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WO1990005490A1 - Canaux de guidage a charge electrique pour nerfs - Google Patents

Canaux de guidage a charge electrique pour nerfs Download PDF

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Publication number
WO1990005490A1
WO1990005490A1 PCT/US1989/004894 US8904894W WO9005490A1 WO 1990005490 A1 WO1990005490 A1 WO 1990005490A1 US 8904894 W US8904894 W US 8904894W WO 9005490 A1 WO9005490 A1 WO 9005490A1
Authority
WO
WIPO (PCT)
Prior art keywords
nerve
membrane
tubular
permanent
quasi
Prior art date
Application number
PCT/US1989/004894
Other languages
English (en)
Inventor
Patrick Aebischer
Paolo Dario
Angelo Sabatini
Robert F. Valentini
Original Assignee
Brown University Research Foundation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Brown University Research Foundation filed Critical Brown University Research Foundation
Publication of WO1990005490A1 publication Critical patent/WO1990005490A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/11—Surgical instruments, devices or methods for performing anastomosis; Buttons for anastomosis
    • A61B17/1128—Surgical instruments, devices or methods for performing anastomosis; Buttons for anastomosis of nerves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/00491—Surgical glue applicators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30108—Shapes
    • A61F2002/30199—Three-dimensional shapes
    • A61F2002/30224—Three-dimensional shapes cylindrical
    • A61F2002/30235—Three-dimensional shapes cylindrical tubular, e.g. sleeves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0063—Three-dimensional shapes
    • A61F2230/0069—Three-dimensional shapes cylindrical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/32—Materials or treatment for tissue regeneration for nerve reconstruction

