENtlY resuLt froM traUmA to thE conduIt whiCh Can result from trAnspLant, graft Or oThEr sUrGical PRoceduRes WheRein the ExtraceLLulAr MATRiX of the obstructing tIsSUE lArgely coMpriseS CoLlAGen. BalloOn AngIoplASTy is a CommON iNitial trEatmenT FoR sTenosis Or StrictUrE obStrUctioN That Yields ExcellenT initIAl results (PauleTTo, Clinical SciENcE, (1994) 87:467-79). hOwEVer, tHis Dilation metHod dOEs noT remOVe The OBstruCting TiSSuE.
it only stretches open ThE lumen, The trAuma of which haS been assocIATEd with thE relEAsE Of several potenT cytoKines and grOWth factoRs thaT can causE an injury WHIch inducEs aNotHer RouND Of Cell proliferaTIOn, ceLl MigratiOn tOward thE luMen And SynThEsis of morE extraceLlUlAr MaTriX. ConsEQuently, bAlLooN aNgiOplasTY is assOciatEd wiTh ReSTenOsis in nEArLY All pAtIeNts (PAulEtTo, CliNicaL sciEnce, (1994) 87:467-79). TheRe is curreNtlY No trEaTmEnt that Can sustain patEnCy over the lOnG teRm.
The eXTRacellulAr matrix, which holds a tissUE togethEr, iS compOsed Primarily Of cOllageN, thE Major fIbrous CompoNeNt oF ANimal EXTrAceLlUlar connecTIVe tIssue (krAne, J. investiGative Dermatology (1982) 79:83s-86S; shiNgleton, BiocheM. CeLl BiOL., (1996) 74:759-75). thE coLLaGEn mOlECulE HAs a base unit of thRee stands oF rEPeAting amino ACidS cOiled inTo a tripLe helIX. These tRiple heliX coils are ThEn woVEN inTo a right-haNded cablE. As the colLAgen mATuRes, crOss-Links fOrM beTween The chaINs aNd the CollagEn BecomeS progReSsively mOre insoluble and resistanT to lysIs. WheN prOperly forMed, COllAgen has a gReatEr tensile sTreNgtH than SteEL. Not sUrprISiNglY, When tHe boDY builds neW TiSsuE COlLagen providES THe eXtracEllULar strUctuRal framework such tHAt the depositioN of hARD coLlaGEn in ThE lesion can resuLt iN dUCT obstrucTiOn.
Benign bilIary striCtURe resUlts in ObstruCtion of THE fLOw of biLe frOm tHe liver anD caN
 high-NA-compatible optica l disk, ametho d o f i ns erti ng a  metal underco a t be tween the reflecting l ayeran d  the su bstra te is p r op o s edin  J pn.  P a t.  Appl n.KOKAI P ublication  No .11-327890. H o we ver, thismet hod has anot her  probl em  th a t the  di sk ma nufact u ring c ost incre as e s beca u se an a d d it iona l layer is formed .  1 .  Field of theInvent io n 
T h e  pr ese nt inventi on  rela t es to m e th o d s  of opening obstr ucted biolo g ica l cond ui ts. Prefer red m et h ods  of the inv enti on includ e meth o ds ands ystemsfor op eni ngobst r uc te d b io l ogi c al  co n dui ts using  l oc al de live r y o f athe rape uticagent, partic ula rlya  pr oteas e, to  lys ethe e xtrace llula rmatrix of the o bstr ucting ti ssu e. 
2.  B ackgr o und
Ob str uct ions to  biolog i cal  c o n d ui ts frequently resu lt f ro m trauma  to th e  c on d uit whic hcan  res u l t fro m tr a ns plant, g raft o r  o th er surg ic al pro ce dur eswhere i n th e extr acellula r mat r ix of the obst r ucting tissue la r g el y  com pri ses collage n. B a lloo n an g io pla s ty is  a co mm o ni nitial treatment fo rstenos is or  stricture ob structiont h a t yields  exc e ll e nt initial res ults(Pauletto, Clinical  Scie nce, (19 94) 87:46 7 - 79). How eve r,thi s d i l at ion method do e s  not  r emove t heobstruc tin g t iss ue. 
