U.S. patent application number 09/983982 was filed with the patent office on 2002-07-04 for bioresorbable nerve guide rail.
Invention is credited to Hierlemann, Helmut, Mueller, Erhard, Planck, Heinrich, SchloBhauer, Burkhard.
Application Number | 20020086047 09/983982 |
Document ID | / |
Family ID | 7661460 |
Filed Date | 2002-07-04 |
United States Patent
Application |
20020086047 |
Kind Code |
A1 |
Mueller, Erhard ; et
al. |
July 4, 2002 |
Bioresorbable nerve guide rail
Abstract
A biologically resorbable nerve guide rail with a microporous
guide tube of polymers of hydroxycarboxylic acids, where the
porosity allows a metabolism through the tube wall, but prevents
the passage of cells, and optionally several monofilaments of
polymers of hydroxycarboxylic acids located in the guide tube, is
characterized in that the inner surface of the tube and/or the
surface of the monofilaments have an orientation aid for
longitudinally oriented colonization with Schwann's cells.
Inventors: |
Mueller, Erhard; (Stuttgart,
DE) ; Hierlemann, Helmut; (Goeppingen, DE) ;
Planck, Heinrich; (Nuertingen, DE) ; SchloBhauer,
Burkhard; (Tuebingen, DE) |
Correspondence
Address: |
NATH & ASSOCIATES PLLC
6th Floor
1030th 15th Street, NW
Washington
DC
20005
US
|
Family ID: |
7661460 |
Appl. No.: |
09/983982 |
Filed: |
October 26, 2001 |
Current U.S.
Class: |
424/426 ;
424/93.7 |
Current CPC
Class: |
A61B 17/1128 20130101;
A61L 31/06 20130101; A61L 31/06 20130101; C08L 67/04 20130101; A61L
2430/32 20130101; A61L 31/146 20130101 |
Class at
Publication: |
424/426 ;
424/93.7 |
International
Class: |
A61K 045/00; A61F
002/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 28, 2000 |
DE |
100 53 611.5 |
Claims
1. Biologically resorbable nerve guide rail with a microporous
guide tube of polymers of hydroxycarboxylic acids, the porosity
permitting a metabolism through the tube wall, but prevents the
passage of cells, and optionally several monofilaments of polymers
of hydroxycarboxylic acids located in the guide tube, wherein the
inner surface of the tube and/or the surface of the monofilaments
have an orientation aid for the longitudinally oriented
colonization with Schwann's cells.
2. Guide rail according to claim 1, wherein the orientation aid is
constituted by a longitudinal profiling, which is preferably formed
by longitudinal ribs and intermediate longitudinal grooves.
3. Guide rail according to claim 1, wherein at least parts of the
inner surface of the guide tube and/or the surface of the
monofilaments have a growth aid for the Schwann's cells.
4. Guide rail according to claim 1, wherein at least the parts of
the surface of the guide tube to be colonized with Schwann's cells
and/or the surface of the monofilaments are hydrophilized,
particularly by a plasma treatment in the presence of oxygen.
5. Guide rail according to claim 1, wherein at least the parts of
the inner surface of the guide tube to be colonized with Schwann's
cells and/or the surface of the monofilaments are at least partly
colonized with Schwann's cells or their precursor cells.
6. Biologically resorbable nerve guide rail according to claim 1,
wherein the resorbability of the guide rail decreases over its
length and at a proximal end the guide rail is more rapidly
resorbable than at a distal end.
7. Guide rail according to claim 1, wherein the monofilaments have
a solid structure.
8. Guide rail according to claim 1, wherein the monofilaments only
fill part of the internal cross-section of the guide tube and the
remaining part is preferably filled with a stimulating aqueous
nutrient gel for the Schwann's cells.
9. Guide rail according to claim 1, wherein approximately a third
to a half of the internal cross-section of the guide tube is filled
with monofilaments.
10. Guide rail according to claim 1, wherein active ingredients
and/or growth factors are incorporated into the guide rail,
particularly in the resorbable material of the guide tube and/or
monofilaments and are released at the latest during biodegradation
of the resorbable material.
