U.S. patent application number 11/084948 was filed with the patent office on 2005-12-22 for surgically implanted devices having reduced scar tissue formation.
This patent application is currently assigned to Afmedica, Inc.. Invention is credited to Fischell, David R., Fischell, Robert E., Fischell, Scott J.S., Fischell, Tim A..
Application Number | 20050281860 11/084948 |
Document ID | / |
Family ID | 24835796 |
Filed Date | 2005-12-22 |
United States Patent
Application |
20050281860 |
Kind Code |
A1 |
Fischell, Robert E. ; et
al. |
December 22, 2005 |
Surgically implanted devices having reduced scar tissue
formation
Abstract
An anti-proliferative drug, such as rapamycin or taxol, is
placed onto or within a sheet of material or mesh. The strands onto
or into which the drug is placed may be either a permanent implant
or it may be biodegradable. Surgical sutures or staples may also be
coated and used for connecting human tissues (i.e., for example, an
anastomosis).
Inventors: |
Fischell, Robert E.;
(Dayton, MD) ; Fischell, David R.; (Fair Haven,
NJ) ; Fischell, Tim A.; (Kalamazoo, MI) ;
Fischell, Scott J.S.; (Glenleg, MD) |
Correspondence
Address: |
MEDLEN & CARROLL, LLP
Suite 350
101 Howard Street
San Francisco
CA
94105
US
|
Assignee: |
Afmedica, Inc.
Kalamazoo
MI
|
Family ID: |
24835796 |
Appl. No.: |
11/084948 |
Filed: |
March 21, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11084948 |
Mar 21, 2005 |
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10351207 |
Jan 24, 2003 |
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10351207 |
Jan 24, 2003 |
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09772693 |
Jan 31, 2001 |
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6534693 |
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09772693 |
Jan 31, 2001 |
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09705999 |
Nov 6, 2000 |
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Current U.S.
Class: |
424/426 ;
514/291 |
Current CPC
Class: |
A61B 17/064 20130101;
A61L 2300/604 20130101; A61F 2013/00451 20130101; A61L 2300/602
20130101; A61B 2017/00831 20130101; A61L 2300/424 20130101; A61L
15/44 20130101; A61L 2300/622 20130101; A61B 17/06166 20130101;
A61L 27/54 20130101; A61L 31/16 20130101; A61F 2/0063 20130101;
A61L 2300/416 20130101; A61L 2300/626 20130101 |
Class at
Publication: |
424/426 ;
514/291 |
International
Class: |
A61K 031/4745; A61F
002/00 |
Claims
We claim:
1. A method of prophylactically treating vasculoproliferative
disease, in a vascular structure following the construction of an
arterio-venous graft, an arterial-arterial graft or an
arterio-venous fistula, the method comprising applying locally and
external to the vascular structure, perivascularly, a therapeutic
agent-eluting sleeve, the sleeve comprising a biocompatible matrix
material imbibed with rapamycin thereby enabling delivery of an
antiproliferative effective amount of rapamnycin to the vascular
structure.
2. A method of treating established vasculoproliferative disease in
a vascular structure following the construction of an
arterio-venous graft, an arterial-arterial graft or an
arterio-venous fistula, the method comprising applying locally and
external to the vascular structure, perivascularly, a therapeutic
agent-eluting sleeve, the sleeve comprising a biocompatible matrix
material imbibed with rapamycin thereby enabling delivery of an
antiproliferative effective amount of rapamycin to the vascular
structure.
3. A method of treating or preventing vasculoproliferative disease
in vascular structures including at least one anastamotic site
wherein the vasculoproliferative disease includes tissue
encroaching on the lumen of the vascular structure following the
construction of arterio-venous grafts, arterial-arterial grafts or
aterio-venous fistulae, the method comprising applying locally and
external to the vascular structure, perivascularly, adjacent to the
site of anastamosis, a therapeutic agent-eluting sleeve, the sleeve
comprising a biocompatible matrix material imbibed with rapamycin
thereby enabling delivery of an antiproliferative effective amount
of rapamycin to the vascular structure.
4. A method according to claims 1-3 wherein the sleeve is
substantially circumvascular.
5. A method according to claims 1-3 wherein a combination of
rapamycin and heparin is administered to the vascular
structure.
6. A method according to claim 5 wherein the amounts of rapamycin
and heparin are sufficient to exhibit a synergistic effect in
treating vasculoproliferative disease.