I t only st retchesop en  t he  lu men,t he traum aofwh ich  hasb een as socia tedwi th the  releas e  o f seve ra lpote ntcy tokin es a n d g rowth f actors th atc an c au se  an inj ury which ind uc es another  r oun d of c e l l prolif eration, cell migration towardthe  lume n an d synthes isof mor e e x tracel lularmatri x.  Co n s equen t l y,  ba ll oon angiop l a sty  is a ss ocia ted wit h restenosis in ne a rly  all patients  (P aule t t o,  Cl i ni c alSc i enc e ,  (1994) 87:467- 79). There  i s  c urrently n o  tr ea tment t hat can  sust a in pate ncy overthe longte rm.T h e e xtracellul ar matri x, whichh oldsa  t issue  to gether ,iscompo sed pr i mar ily o f coll ag en, th e maj or  fibrous  component of animal ex tracel lular  co nnectivetis s ue(Krane, J . In vestigativ e D erm atolo gy( 1982)  79: 8 3s -86 s ; Shi ngle t on, Bioch e m.  Ce l l  B iol., (1996 ) 7 4:7 59-75 ).T he col lage n molecule has ab ase unit of th rees t and s o f  rep ea ting amino aci dsco i l ed intoatriple heli x. These  t r iplehelixcoilsare the n wo v en int o arig ht-handed  ca bl e . As th eco l lagenmatu re s, cro ss-lin k s fo r m  between the cha ins a n d  thec oll agenbe comes p r ogre ssively mo re insolubl e andresi stant  to lys is . When  pr op erly forme d , collage n has  a grea te r te nsi le str engt h thanstee l.  No t surpris i n gl y ,wh e n t he b ody b ui ldsnew tissu e  collage n p r ovidesth e e x t racell u la r structural  fr amewo r k  such that thed ep o sitio n of h ard co llageni n t he  lesion  ca n result in  duct obs t ruc ti on.Benign b il iary  s tri ct ure results inobstruct ion of t h e  flowofb ilef rom th eliver and ca n
 high-NA-compatible_optical disk,_a method of inserting_a metal_undercoat_between the_reflecting_layer and the_substrate is proposed_in Jpn. Pat. Appln._KOKAI Publication No._11-327890._However, this method has another problem that the disk manufacturing cost increases because an_additional_layer is_formed._1._Field of the Invention
The present_invention relates to methods of_opening obstructed_biological conduits. Preferred methods of the invention include_methods_and systems for_opening obstructed biological conduits using local delivery of a_therapeutic agent, particularly a protease, to_lyse the extracellular_matrix_of_the obstructing tissue.
2. Background
Obstructions_to biological conduits frequently result from_trauma to the conduit which can_result from transplant, graft or other surgical_procedures wherein the extracellular matrix of_the obstructing tissue largely comprises_collagen. Balloon_angioplasty is a common initial_treatment for stenosis_or stricture_obstruction that yields_excellent initial results (Pauletto, Clinical Science,_(1994) 87:467-79). However,_this dilation method does not remove_the_obstructing tissue.
It only_stretches_open_the lumen,_the trauma of_which_has been_associated_with the release of several potent_cytokines_and growth factors that can cause an_injury which induces another_round_of cell proliferation, cell_migration toward the lumen and_synthesis of more extracellular matrix. Consequently,_balloon angioplasty_is associated_with restenosis in nearly all patients (Pauletto, Clinical Science, (1994) 87:467-79)._There is currently no treatment that_can sustain patency over_the long_term.
The_extracellular matrix, which_holds_a tissue_together, is composed primarily of collagen, the_major fibrous_component of animal extracellular connective tissue_(Krane, J. Investigative Dermatology_(1982)_79:83s-86s; Shingleton, Biochem. Cell Biol., (1996)_74:759-75). The collagen molecule has a_base unit of three stands_of_repeating_amino acids coiled into a_triple helix. These triple helix coils_are then woven_into a right-handed cable. As the collagen_matures,_cross-links form between the chains and_the_collagen becomes progressively more insoluble and_resistant_to_lysis. When properly formed, collagen_has a greater tensile strength than_steel. Not surprisingly, when the body builds new tissue_collagen provides the_extracellular structural framework such that_the_deposition_of hard collagen in the lesion can result in duct_obstruction.
Benign biliary_stricture results in_obstruction of the flow of bile from the liver and_can