11. Guide rail according to claim 1, wherein acid-absorbing buffer
substances are incorporated into the guide rail, particularly into
the interior of the guide tube.
12. Guide rail according to claim 1, wherein inhibitors for stop
signals of the surrounding tissue are incorporated in the ends of
the guide rail provided for linking with the surrounding
tissue.
13. Monofilaments of biologically resorbable material for nerve
guide rails with an orientation aid, particularly a longitudinal
profiling, for the longitudinally oriented growth of Schwann's
cells.
14. Monofilaments of biologically resorbable material for nerve
guide rails, the resorption duration increasing over the length of
the monofilaments.
15. Monofilaments according to claim 13, wherein at least part of
their surface is colonized with Schwann's cells.
16. Monofilaments according to claim 14, wherein at least part of
their surface is colonized with Schwann's cells.
17. Biologically resorbable nerve rail guide with a microporous
guide tube of polymers of hydroxycarboxylic acids, the porosity
permitting a metabolism through the tube wall, but prevents the
passage of cells, and optionally several monofilaments of polymers
of hydroxycarboxylic acids located in the guide tube, wherein the
resorbability of the guide rail decreases over its length and at a
proximal end the guide rail is more rapidly resorbable than at a
distal end.
18. Guide rail according to claim 17, wherein the monofilaments
have a solid construction.
19. Guide rail according to claim 17, wherein the monofilaments
only fill part of the internal cross-section of the guide tube and
the remaining part is preferably filled with a stimulating aqueous
nutrient gel for the Schwann's cells.
20. Guide rail according to claim 17, wherein approximately a third
to a half of the internal cross-section of the guide tube is filled
with monofilaments.
21. Guide rail according to claim 17, wherein active substances
and/or growth factors are incorporated into the guide rail,
particularly into the resorbable material of the guide tube and/or
monofilaments and are released at the latest during biodegradation
of the resorbable material.
22. Guide rail according to claim 17, wherein acid-absorbing buffer
substances are incorporated into the guide rail, particularly into
the interior of the guide tube.
23. Guide rail according to claim 17, wherein inhibitors for stop
signals of the surrounding tissue are incorporated into ends of the
guide rail provided for linking with the surrounding tissue.
Description
[0001] The invention relates to a bioresorbable nerve guide rail
having a microporous guide tube of polymers of hydroxycarboxylic
acids, in which the porosity allows a metabolism through the tube
wall, but prevents the passage of cells, and several filaments of
polymers of hydroxycarboxylic acids located in the guide tube.
[0002] In the case of damage to nerve tracts in the central or
peripheral nervous system, e.g. as a result of injury, the nerve
cells are admittedly able to allow the growth of new axons, but
generally they only find the other nerve end by chance or not at
all. Thus, for bridging the defect in the nerve tract use is made
of so-called nerve guide rails, which provide the axon with a
directional orientation aid for growth.
[0003] It is already known to form such nerve guide rails from
biodegradable material, particularly polymers of hydroxycarboxylic
acids. Thus, when the nerve tract has regenerated, the nerve guide
rail automatically dissolves, obviating the need for a second
operation, which would otherwise be required to remove the nerve
guide rail.
[0004] Normally a nerve has several parallel tracts, it has already
been proposed to place monofilaments in the form of hollow
microfibres in a biodegradable guide tube. However, hitherto the
results have not been satisfactory.
[0005] Therefore the problem of the invention is to provide a nerve
guide rail, which accelerates a directional growth of operable
nerve cells.
[0006] This problem is solved in that the inner surface of the
guide tube and/or the surface of the monofilaments has an
orientation aid for longitudinally oriented colonization with
Schwann's or sheath cells.
[0007] Schwann's cells or their precursor cells aid the growth of
axons through nerve guide rails and subsequently form an envelope
or sheath around the axons which have grown. Schwann's cells have
already been added to nerve guide rails to aid the growth of axons.
The invention is based on the principle of allowing the Schwann's
cells in longitudinal orientation to grow in joined manner along
the guide tube and/or along the monofilaments, which brings about a
forced longitudinal orientation of the axons, so that a faster
joining of the nerve ends is brought about by a linear axon
growth.