7. A method according to claims 1-3 wherein the amount of rapamycin
is about 2 micrograms/cm.sup.2 to about 10.0 mgs/cm.sup.2 and the
amount of heparin is about 70 units/cm.sup.2 to about 20,000
units/cm.sup.2 before contacting the sleeve to the vascular
structure.
8. A method according to claims 12 wherein a combination of
rapamycin analogue(s) and heparin is administered to the vascular
structure.
9. A method according to claim 18 wherein the amounts of rapamycin
analogues and heparin are sufficient to exhibit a synergistic
effect in treating vasculoproliferative disease.
10. A method according to claim 12 wherein the biocompatabile
matrix is biodegradable.
Description
REFERENCE TO A PREVIOUS PATENT APPLICATION
[0001] This is a continuation-in-part application of the patent
application Ser. No. 09/705,999 filed on Nov. 6, 2000.
FIELD OF USE
[0002] This invention is in the field of materials used to prevent
the formation of scar tissue subsequent to a surgical procedure or
accidental skin cut of a human subject.
BACKGROUND OF THE INVENTION
[0003] Post-operative adhesions are a major problem following
abdominal and other surgical procedures. These adhesions are caused
by the unwanted proliferation of scar tissue between internal
tissues and structures of the human body generally after surgery.
Several companies have developed sheets of biodegradable mesh that
can be placed between these structures to reduce the tissue growth.
None are entirely effective as some scar tissue typically grows
through the mesh. U.S. Pat. No. 5,795,286 describes the use of a
beta emitting radioisotope to reduce the proliferation of tissue
through a biocompatible material placed into the human body.
Although radioisotopes may be effective at preventing the cell
proliferation associated with adhesions, the limited shelf life and
safety issues associated with radioisotopes makes them less than
ideal for this purpose.
[0004] Recent publications (Transcutaneous Cardiovascular
Therapeutics 2000 Abstracts) report a greatly reduced cell
proliferation within angioplasty injured arteries when vascular
stents used for recannalization are coated with an
anti-proliferative drug such as Rapamycin (Sirolmus) or Taxol.
However, these drugs have never been used for reducing cellular
proliferation of tissues separated by a surgical procedure.
SUMMARY OF THE INVENTION
[0005] A first embodiment of this invention is a device consisting
of a drug impregnated into, coated onto or placed onto a material
sheet or mesh designed to be placed between internal body tissues
that have been surgically separated to prevent the formation of
post-operative adhesions, which adhesions are really scar tissue
formation. A drug that is impregnated into a gauze-like material or
coated onto the material or joined to the material by adhesion
and/or capillary action is defined herein as a drug "attached" to a
mesh. This mesh or gauze onto which the drug is attached may be
either a permanent implant or it may be biodegradable. The drug can
be attached to an existing product such as the Johnson &
Johnson SURGICEL.TM. absorbable hemostat gauze-like sheet. With an
anti-proliferative drug such as Rapamycin or Taxol which have a
known effect on proliferating cells, the biodegradable mesh would
decrease cellular proliferation and hence be a deterrent to the
formation of adhesions. It is also envisioned that an
anti-proliferative drug attached to a bandage could be placed onto
a cut in the skin for reducing scar tissue formation. This cut
could be accidental or a result of a surgical incision. It is also
envisioned that an anti-proliferative drug could be attached to
surgical suture material that is used (for example) to join
together two blood generally cylindrical cavitys, i.e., an
anastomosis, with the attached drug causing a reduction in cellular
proliferation in the vicinity where the sutures penetrate through
the human tissue. It should be understood that the suture material
could be either soluble or insoluble and could be used for any
application for which sutures are used. Still another embodiment of
the present invention is an anti-proliferative drug coated onto a
surgical staple thus reducing scar tissue around that staple. Still
another embodiment of this invention is to attach an
anti-proliferative drug to a device such as a buckle that is used
for the treatment of a detached retina. Since scar tissue formation
is one of the main complications of a retinal attachment procedure,
by attaching an anti-proliferative drug to the buckle that is
placed around the eye, there can be some reduction in scar tissue
formation. It is also envisioned to attach an anti-proliferative
drug attached to the outside of a cylindrical tube that is placed
within a generally cylindrical cavity of the human body to decrease
scar tissue formation after a surgical procedure on that generally
cylindrical cavity. Such a generally cylindrical cavity might be a
nostril after an operation for a deviated septum, a fallopian tube,
a billiary duct, a urethra, (for example after prostate surgery) a
ureter, a bronchial tube, etc. For such an application, the tube
with the attached anti-proliferative drug could be biodegradable,
remain implanted or it could be removed after a few days or
weeks.
