CA2065570A1 - Method and apparatus for treatment of fibrotic lesions - Google Patents
Method and apparatus for treatment of fibrotic lesionsInfo
- Publication number
- CA2065570A1 CA2065570A1 CA002065570A CA2065570A CA2065570A1 CA 2065570 A1 CA2065570 A1 CA 2065570A1 CA 002065570 A CA002065570 A CA 002065570A CA 2065570 A CA2065570 A CA 2065570A CA 2065570 A1 CA2065570 A1 CA 2065570A1
- Authority
- CA
- Canada
- Prior art keywords
- agent
- lathyrogenic
- beta
- scar
- lathyrogenic agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/104—Balloon catheters used for angioplasty
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
- A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
- A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M2025/1043—Balloon catheters with special features or adapted for special applications
- A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
Abstract
Abstract of the Disclosure A method of controlling scar formation in humans by applying a force to tissue in an amount to create a wound; applying a lathyrogenic agent to the wound; forming the wound into a predetermined stationary or movable beneficial configuration; and maintaining the wound in the predetermined configuration and in contact with lathyrogenic agent during healing.
Description
3 2 ~ ~ ~ 5 ~ ~
M~5TROD AND APPARATUS FOR TREATMENT OF FIBROTIC ~E~IONS
Field of the Invention This invention relates to a novel method and apparatus for treating fibrotic lesiGns, particularly to tr~ating scar tissue wherever located, an~ ~o trea~ing strictures OL tubular structures, hollow orsans and the like.
BackGrourld of the Invention Whe~her crea~ed by ~isease, acci~ent or t.-e-apeutic in~el-vention, mammals hea1 hel1- ~-ounds ~y form,atian OL scar ~iS3UG. The heal ng p~-GCeS5, name-y scar formation, often leaves mammals with limitations o~ motior, constricting skin scars, frozen joints or restriction of orsan functiorl such as in urethral stenosis or gastric outlet obstruction, for example.
For many years, medical practitioners and researchers have struggle~ unsuccessfully with the difficult task of controlling scar formation by either reducing scar production or promoting scar resorption in their e~orts to reduce limitations of motion, scarring, freezin~ of joints or restriction of organ function.
Their efforts prior to this time have not been successful in alleviating these problems in human patients.
Description of the Prior Art During the past quarter century much knowledge has been gained relative to the biochemistry of scar formation~ E.E.
5 7 ~3 Peacock, Jr. & Walton VanWinkle ln Wound Repair, Sanders Company, Philadelphia, USA, 1976, amo~g others, have repor~ed their work in this regard. In simple terms, scar is a woven protein consisting primarily of sp~cial amino acid 3trands of fi~ers called collagen. Collagen is formed in special wound ce ls ~fibroblast) which is extruded to mature irl an extracellular matrix where eventual strength is obtained by crosslinking of pro~ein collagen fibers. The cross-linking process, which gives scar its strength arld hardness, is facilitated by the enzyme lysyl oxidase.
U.~. Paten~ No. 4,4~5,0~O to Chvapll discloses that crosslin~ing can ~e inhibited by al~ering several chemical pa~hways with compounds ca~led lathyl-ogens, such as D-Penicillamine and Beta-aminopropionitrile (BAPN). These compounds have been administered systemically to insure their incorp~ration ir.to the healing process. Unfor~unately, their therapeutic and toxic concentrations are 50 close that they cannot be systemically tolerated by humans, thereby precluding their application to human patients.
The therapeutic e~ects of ir~hibiting Ol^ modifyirlg collagen crosslin~ing has been demonstrated with tOpicâl applica~ion to healing wound scars by Chvapil. One of the lathyrogens, BAPN, penetrates the skin and other surroundin~ tis~ues a few millimeters in thickness. The eCfective dose of topical ~APN has bPen reported to be approximately 1/100th the systemically effective dose, ~thereby reducing in importance, but not eliminating, the issue OL safety. Chvapil describ~s t~pical application to burn scars, skin and chic~sen ten~on3 at or near the time of injury and new scar formation. However, Chvapil's technique is limited to topical applications or appiications where the lathyrogens may be injected into a localized area, such a3 a jGint or tend~n.
~ imilar experimentai WOl^k has been perLormed for treatmer~
of dogs Witil regard to bu~-rs in .he esGphagus; Davis et al in "~
New ~pproach to the Con~rGl OL Esophageal Ster.Gsis", nn. ~u~
Vol. ~7~, No. ~ (Octobel- 1972). However, serious ~o~ic ~y pro~lems ~e-e encountere~ with sstemical y introducc~ ~e.a-amin~prop,onl~l-ile fu~,ara~e (B~PN-F). Moreover, during the ~rea~merl~ ~me, ~he subjects exhibite~ sevel-e problems in t.-e inges~ion of Cood.
Ma~den et al repor ed in "Experimental ~sophageal ~ye ~urns", Aaa~ 3E5- Vol. 17~, No. 3 (~eptember 1973), that _, althoush t~ey believed ~hat mechanical splints should be applied continuously for m~ny months to achieve permanent correction in artiLicially induced esopbageal burns, bougienage could onlg be performed intermittently.
Objects of the Inve~tion It i3 according~y an obiect of thi6 invention to provide a method of treatment of fibrotic lesions to reduce limitations Of motion, scarring, freezing of joints or restricticn of organ function, all without encountering problems as to ~ystemic "' ~ 7~
toleration.
A further obj~ct is to provide novel equipment Lor carryiny the method into effect.
Summary OL the Inventioll This lnvention reiates to a novel method OL controlling scar Lorma~ion in a mannel- which prese1-ves organ functiorls by the co;nbinatiGn o biGchemis~ry, pharmacGlogy an~ ~hysics ~y ~
orceful resec~ion or ~ilation of a scarred area in a human ~at, enL LO create a new wound, followe~ ~- (2) continuous ~opical apyllsation o a la~hyrogenic agent tG the ~i ated scar1-eJ area and (~ ~uring healing o. ~he new wGun~ corl~lnuously suppor~ing the di,ated scarred area in the desired con.iguration.
The in~-ertion iurther relates to a special catheter for controlling scar fo1-mation, onto which a selected lathyrosen may be bonded prior to i~sertion into generally tubular portions of the human or animal ~ody, followed by rehealing while supporting the tu~ular body por~ion in tlle desired confisuration.
Brief Descri~tion o~ the Drawinqs Fig. 1 shows a schematic front elevational view taken in section, of a tukular organ exhibiting severe stenosis.
Fig. 2 shows a section o, the tubular orgar, taken along the lines and arrows II of Fig. 1.
Fig. 3 shows a section of the tubular organ taken along the lines and arrows III of Fig. 1.
r~ ~3 Fig 4 is a schematic sectional view of a catheter having a lathyrogenic agent applied thereto Fig. 5 is a schematic sectional vie~ of a balloon catheter having a lathyrogenic agent applied thereto Fig. 6 is a schematic view, taker in sectiGn, of a catheter inserted in a tubular ol-gan in accordance with aspects OL the inventlon Fis 7 is a schematic vlew, taken in section, o~ a balloon cathe.er lnserted in a tubular orsan in accordance with aspects of he inven~ion Fig S shows a schema~ic -~iew, aken in sec ~iGn ~ OL a tubu ar ol-yan a~ter treatment in accGl-dance with ~he method o, the inven~ L on Detailed ~escription of the Invention Al.hough a particular fGrm of appara~us and method has bean selected ~or illustration in the drawings, and although specific terms will be used ir. the specifica~ion for the sake of clarity in describing the apparatus and method shown, the ~cope of this invention is defined in the appended claims and is not intended to be limited either by the drawin~s selected or the terms used in the specification or abstract For example, althouyh fi~rotic lesion on hollow organs have heen illustrated in the drawings for convenience, the method of the inve~tion i5 not inten~ed to be limited to such hollow organs As shown in Fig. 1, which is a schematic of a tubular oryan ;
-~ ~ 2 ~ l~3 ~ rj 7 ,~
10, a portion of the tissue 1~ exhibits se-~ere stenosis. The portion exhibiting such stenosis is designated by the numeral 14.
The stenotic portion 14 may ~e tl-le result Gf any numbeY of naturally occur~ing or artific ally induced Gccurrences. For example, portion 14 may have been previously injured, such as ~y surgical opel-ation, severe injury, 'rauma or the like. SLenoLic portion 14 resulted Lrom the formation OL scar tissue, which grew into and toward the cen~er portion GL tubular organ 10. The result of the Cormation of such scar tissue is the severe narrowing of tubular orgar, 10.
Narrowirlg Ol tub-ular organ 10 can ha~e severe consequences with regard to the ~assage o fluids through the tube. For example, in the case where tubular organ 10 represen~s the urethral canal, almo~t complete blockage of ~low can occur.
This, of course, is highly undesirable. The same severe consequences may result in instances where tubular organ 10 represents the esophagus, blood ~essels, intestinal passageways, 'allopian tubes and the like.
Fig. 2 of the drawings shows a portion of tu~ular or0an 10 which is in a normal, non-stenotic condition. Tissue 12 i5 OL
ordinary thickness. On the other hand, Fiy. 3 shows a stenotic portion 14 of tubular organ 10 wherein tissue 12 has a far sreater thickness, and reduces the interior diameter of the tube.
Referring now to Figs. 4 and 5, different forms of catheters are shown. Fig. 4 illustrates a simple tubular catheter 16.
Tubular catheter 16 includes a hollow tube 18 surrounded by 7 ~
lathyrogenic ayent 20. Similarly, Fig. 5 shows balloon c~thetex 22. ~alloon catheter 22 con3ists oL a central tu~e 24 and a ~alloon 26. Ealloon 26 is coated with and i5 surrounded by lathyrogenic agent 20.
Fig. 6 schematica,ly illustrates insertion of one LGrm of tubular catheter 16 into tubular Grgan 10. Tubular catheter 16, aS sho~-n, has an outer diametel- OD which is greate1- than the inner diam~ter ID of tubular organ 10. Tubular ca~heter .6 extend3 intG t~bular organ 10 for a distance su ficient to engage stenot.c por~ion 14. Tubu.ar cat..eter 1~ is inserted to a point whe-l-e.ll la~hyrogenic asent 20 directly ar,d closel~ contacts suus~an~lally all of s~enotic portion 14.
Fiy . 7 shows ba-loon catheter 22 in an inflated condition ~i~hin tu~u~ar orgarl 10. ~alloon catheter 22 extends inwardly into tubu.ar organ 10 to a point wherein lathyrogenic agent 20, which surrounds balloon 26, directly and closel~ contacts steno~ic portion 14.
Fig. ~ shows tubular organ 10 a ter removal o~ either tubular catheter 16 or balloon catheter 2~. Tiss.lle 12 is in a normal condition and thickness throughout. the entire length o~
tubular organ 10. Stenotic portion 14 i~ no longel- present~
In accordance with a preferred ~orm of the invention, the physician locates a stenotic portiGn Gf the tubular organ by ordinary means well known in the art. Ol,ce the stenotic portion has been identified and located, it is dilated, resected, incised or removed to create a fresh, open woun~. Then a lathyrogenic 0~57~
agent, pre~erably D-penicillinamine or Beta-amlnopropionitrile (B~P~), or Eeta-aminopropionitril~ fumarate ts~pN~F), or amir,oacetonitrLle, for example, is applied to a cath~ter o~ the physician's choice. Depending upon the tubular organ to which the ca.hete~- is applied, various well known catheters may be u~ ed. in the case where a balloon catheter is chosen, the athyl-ogenic agent (soi~etimes ~-e~erFed ~o hereir.after OF
convenience a3 ~PN-F; is applied ir, a coating tG the ba'loon por~ion o~ the cathe~er, such as shown in Fig. 5 o. the drawings.