[0008] Due to the fact that the orientation aid is provided on the
inside of the guide tube or on the outer surface of the
monofilaments, during their growth the Schwann's cells and
subsequently also the axons are linked with the interior of the
guide tube, which can be supplied with the substances necessary for
metabolism through the porosity of said guide tube.
[0009] The pore size of the porous wall or membrane of the guide
tube is in the range 0.1 to 50 .mu.m, preferably 0.5 to 3 .mu.m.
With such pore sizes nutrient media and the oxygen contained
therein can pass through the guide tube wall. However, this also
prevents the prejudicial growing in of connective tissue cells
present outside the nerve guide rail.
[0010] The internal diameter of the tube is preferably in the range
0.5 to 10 mm, particularly 1 to 5 mm. This roughly corresponds to
the thickness of naturally occurring nerves.
[0011] The production of the guide tube with the porous wall can
take place in accordance with known membrane procedures. One
possibility is the phase inversion or reversal method. For this
purpose a solution of the biodegradable polymer can be extruded in
tubular form in a bath, which is miscible with the solvent for the
polymer, but which is not itself a solvent for the polymer. Another
suitable membrane method is lyophilization. For this purpose a rod
of suitable diameter and shape can be coated with a solution of the
polymer and the latter can then be transformed into solid form by
lyophilization and the pores form during drying.
[0012] The polymers can be homopolymers, copolymers and terpolymers
of hydroxycarboxylic acids, carbonates or lactones, preference
being given to copolymers and terpolymers. Suitable monomers are
glycolide, lactide, particularly in the L or DL form, trimethyl
carbonate (TMC), dioxanone, hydroxybutyric acid and
epsilon-caprolactone. Examples of suitable polymer materials are
polyglycolide, polylactide, polycaprolactone, polytrimethylene
carbonate, polydioxanone, polyhydroxybutyric acid, as well as
copolymers, terpolymers or blends of these polymers.
[0013] The resorbability duration or its half-life can be adjusted
through a suitable choice of the monomers and by correspondingly
controlled quantity ratios. This applies both to the guide tube and
to the monofilaments. As a rule the guide rail has disappeared
within six months or has been dissolved to such an extent that a
normal metabolism is possible.
[0014] Schwann's cells have the property of colonizing surfaces in
monolayer form and grow on said surfaces. Thus, advantageously
according to the invention the surface on which the Schwann's cells
accumulate or are attached, is longitudinally subdivided into
narrow guide surfaces along which the Schwann's cells can be
accumulated longitudinally in lancet-like manner. For this purpose
the inner surface of the guide tube and/or the surface of the
monofilaments are advantageously provided with longitudinal ribs
and intermediate longitudinal grooves, so that both the
longitudinal ribs and the longitudinal grooves can serve as narrow,
axial guide surfaces for the Schwann's cells. The width of the ribs
and/or grooves is preferably of the same order of magnitude as the
width of a lancet-shaped Schwann's cell, so that there is a
longitudinally directed joining together of the Schwann's cells in
the form of a chain. The transitions between the longitudinal ribs
and the intermediate valleys or longitudinal grooves are preferably
given an angular construction as edges. Following the implantation
of the guide rail, the axons can subsequently grow in a straight
line along the chains of Schwann's cells. The width of the
longitudinal ribs and preferably also the grooves is preferably
between 5 and 30 .mu.m. The depth of the grooves preferably does
not exceed 10 .mu.m and is in particular between 5 and 10
.mu.m.
[0015] The inner surface of the guide tube and/or the surface of
the monofilaments can advantageously be provided with a growing aid
for a faster colonization of Schwann's cells. For this purpose are
particularly suitable coatings with peptides or polypeptides,
particular preference being given to polylysine. The polyamines or
polypeptides to be used for coating with biologically active
molecules can e.g. be derived from extracellular matrix proteins or
enzymes. It is merely necessary to introduce a few Schwann's cells
or precursor cells of said Schwann's cells into the nerve guide
rail. They then propagate in the desired manner along the guide
rail. It is also advantageous to hydrophilize the inner surface of
the guide tube and/or the surface of the monofilaments. This can
appropriately take place by a plasma treatment in the presence of
oxygen, which leads to a better adhesion of the growing aid,
particularly the peptides.