[0006] Another device that would benefit from a coating of an
anti-proliferative agent such as Rapamycin is a prosthetic implant
that is placed into a woman's breast after reconstructive or
augmentative surgery. Breast implants typically form significant
scar tissue around their surface after implantation. Coating the
surface of the breast implant with a slowly releasing
anti-proliferative agent can significantly reduce this scar tissue
formation.
[0007] Still another application of these concepts is for
aterio-venous fistulas that are used for kidney dialysis patients.
These devices (which are also called a-v shunts) are used to
connect an artery in an arm to a large vein in the same arm. The
plastic a-v shunt is then penetrated by comparatively large needles
through which the patient's blood is cleansed typically every other
day. A frequent cause of failure for these shunts is caused by
proliferative cell growth at the anastamosis where the shunt is
joined to a vein. By having sutures coated with an
anti-proliferative agent and by coating the interior and/or
exterior of the a-v shunt with an anti-proliferative agent it is
expected that the time for maintaining adequate blood flow through
the vein will be extended.
[0008] In addition to applying the anti-proliferative drug by means
of a device to which the anti-proliferative drug is attached, it is
also envisioned to apply the anti-proliferative drug systemically
by any one or more of the well known means for introducing a drug
into a human subject. For example, an anti-proliferative drug could
be applied by oral ingestion, by a transdermal patch, by a cream or
ointment applied to the skin, by inhalation or by a suppository.
Any of these methods being a systemic application of an
anti-proliferative drug. It should be understood that such a drug
should be applied systemically starting at least one day prior to a
surgical procedure but could be started as long as 5 days prior to
a surgical procedure. Furthermore, the drug should be applied for a
period of at least one day after the procedure and for some cases
as long as 60 days. It should be understood that an
anti-proliferative drug could be given systemically without using
any of the devices described herein. Preferably, the
anti-proliferative drug would be given systemically in addition to
the application of an anti-proliferative drug attached to any one
or more of the devices described herein. It should also be
understood that an optimum result might be obtained with using one
anti-proliferative drug attached to a device with a second and/or
third drug being used for systemic administration. A typical dose
for a patient, for example with Rapomycin, would be 1.5 mg/kg per
day. The dose would of course depend on the anti-proliferative drug
that was used.
[0009] Thus it is an object of this invention to have a sheet of
material that can be placed between internal body tissues, the
material having an anti-proliferative drug attached to reduce scar
tissue formation between adjacent layers of the human tissue.
[0010] Another object of this invention is to have a biodegradable
sheet of material or mesh suitable for placement between body
tissues including an attached drug that prevents the cellular
proliferation associated with post-surgical adhesions.
[0011] Still another object of the invention is to have a bandage
to which an anti-proliferative drug is attached that is placed onto
a cut in the skin to reduce scar tissue formation.
[0012] Still another object of the invention is to have a suture
material or surgical staple to which an anti-proliferative drug is
attached.
[0013] Still another object of the invention is to have an
anti-proliferative drug attached to the exterior of a cylindrical
tube that is placed into a generally cylindrical cavity of the
human body after a surgical procedure on that generally cylindrical
cavity.
[0014] Still another object of the invention is to have a device
implanted in a human subject, the device having an
anti-proliferative agent attached; the device being a breast
implant, an a-v shunt or an equivalent device for implantation into
the human subject.
[0015] Still another object of this invention is to have the
anti-proliferative drug be Rapamycin or an equivalent drug.
[0016] Still another object of this invention is to have the
anti-proliferative drug be Taxol or an equivalent drug.
[0017] Still another object of the invention is to employ a device
placed into or onto the body of a human subject, which device has
an attached anti-proliferative drug, plus using the same or a
different anti-proliferative drug as a medication to be applied
systemically to the human subject from some time prior to a
surgical procedure to some time after that procedure.
[0018] These and other objects and advantages of this invention
will become obvious to a person of ordinary skill in this art upon
reading of the detailed description of this invention including the
associated drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a plan view of a sheet or mesh onto which an
anti-proliferative drug has been attached.
[0020] FIG. 2 is an enlargement of the cross section of a single
strand of the mesh where the drug is embedded within the
strand.