The cathe~er i3 ~hen in3elted ih ~O ~he tubular ol-gan b-~ordi..ary means wcll ~nowrl in the ar~. The balloon ca~cter is inser~ed to a point whexe ~he B~P~ is in po3ition to diFectly and closely contac~ s~enotic portion 14 upGn expansion of the balloon. The balloon i3 then inflated arld le ~ in position lor the prescribed ~reatment time.
It has been discovered tha~ the lathyrogenic agent should be applied to target tissue in a dosa of about ~.5 mM to about o.5 mM for BAPN-F and about 20 mM to about 40 mM for D-penicillamine.
The pre erred dose i5 between about 5.0 m~ and about 5.5 mr~ for BAPN-F and abou~ 22mM to about 25 mM for D-penicillamine.
~ n another preferred form of the invention, the B~PN-F i3 ionically bonded to a special catheter capable o ionically bonding the EAPN-F to the outer surface of the catheter. This ionic bonding permits insertion of the catheter within the tube and up to the stenotic portion, without the danger of BAPN-F
being wiped off the catheter prior to contact with the stenotic 7 a portion. In t~is manner, the coated catheter i8 inserted a,ter the stenotic portion has ~en expanded or resected to a d~yr~e whic~ tears or l-emoves t~e existing 3car tissue. Th~ BAPN-F then directly contacts the tissue in the new wound to sorten the healing prGcess. The resulting forme~ tissue is substantially in the shape and size of the outel- ~iameter of ~e catheter an~
retains its normal pliant condition, and exhibi~s the ~ha~-a~teristics Oc llormal, urlinjured tissue.
In still anothe~ preferred form of the invention, the same steps may be applled .o non-~ubu'ar tissue. For example, the me.hOd OL the inven~iorl may be applled ~o exterior burns such as s~in burns. Howe-~er, i~ is impo-tant that the same steps be ol owed to achie-~e the excellent results achievable with this aspect OL the lnvention. Examples of various applications of ~he ~,ethod of the inventiGn are l lustrated as ~ollows:
EXAMP~E 1 -- BU~N SCAR-E~EOW
A patient with a full thickness dermal scar around 'he elbow exhibits complete contracture and cannot ~ully extend the elbow. This restricts use. The hard scar is surgically "released" u~der general anesthesia by cutting in several places with or without a sl~in graft. The patient then has A lathyrogen applied and is placed in an elbow dynamic splint. This allows the elbow to be protected and at the same time to fully exercise the joint on a daily basis with or without the supervision of a physical therapist.
A lathyrogen jelly with 5.0 mM of BAPN-F and/or 20-25 mM D-penicillamine or a B~PN-F impregnated gauze ~40 mg/10~ cm2 of gauze) is continuously applied to the wound during its healing phase beginning 4-O days after surgical treatment and continued LoF four to six weeks in combination with physical therapy. ~t the end of healing, the splint is remGved, the lathyrogen discontinued anZ the patient resumes full ranse of moLion at the elbow due tG Lhe lac~ of cross-linking OL newly formed cGllasen in p'ace of old scar tissue.
EX~MPLE 2 -- FAI,LOP~A~ TUE~ STENO~ FERTIL T~' A patienL having scaL^lred and blocked .allopian tu~e3 as a result OL in ecLlorl has incisions made in ~he scar ~lssuc and a E~PN-F coaLed sLlastic tu~e s~lnt placed in the ~allopian tu~e after one weel- and 'e~t in p'ace durirlg the healing phase. The 3 ~int is conLlnuously maintair.eu in contac L with the fre3h wound and is chansed two or Lhree times during Lhe Lour L~ six wee~
healing phase as the lathyrogenic agent leaches off the surface of the silastic stint and is incorporated into the newly healins scar. The newly forme~ scar takes the shape of the stint. Th~
stint is removed, the opening of the fallopian tube is pl~served and egy and sperm transport can now cross the previously blocked fallopian tube.
EXAMPLE 3 -- ESOP~IAGEAL STRUCTURE
A young teenager, who as a child swallowed a Zrain cleaning solution, has a lye burn to the lower esophagus and has great difficulty with maintaining proper nutrition. The result is stunted growth. The scar formed from the burn is dilated under 2 ~ r7 ~
direct endoscopic vision with a dilator or sur~ically r~sected to create fresh wound tissue. A Cellestin tu~e i~ immediately at~ached across the new wound area and continuously maintair.ed in position for ~he duration of healing. The outer lining OL the Cellestin tube consists of silicone to which a com~ination o~ 2-Penlci~lamine and ~APN-F is bonded, which leaches into the healing area. Wherl healing is complete the tu~e i5 removed and a normal esophageal diame~er remains because the 5.0 mM s~lutiGr,s of .he ~a~hyrogens have ~een incorporated into the new scar allowing it to form itselL around the tube with~ut fu;-~he.-s~enosi3.EXAEi~PLE ~ -- UR~T~ PRO~TATIC CANCER
~ patient with prostatic cancer detected with sonography and a candidate fo1- total pro3tatectomy has the prostate removed and the c~-f of the bladder sewn to ~he most proximal remainLng por.ion o, .he urethra. This circumferential suture line often progres3es to hea~y scarring preventin~ complete emptying of the bladder. The scar is cut away under anes~hesia and direct resectoscope ~ision and immediately stinted with a silicone ca~heter coated with 5.0 mM BAPN-F. The catheter remains in continuous direct contact with the new wound tissue during healing. The BAPN-F leaches ~rom the surface o~ the catheter, thereby inhibiting hardening of the healing scar during the next three weeks. The catheter is changed on a weekly basis to renew the BAPN-F supply. Once healing is complete and the newly formed scar is laid down around the stint o~ the indwellin~ bladder -) ? ~ 3~37 ~1 urethra catheter, no new sc~rriny takes ~lace.
EXAMPL~ 5 -- U~N SCAR-H~ND
A patient with a well healed full thickness ~urn o~ the hand has severe scarring of the fin~ers and har.d in a claw-li~e form~ The old scars are surgically released to create full mobility oL t~e joints. The hand is placed in a "dyna~,ic splint." The sp'int contains rubber bar,d ,ixation to a rigid Lrame allowing the patient to exercise his Lingers t~rough a full ~-ange of mo~ion. Durins the ~ealing phase and on a Zaily basis, a Jelly containins 5 mM~L OL the lathyrogenic agen~ ~PN-F i3 con~inuously applied to ~he suxgically "released" a~-eas. L',e pa~ier,~ con~inue3 ~o exercise and use the dynamic splin~ durihg ~he ~ea'in~ phase over the next fOUl- to six weeks. Once re-epitheliali~ation and healing ls complete, th2 newly formed scar, beins soLtened by the cGntinuous applicatior. of B~PN-F, has Lull range of motion without further restriction of hand mGtion. The dynamic splint is removed. IIealing is complete and range OL
motion restored.
EXAMPLE 6 -- BURN SCAR-NEC~
A patient with severe third degree burn of the neck has completed healing, bu~ the resulting scar is so severe that the hea~ cannot be strai~htened. The scar is surgically released (incised) with or without a skin graft, thereby creating a new wound. ~ s~iLf plastic collar having a soft lining is applied to the neck to hold i~ in a new desired position. ~ combination of 5.0 mM B~PN-F and 20-25 mM D-Penicillinamine jelly or a BAPN-F
2 ~-35 7 ~
impregnaLed gauze (40 mgtl00 cm2 of gauze) is continuously appli~d to the newly created wound ti5sue so that as new scar is formed, it will be soft, plastic-like, and uncross-linked ur,til healing is complete in four to six weeks. ~t th~ end Gf that time r,o new medication need be applied, the collar is removed and the patient has been re3tored to full range of motion of the nec~.
EX~.P~E 7 -- URETXRA-INFEClION
~ patient with urethral stenosis (narrowing OL the tu~e betweer. ~he ~ladder ~nd the erd oS ~he penis) secondary ~o a gGnococcal inSec.ion exhibi~s bladder Gu~leL obstruction. The old scar in ~ne urethra s Gpened under direc~ surgical resection. I.r,mediately afterward d silicone urethral bladder cat~eter is inserte~. ~fter one weeX, this cathet2r is exchanged or one with the lathyrogenic agent ~APN-F bonded onto its surf ace. The coa8ed catheter is continuously maintained in place and changed every week for about six weeks durin~ the healing phase. During the healiny phase new scar tissue is aid down.
However, its streIlyth is beneficially alLered by the ~athyrogen EAPN-F which inhibits the bonding of one protein scar fiber to the next protein scar fiber allowing the wound to ~e ~lolded in the shape of the intraluminal stint (urinary bladder catheter).
At the end of the healing phase, the stint i5 removed and normal unobstruct~d urination can prGceed.
EXA~PLE 8 -- URETHRA-TRAUMA
Following fractured hips, 5-10% o~ human males suffer ' rl ~
transection of the membranous urethra as it leaves the bladder.
This transection requires primary anastam~sis with catheter stinting, often resulting in severe scar formation and secondary bladdel- outlet obstruction. ~alloon dilation (pressure balloon) LO create new wound tissue may be performed or direct surgical resection removes the narrowed scar tissue. After Gne week, the original bladder catheter is exchanged for a silicone catheter coated with either B~PN-F or another lathyrogenic agent such as D-Pen,cillamine, which inhlbits cross-,inking ~3trong bondins) between scar collagen fi~ers. The coated catheter is continuous y mainLained in place and changed once a week for a~out six weeks during the healing phase. AfteL- catheter rem6val a normal sized oper,ing is present, with the new scar ~eing molded ~o Lhe shape OL the in~raluminal stint (bladder urethral catheLer.) EX~r~PLE 9 ~- URETXR~-PROSTATE RESECTION
Following partial prostatic resection for bladder nec~
obstruction in human males, approximately 10~ of patients develop 'ubal narrowing at the ori~in o~ the urethra. The 3car is resected to reopen the lumen under direc L surgical endoscopic vision. After one week, the lumen is protected with a catheter stint of silicone coated with a comhination of D-Penicillamine and BAPN-F to inhibit cross-linking or hardening of the newly formed scar tissue. The catheter is continuously maintaine~ in place and changed once a week for 5iX weeks as healing is completed and new-soft scar is layered around in the shape of the i 7 ~
intraluminal stint. Once the stint is removed, the openin~
~etween the bladder and the begir.ning o~ Lhe urethra is protected by the shape of the mature collagen scar which now p7-ogresses to slow cross-linking or hardenirlg without narrowin~ the lumen.
EXAMPLE 10 -- TRAC~EA
The patient suffering ~racheal injury either due to a tracheostomy on an emergercy basis or sèco~dary to an automGbile accident has prir,.al-y anastGmosis GL the ~rachea re3ulting in a severe scar and impairmen. of the airway. The scar is excised and an endo~racheaL silastic s.int cGated with 5.0 mM E~PN-F or D~Penicillamine is pu. in place a'ter one wee~ and conlinuously main.ained and changed on a weekly basis for L lve or six wee~s durirg the healing phase. The lath~rogen is incorporated in the newly formed and healirls wound where it allows the newly formed scar to be soft, plastic-like and conform to the diameter OL the endotracheal stint. Once healing is complete no lurthe.- scarring takes place, the medication and stint is discontinued and the patient returns to normal airway dynamlcs.