[0016] It is also possible and preferred if on the outside of the
nerve guide rails are provided corresponding growing aids for
connective tissue cells, particularly fibroblasts, in order to aid
the growth of connective tissue around the nerve guide rail and in
which following the resorption of the guide rail the nerve is
embedded.
[0017] In a particularly preferred embodiment of the invention,
which can also be provided independently of the orientation aid for
the Schwann's cells, the nerve guide rail is constructed in such a
way that the resorbability of the guide rail decreases over its
length. Tests have shown that it is advantageous if at points where
it has already grown again and where there has already been an
enveloping of the axon with the Schwann's cells, the nerve is
exposed as early as possible so as to permit a normal metabolism
with the environment. At this time there is no longer any risk of a
misorientation of the axon and external cells can also no longer
inhibit growth. As axon growth takes place from the proximal nerve
end, according to the invention the nerve guide rail is more
rapidly resorbable at the proximal end than at the distal end. As
hydrolytic degradation of the polymers of hydroxycarboxylic acids
commences shortly after the implementation of the nerve guide rail,
the different resorption duration of the nerve guide rail over its
length is advantageously obtained by different polymers. This can
be obtained through a different composition, i.e. via the use of
different monomers or monomer ratios, as well as through different
molecular weights.
[0018] The resorption time can increase continuously or
discontinuously from the proximal to the distal end. A continuous
increase can in particular be brought about in that the pre-formed
guide tube and/or monofilaments are treated in different intensity
with gamma rays as a function of their length. This can be achieved
by different residence times. In a preferred production procedure
the pre-formed parts of the guide rail can be placed in lead
chambers, whose wall thickness increases from one end to the other,
so that the radiation intensity decreases corresponding to the
increase in the wall thickness.
[0019] Preference is given to a degradation time of 0.5 to 6 months
along the length. The guide rail length is dependent on the size of
the distance to be bridged and is normally between 1 and 10 cm.
[0020] However, it is also possible to obtain a different
degradation duration over the guide rail length by the use of
different polymers. It is known that lactide-containing polymers
have a longer degradation period than glycolide-containing
polymers. The degradation durations can be controlled by
corresponding copolymer or terpolymer percentages. For example the
degradation time of epsilon-caprolactone-lactide polymer (50:50) is
approximately one month and in the case of a corresponding
copolymer with a monomer ratio of 90:10 three months. The
degradation time is less than one month for an
epsilon-caprolactone-trimethyl carbonate-glycolide polymer.
[0021] The thickness of the wall or membrane of the guide tube is
advantageously 50 to 400 .mu.m. Preferably the wall thickness is
kept substantially constant considered over the length, so as not
to impair metabolic processes through the porous wall as a result
of excessive thicknesses thereof. Nevertheless, it is
advantageously possible to control the different degradation
duration by a different layer structure. Thus, the guide tube can
be formed from several length-stepped layers, the lower, longest
layer being formed from readily resorbable material and the
following layers, which are correspondingly stepped shorter, have
an increased degradation time. The bottom, rapidly resorbable layer
on the multiply coated points is then protected by less resorbable
covering layers, so that in this way there is a time-controlled,
length-increasing resorption duration. Combinations of different
compositions and irradiation are also possible.
[0022] The monofilaments can be constructed as hollow fibres, but
they are preferably constructed as solid, compact fibres. This
gives them the necessary stability and also facilitates the
construction of the longitudinally structured surface as an
orientation aid for the Schwann's cells.
[0023] The production of the monofilaments takes place with
particular advantage by extrusion through correspondingly shaped
dies with a roughly meander-shaped circumferential line. The
setting of the increasing resorption duration from the proximal to
the distal end advantageously takes place through the
aforementioned irradiation. The monofilaments have a preferred
diameter of 30 to 200 .mu.m, particularly 100 to 150 .mu.m.