[0021] FIG. 3 is an enlargement of the cross section of a single
strand of the mesh where the drug is coated onto the strand.
[0022] FIG. 4 is an enlargement of two strands of the mesh that
have been dipped into a solution of an anti-proliferative drug
thereby attaching the drug to the strands by adhesion and capillary
action.
[0023] FIG. 5 shows a cross section of the mesh to which an
anti-proliferative drug has been attached, the mesh being placed
between two layers of tissue of the human body.
[0024] FIG. 6 is a cross section of the skin onto which is taped a
bandage to which an anti-proliferative drug has been attached.
[0025] FIG. 7 is a cross section of a human breast into which a
breast implant has been placed.
DETAILED DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 shows an absorbable hemostat mesh sheet 10 with mesh
strands 12 and open spaces 11. The sheet 10 is designed to be
placed post-operatively between internal body tissues that have
been separated by a surgical procedure. The mesh strands 12 can be
made from oxidized regenerated cellulose or other biodegradable
materials with the anti-proliferative drug either embedded within
the strands, coated onto the outer surfaces of the strands or held
onto the strands by adhesion or capillary action. Any of these
possibilities will be described herein as the drug being attached
to the mesh or attached to the strand of the mesh.
[0027] FIG. 2 is an enlargement of a cross section of a single
strand 12 of the mesh 10 in which the anti-proliferative drug 14 is
embedded within the strand 12.
[0028] FIG. 3 is an enlargement of the cross section of a single
strand 12 of the mesh where the anti-proliferative drug 17 is
coated onto the exterior surface of the strand.
[0029] FIG. 4 is an enlargement of two adjacent strands 12 of the
mesh 10 onto which an anti-proliferative drug 18 is attached by
means of adhesion and capillary action.
[0030] FIG. 5 shows the anti-proliferative drug attached to the
mesh 10 placed between two adjacent tissues 20 and 21 of a human
body. The mesh 10 would be inserted during a surgical procedure
typically just before closing of the surgical incision. When the
biodegradable mesh 10 dissolves or is absorbed into the tissues 20
and 21, the anti-proliferative drug attached to the mesh 10 will
become dispersed into the tissues 20 and 21. On the other hand, if
the biocompatible sheet of material is not biodegradable, the
anti-proliferative drug will remain at the site where it is placed
for a longer period of time than if the material sheet is
biodegradable. Similarly, the drug itself may be produced in a
soluble or insoluble form. An insoluble form would remain at the
treatment site longer than a soluble form.
[0031] The anti-proliferative drugs that may be used include cancer
drugs such as Taxol and other known anti-proliferative drugs such
as Rapamycin. Other drugs that could be used are Alkeran, Cytoxan,
Leukeran, Cis-platinum, BiCNU, Adriamycin, Doxorubicin, Cerubidine,
Idamycin, Mithracin, Mutamycin, Fluorouracil, Methotrexate,
Thoguanine, Toxotere, Etoposide, Vincristine, Irinotecan,
Hycamptin, Matulane, Vumon, Hexalin, Hydroxyurea, Gemzar, Oncovin
and Etophophos, taclolimus (FK506), and the following analogs of
sirolimus: SDZ-RAD, CCI-779, 7-epi-rapamycin,
7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin,
7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy,
2-desmethyl and proline.
[0032] Although a mesh has been discussed herein, more generally,
an anti-proliferative drug can be made to be part of any sheet of
material that is or is not biodegradable, as long as the sheet of
material is biocompatible. In any case the effect of the
anti-proliferative drug that is attached to at least part of the
sheet of material will decrease cellular proliferation and
therefore decrease the formation of scar tissue and adhesions.
[0033] It should also be understood that the mesh 10 could be
rolled into a cylinder and placed into a generally cylindrical
cavity of the human body that has undergone a surgical procedure.
The mesh 10, in a cylindrical form, could also be placed around an
elastomer tube prior to placement in the human generally
cylindrical cavity.
[0034] FIG. 6 is a cross section of a cut 23 in the skin 22 that is
situated above the subcutaneous tissue 24. A bandage 25 to which an
anti-proliferative drug has been attached is shown attached to the
skin 22 by means of an adhesive tape 26. The purpose of the
anti-proliferative drug is to reduce scar tissue formation in order
to have an improved appearance of the skin. The bandage may also
include an antiseptic agent to decrease the possibility of
infection.