Definitions

  • the technical field of this invention concerns medical devices useful for the repair of severed nerves and methods for fabricating and using such devices for nerve repair.
  • a nerve When a nerve is severed, the functions supplied by that nerve, both motor and sensory, are lost.
  • the axons in the proximal stump that remain connected to the spinal cord or dorsal root ganglion also suffer some degeneration. However, degeneration generally does not proceed to the death of all of the nerve cell bodies. Moreover, if the injury occurs far enough from the nerve cell bodies, regeneration will occur. Axonal sprouts will appear from the tip of the regenerating axon.
  • the chief hazard to the successful repair is the trauma produced by the manipulation of the nerve ends and the subsequent suturing to maintain alignment.
  • the trauma appears to stimulate the growth and/or migration of fibroblasts and other scar-forming, connective tissue cells.
  • the scar tissue prevents the regenerating axons in the proximal stump from reaching the distal stump to reestablish a nerve charge pathway. The result is a permanent loss of sensory or motor function.
  • the total number of axons, the number of myelinated axons, the thickness of the epineurial, and the fascicular organization of nerves regenerated within guidance channels are all typically less than satisfactory and compare poorly with the original nerve structure of- the test animals. Moreover, the loss of sensory or motor function is still the most common outcome of such laboratory experiments.
  • nerve guidance channels can be formed from materials that are capable of generating electrical charges on their surfaces. These electrical charges apparently augment the ability of axons to bridge the gap between the proximal and distal nerve stumps.
  • parent Application Serial Number 025,529 discloses the use of polyvinylidene difluoride (PVDF) which is subjected to a strong, electric field to create strong, permanent dipole moments throughout the material.
  • PVDF polyvinylidene difluoride
  • the present application discloses improved, electrically-charged, medical prosthesis for use as guidance channels in the repair of severed or otherwise damaged nerves. Additional electret materials are disclosed which can be poled in accordance with the teachings of U.S. Serial Number 025,529, or by alternative techniques, to obtain nerve guidance channels displaying quasi-permanent, surface charges.
  • the devices include a tubular structure composed of a polymeric, electret material adapted to receive the ends of a severed nerve and defining a lumen through which axons can be regenerated.
  • the electret materials generate static electrical charges which greatly augment the ability of the severed nerve ends to bridge the gap therebetwee .
  • nerve is used herein to mean both monofascicular and polyfascicular nerves. The same general principals of regeneration within the nerve guidance channels of the present invention are applicable to both.
  • electrode is intended to broadly encompass natural materials and synthetic materials displaying surface electrical charge storage capabilities.
  • the guidance channels of the present invention may be negative or positively poled (or a combination thereof) and may have electrical charges on the inner or outer surface of the tubular membrane (or both) .
  • a preferred electret material is polytetrafluoroethylene (PTFE) .
  • the invention further encompasses methods of repairing a severed nerve. In these methods, the cut ends of the nerve are placed into the openings of the nerve guidance channel and secured therein.
  • Methods of fabricating the device useful in regenerating a severed nerve include producing the tubular, polymeric, electret material, and then poling it to establish the accumulation of negative or positive charges on the inner or outer surface of the channel.
  • the nerve guidance channels described in the examples below are generally tubular in shape, it should be clear that various alternative shapes can be employed.
  • the lumens of the guidance channels can be oval or even square in cross-section.
  • the guidance channels can also be constructed from two or more parts which are clamped together to secure the nerve stumps.
  • polymeric, electret sheet materials can be employed and formed into channels in situ. In such a procedure, the nerve stumps can be placed on top of the sheet and then secured thereto by sutures, adhesives, or friction. The sheet can then be wrapped around the nerve segments, and the resulting channel closed by further sutures, adhesives, or friction.
  • FIG. 1 is a schematic representation of a nerve guidance channel of the present invention.
  • FIG. 2 is a series of electron micrographs of toluidine blue-stained transverse- sections of nerves regenerated at the midpoint of unpoled (A) , negatively poled (C) , and positively poled (E) PTFE channels four weeks postimplantation.
  • (B) , (D) , and (F) are higher power micrographs of the nerves shown at lower power in (A) , (C) , and (E) , respectively.
  • the nerve guidance channels of the present invention are composed of a tubular membrane 10 having openings 12 and 14 adapted to receive severed nerve ends 16 and 18 into lumen 20.
  • the thickness of the membrane wall ranges from about 0.05 to about 1.0 millimeters (mm) .
  • Lumen 8 typically has a diameter which can vary from about 0.5 mm to about 3 centimeters (cm), depending upon the size of nerve to be repaired.
  • the membrane is composed of one of a class of electret materials which can be endowed with a transient or static electrical charge due to their physico/chemical properties.
  • Electrets are attractive for in vivo applications since they can be fabricated from biocompatible polymers and can produce electrical charges without an external power source.
  • the electret materials of the present invention are preferably poled. Poling can be performed during manufacture or prior to use and may result in negative or positive charge accumulation on the inner or outer surface of the tubular membrane.
  • One class of electrets are piezoelectric materials which depend primarily on dynamic mechanical deformation in order to produce transient charge generation on their surface. Charge generation is due to the presence of stable molecular dipoles found throughout the bulk of the polymer.
  • PVDF piezoelectric polyvinylidene fluoride
  • a non-piezoelectric electret material exhibits a charge storage mechanism consisting primarily of monopolar charges entrapped throughout the polymer. The distribution and stability of this static surface charge are related to the method of fabrication (including poling).
  • Electret materials useful in the present invention include polytetrafluoroethylene (PTFE) , polyvinylchloride, polyethylene, polyamides, polymethyl methacrylate, polypropylene, polyethylene terapthalate, or mixtures thereof.
  • PTFE polytetrafluoroethylene
  • nerve guidance channels include positively poled electret material, having a preferable average charge density ranging from about 1 to 100 nanoColoumbs per square 5 centimeter (nC/cm 2 ) and, more preferably, about 21 (nC/cm 2 ) .