[0024] The guide tube can contain many monofilaments, generally 10
to 1000, as a function of the guide tube size. However, the
internal cross-section of the tube is not completely filled with
monofilaments, because the cells on the one hand require space for
growth and there is also a need for space for the nutrient medium
within the tube. Normally the internal cross-section of the guide
tube is roughly filled half to a third with monofilaments. With
particular advantage both the inner surface of the guide tube and
the surfaces of the monofilaments are intended for colonization by
Schwann's cells and are provided with the corresponding orientation
aids for the same.
[0025] In the guide rail, particularly in its resorbable material,
can be incorporated active ingredients and/or growth factors, which
at the latest are released during the biodegradation of the
resorbable material. Thus, within the guide rail are advantageously
incorporated acid-binding buffer substances. During the hydrolysis
of the hydroxycarboxylic acid polymers fragments or monomers having
carboxyl groups are formed. The thus possible undesired reduction
of the pH-value can be absorbed by the buffers, which are
preferably present in the resorbable polymers.
[0026] It is also possible to incorporate antibiotics, which in
particular as a result of retarded release, prevent infections
after implanting the guide rail.
[0027] Guide rails, which are provided for linking with the
surrounding tissue, are advantageously provided at the ends, which
are to be connected to the surrounding tissue, with inhibitors for
stop signals of the surrounding tissue. These stop signals normally
prevent the growth of axons and the joining of the exposed nerve
ends of the spinal cord. These stop signals can have their stopping
function inhibited by inhibitors such as antibodies or enzyme
inhibitors.
[0028] The internal area of the guide tubes not taken up by the
monofilaments and the initial colonization with Schwann's cells is
preferably filled with a nutrient gel for Schwann's cells. It is
preferably in the form of an aqueous gel, in which can be
incorporated with particular advantage growth factors for the
Schwann's cells.
[0029] The nerve guide rails according to the invention preferably
have a flexible construction, which is possible through a
corresponding choice of the polymers, even without adding
plasticizers. If desired, the nerve guide rails can also have
branches. Tubular branches can e.g. be produced in that for shaping
collapsible Y-shaped rods are coated, as is known in connection
with vascular prostheses.
[0030] The production of the guide rails prepared for implantation
preferably takes place in that the guide tube and monofilaments are
separately prepared and the monofilaments are slid into the guide
tube. Prior to sliding in, the monofilaments are preferably at
least partly colonized with Schwann's cells or precursor cells.
[0031] Therefore the invention also relates to the monofilaments as
such, finished with the orientation aid, particularly the
longitudinal profiling, and optionally the growth aid for the
Schwann's cells, in particular with the at least partial
colonization with said cells or their precursors.
[0032] Further features of the invention can be gathered from the
following description of a preferred embodiment of the invention in
conjunction with the claims and the attached drawings, wherein
show:
[0033] FIG. 1A perspective view of a longitudinal portion of a
nerve guide rail according to the invention.
[0034] FIG. 2A partial cross-section through the porous membrane
wall of the guide rail according to FIG. 1.
[0035] FIG. 3A perspective partial view of a monofilament for the
guide rail of FIG. 1.
[0036] FIG. 4 In symbolized form a gel matrix filling the interior
of the guide tube.
[0037] In the embodiment shown in the drawings a guide rail 1 has a
guide tube 2, in whose interior are longitudinally arranged
approximately 10 to 50 monofilaments 3 (in the drawing only three
are shown on a larger scale). The monofilaments 3 are embedded in a
gel 4 (FIG. 4), which keeps them spaced.
[0038] The guide tube 2 is made from bioresorbable polymers of
hydroxycarboxylic acids and has a structure in the form of several
layers 5 to 11 of different length. They also differ in their
composition, which is matched in such a way that the innermost
layer 5 at the proximal end can be degraded fastest, namely within
0.5 months, whereas the outermost, shortest layer 11 is only
degraded within 6 months. The degradation time of layers 6 to 10,
which are shortened in stepped manner, is correspondingly in
stepped rising form between the same.