EXAMPLE 11 -- CO~MON BILE_DUCT ~TENOS~S
A patient who has had an injury of the common bile duct secondary to a complicated gallbladder operation is jaundiced.
The scar is partially resected and after one week an original silastic stint is e~changed for ar. intraluminal silastic tube coated with BAP~-F with one arm of the tube protruding into the duodenum. The BAPN-F leaches off the silastic tube and is incorporated into the newly formed scar, which is soft because ~ r~
BAPN-F blocks cross-linkin~. The tube is cGntinuously maintairled in place and on a weekly basis the patient retUrns to the gastroenterology lab where, under direct manipulation, the tu~e is exchanged every wee~ for six wee~s. Once healing is complete the tube is ~-emoved and the new lumen of the common bile duct is preserved. The patiert i3 no longer jaundiced and fluids from the liver can pass into ~he duodenum urinhibited.
In many of the foregoiny examples it is beneficial to use a speciai catheter containing directly bonded ~PN-F. This provide3 the advantage that the B~N-F will ~e delivered direc~ly to ~he desired .iS3ue w ~hou~ the danger OL being partia~ly Gr completely ~-iped OC ' ~he ca~heter during insertion into the tubular organ.
Linking a druy such as ~APN-F to a po~ymer forming a cathe.er or wound dressing may ~e achieved ~y severa methods including:
a. direct ~inding OL the drug to available Lunctional binding groups in the polyme1-ic surface of the catheter, b. linking the drug to newly created Lunctional bindin~ sites after chemical or physical modification of the polymeric surface;
c. direct incorporation of the drug into the polymeric surface either during the catheter manufacturing process or into the final catheter product by programmed, cont~-olled soaking in the appropriate solution of the drug;
d. deposition of a drug in another polymeric substance 2 ~ r~
~hydrogel, gelatin, collayen and the like) which is tl,an chemically attach~d to the polymeric sur~ace of the d~vice.
By this method large ~uantities of the dru~ can be associated with the effective surface OL the device. T~le drug can ke linked chemicaily to this coatins material as well as physically sorbed if added in quantities exce~ding the bindir.g capacity of the cGating polymer ~hydrogel). ~n a~ditional ad~-an~age OL this process is Lhat the coating polymer r,ay add new propel-Lies to ~he ~evice polyme;-, such as slipperiness, ~iocompatibility ~o ti-sue cells, ;-e~uction OL mineral crys~al Eol-ma~ion when in contuct Witl~ ~ome biolGgical fluid3 (urine).
Examples of manu~acturing procedures for the above ouLlined processes are shown ~elow:
A la~ex polymer may be partially hydrolyzed-depolymal-ized, for instance, in a strong oxidizing en~ironment to p~ovide Lree carboxyl, hydroxyl or aminG sroups when the polymer does not contain available ~unctional groups. The ~roups then ~erve as sites for chemical bi.nding of BAPN. In the case of BAPN binZing, the availability of C00- group~ is optional.
ln practice, the latex polymer may be dipped into an Iqueous solution of 2~ sodium hypochlorite, wherein the solution contains 0.5% sul~uric acid. After ~-10 minutes of incubation at 25C, the solution i5 decanted and the latex polymer incubated for another 5-10 minutes in 5~ ammonium hydroxida solution. Removed polymer is then excessively washed in iced water. Activation of ) 2 ~ 7 ~
the COO- groups oL the latex is achieved at 25QC in the presence of carb~diimi~ mg/ml) at p~ 4.75 o~ 0.1 M ME~ bu~fer. The incubation lasts 30 minutes, L ollowed by quicX ice water washing and then exposing the activated polymer to the solutiGn of ~APN for 12 hours in 0.1 M MES at pH 4.75.
After completion G. tlle reaction, the .inal product is r,Gt washed .rom the excess of the drug, which under these conditions contains both chemically anZ physically linked ~PN to the device polymer. In this meZium, the carboxyl groups are activated and these react with the ~-amino group o. the EAPN-F to Grm a rather 5 tlong linkage. Car~odiimide ha~lng the chemical ~ormula (1-eth~ 3 (J-dime.hylamine-propyl) carbodiilr,ide-HCL (EDC) has ~een recognized as a pctent coupling agant activating the availa~le carboxyl groups in hydrogel, co lagen or gelatin.
~ hen the device is made of inert or su~stantially inert silicones, known Lor their low polarity group content, the surLace of the device may be modified to render more birldin~
sites. The methods of modif~ing the silicone may be either chemical or physical. The example Gf using stron~ oxidizirlg agents was described a~ove. ~r.other method of forming reactiv~
side groups in the silicone ~activating the surface) is exposing a silicone surface to high energ~ ionizing radiation such as high energy electrons, X-ray or gamma radiation first and then interacting such a sur-ace with BAPN-F under similar conditions as shown above. The radiation exposure total dose corresponds to 0.~0 to 0.45 Merads. The princi~les of this method are the .
? ~ rj r~
object of U~S. Patent~ 3, 453 ,194 or 3, ~2~, 67d .
There is anGther method of ~ringing l~rger amounts of E~PN-F
onto the surLace OL a polymex, such as latex or silicone. Either polymer is partially hydrolyzed as descri~ed above. To the acLivated surface Gf a polymer ~a hydrogel, collagen Gr gelatin soluble in ethanol) is interacted to ,'orm a unifGrm coating. A
reasonable amount o~ BAPN-F can ~e incorporated in such a cGating OL hy~rogel, collagen or gelatirl. The release GL ~APN-F ~ill then depend on the rate o' diffusion o. thi3 molecule .rom the hydrogel, cGllagen or gelati.l. This then w,'l ~e controlled by Lhe swellability of the hydro~el, collagen or gelatin. There are -various types of hyd~-oge~s, ~ased on polyac-ylGnitrlle Gr polyure~hanes, where hydl-ation can vary from a few weisht percent of water to almost 90"O OL water.
A purified collagen simila1 to hydrogels car. ~e used ~o link with the funcLional ~roups of the polymel- device, using known, described various procedures known in the art.
Selectiorl of the appropriate hydrogel, collayen or gelatir~
will allow the desired release of ~APN-F. For in~tanc~, hydrogel based on polyurethane is availa~le with ~'ree car~oxyl groups (for example, see U.S. Patent 4,255,550), lactone or hydroxyl groups (.or example, see U.S. Patent~ 4,156,066 and 4,156,~67). ~n general, hydrGphilic polymers or hydrogels are use'ul carriers for pharmaceutical agents (U.S. Patents 3,975,35~ or 4,43g,585).
Another factor controlling the rate of drug release from the hydrogel, collagen or gelatin coat (besides dif,usibility) is the r3 ~ ~ ~
option of chemical binding of the druy to the functional (mainly carboxyl) gl-oups of the hydrogel, collagen or gelatin.
It is known that lysyl oxidase, an enzyme essential for cross-lin~ing of collagen ~which resu ts in 5 ~rictures arld contractures), is effectively and irreversi~ly inhibited at 1~-1G
~ APN tissue corlcer.tl-ation. Given that a~ thi3 cGrlcentration Gf E~PN, released every hour ~o reach a steady statc in the tissue, is the safe and effective inhi~itory dose and ~) the treatment will last ~0 days, the dose of B~PN deposited within the device to obtain zero order sustained release should exceed 2~ mg of B~PlY~de~-ice. In order ~o obtaln zerG order ~linear) L-elcasc o' a drug from a matrix, it is ir,portant ~o com~ine at least two diLfe.-ent mechanisms OL a ærus sGrption (~inding~ in a polymer or matrix. These mechanisms include a) chemical ~inding G moderate strength providing slower release OL a drug af~er its dissociation from the chemical bond and b) physical sorption, which is a very weak bond and allows immediate release of the drug once the device is exposed to tissue fluid and moisture. The ~inetics OL the release for each m6chanism ~iLfer Lor various polymers and drugs.
One important factor favoring using hydrogels, collagen.s or gelatins as a carrier for BAPN-F and other lathyrogenic substances is the similarity of hydrogel characteristics with tissue composition ~same content of water, absence of toxic elements, similarity to collagen molecule chain in phy-qical and physico-chemical aspects). Thus, hydrogel-drug implants or ~ ~ 2 ~ ~ j 1`~ r~ ~
coatings of other polymer devices provides foiA better tissue tolerance.
Although several classes o~ hydrophilic polymers swellable in tissue fluids are available, the selection of the ~IGSt appropriate ~ydroyel, collagen or gela~in is directed by criteria of safe~y, reflecting nontoxicity, noncarcinosehicity, mutagenicity, teratogenicity, etc. Ful-thermore, che~,ical reacti~ns w,hich lead to establishillg a polymer (hydr~gel)-drug complex, Gr which re~uire additional cross-lin~ing agents or actit-a~ors, or which ~lay cause diCficul~y in washir.g out ~he 'ina product wl~.lou~ compromisins ~he stab lity of the lirlked drug, must ~e consid~-ed ln the selectior of an adequa~e coating po~ymer LO be used as ~he reservoir or EAPN~F or other lathyrogen.
Other drus delivery systen,s Lor time release OL
lathyrogenic medications have been developed. ~uch delivery systems use biodegradable vehicles which are ~iologically safe, induce minimal local tissue reaction without any side toxic effects, are easy to handle, and are economically feasi~le.
For several years, gelatine-resorcinol-glutaraldehyde (G-R-Gl) tissue adhesive showed to ~e one of the least toxic tissue adhesives used in various surgical applications. The glue quickly polymerizes and efficiently adheres the tissue surfaces together when in contact with tissue and when reacted with formaldehyde or glutaraldehyde. The adhesive capacity depends on the content of R- which usually is 30~ of total solids and on the rj 7 i~
concentl-ation of the tanning agent used in the concentrated ~orm.
G-R-Gl as ti~sue adhesive has been appli~d to tissues in or~ly minimal amounts, because the strenyth of the bonds is indirectly proportional to the thickness o, the polymer in between the tissue su~aces.
Use of earlier tissue adhesive G-R-Gl polymers as vehicles for delivering lathyrogenic age~lts in the method OL this invenion is disadvantageous because the polymer consists of gelatin and resorcinol in weisht ratio ~:1, G forms ~ % and R
forms 10Jo of the nonpolymerized solution. In other words, the original tissue adhesive mixt~;-e i3 a 60'~ aqueous soluLion consisting of 45 weight vvlumes OL gelatin, 1~ weight volumes GL
resorcinol and ~0 volumes of water. After polym,erization with 37'~ formaldehvde or 25~ gluLaraldehyde, a firl,-, polymer is formed which undergoes, in biological environment, minimal swelling an slow ~esorption. High content of gelatin, resorcinol and tanning agent are essential to obtain solid tissue adhesion OL hiY11 tensile strength. l'hus, the lathyrogenic agent added to thls earlier system would be released at an extremely 510W rate.
We have found that by decreasing the content of Lhe individual components and by varying the content of G" R and the concentration of tanning agent, mainly of Gl, it is possible to control the consistency and hydrophility of the Linal fol-m OL
gel-polymer to release the lathyrogenic agent at a beneficial rate.
We have also found that if the lathyrogenic asent is added to the G-R-water mixture in appropriate concen~ration, then after quick mixing with selected conc~rtration3 of Gl in a syringe, the sti l fluid gel may ~e applied to the subject to form a polymer.