[0035] It should also be understood that an ointment that includes
an anti-proliferative agent could be used separately from the
bandage 25 of FIG. 6. The anti-proliferative agent would be
selected from the group that includes Alkeran, Cytoxan, Leukeran,
Cis-platinum, BiCNU, Adriamycin, Doxorubicin, Cerubidine, Idamycin,
Mithracin, Mutamycin, Fluorouracil, Methotrexate, Thoguanine,
Toxotere, Etoposide, Vincristine, Irinotecan, Hycamptin, Matulane,
Vumon, Hexalin, Hydroxyurea, Gemzar, Oncovin and Etophophos,
taclolimus (FK506), and the following analogs of sirolimus:
SDZ-RAD, CCI-779, 7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy, 2-desmethyl and proline.
[0036] Another alternative embodiment of the invention is a suture
material to which an anti-proliferative drug is attached. A drawing
of a highly enlarged cross section of such a suture would be shown
by FIG. 2 or 3. That is, FIG. 2 could be considered to be a cross
section of a suture 12 into which is embedded an anti-proliferative
drug 14. FIG. 3 could be considered a highly enlarged cross section
of a suture 12 that is coated with an anti-proliferative drug 17.
The object of attaching an anti-proliferative drug to a suture
would be to reduce scar tissue formation where the suture
penetrates through human tissue. This would be particularly true
for the use a suture to join together two generally cylindrical
cavitys, i.e., an anastamosis. This could be used for both soluble
and insoluble suture materials. Furthermore, an anti-proliferative
drug could be attached to any surgical staple that is used to join
together human tissue after a surgical procedure. It should be
understood that sutures or staples with an anti-proliferative agent
attached could be used for joining any tissue of a human subject
where it is desired to reduce cellular proliferation, i.e., the
formation of adhesions or scar tissue.
[0037] FIG. 7 illustrates the implant into the breast of a human
subject of a breast implant 31. Attached to the breast implant 31
would be an anti-proliferative agent selected from the group that
includes Rapamycin, Taxol, Alkeran, Cytoxan, Leukeran,
Cis-platinum, BiCNU, Adriamycin, Doxorubicin, Cerubidine, Idamycin,
Mithracin, Mutamycin, Fluorouracil, Methotrexate, Thoguanine,
Toxotere, Etoposide, Vincristine, Irinotecan, Hycamptin, Matulane,
Vumon, Hexalin, Hydroxyurea, Gemzar, Oncovin and Etophophos,
taclolimus (FK506), and the following analogs of sirolimus:
SDZ-RAD, CCI-779, 7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy, 2-desmethyl and proline. When
a breast implant has an attached anti-proliferative agent, the scar
tissue that typically forms around such an implant will be
significantly reduced.
[0038] If an arterio-venus fistula shunt is placed into the arm of
a dialysis patient, then the same type of anti-proliferative
agent(s) as described above could be attached to that implanted
device to increase the time during which the associated vein in the
arm would remain patent.
[0039] Another application of the present invention is for
prevention of scar tissue formation subsequent to a procedure for
attaching a detached retina. This procedure uses what is called a
"buckle" placed around the eye to cause re-attachment of the
retina. The extent of scar tissue formation after this procedure is
performed can be decreased by attaching an anti-proliferative drug
to the buckle. The anti-proliferative drug would then find its way
into the eye to decrease scar tissue formation.
[0040] For any of the applications described herein, the systemic
application of one or more of the anti-proliferative agents that
have been described could be used conjunctively to further minimize
the creation of scar tissue.
[0041] Although only the use of certain anti-proliferative agents
has been discussed herein, it should be understood that other
medications could be added to the anti-proliferative drugs to
provide an improved outcome for the patients. Specifically, for
applications on the skin, an antiseptic, and/or anti-biotic, and/or
analgesic agent could be added to an anti-proliferative ointment to
prevent infection and/or to decrease pain. These other agents could
also be applied for any other use of the anti-proliferative drugs
that are described herein. It is further understood that any human
subject in whom an anti-proliferative agent is used plus at least
one of the other drugs listed above could also benefit from the
systemic administration of one or more anti-proliferative agent
that has been listed herein.
[0042] Various other modifications, adaptations, and alternative
designs are of course possible in light of the above teachings.
Therefore, it should be understood at this time that within the
scope of the appended claims, the invention can be practiced
otherwise than as specifically described herein.
* * * * *