[0039] This layer structure can in particular be achieved by a
stepped immersion of a correspondingly pre-formed rod, particularly
of PTFE (polytetrafluoroethylene) in polymer solutions of the
different polymers, the rod for layer 5 being immersed deepest and
for layers 6 to 11 increasingly less deep.
[0040] A porosity of the tube wall 12 constructed as a
semipermeable membrane is obtained by lyophilization of the polymer
solutions after immersion. The partial cross-section of FIG. 3
shows pores 13, which allow an exchange of nutrient medium and
oxygen, but prevent the growing in of cells such as fibroblasts
14.
[0041] The monofilaments 3 are compact, i.e. having a solid
construction and have a longitudinal profile of longitudinal ribs
15 and intermediate longitudinal grooves 16, which in each case
roughly have the same width and which are present over the entire
outer circumference of the monofilaments. The monofilaments are
made from a polymer of hydroxycarboxylic acids having a resorption
time in vivo of approximately six months. They are produced by
extrusion from a correspondingly shaped die.
[0042] Through a stepped treatment with gamma rays, the resorption
time is set in a substantially continuously decreasing form and at
the proximal end like the layer 5 of guide tube 2 is only 0.5
month.
[0043] The surface of the monofilaments is coated with not shown
polylysine, which aids the colonization with and growth of
Schwann's cells 17 or their precursor cells. These cells are
successively accumulated in lancet-shaped longitudinal orientation
on the longitudinal ribs 15 and/or in the longitudinal groove 16
and in this way, after implantation, aid the regenerating growing
in of an axon 18 of a nerve cell from the proximal nerve end along
the chain of Schwann's cells shown in FIG. 3. The adhesion of the
polylysine layer can be aided by prior plasma treatment of the
monofilaments in the presence of oxygen, so that a hydrophilizing
of the polymer surface takes place.
[0044] In the same way the inner surface 19 of the guide tube 2 is
provided with longitudinal ribs and longitudinal grooves and coated
with polylysine. There again, in the same way the Schwann's cells
or their precursor cells are oriented. Thus, the nerve growth
necessarily takes place along the guide rails in a plurality, but
independent tracts.
[0045] The formation of the longitudinal ribs and longitudinal
grooves on the inner surface 19 of the guide tube 2 can be brought
about in that a corresponding rod, on which the guide tube is
shaped, has a correspondingly structured surface.
[0046] In the gel 4 in the interior of the guide tube are
incorporated growth factors aiding the proliferation of the
Schwann's cells and optionally nutrients for said cells. In turn,
the Schwann's cells give off factors, which activate axon growth
and cause said axons to grow along the longitudinally oriented
Schwann's cells. As axon growth starts from the proximal nerve end
and there healing is terminated fastest, the support structure of
the nerve guide rail, considered timewise, is initially no longer
required at this end. Thus, this point can be degraded,
particularly by hydrolytic degradation, after the Schwann's cells
have been placed in the form of a jacket around the subsequently
grown axons. With advancing axon growth the nerve guide rail loses
its function and can be progressively and finally completely
eliminated, which is achieved by the progressive resorption
duration.
[0047] On the outer surface of the guide rail 1 is formed an
envelope of fibroblasts 14, which take over the protective function
of the guide tube. The growth of such cells can, in much the same
way as for the monofilaments, be aided by hydrophilizing plasma
treatment in the presence of oxygen and/or by peptide coating.
[0048] Prior to the sliding in of the monofilaments 3, the guide
tube 2 can be filled with gel 4, e.g. a fibrin or collagen gel, the
excess gel being displaced by the sliding in of the monofilaments.
However, it is also possible to press in the gel together with the
monofilaments or following the introduction of the latter.
Preferably a colonization with Schwann's cells takes place prior to
the introduction of the monofilaments into the guide tube. Further
growth then takes place after joining together.
[0049] The Schwann's cells or their precursors are preferably taken
from the patient beforehand. Since following nerve injury it is
frequently necessary to wait for several weeks up to the resorption
of the destroyed tissue, the time up to implantation is sufficient
to culture the necessary quantity of Schwann's cells or their
precursor cells.
* * * * *