Ne have also found that in ~ase fa3ter drug release i5 desirable, R need not ke present or added to the collagen solution dul-ing crosslinking ~y any tanning agent.
We found that a mi~ture consisting of 15 to 30 parts o' G, 0.1-2 parts OL R ~ 20 to 30 parts of water component and usins 5 ~o 30 'old dilutiGn OL the G as polymerizing agent are op'imal 'or long-~erm release of EAPN or other lathyrogenic agents ovei the period OL 3evel al week3 or months.
A polymer cGnsisting OL only 1 to 5 parts OL gelatin, 20 parts o' water, of appropriate concentration ol the lathyrGgenic agent and polymerization induced by 0.05 ml OL 0 . 5 10 ~
glutaraldehyde per 1 millili~er of the mixture is optimal for short time release OL the lathyrogenic agent over a ~eriod of a few weeks.
It was also found that the a~ueous mi~ture co~sistiny o.
collagen-resorcinol and the lathyrogenic agent can ~e coated on any biomaterial, prosthesis or device consisting of a ~iopolymer and then polymerized. After the plantation of the biomaterial on the healing wound a continuou3 release of the drug from the coat layer follow3.
We have also found that when the lathyrogenic agent is added to the G-R mixture with another agent which ha~ antithrombogenic ) i 7 ~
properties such as heparin, a polymer can be coated on the healing ~iolo~ical tissue surface to prevent th~ ~ormation of blood clots.
As indicated a~ove, the rate of the release of the lathyroyenic agent depends on the degree of polymerization of the formed gel ar,d also on the surCace area of the polymer n contact with the healing wound. The ra~e of release of the lathyrogenic agent is controlled by the laws of physical difLusion as well as by the degree of biodegradability of the polymer. The rate of athyrogenic agent diffusion ~hen depends on the degree Gf hydra~ion of the polymer.
lhe L ollo~ing examp e3 seL-ve to illus~rate the practlce of the in~ention, ~ut arc not to be ~-egarded as limiting. All par~s are given by weight, unless otherwise specified.
This example illustrates the efficacy of collagen-resorcinol-glutaraldehyde polymer as a EAP~-F delivery system.
One hundred parts of medical grade purity collagen, prepared by a known procedure, i3 mixed with three hundred parts of water and heated until collagen dissolves to form a ~iscous solution. To this solution six parts of resorcinol are added and when this component dissolves, 5iX parts of BAPN~F (Solution 1) or fifteen parts of BAPN-F (Solution 2) are mixed in. One milliliter of this mixture per kilogram of rabbit body weight was injected under the skin, af te~ quick mi~ing of the appropriate volume of the mixture with lJ10 of its volume of 3 percent ylutaraldehyde .
in a 5 ml plastic syringe. When this composite i5 injected under the skin, it polymerizes within a few minutes to form a pllable disk. The rate Of the release of the E~PN-F ~rom the polymer was studied by direct measuring of the amount of BAPN-F in the blGod, collected from the ear vein of the rabbit at time intervals shown ir, Table 1.
For compa~-ison, the same amour.t 6L EAPN-F was lnj~cted undel-the s~in o~ contl-ol rabbits as water solution. It was four.d that while injection of the same amount of ~APN-F in water solution ;eaches a maximum in serum within two hours a.~er injectioh, E~PN-F injected in the pGlymer mixture is release~ continuously and at a steady ~-ate for seve-- days. Then its concen~ration in the blood slowly decreases.
Ta~
Release of sAFN-F From Two Polym~r ~ixtur~s as Compar~d ~Jith Water 501ution o the Dru~
Time Afte~- the Plasma Level~ (BAPN-F~
Injection (hrs) Water Solution 1 Solution 2 2 3.2 0.2 0.35 4 2.9 ~.35 0.67 2.1 0.40 1.4 ~0 1.~ 0.37 1.3 1~ 0.............. 0.33 ~.2 4~ 0 0.38 1.1 72 0 0.4~ 1.1 96 0 0.~0 1.0 l~S 0 0.~7 1.1 ,, _ . ., _ _ , " , .
') ~AFN-F was measu1ed at given time intervals in the plasma of rabbits ~y a fluorometric method. Each point is the average of two determinations.
This example illustrates that the ra~e of the release of a drug from the polymer is controllable by changing the proportion of individual components of the mixture.
The mixture consisting of the above components, i.e. of collagen-resorcinol-water, was prepared in proportions given in Table 2.
Table 2 Plasma I,evel BAPN-F
Colla~entJater Resorcinol BAPN-F~ q/ml) 100 300 10 0. 2 1a~0 3~0 5 0 . 45 100 ~00 1 ~ . 2 Refers to values determined fi-~e days after irljection of the delivery system with a drug.
~ par~s of E~PN-F were added to each type of mixture. One millili~eL of each mixture per kilogram o ~ rabbit body weight -was injected and bloGd measurements were ob~aine~ as descri~ed in Example 1~. The rate of }-elease is shown in ~able 2.
E~AMPLE 14 -- PXYSICAL AND FUN'CTIO~L STAPrILIlmY OF B~PN-F FI~M
In order to demonstrate the functional stability o, the BAPN-F film, a mixture of collagen-resorcinc,l-EAPN-F is prepared as follows: 10 5 gelatin are mixed with 31 ml water and heated on a water bath until a clear solution i5 formed. 3.3 g resorcinol are added and di.ssolved with stirring, and finally 200 mg BAPN-F are added to the solution. The mixture (1) remains liquid when kept at 40 - 500C. A similar mixture (2) is prepared omitting BAPN-F. Two samples of a wet collayen membrane, containing 60~, water by weight are coated on one side with a thin film of each mixture, the mixtures being kept at 500C
when applied. When a homo~enous film is obtained it is s~rayed with 0.5~ formaldehyde solution (concentrated HCHO - 40~) and allow~d to dry i~ 5 minutes. The ~xcess of fo~maldehyde is washed out with water. The mixtur~ is c~ted ~rto a plastic sheet at 500C. When a co~tinuous thin layer is .ormed th~
material is dipped into 2.0~ glutaraldehyde solution for 1 second, and kept dry at 60~C until constant w~ight is ~-eached.
The net dry weight OL the coating .ilm is 320 mg. This film is remo-ved from the plastic she~t and placed in an Erlenmeyer ,las~
with 50 ml physiological saline solution and ~laced in a wat0r bath fit~ed with a sha~er. At time intervals as indicated ~n Tabl~ 3, samples were collected, hydrolyzed anZ aralyzed fGr the presence o. hydro~ypro,ines and he~osamines. Th~ amoun~ G~
hydroxyp}-oline multiplied by 7.4~ indicates the amount o.
dissolved collagen in m,g, while the amount of hexosamines present multip].ied by 3 indicates the amount of BAPN-F in solution. Th0 ratio OL solubility of collagen and ~APN-F was measured in saline at 37~C in t~e incubation medium at periods during a ~ wee~
interval. The dry weight of the incukated f ilm totaled 335 my.
The data in Table 3 shows that there is a negligible and propol-tional dissolution of both colla~en and B~PN-F from the film into the 37C saline medium durirg extraction lastiny almo~t 3 wee~s, but that 10ss than 5~ collagen is dissolved, and no more than 2i~ BAPN-F.
-`~ 2 ~ rl ~
Table 3 Physical and Functional Stability of Collagen-Resol-cinol-BAPN-F-Glutaraldehyde Film irl_Salirle at 37C
Sampling Dissolved ~ of Total Dissolved D GL Total Period~hl Collaqen(m~) Colla~en in Fil~G BAPN-F(~q) BAPN-F in Film 2 0.~2 0.~ 12 0.
19 1.~& 0.~ 41 0.~
.72 1.~ 7a 1.5 ~4 4.~;5 2.~ 1~)0 2.0 1~2 ~.2~ l.g5 ~12 2.0 ~50 g.S 2 . 1 105 2 . 0 o2~4 . 64 2 . 1 110 2 . 0 -In or~er to obtain long shelf life Gf EAPN medications the drug should be ~ept dry and out of cor.tact with water. For this reason adminisLraLion of ~APN as an oin~men L, in sels or solutions i3 rather impractical, as the medication has to be freshly prepare~ avery 6-8 weeks. 6-~ weeks is the time Gf detection of the fir3t decomposition product of BAPN into ammonia, aminonitrile and C02. This invention can overcome the above problem by ir,corporating a solution with the ~nown concentration of BAPN into the dressing material (gauze, collagen sponge) with a known surface area. The dressin~ material may be soaked with a krlown volume of BAPN solution, frozen and freeze dried to complete dryness. It has been established that at the dose of 20-40 mg BAPN-F per 100 cmZ of the gauze there is an 3 ~ ~ ~ 7 ,J~
evident clinical effect of a topically applied gauze-placed wet over the lesions, such as peritendinous, perineural adhesions with prevention or reduction of the incidence o~ fibrotic adhesions.
Although this inver,tion has been described in CGnneCtiOn with specific forms thereof, it should ~e appreciated that a wide array OL equivalents may be su~stltuted for the specific elements shown and described herein wlthout departing from the spii-it and scope OL this invention as described in the appended claims.
~0
M~5TROD AND APPARATUS FOR TREATMENT OF FIBROTIC ~E~IONS
Field of the Invention This invention relates to a novel method and apparatus for treating fibrotic lesiGns, particularly to tr~ating scar tissue wherever located, an~ ~o trea~ing strictures OL tubular structures, hollow orsans and the like.
BackGrourld of the Invention Whe~her crea~ed by ~isease, acci~ent or t.-e-apeutic in~el-vention, mammals hea1 hel1- ~-ounds ~y form,atian OL scar ~iS3UG. The heal ng p~-GCeS5, name-y scar formation, often leaves mammals with limitations o~ motior, constricting skin scars, frozen joints or restriction of orsan functiorl such as in urethral stenosis or gastric outlet obstruction, for example.
For many years, medical practitioners and researchers have struggle~ unsuccessfully with the difficult task of controlling scar formation by either reducing scar production or promoting scar resorption in their e~orts to reduce limitations of motion, scarring, freezin~ of joints or restriction of organ function.
Their efforts prior to this time have not been successful in alleviating these problems in human patients.
Description of the Prior Art During the past quarter century much knowledge has been gained relative to the biochemistry of scar formation~ E.E.
5 7 ~3 Peacock, Jr. & Walton VanWinkle ln Wound Repair, Sanders Company, Philadelphia, USA, 1976, amo~g others, have repor~ed their work in this regard. In simple terms, scar is a woven protein consisting primarily of sp~cial amino acid 3trands of fi~ers called collagen. Collagen is formed in special wound ce ls ~fibroblast) which is extruded to mature irl an extracellular matrix where eventual strength is obtained by crosslinking of pro~ein collagen fibers. The cross-linking process, which gives scar its strength arld hardness, is facilitated by the enzyme lysyl oxidase.
U.~. Paten~ No. 4,4~5,0~O to Chvapll discloses that crosslin~ing can ~e inhibited by al~ering several chemical pa~hways with compounds ca~led lathyl-ogens, such as D-Penicillamine and Beta-aminopropionitrile (BAPN). These compounds have been administered systemically to insure their incorp~ration ir.to the healing process. Unfor~unately, their therapeutic and toxic concentrations are 50 close that they cannot be systemically tolerated by humans, thereby precluding their application to human patients.