  • nerve guidance channels consist of negatively poled electret material, having a preferable average charge density of from about 5 to 10 30 nC/cm 2 , with 9 nC/cm 2 being a preferred value.
  • the lumen of the device may be "seeded" or prefilled with a substance that protects, soothes, nutures, and/or enhances nerve growth
  • the membrane is designed to be impermeable to such substances so that they remain within the walls or lumen of the device and, hence, in close contact with the regenerating nerve ends.
  • Useful substances may include, for example, a saline 0 solution or a matrix material, such as laminin, collagen, fibrin, glycosaminoglycan, biologically active factors, such as nerve growth factors and enhancers, or mixtures thereof.
  • the lumen may be seeded with glial cells, such as Schwann 5 cells which are known to stimulate and protect neuronal appendages.
  • useful substances include active factors or any diffusible substances with bioactivity that stimulates nerve growth.
  • Useful active factors include, for example, second messenger substances, such as cAMP, or membrane-permeable permanent cAMP analogs, such as 8-bromo cAMP or chlorophenylthio cAMP.
  • a "second messenger" substance is one that initiates a cellular response to a specific signal external to that cell. Second messenger inducers such as forskolin are also useful.
  • growth factors such as nerve growth factor, brain-derived growth factor, fibroblast growth factor, and mixtures thereof, are also useful active factors.
  • the invention further encompasses methods of repairing a severed nerve.
  • the nerve guidance channels of the present invention as described above, are used by locating the severed nerve ends and selecting and providing an appropriately-sized, tubular device for the repair.
  • the cut ends of the nerve are then gently drawn into channel by manual manipulation or suction, placed in optimal proximity and then secured in position without undue trauma by sutures through the channel, or by a biocompatible adhesive (e.g., fibrin glue) or by frictional engagement with the channel.
  • the channel is then situated in the general in vivo location of the nerve.
  • Antibiotics can be administered to the site, and the wound is then closed.
  • the nerve repair method of the present invention may further include splitting of the channel along a line of weakness and removing it from the nerve ends after they have regenerated and joined.
  • implanted nerve guidance channels of the present invention have been found to contain regenerated nerve cables.
  • channels composed of poled electret material were observed to enhance the regeneration of more morphologically normal myelinated nerves when compared with channels composed of unpoled materials.
  • PTFE tubes were submitted to a corona poling procedure in order to inject electrical carriers into them.
  • a brass wire fitted into the lumen of the tube was used as a reference electrode.
  • the outer electrode array was connected to the positive output of the power supply with the inner electrode grounded during positive corona discharge, polarities were reversed for negative corona discharge.
  • the corona poling was performed at a relatively high temperature (150°C) in order to obtain electrets with high charge storage capabilities. At high temperatures, it is possible 5 for the charge carriers to achieve greater depths of penetration into the polymer bulk, although penetration depth rarely exceeds a few microns.
  • the applied voltage was gradually increased to a level of 14 KV and maintained at that voltage for 20 min. at 10 150°C.
  • the net surface charge density on the outer surface of each electret tube was measured using an induction-based method.
  • a capacitative probe was
  • the probe When exposed to the electric field produced by the electret, the probe acquires a charge derived from the capacitance at the input of
  • the meter voltage is thus directly related to the quantity of charge trapped in the electret.
  • the average charge density measured for positively poled tubes was 21 nanoCoulombs per square centimeter (nC/cm 2 ) ; and for negatively poled tubes,
  • the nerve guidance channels were then surgically implanted.
  • the left sciatic nerve of methoxyflurane-anesthetized female CD-I mice (Charles River, Wilmington, MA) was exposed through an incision along the anterior-medial aspect of the upper thigh.
  • a 4 mm segment of nerve proximal to the tibio-peroneal bifurcation was resected and discarded.
  • a 4 mm nerve gap was created by anchoring the proximal and distal nerve stumps 4 mm apart within 6 mm long positively or negatively poled or unpoled PTFE tubes using single 10-0- nylon sutures.
  • the PTFE tubes were prefilled with physiologic saline in order to prevent trapping of air bubbles within their lumens. Cohorts of 5 animals were implanted with PTFE electret tubes and control PTFE tubes (not submitted to electrical poling) .
  • the guidance channels were recovered after 4 weeks of implantation.
  • the mice were deeply anesthetized with Nembutal and then perfused transcardially with 5 ml of heparanized phosphate-buffered saline (PBS), followed by 10 ml of a fixative containing 3.0% paraformaldehyde, 2.5% glutaraldehyde, pH 7.4.
  • PBS heparanized phosphate-buffered saline
  • the operative site was reopened, and the guidance channel and native sciatic nerve removed.
  • the recovered specimens were postfixed in a 1.0% osmium tetroxide solution, dehydrated, and embedded in Spurr resin. Transverse sections taken at the midpoint of the guidance channel were cut on a Sorvall MT-5000 microtome (E.I. Dupont DeNeneus & Co. Wilmington, Delaware) . Semi-thin and ultra-thin sections were stained and prepared for light and electron microscopy.
  • FIG. 2 shows toluidine blue-stained transverse sections of nerve regenerated at the midpoint of unpoled (A, B), negatively poled (C, D) , and positively poled (E, F) PTFE tubes 4 weeks post-implantation.
  • A, B unpoled
  • C, D negatively poled
  • E, F positively poled
  • PTFE tubes 4 weeks post-implantation.
  • Several mast cells are seen within the regenerated cable.
  • the cross-sectional area of the regenerated cable, the total blood vessel area, and the number of myelinated axons and blood vessels were measured with a Zeiss IM 35 microscope interfaced with a computerized morphometric system (CUE-2, Olympus, Lake Success, NY). The Mann-Whitney rank sum test was used to assess statistical difference between the various populations.
  • the cross-sectional area of nerves regenerated in positive poled PTFE channels was significantly greater than nerves regenerated in negatively poled and unpoled PTFE channels, as shown above in Table 1 and in FIG. 2. Cables regenerated in negatively poled channels were larger than those regenerated in unpoled channels, although the difference was not statistically significant.
  • the ratio of blood vessel area to total cable area was greater in both poled channels as compared to unpoled channels (Table 1) .
  • the number of myelinated axons regenerated in positively and negatively poled channels was significantly greater than the number seen in unpoled channels but were similar to one another.
  • the geometry of the myelinated axons regenerated in both types of poled channels appeared to be more similar to those seen in normal nerves than those in unpoled channels.