The therapeutic e~ects of ir~hibiting Ol^ modifyirlg collagen crosslin~ing has been demonstrated with tOpicâl applica~ion to healing wound scars by Chvapil. One of the lathyrogens, BAPN, penetrates the skin and other surroundin~ tis~ues a few millimeters in thickness. The eCfective dose of topical ~APN has bPen reported to be approximately 1/100th the systemically effective dose, ~thereby reducing in importance, but not eliminating, the issue OL safety. Chvapil describ~s t~pical application to burn scars, skin and chic~sen ten~on3 at or near the time of injury and new scar formation. However, Chvapil's technique is limited to topical applications or appiications where the lathyrogens may be injected into a localized area, such a3 a jGint or tend~n.
~ imilar experimentai WOl^k has been perLormed for treatmer~
of dogs Witil regard to bu~-rs in .he esGphagus; Davis et al in "~
New ~pproach to the Con~rGl OL Esophageal Ster.Gsis", nn. ~u~
Vol. ~7~, No. ~ (Octobel- 1972). However, serious ~o~ic ~y pro~lems ~e-e encountere~ with sstemical y introducc~ ~e.a-amin~prop,onl~l-ile fu~,ara~e (B~PN-F). Moreover, during the ~rea~merl~ ~me, ~he subjects exhibite~ sevel-e problems in t.-e inges~ion of Cood.
Ma~den et al repor ed in "Experimental ~sophageal ~ye ~urns", Aaa~ 3E5- Vol. 17~, No. 3 (~eptember 1973), that _, althoush t~ey believed ~hat mechanical splints should be applied continuously for m~ny months to achieve permanent correction in artiLicially induced esopbageal burns, bougienage could onlg be performed intermittently.
Objects of the Inve~tion It i3 according~y an obiect of thi6 invention to provide a method of treatment of fibrotic lesions to reduce limitations Of motion, scarring, freezing of joints or restricticn of organ function, all without encountering problems as to ~ystemic "' ~ 7~
toleration.
A further obj~ct is to provide novel equipment Lor carryiny the method into effect.
Summary OL the Inventioll This lnvention reiates to a novel method OL controlling scar Lorma~ion in a mannel- which prese1-ves organ functiorls by the co;nbinatiGn o biGchemis~ry, pharmacGlogy an~ ~hysics ~y ~
orceful resec~ion or ~ilation of a scarred area in a human ~at, enL LO create a new wound, followe~ ~- (2) continuous ~opical apyllsation o a la~hyrogenic agent tG the ~i ated scar1-eJ area and (~ ~uring healing o. ~he new wGun~ corl~lnuously suppor~ing the di,ated scarred area in the desired con.iguration.
The in~-ertion iurther relates to a special catheter for controlling scar fo1-mation, onto which a selected lathyrosen may be bonded prior to i~sertion into generally tubular portions of the human or animal ~ody, followed by rehealing while supporting the tu~ular body por~ion in tlle desired confisuration.
Brief Descri~tion o~ the Drawinqs Fig. 1 shows a schematic front elevational view taken in section, of a tukular organ exhibiting severe stenosis.
Fig. 2 shows a section o, the tubular orgar, taken along the lines and arrows II of Fig. 1.
Fig. 3 shows a section of the tubular organ taken along the lines and arrows III of Fig. 1.
r~ ~3 Fig 4 is a schematic sectional view of a catheter having a lathyrogenic agent applied thereto Fig. 5 is a schematic sectional vie~ of a balloon catheter having a lathyrogenic agent applied thereto Fig. 6 is a schematic view, taker in sectiGn, of a catheter inserted in a tubular ol-gan in accordance with aspects OL the inventlon Fis 7 is a schematic vlew, taken in section, o~ a balloon cathe.er lnserted in a tubular orsan in accordance with aspects of he inven~ion Fig S shows a schema~ic -~iew, aken in sec ~iGn ~ OL a tubu ar ol-yan a~ter treatment in accGl-dance with ~he method o, the inven~ L on Detailed ~escription of the Invention Al.hough a particular fGrm of appara~us and method has bean selected ~or illustration in the drawings, and although specific terms will be used ir. the specifica~ion for the sake of clarity in describing the apparatus and method shown, the ~cope of this invention is defined in the appended claims and is not intended to be limited either by the drawin~s selected or the terms used in the specification or abstract For example, althouyh fi~rotic lesion on hollow organs have heen illustrated in the drawings for convenience, the method of the inve~tion i5 not inten~ed to be limited to such hollow organs As shown in Fig. 1, which is a schematic of a tubular oryan ;
-~ ~ 2 ~ l~3 ~ rj 7 ,~
10, a portion of the tissue 1~ exhibits se-~ere stenosis. The portion exhibiting such stenosis is designated by the numeral 14.
The stenotic portion 14 may ~e tl-le result Gf any numbeY of naturally occur~ing or artific ally induced Gccurrences. For example, portion 14 may have been previously injured, such as ~y surgical opel-ation, severe injury, 'rauma or the like. SLenoLic portion 14 resulted Lrom the formation OL scar tissue, which grew into and toward the cen~er portion GL tubular organ 10. The result of the Cormation of such scar tissue is the severe narrowing of tubular orgar, 10.
Narrowirlg Ol tub-ular organ 10 can ha~e severe consequences with regard to the ~assage o fluids through the tube. For example, in the case where tubular organ 10 represen~s the urethral canal, almo~t complete blockage of ~low can occur.
This, of course, is highly undesirable. The same severe consequences may result in instances where tubular organ 10 represents the esophagus, blood ~essels, intestinal passageways, 'allopian tubes and the like.
Fig. 2 of the drawings shows a portion of tu~ular or0an 10 which is in a normal, non-stenotic condition. Tissue 12 i5 OL
ordinary thickness. On the other hand, Fiy. 3 shows a stenotic portion 14 of tubular organ 10 wherein tissue 12 has a far sreater thickness, and reduces the interior diameter of the tube.
Referring now to Figs. 4 and 5, different forms of catheters are shown. Fig. 4 illustrates a simple tubular catheter 16.
Tubular catheter 16 includes a hollow tube 18 surrounded by 7 ~
lathyrogenic ayent 20. Similarly, Fig. 5 shows balloon c~thetex 22. ~alloon catheter 22 con3ists oL a central tu~e 24 and a ~alloon 26. Ealloon 26 is coated with and i5 surrounded by lathyrogenic agent 20.
Fig. 6 schematica,ly illustrates insertion of one LGrm of tubular catheter 16 into tubular Grgan 10. Tubular catheter 16, aS sho~-n, has an outer diametel- OD which is greate1- than the inner diam~ter ID of tubular organ 10. Tubular ca~heter .6 extend3 intG t~bular organ 10 for a distance su ficient to engage stenot.c por~ion 14. Tubu.ar cat..eter 1~ is inserted to a point whe-l-e.ll la~hyrogenic asent 20 directly ar,d closel~ contacts suus~an~lally all of s~enotic portion 14.
Fiy . 7 shows ba-loon catheter 22 in an inflated condition ~i~hin tu~u~ar orgarl 10. ~alloon catheter 22 extends inwardly into tubu.ar organ 10 to a point wherein lathyrogenic agent 20, which surrounds balloon 26, directly and closel~ contacts steno~ic portion 14.
Fig. ~ shows tubular organ 10 a ter removal o~ either tubular catheter 16 or balloon catheter 2~. Tiss.lle 12 is in a normal condition and thickness throughout. the entire length o~
tubular organ 10. Stenotic portion 14 i~ no longel- present~
In accordance with a preferred ~orm of the invention, the physician locates a stenotic portiGn Gf the tubular organ by ordinary means well known in the art. Ol,ce the stenotic portion has been identified and located, it is dilated, resected, incised or removed to create a fresh, open woun~. Then a lathyrogenic 0~57~
agent, pre~erably D-penicillinamine or Beta-amlnopropionitrile (B~P~), or Eeta-aminopropionitril~ fumarate ts~pN~F), or amir,oacetonitrLle, for example, is applied to a cath~ter o~ the physician's choice. Depending upon the tubular organ to which the ca.hete~- is applied, various well known catheters may be u~ ed. in the case where a balloon catheter is chosen, the athyl-ogenic agent (soi~etimes ~-e~erFed ~o hereir.after OF
convenience a3 ~PN-F; is applied ir, a coating tG the ba'loon por~ion o~ the cathe~er, such as shown in Fig. 5 o. the drawings.
The cathe~er i3 ~hen in3elted ih ~O ~he tubular ol-gan b-~ordi..ary means wcll ~nowrl in the ar~. The balloon ca~cter is inser~ed to a point whexe ~he B~P~ is in po3ition to diFectly and closely contac~ s~enotic portion 14 upGn expansion of the balloon. The balloon i3 then inflated arld le ~ in position lor the prescribed ~reatment time.
It has been discovered tha~ the lathyrogenic agent should be applied to target tissue in a dosa of about ~.5 mM to about o.5 mM for BAPN-F and about 20 mM to about 40 mM for D-penicillamine.
The pre erred dose i5 between about 5.0 m~ and about 5.5 mr~ for BAPN-F and abou~ 22mM to about 25 mM for D-penicillamine.
~ n another preferred form of the invention, the B~PN-F i3 ionically bonded to a special catheter capable o ionically bonding the EAPN-F to the outer surface of the catheter. This ionic bonding permits insertion of the catheter within the tube and up to the stenotic portion, without the danger of BAPN-F
being wiped off the catheter prior to contact with the stenotic 7 a portion. In t~is manner, the coated catheter i8 inserted a,ter the stenotic portion has ~en expanded or resected to a d~yr~e whic~ tears or l-emoves t~e existing 3car tissue. Th~ BAPN-F then directly contacts the tissue in the new wound to sorten the healing prGcess. The resulting forme~ tissue is substantially in the shape and size of the outel- ~iameter of ~e catheter an~
retains its normal pliant condition, and exhibi~s the ~ha~-a~teristics Oc llormal, urlinjured tissue.
In still anothe~ preferred form of the invention, the same steps may be applled .o non-~ubu'ar tissue. For example, the me.hOd OL the inven~iorl may be applled ~o exterior burns such as s~in burns. Howe-~er, i~ is impo-tant that the same steps be ol owed to achie-~e the excellent results achievable with this aspect OL the lnvention. Examples of various applications of ~he ~,ethod of the inventiGn are l lustrated as ~ollows:
EXAMP~E 1 -- BU~N SCAR-E~EOW
A patient with a full thickness dermal scar around 'he elbow exhibits complete contracture and cannot ~ully extend the elbow. This restricts use. The hard scar is surgically "released" u~der general anesthesia by cutting in several places with or without a sl~in graft. The patient then has A lathyrogen applied and is placed in an elbow dynamic splint. This allows the elbow to be protected and at the same time to fully exercise the joint on a daily basis with or without the supervision of a physical therapist.
A lathyrogen jelly with 5.0 mM of BAPN-F and/or 20-25 mM D-penicillamine or a B~PN-F impregnated gauze ~40 mg/10~ cm2 of gauze) is continuously applied to the wound during its healing phase beginning 4-O days after surgical treatment and continued LoF four to six weeks in combination with physical therapy. ~t the end of healing, the splint is remGved, the lathyrogen discontinued anZ the patient resumes full ranse of moLion at the elbow due tG Lhe lac~ of cross-linking OL newly formed cGllasen in p'ace of old scar tissue.
EX~MPLE 2 -- FAI,LOP~A~ TUE~ STENO~ FERTIL T~' A patienL having scaL^lred and blocked .allopian tu~e3 as a result OL in ecLlorl has incisions made in ~he scar ~lssuc and a E~PN-F coaLed sLlastic tu~e s~lnt placed in the ~allopian tu~e after one weel- and 'e~t in p'ace durirlg the healing phase. The 3 ~int is conLlnuously maintair.eu in contac L with the fre3h wound and is chansed two or Lhree times during Lhe Lour L~ six wee~
healing phase as the lathyrogenic agent leaches off the surface of the silastic stint and is incorporated into the newly healins scar. The newly forme~ scar takes the shape of the stint. Th~
stint is removed, the opening of the fallopian tube is pl~served and egy and sperm transport can now cross the previously blocked fallopian tube.
EXAMPLE 3 -- ESOP~IAGEAL STRUCTURE
A young teenager, who as a child swallowed a Zrain cleaning solution, has a lye burn to the lower esophagus and has great difficulty with maintaining proper nutrition. The result is stunted growth. The scar formed from the burn is dilated under 2 ~ r7 ~
direct endoscopic vision with a dilator or sur~ically r~sected to create fresh wound tissue. A Cellestin tu~e i~ immediately at~ached across the new wound area and continuously maintair.ed in position for ~he duration of healing. The outer lining OL the Cellestin tube consists of silicone to which a com~ination o~ 2-Penlci~lamine and ~APN-F is bonded, which leaches into the healing area. Wherl healing is complete the tu~e i5 removed and a normal esophageal diame~er remains because the 5.0 mM s~lutiGr,s of .he ~a~hyrogens have ~een incorporated into the new scar allowing it to form itselL around the tube with~ut fu;-~he.-s~enosi3.EXAEi~PLE ~ -- UR~T~ PRO~TATIC CANCER
~ patient with prostatic cancer detected with sonography and a candidate fo1- total pro3tatectomy has the prostate removed and the c~-f of the bladder sewn to ~he most proximal remainLng por.ion o, .he urethra. This circumferential suture line often progres3es to hea~y scarring preventin~ complete emptying of the bladder. The scar is cut away under anes~hesia and direct resectoscope ~ision and immediately stinted with a silicone ca~heter coated with 5.0 mM BAPN-F. The catheter remains in continuous direct contact with the new wound tissue during healing. The BAPN-F leaches ~rom the surface o~ the catheter, thereby inhibiting hardening of the healing scar during the next three weeks. The catheter is changed on a weekly basis to renew the BAPN-F supply. Once healing is complete and the newly formed scar is laid down around the stint o~ the indwellin~ bladder -) ? ~ 3~37 ~1 urethra catheter, no new sc~rriny takes ~lace.
EXAMPL~ 5 -- U~N SCAR-H~ND
A patient with a well healed full thickness ~urn o~ the hand has severe scarring of the fin~ers and har.d in a claw-li~e form~ The old scars are surgically released to create full mobility oL t~e joints. The hand is placed in a "dyna~,ic splint." The sp'int contains rubber bar,d ,ixation to a rigid Lrame allowing the patient to exercise his Lingers t~rough a full ~-ange of mo~ion. Durins the ~ealing phase and on a Zaily basis, a Jelly containins 5 mM~L OL the lathyrogenic agen~ ~PN-F i3 con~inuously applied to ~he suxgically "released" a~-eas. L',e pa~ier,~ con~inue3 ~o exercise and use the dynamic splin~ durihg ~he ~ea'in~ phase over the next fOUl- to six weeks. Once re-epitheliali~ation and healing ls complete, th2 newly formed scar, beins soLtened by the cGntinuous applicatior. of B~PN-F, has Lull range of motion without further restriction of hand mGtion. The dynamic splint is removed. IIealing is complete and range OL
motion restored.
EXAMPLE 6 -- BURN SCAR-NEC~
A patient with severe third degree burn of the neck has completed healing, bu~ the resulting scar is so severe that the hea~ cannot be strai~htened. The scar is surgically released (incised) with or without a skin graft, thereby creating a new wound. ~ s~iLf plastic collar having a soft lining is applied to the neck to hold i~ in a new desired position. ~ combination of 5.0 mM B~PN-F and 20-25 mM D-Penicillinamine jelly or a BAPN-F
2 ~-35 7 ~
impregnaLed gauze (40 mgtl00 cm2 of gauze) is continuously appli~d to the newly created wound ti5sue so that as new scar is formed, it will be soft, plastic-like, and uncross-linked ur,til healing is complete in four to six weeks. ~t th~ end Gf that time r,o new medication need be applied, the collar is removed and the patient has been re3tored to full range of motion of the nec~.
EX~.P~E 7 -- URETXRA-INFEClION
~ patient with urethral stenosis (narrowing OL the tu~e betweer. ~he ~ladder ~nd the erd oS ~he penis) secondary ~o a gGnococcal inSec.ion exhibi~s bladder Gu~leL obstruction. The old scar in ~ne urethra s Gpened under direc~ surgical resection. I.r,mediately afterward d silicone urethral bladder cat~eter is inserte~. ~fter one weeX, this cathet2r is exchanged or one with the lathyrogenic agent ~APN-F bonded onto its surf ace. The coa8ed catheter is continuously maintained in place and changed every week for about six weeks durin~ the healing phase. During the healiny phase new scar tissue is aid down.
However, its streIlyth is beneficially alLered by the ~athyrogen EAPN-F which inhibits the bonding of one protein scar fiber to the next protein scar fiber allowing the wound to ~e ~lolded in the shape of the intraluminal stint (urinary bladder catheter).
At the end of the healing phase, the stint i5 removed and normal unobstruct~d urination can prGceed.
EXA~PLE 8 -- URETHRA-TRAUMA
Following fractured hips, 5-10% o~ human males suffer ' rl ~
transection of the membranous urethra as it leaves the bladder.
This transection requires primary anastam~sis with catheter stinting, often resulting in severe scar formation and secondary bladdel- outlet obstruction. ~alloon dilation (pressure balloon) LO create new wound tissue may be performed or direct surgical resection removes the narrowed scar tissue. After Gne week, the original bladder catheter is exchanged for a silicone catheter coated with either B~PN-F or another lathyrogenic agent such as D-Pen,cillamine, which inhlbits cross-,inking ~3trong bondins) between scar collagen fi~ers. The coated catheter is continuous y mainLained in place and changed once a week for a~out six weeks during the healing phase. AfteL- catheter rem6val a normal sized oper,ing is present, with the new scar ~eing molded ~o Lhe shape OL the in~raluminal stint (bladder urethral catheLer.) EX~r~PLE 9 ~- URETXR~-PROSTATE RESECTION
Following partial prostatic resection for bladder nec~
obstruction in human males, approximately 10~ of patients develop 'ubal narrowing at the ori~in o~ the urethra. The 3car is resected to reopen the lumen under direc L surgical endoscopic vision. After one week, the lumen is protected with a catheter stint of silicone coated with a comhination of D-Penicillamine and BAPN-F to inhibit cross-linking or hardening of the newly formed scar tissue. The catheter is continuously maintaine~ in place and changed once a week for 5iX weeks as healing is completed and new-soft scar is layered around in the shape of the i 7 ~
intraluminal stint. Once the stint is removed, the openin~
~etween the bladder and the begir.ning o~ Lhe urethra is protected by the shape of the mature collagen scar which now p7-ogresses to slow cross-linking or hardenirlg without narrowin~ the lumen.
EXAMPLE 10 -- TRAC~EA
The patient suffering ~racheal injury either due to a tracheostomy on an emergercy basis or sèco~dary to an automGbile accident has prir,.al-y anastGmosis GL the ~rachea re3ulting in a severe scar and impairmen. of the airway. The scar is excised and an endo~racheaL silastic s.int cGated with 5.0 mM E~PN-F or D~Penicillamine is pu. in place a'ter one wee~ and conlinuously main.ained and changed on a weekly basis for L lve or six wee~s durirg the healing phase. The lath~rogen is incorporated in the newly formed and healirls wound where it allows the newly formed scar to be soft, plastic-like and conform to the diameter OL the endotracheal stint. Once healing is complete no lurthe.- scarring takes place, the medication and stint is discontinued and the patient returns to normal airway dynamlcs.
EXAMPLE 11 -- CO~MON BILE_DUCT ~TENOS~S
A patient who has had an injury of the common bile duct secondary to a complicated gallbladder operation is jaundiced.
The scar is partially resected and after one week an original silastic stint is e~changed for ar. intraluminal silastic tube coated with BAP~-F with one arm of the tube protruding into the duodenum. The BAPN-F leaches off the silastic tube and is incorporated into the newly formed scar, which is soft because ~ r~
BAPN-F blocks cross-linkin~. The tube is cGntinuously maintairled in place and on a weekly basis the patient retUrns to the gastroenterology lab where, under direct manipulation, the tu~e is exchanged every wee~ for six wee~s. Once healing is complete the tube is ~-emoved and the new lumen of the common bile duct is preserved. The patiert i3 no longer jaundiced and fluids from the liver can pass into ~he duodenum urinhibited.
In many of the foregoiny examples it is beneficial to use a speciai catheter containing directly bonded ~PN-F. This provide3 the advantage that the B~N-F will ~e delivered direc~ly to ~he desired .iS3ue w ~hou~ the danger OL being partia~ly Gr completely ~-iped OC ' ~he ca~heter during insertion into the tubular organ.
Linking a druy such as ~APN-F to a po~ymer forming a cathe.er or wound dressing may ~e achieved ~y severa methods including:
a. direct ~inding OL the drug to available Lunctional binding groups in the polyme1-ic surface of the catheter, b. linking the drug to newly created Lunctional bindin~ sites after chemical or physical modification of the polymeric surface;
c. direct incorporation of the drug into the polymeric surface either during the catheter manufacturing process or into the final catheter product by programmed, cont~-olled soaking in the appropriate solution of the drug;
d. deposition of a drug in another polymeric substance 2 ~ r~
~hydrogel, gelatin, collayen and the like) which is tl,an chemically attach~d to the polymeric sur~ace of the d~vice.
By this method large ~uantities of the dru~ can be associated with the effective surface OL the device. T~le drug can ke linked chemicaily to this coatins material as well as physically sorbed if added in quantities exce~ding the bindir.g capacity of the cGating polymer ~hydrogel). ~n a~ditional ad~-an~age OL this process is Lhat the coating polymer r,ay add new propel-Lies to ~he ~evice polyme;-, such as slipperiness, ~iocompatibility ~o ti-sue cells, ;-e~uction OL mineral crys~al Eol-ma~ion when in contuct Witl~ ~ome biolGgical fluid3 (urine).
Examples of manu~acturing procedures for the above ouLlined processes are shown ~elow:
A la~ex polymer may be partially hydrolyzed-depolymal-ized, for instance, in a strong oxidizing en~ironment to p~ovide Lree carboxyl, hydroxyl or aminG sroups when the polymer does not contain available ~unctional groups. The ~roups then ~erve as sites for chemical bi.nding of BAPN. In the case of BAPN binZing, the availability of C00- group~ is optional.
ln practice, the latex polymer may be dipped into an Iqueous solution of 2~ sodium hypochlorite, wherein the solution contains 0.5% sul~uric acid. After ~-10 minutes of incubation at 25C, the solution i5 decanted and the latex polymer incubated for another 5-10 minutes in 5~ ammonium hydroxida solution. Removed polymer is then excessively washed in iced water. Activation of ) 2 ~ 7 ~
the COO- groups oL the latex is achieved at 25QC in the presence of carb~diimi~ mg/ml) at p~ 4.75 o~ 0.1 M ME~ bu~fer. The incubation lasts 30 minutes, L ollowed by quicX ice water washing and then exposing the activated polymer to the solutiGn of ~APN for 12 hours in 0.1 M MES at pH 4.75.