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  • Health & Medical Sciences (AREA)
  • Surgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)
  • Surgical Instruments (AREA)

Abstract

Dispositif médical pour la régénération d'un nerf sectionné, comprenant une membrane ou un canal de guidage (10) tubulaire biocompatible à charge électrique, muni d'ouvertures (12, 14) pour recevoir les extrémités dudit nerf sectionné et délimitant une lumière (20) au travers de laquelle le nerf peut se régénérer. Ladite membrane à charge électrique peut, de plus, comprendre un matériau électrète polymère à polarisation électrique. On décrit également un procédé permettant de réparer un nerf sectionné, qui consiste à rapprocher les extrémités dudit nerf (16, 18) au sein de la lumière définie par le canal de guidage de la présente invention et à les fixer dans ledit dispositif.
PCT/US1989/004894 1988-11-17 1989-10-31 Canaux de guidage a charge electrique pour nerfs WO1990005490A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27255588A 1988-11-17 1988-11-17
US272,555 1988-11-17

Publications (1)

Publication Number Publication Date
WO1990005490A1 true WO1990005490A1 (fr) 1990-05-31

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PCT/US1989/004894 WO1990005490A1 (fr) 1988-11-17 1989-10-31 Canaux de guidage a charge electrique pour nerfs

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EP (1) EP0408687A1 (fr)
JP (1) JPH03502296A (fr)
AU (1) AU4510189A (fr)
WO (1) WO1990005490A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019796A1 (fr) * 1994-01-21 1995-07-27 Brown University Research Foundation Implants biocompatibles
WO1999011181A3 (fr) * 1997-09-02 1999-05-06 Childrens Medical Center Conduit de guidage de nerfs a plusieurs lumieres et procede de fabrication associe
CN113576574A (zh) * 2021-07-28 2021-11-02 中国科学院深圳先进技术研究院 一种神经套管的制备方法、装置、电子设备及存储介质

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4721482B2 (ja) * 1999-05-18 2011-07-13 株式会社高研 神経再建用基材

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2442713A1 (fr) * 1978-11-30 1980-06-27 Sumitomo Electric Industries Structure poreuse de polytetrafluorethylene et procede pour sa preparation
US4662884A (en) * 1984-04-25 1987-05-05 University Of Utah Research Foundation Prostheses and methods for promoting nerve regeneration
WO1988006866A1 (fr) * 1987-03-13 1988-09-22 Brown University Research Foundation, Inc. Canaux piezoelectriques de guidage de nerfs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2442713A1 (fr) * 1978-11-30 1980-06-27 Sumitomo Electric Industries Structure poreuse de polytetrafluorethylene et procede pour sa preparation
US4662884A (en) * 1984-04-25 1987-05-05 University Of Utah Research Foundation Prostheses and methods for promoting nerve regeneration
WO1988006866A1 (fr) * 1987-03-13 1988-09-22 Brown University Research Foundation, Inc. Canaux piezoelectriques de guidage de nerfs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Society for Neuroscience Abstracts, Vol. 12, 1986, page 13, Abstract No. 7.11 (Bethesda, US) J.M. KERNS et al.: "D.C. Electrical Fields Promote Regeneration in the rat Sciatic Nerve After Axotomy" *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019796A1 (fr) * 1994-01-21 1995-07-27 Brown University Research Foundation Implants biocompatibles
WO1999011181A3 (fr) * 1997-09-02 1999-05-06 Childrens Medical Center Conduit de guidage de nerfs a plusieurs lumieres et procede de fabrication associe
US6214021B1 (en) 1997-09-02 2001-04-10 Children's Medical Center Corporation Multi-lumen polymeric guidance channel and method of manufacturing a polymeric prosthesis
CN113576574A (zh) * 2021-07-28 2021-11-02 中国科学院深圳先进技术研究院 一种神经套管的制备方法、装置、电子设备及存储介质
WO2023005105A1 (fr) * 2021-07-28 2023-02-02 中国科学院深圳先进技术研究院 Procédé et appareil de préparation de conduit nerveux, et dispositif électronique et support de stockage

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Publication number Publication date
AU4510189A (en) 1990-06-12
JPH03502296A (ja) 1991-05-30
EP0408687A1 (fr) 1991-01-23

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