After completion G. tlle reaction, the .inal product is r,Gt washed .rom the excess of the drug, which under these conditions contains both chemically anZ physically linked ~PN to the device polymer. In this meZium, the carboxyl groups are activated and these react with the ~-amino group o. the EAPN-F to Grm a rather 5 tlong linkage. Car~odiimide ha~lng the chemical ~ormula (1-eth~ 3 (J-dime.hylamine-propyl) carbodiilr,ide-HCL (EDC) has ~een recognized as a pctent coupling agant activating the availa~le carboxyl groups in hydrogel, co lagen or gelatin.
~ hen the device is made of inert or su~stantially inert silicones, known Lor their low polarity group content, the surLace of the device may be modified to render more birldin~
sites. The methods of modif~ing the silicone may be either chemical or physical. The example Gf using stron~ oxidizirlg agents was described a~ove. ~r.other method of forming reactiv~
side groups in the silicone ~activating the surface) is exposing a silicone surface to high energ~ ionizing radiation such as high energy electrons, X-ray or gamma radiation first and then interacting such a sur-ace with BAPN-F under similar conditions as shown above. The radiation exposure total dose corresponds to 0.~0 to 0.45 Merads. The princi~les of this method are the .
? ~ rj r~
object of U~S. Patent~ 3, 453 ,194 or 3, ~2~, 67d .
There is anGther method of ~ringing l~rger amounts of E~PN-F
onto the surLace OL a polymex, such as latex or silicone. Either polymer is partially hydrolyzed as descri~ed above. To the acLivated surface Gf a polymer ~a hydrogel, collagen Gr gelatin soluble in ethanol) is interacted to ,'orm a unifGrm coating. A
reasonable amount o~ BAPN-F can ~e incorporated in such a cGating OL hy~rogel, collagen or gelatirl. The release GL ~APN-F ~ill then depend on the rate o' diffusion o. thi3 molecule .rom the hydrogel, cGllagen or gelati.l. This then w,'l ~e controlled by Lhe swellability of the hydro~el, collagen or gelatin. There are -various types of hyd~-oge~s, ~ased on polyac-ylGnitrlle Gr polyure~hanes, where hydl-ation can vary from a few weisht percent of water to almost 90"O OL water.
A purified collagen simila1 to hydrogels car. ~e used ~o link with the funcLional ~roups of the polymel- device, using known, described various procedures known in the art.
Selectiorl of the appropriate hydrogel, collayen or gelatir~
will allow the desired release of ~APN-F. For in~tanc~, hydrogel based on polyurethane is availa~le with ~'ree car~oxyl groups (for example, see U.S. Patent 4,255,550), lactone or hydroxyl groups (.or example, see U.S. Patent~ 4,156,066 and 4,156,~67). ~n general, hydrGphilic polymers or hydrogels are use'ul carriers for pharmaceutical agents (U.S. Patents 3,975,35~ or 4,43g,585).
Another factor controlling the rate of drug release from the hydrogel, collagen or gelatin coat (besides dif,usibility) is the r3 ~ ~ ~
option of chemical binding of the druy to the functional (mainly carboxyl) gl-oups of the hydrogel, collagen or gelatin.
It is known that lysyl oxidase, an enzyme essential for cross-lin~ing of collagen ~which resu ts in 5 ~rictures arld contractures), is effectively and irreversi~ly inhibited at 1~-1G
~ APN tissue corlcer.tl-ation. Given that a~ thi3 cGrlcentration Gf E~PN, released every hour ~o reach a steady statc in the tissue, is the safe and effective inhi~itory dose and ~) the treatment will last ~0 days, the dose of B~PN deposited within the device to obtain zero order sustained release should exceed 2~ mg of B~PlY~de~-ice. In order ~o obtaln zerG order ~linear) L-elcasc o' a drug from a matrix, it is ir,portant ~o com~ine at least two diLfe.-ent mechanisms OL a ærus sGrption (~inding~ in a polymer or matrix. These mechanisms include a) chemical ~inding G moderate strength providing slower release OL a drug af~er its dissociation from the chemical bond and b) physical sorption, which is a very weak bond and allows immediate release of the drug once the device is exposed to tissue fluid and moisture. The ~inetics OL the release for each m6chanism ~iLfer Lor various polymers and drugs.
One important factor favoring using hydrogels, collagen.s or gelatins as a carrier for BAPN-F and other lathyrogenic substances is the similarity of hydrogel characteristics with tissue composition ~same content of water, absence of toxic elements, similarity to collagen molecule chain in phy-qical and physico-chemical aspects). Thus, hydrogel-drug implants or ~ ~ 2 ~ ~ j 1`~ r~ ~
coatings of other polymer devices provides foiA better tissue tolerance.
Although several classes o~ hydrophilic polymers swellable in tissue fluids are available, the selection of the ~IGSt appropriate ~ydroyel, collagen or gela~in is directed by criteria of safe~y, reflecting nontoxicity, noncarcinosehicity, mutagenicity, teratogenicity, etc. Ful-thermore, che~,ical reacti~ns w,hich lead to establishillg a polymer (hydr~gel)-drug complex, Gr which re~uire additional cross-lin~ing agents or actit-a~ors, or which ~lay cause diCficul~y in washir.g out ~he 'ina product wl~.lou~ compromisins ~he stab lity of the lirlked drug, must ~e consid~-ed ln the selectior of an adequa~e coating po~ymer LO be used as ~he reservoir or EAPN~F or other lathyrogen.
Other drus delivery systen,s Lor time release OL
lathyrogenic medications have been developed. ~uch delivery systems use biodegradable vehicles which are ~iologically safe, induce minimal local tissue reaction without any side toxic effects, are easy to handle, and are economically feasi~le.
For several years, gelatine-resorcinol-glutaraldehyde (G-R-Gl) tissue adhesive showed to ~e one of the least toxic tissue adhesives used in various surgical applications. The glue quickly polymerizes and efficiently adheres the tissue surfaces together when in contact with tissue and when reacted with formaldehyde or glutaraldehyde. The adhesive capacity depends on the content of R- which usually is 30~ of total solids and on the rj 7 i~
concentl-ation of the tanning agent used in the concentrated ~orm.
G-R-Gl as ti~sue adhesive has been appli~d to tissues in or~ly minimal amounts, because the strenyth of the bonds is indirectly proportional to the thickness o, the polymer in between the tissue su~aces.
Use of earlier tissue adhesive G-R-Gl polymers as vehicles for delivering lathyrogenic age~lts in the method OL this invenion is disadvantageous because the polymer consists of gelatin and resorcinol in weisht ratio ~:1, G forms ~ % and R
forms 10Jo of the nonpolymerized solution. In other words, the original tissue adhesive mixt~;-e i3 a 60'~ aqueous soluLion consisting of 45 weight vvlumes OL gelatin, 1~ weight volumes GL
resorcinol and ~0 volumes of water. After polym,erization with 37'~ formaldehvde or 25~ gluLaraldehyde, a firl,-, polymer is formed which undergoes, in biological environment, minimal swelling an slow ~esorption. High content of gelatin, resorcinol and tanning agent are essential to obtain solid tissue adhesion OL hiY11 tensile strength. l'hus, the lathyrogenic agent added to thls earlier system would be released at an extremely 510W rate.
We have found that by decreasing the content of Lhe individual components and by varying the content of G" R and the concentration of tanning agent, mainly of Gl, it is possible to control the consistency and hydrophility of the Linal fol-m OL
gel-polymer to release the lathyrogenic agent at a beneficial rate.
We have also found that if the lathyrogenic asent is added to the G-R-water mixture in appropriate concen~ration, then after quick mixing with selected conc~rtration3 of Gl in a syringe, the sti l fluid gel may ~e applied to the subject to form a polymer.
Ne have also found that in ~ase fa3ter drug release i5 desirable, R need not ke present or added to the collagen solution dul-ing crosslinking ~y any tanning agent.
We found that a mi~ture consisting of 15 to 30 parts o' G, 0.1-2 parts OL R ~ 20 to 30 parts of water component and usins 5 ~o 30 'old dilutiGn OL the G as polymerizing agent are op'imal 'or long-~erm release of EAPN or other lathyrogenic agents ovei the period OL 3evel al week3 or months.
A polymer cGnsisting OL only 1 to 5 parts OL gelatin, 20 parts o' water, of appropriate concentration ol the lathyrGgenic agent and polymerization induced by 0.05 ml OL 0 . 5 10 ~
glutaraldehyde per 1 millili~er of the mixture is optimal for short time release OL the lathyrogenic agent over a ~eriod of a few weeks.
It was also found that the a~ueous mi~ture co~sistiny o.
collagen-resorcinol and the lathyrogenic agent can ~e coated on any biomaterial, prosthesis or device consisting of a ~iopolymer and then polymerized. After the plantation of the biomaterial on the healing wound a continuou3 release of the drug from the coat layer follow3.
We have also found that when the lathyrogenic agent is added to the G-R mixture with another agent which ha~ antithrombogenic ) i 7 ~
properties such as heparin, a polymer can be coated on the healing ~iolo~ical tissue surface to prevent th~ ~ormation of blood clots.
As indicated a~ove, the rate of the release of the lathyroyenic agent depends on the degree of polymerization of the formed gel ar,d also on the surCace area of the polymer n contact with the healing wound. The ra~e of release of the lathyrogenic agent is controlled by the laws of physical difLusion as well as by the degree of biodegradability of the polymer. The rate of athyrogenic agent diffusion ~hen depends on the degree Gf hydra~ion of the polymer.
lhe L ollo~ing examp e3 seL-ve to illus~rate the practlce of the in~ention, ~ut arc not to be ~-egarded as limiting. All par~s are given by weight, unless otherwise specified.
This example illustrates the efficacy of collagen-resorcinol-glutaraldehyde polymer as a EAP~-F delivery system.
One hundred parts of medical grade purity collagen, prepared by a known procedure, i3 mixed with three hundred parts of water and heated until collagen dissolves to form a ~iscous solution. To this solution six parts of resorcinol are added and when this component dissolves, 5iX parts of BAPN~F (Solution 1) or fifteen parts of BAPN-F (Solution 2) are mixed in. One milliliter of this mixture per kilogram of rabbit body weight was injected under the skin, af te~ quick mi~ing of the appropriate volume of the mixture with lJ10 of its volume of 3 percent ylutaraldehyde .
in a 5 ml plastic syringe. When this composite i5 injected under the skin, it polymerizes within a few minutes to form a pllable disk. The rate Of the release of the E~PN-F ~rom the polymer was studied by direct measuring of the amount of BAPN-F in the blGod, collected from the ear vein of the rabbit at time intervals shown ir, Table 1.
For compa~-ison, the same amour.t 6L EAPN-F was lnj~cted undel-the s~in o~ contl-ol rabbits as water solution. It was four.d that while injection of the same amount of ~APN-F in water solution ;eaches a maximum in serum within two hours a.~er injectioh, E~PN-F injected in the pGlymer mixture is release~ continuously and at a steady ~-ate for seve-- days. Then its concen~ration in the blood slowly decreases.
Ta~
Release of sAFN-F From Two Polym~r ~ixtur~s as Compar~d ~Jith Water 501ution o the Dru~
Time Afte~- the Plasma Level~ (BAPN-F~
Injection (hrs) Water Solution 1 Solution 2 2 3.2 0.2 0.35 4 2.9 ~.35 0.67 2.1 0.40 1.4 ~0 1.~ 0.37 1.3 1~ 0.............. 0.33 ~.2 4~ 0 0.38 1.1 72 0 0.4~ 1.1 96 0 0.~0 1.0 l~S 0 0.~7 1.1 ,, _ . ., _ _ , " , .
') ~AFN-F was measu1ed at given time intervals in the plasma of rabbits ~y a fluorometric method. Each point is the average of two determinations.
This example illustrates that the ra~e of the release of a drug from the polymer is controllable by changing the proportion of individual components of the mixture.
The mixture consisting of the above components, i.e. of collagen-resorcinol-water, was prepared in proportions given in Table 2.
Table 2 Plasma I,evel BAPN-F
Colla~entJater Resorcinol BAPN-F~ q/ml) 100 300 10 0. 2 1a~0 3~0 5 0 . 45 100 ~00 1 ~ . 2 Refers to values determined fi-~e days after irljection of the delivery system with a drug.
~ par~s of E~PN-F were added to each type of mixture. One millili~eL of each mixture per kilogram o ~ rabbit body weight -was injected and bloGd measurements were ob~aine~ as descri~ed in Example 1~. The rate of }-elease is shown in ~able 2.
E~AMPLE 14 -- PXYSICAL AND FUN'CTIO~L STAPrILIlmY OF B~PN-F FI~M
In order to demonstrate the functional stability o, the BAPN-F film, a mixture of collagen-resorcinc,l-EAPN-F is prepared as follows: 10 5 gelatin are mixed with 31 ml water and heated on a water bath until a clear solution i5 formed. 3.3 g resorcinol are added and di.ssolved with stirring, and finally 200 mg BAPN-F are added to the solution. The mixture (1) remains liquid when kept at 40 - 500C. A similar mixture (2) is prepared omitting BAPN-F. Two samples of a wet collayen membrane, containing 60~, water by weight are coated on one side with a thin film of each mixture, the mixtures being kept at 500C
when applied. When a homo~enous film is obtained it is s~rayed with 0.5~ formaldehyde solution (concentrated HCHO - 40~) and allow~d to dry i~ 5 minutes. The ~xcess of fo~maldehyde is washed out with water. The mixtur~ is c~ted ~rto a plastic sheet at 500C. When a co~tinuous thin layer is .ormed th~
material is dipped into 2.0~ glutaraldehyde solution for 1 second, and kept dry at 60~C until constant w~ight is ~-eached.
The net dry weight OL the coating .ilm is 320 mg. This film is remo-ved from the plastic she~t and placed in an Erlenmeyer ,las~
with 50 ml physiological saline solution and ~laced in a wat0r bath fit~ed with a sha~er. At time intervals as indicated ~n Tabl~ 3, samples were collected, hydrolyzed anZ aralyzed fGr the presence o. hydro~ypro,ines and he~osamines. Th~ amoun~ G~
hydroxyp}-oline multiplied by 7.4~ indicates the amount o.
dissolved collagen in m,g, while the amount of hexosamines present multip].ied by 3 indicates the amount of BAPN-F in solution. Th0 ratio OL solubility of collagen and ~APN-F was measured in saline at 37~C in t~e incubation medium at periods during a ~ wee~
interval. The dry weight of the incukated f ilm totaled 335 my.
The data in Table 3 shows that there is a negligible and propol-tional dissolution of both colla~en and B~PN-F from the film into the 37C saline medium durirg extraction lastiny almo~t 3 wee~s, but that 10ss than 5~ collagen is dissolved, and no more than 2i~ BAPN-F.
-`~ 2 ~ rl ~
Table 3 Physical and Functional Stability of Collagen-Resol-cinol-BAPN-F-Glutaraldehyde Film irl_Salirle at 37C
Sampling Dissolved ~ of Total Dissolved D GL Total Period~hl Collaqen(m~) Colla~en in Fil~G BAPN-F(~q) BAPN-F in Film 2 0.~2 0.~ 12 0.
19 1.~& 0.~ 41 0.~
.72 1.~ 7a 1.5 ~4 4.~;5 2.~ 1~)0 2.0 1~2 ~.2~ l.g5 ~12 2.0 ~50 g.S 2 . 1 105 2 . 0 o2~4 . 64 2 . 1 110 2 . 0 -In or~er to obtain long shelf life Gf EAPN medications the drug should be ~ept dry and out of cor.tact with water. For this reason adminisLraLion of ~APN as an oin~men L, in sels or solutions i3 rather impractical, as the medication has to be freshly prepare~ avery 6-8 weeks. 6-~ weeks is the time Gf detection of the fir3t decomposition product of BAPN into ammonia, aminonitrile and C02. This invention can overcome the above problem by ir,corporating a solution with the ~nown concentration of BAPN into the dressing material (gauze, collagen sponge) with a known surface area. The dressin~ material may be soaked with a krlown volume of BAPN solution, frozen and freeze dried to complete dryness. It has been established that at the dose of 20-40 mg BAPN-F per 100 cmZ of the gauze there is an 3 ~ ~ ~ 7 ,J~
evident clinical effect of a topically applied gauze-placed wet over the lesions, such as peritendinous, perineural adhesions with prevention or reduction of the incidence o~ fibrotic adhesions.
Although this inver,tion has been described in CGnneCtiOn with specific forms thereof, it should ~e appreciated that a wide array OL equivalents may be su~stltuted for the specific elements shown and described herein wlthout departing from the spii-it and scope OL this invention as described in the appended claims.
~0
Claims (16)
1. The use of a lathyrogenic agent for treating fibrotic lesions to reduce limitations of motion, scarring, freezing of joints or restriction of organ function in a patient.
A use according to claim 1, wherein said lathyrogenic agent is selected from the group consisting of Beta- aminopropionitrile, Beta-aminopropionitrile fumarate and aminoacetonitrile .
3. A use according to claim 1, wherein said lathyrogenic agent is applied topically.
4. The use of a lathyrogenic agent for treating tubular organ stenosis in a patient.
5. A use according to claim 4 wherein said lathyrogenic agent is selected from the group consisting of Beta-aminopropionitrile, Beta-aminopropionitrile fumarate and aminoacetonitrile.
6. The use of a lathyrogenic agent for reshaping scar tissue in a patient.
7. A use according to claim 1, 4 or 6, wherein said lathyrogenic agent is mixed with a heat denaturated collagen-resorcinol-water solution.
8. A use according to claim 7, wherein said collagen mixture is an aerosol spray solution.
9. A topic composition for treating fibrotic lesions to reduce limitations of motion, scarring, freezing of joints or restriction of organ function, which comprises a lathyrogenic agent in association with a pharmaceutically acceptable carrier.
10. A composition according to claim 9, wherein said lathyrogenic agent is selected from the group consisting of Beta-aminopropionitrile, Beta-aminopropionitrile fumarate and aminoacetonitrile.
11. A topic composition for treating tubular organ stenosis in a patent, which comprises a lathyrogenic agent in association with a pharmaceutically acceptable carrier.
12. A composition according to claim 11 wherein said lathyrogenic agent is selected from the group consisting of Beta-aminopropionitrile, Beta-aminopropionitrile fumarate and aminoacetonitrile.
13. A topic composition for reshaping scar tissue in humans, which comprises a lathyrogenic agent in association with a pharmaceutically acceptable carrier.
14. A composition according to claim 9, 11 or 13, wherein said carrier is a heat denaturated collagen-resorcinol-water solution.
15. A composition according to claim 14, wherein said collagen mixture is an aerosol spray solution.
16. A scar inhibiting composition adapted for application to the biological surface, said composition comprising a lathyrogenic agent, a condensation product of high molecular weight protein and a dihydric phenol, said condensation product being crosslinked with a biologically nontoxic tanning agent.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/538,025 US5120322A (en) | 1990-06-13 | 1990-06-13 | Method and apparatus for treatment of fibrotic lesions |
| EP92303012A EP0564722A1 (en) | 1990-06-13 | 1992-04-06 | Lathyrogenic agents and apparatus for the treatment of fibrotic lesions |
| CA002065570A CA2065570A1 (en) | 1990-06-13 | 1992-04-08 | Method and apparatus for treatment of fibrotic lesions |
| JP4112582A JPH05305130A (en) | 1990-06-13 | 1992-05-01 | Treatment of fibrotic lesion |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/538,025 US5120322A (en) | 1990-06-13 | 1990-06-13 | Method and apparatus for treatment of fibrotic lesions |
| EP92303012A EP0564722A1 (en) | 1990-06-13 | 1992-04-06 | Lathyrogenic agents and apparatus for the treatment of fibrotic lesions |
| CA002065570A CA2065570A1 (en) | 1990-06-13 | 1992-04-08 | Method and apparatus for treatment of fibrotic lesions |
| JP4112582A JPH05305130A (en) | 1990-06-13 | 1992-05-01 | Treatment of fibrotic lesion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2065570A1 true CA2065570A1 (en) | 1993-10-09 |
Family
ID=27426906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002065570A Abandoned CA2065570A1 (en) | 1990-06-13 | 1992-04-08 | Method and apparatus for treatment of fibrotic lesions |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US5120322A (en) |
| EP (1) | EP0564722A1 (en) |
| JP (1) | JPH05305130A (en) |
| CA (1) | CA2065570A1 (en) |
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| EP2380604A1 (en) | 2010-04-19 | 2011-10-26 | InnoRa Gmbh | Improved coating formulations for scoring or cutting balloon catheters |
| US8632559B2 (en) | 2010-09-21 | 2014-01-21 | Angioscore, Inc. | Method and system for treating valve stenosis |
| US10117668B2 (en) | 2013-10-08 | 2018-11-06 | The Spectranetics Corporation | Balloon catheter with non-deployable stent having improved stability |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4444787A (en) * | 1981-07-06 | 1984-04-24 | Board Of Regents, University Of Texas | Ophthalmic topical use of collagen cross-linking inhibitors |
| US4485088A (en) * | 1982-03-26 | 1984-11-27 | Bio-Products, Inc. | Method of treatment of fibrotic lesions by topical administration of lathyrogenic drugs |
| US4886545A (en) * | 1986-01-31 | 1989-12-12 | Nelson Research & Development Company | Compositions comprising 1-substituted azacycloalkanes and their uses |
| US5021404A (en) * | 1988-04-20 | 1991-06-04 | The Children's Medical Center Corporation | Angiostatic collagen modulators |
| DE3821544C2 (en) * | 1988-06-25 | 1994-04-28 | H Prof Dr Med Just | Dilatation catheter |
| US4997854A (en) * | 1989-08-25 | 1991-03-05 | Trustees Of Boston University | Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in-situ using adjacently positioned diamine analogue substrates |
-
1990
- 1990-06-13 US US07/538,025 patent/US5120322A/en not_active Expired - Fee Related
-
1992
- 1992-04-06 EP EP92303012A patent/EP0564722A1/en not_active Withdrawn
- 1992-04-08 CA CA002065570A patent/CA2065570A1/en not_active Abandoned
- 1992-05-01 JP JP4112582A patent/JPH05305130A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| US5120322A (en) | 1992-06-09 |
| EP0564722A1 (en) | 1993-10-13 |
| JPH05305130A (en) | 1993-11-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |