U.S. patent application number 17/353969 was filed with the patent office on 2021-10-07 for drug eluting graft constructs and methods.
This patent application is currently assigned to Cook Medical Technologies LLC. The applicant listed for this patent is Cook Biotech Incorporated, Cook Medical Technologies LLC. Invention is credited to Steven Charlebois, Krista Gearhart, Keith Milner, Umesh H. Patel, Rhonda Peck, Eric J. Rodenberg, Bhavin B. Shah.
Application Number | 20210308342 17/353969 |
Document ID | / |
Family ID | 1000005669006 |
Filed Date | 2021-10-07 |
United States Patent
Application |
20210308342 |
Kind Code |
A1 |
Peck; Rhonda ; et
al. |
October 7, 2021 |
DRUG ELUTING GRAFT CONSTRUCTS AND METHODS
Abstract
The present invention provides, in certain aspects, medical
graft products that incorporate multiple drug depots in and/or on
the products. One such product is a sheet graft construct, for
example for tissue support that includes a sheet graft material
with a plurality of drug depots. The drug depots can be hardened
deposits formed directly onto the sheet graft material and/or can
be capable of eluting a drug for a minimum of 72 hours.
Inventors: |
Peck; Rhonda; (West
Lafayette, IN) ; Shah; Bhavin B.; (West Lafayette,
IN) ; Patel; Umesh H.; (West Lafayette, IN) ;
Gearhart; Krista; (Lafayette, IN) ; Charlebois;
Steven; (West Lafayette, IN) ; Milner; Keith;
(West Lafayette, IN) ; Rodenberg; Eric J.; (Battle
Ground, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cook Medical Technologies LLC
Cook Biotech Incorporated |
Bloomington
West Lafayette |
IN
IN |
US
US |
|
|
Assignee: |
Cook Medical Technologies
LLC
Bloomington
IN
Cook Biotech Incorporated
West Lafayette
IN
|
Family ID: |
1000005669006 |
Appl. No.: |
17/353969 |
Filed: |
June 22, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14210903 |
Mar 14, 2014 |
11065368 |
|
|
17353969 |
|
|
|
|
61799080 |
Mar 15, 2013 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 27/56 20130101;
A61L 31/16 20130101; A61L 2300/406 20130101; A61L 27/54 20130101;
A61L 31/005 20130101; A61L 2300/414 20130101; A61L 31/146 20130101;
A61L 27/3633 20130101 |
International
Class: |
A61L 31/14 20060101
A61L031/14; A61L 31/16 20060101 A61L031/16; A61L 31/00 20060101
A61L031/00; A61L 27/56 20060101 A61L027/56; A61L 27/54 20060101
A61L027/54; A61L 27/36 20060101 A61L027/36 |
Claims
1. An implantable device, comprising: a sheet graft material having
a top side and a bottom side; a plurality of drug depots attached
to the sheet graft material.
2. The implantable device of claim 1, wherein the sheet graft
material comprises an extracellular matrix sheet material.
3. The implantable device of claim 1 or 2, wherein: the sheet graft
material has a porous matrix formed by a network of fibers, the
porous matrix having pores formed between the fibers of the
network; and the drug depots each comprise solid deposits including
a polymeric carrier and a drug, the solid deposits each including a
first portion infiltrating pores of the porous matrix and a second
portion external of the porous matrix.
4. The implantable device of any preceding claim, wherein the drug
is an antibiotic agent.
5. The implantable device of any preceding claim, wherein the drug
is gentamycin.
6. The implantable device of any preceding claim, wherein the
depots are capable of eluting the drug over a period of time
greater than about 72 hours when the device is immersed in 66.7 mM
phosphate buffered saline at 37.degree. C.
7. The implantable device of any preceding claim, wherein the
depots are attached to the top side of the sheet graft material,
and wherein the depots in combination cover less than about 50% of
the surface area of the top side of the sheet material.
8. The implantable device of any preceding claim, having from 2 to
about 120 of said drug depots attached to the sheet graft.
9. The implantable device of any preceding claim, wherein: the
sheet graft material has a porous matrix formed by a network of
fibers, the porous matrix having pores formed between the fibers of
the network; the drug depots each comprise solid deposits including
a polymeric carrier and the at least one drug, the solid deposits
each including a first portion infiltrating pores of the porous
matrix and a second portion external of the porous matrix; the
sheet graft material has a thickness extending between the top
surface and the bottom surface; and the first portions of the drug
depots extend only partially through the thickness of the sheet
graft material.
10. The implantable device of any preceding claim, wherein: each
said drug depot covers a corresponding depot-bearing portion of the
sheet graft material, and preferably wherein each depot-bearing
portion has a surface area constituting about 0.5% to about 15% of
the surface area of the top surface of the sheet graft material,
and more preferably wherein each depot-bearing portion has a
surface area constituting about 2% to about 10% of the surface area
of the top surface of the sheet graft material.
11. The implantable device of claim 10, wherein: each said drug
depot has a maximum thickness that is greater than a maximum
thickness of the corresponding depot-bearing portion of the sheet
graft material covered by the depot.
12. The implantable device of claim 10 or 11, wherein: each said
depot-bearing portion of the sheet graft material is thinner than
depot-free portions of the sheet graft material occurring between
the depot-bearing portions.
13. The implantable device of any one of claims 10 to 13, wherein:
each said depot-bearing portion of the sheet graft material is
denser than depot-free portions of the sheet graft material
occurring between the depot-bearing portions.
14. The implantable device of any one of claims 10 to 14, wherein:
each said depot-bearing portion of the sheet graft material is less
porous than depot-free portions of the sheet graft material
occurring between the depot-bearing portions.
15. The implantable device of any preceding claim, wherein: the
drug depots are formed by a process including: depositing a
flowable material including a carrier polymer and the at least one
drug onto the top side of the sheet graft material so as to form a
plurality of deposited material portions; and hardening the
deposited material portions.
16. The implantable device of any preceding claim, wherein: the
sheet graft material comprises one or more membranous tissue layers
harvested from a source tissue of a warm-blooded vertebrate animal
and decellularized, the one or more membranous tissue layers each
having a porous matrix comprised of a network of collagen fibers,
wherein the network of collagen fibers retains an inherent network
structure from the source tissue.
17. The implantable device of claim 16, wherein the one or more
membranous tissue layers is effective when implanted in a subject
to become infiltrated with cells of the subject.
18. The implantable device of claim 16 or 17, wherein the one or
more membranous tissue layers is effective when implanted in a
subject to become replaced by tissue of the subject.
19. The implantable device of any one of claims 16 to 18, wherein
the one or more membranous tissue layers retains native collagen
and native elastin from the source tissue.
20. The implantable device of any one of claims 16 to 19, wherein
the one or more membranous tissue layers retains from the source
tissue least one of native glycosaminoglycans, native
proteoglycans, and native growth factors.
21. The implantable device of claim 20, wherein the one or more
membranous tissue layers retains from the source tissue native
glycosaminoglycans, native proteoglycans, and native growth
factors.
22. The implantable device of any one of claims 16 to 21, wherein
the sheet graft material comprises a laminate structure including a
plurality of said membranous tissue layers.
23. The implantable device of claim 22, wherein said membranous
tissue layers are bonded to one another.
24. The implantable device of claim 23, wherein said membranous
tissue layers are dehydrothermally bonded to one another.
25. The implantable device of any one of claims 16 to 24, wherein
said membranous tissue layers have not been subjected to
crosslinking by contact with a chemical crosslinking agent.
26. The implantable device of any one of claims 16 to 25, wherein
said membranous tissue layers retain substantially their native
level of crosslinking.
27. The implantable device of any preceding claim, wherein the
bottom side of the sheet graft material is free from any drug
depots.
28. The implantable device of any preceding claim, wherein the
bottom side of the sheet graft material has a surface provided by
one or more membranous tissue layers harvested from a source tissue
of a warm-blooded vertebrate animal and decellularized, the one or
more membranous tissue layers each having a porous matrix comprised
of a network of collagen fibers, wherein the network of collagen
fibers retains an inherent network structure from the source
tissue.
29. A method of manufacturing a medical graft, comprising:
depositing at least one volume of a flowable material comprising a
drug onto at least one region of a graft material; and causing the
flowable material to harden.
30. The method of claim 29, wherein the graft material includes a
porous matrix, said method also comprising causing at least a
portion of the flowable material to infiltrate pores of the porous
matrix in the at least one region.
31. The method of claim 29 or 30, wherein the graft material
comprises one or more membranous tissue layers harvested from a
source tissue of a warm-blooded vertebrate animal and
decellularized, the one or more membranous tissue layers each
having a porous matrix comprised of a network of collagen
fibers.
32. The method of any one of claims 29 to 31, wherein said
depositing comprises depositing a plurality of discrete volumes of
the flowable material onto a plurality of discrete regions of the
graft material.
33. The method of any one of claims 29 to 32, wherein the drug is
an antimicrobial agent.
34. The method of any one of claims 29 to 33, wherein said causing
comprises removing a solvent from the flowable material.
35. The method of any one of claims 29 to 34, wherein the graft
material comprises an extracellular matrix sheet material.
36. The method of any one of claims 29 to 35, wherein said at least
one region comprises a reservoir formed in the graft material.
37. The method of any one of claims 29 to 36, wherein said causing
forms a hardened material, and wherein the method also comprises
reshaping the hardened material.
38. The method of claim 37, wherein said reshaping includes
reducing the thickness of the hardened material.
39. The method of claim 37 or 38, wherein said reshaping includes
smoothing an upper surface of the hardened material.
40. The method of claim any one of claims 37 to 39, wherein the
hardened material includes pores, and wherein said reshaping
includes collapsing the pores.
41. The method of any one of claims 37 to 40, wherein said
reshaping includes compressing the hardened material against a
surface.
42. The method of any one of claims 29 to 41, wherein said graft
material is a flexible sheet graft material.
43. The method of any one of claims 29 to 41, conducted so as to
form a plurality of drug depot wafers from the flowable material,
the drug depot wafers attached to the graft material.
44. The method of claim 43, wherein the medical graft has a total
dose of the drug, and wherein said plurality of drug depot wafers
includes 2 to 100 drug depot wafers incorporating at least 50% of
the total dose of the drug.
45. The method of claim 44, wherein said plurality of drug depot
wafers includes 10 to about 60 drug depot wafers incorporating at
least 80% of the total dose of the drug.
46. The method of any one of claims 29 to 45, wherein the graft
material is a sheet graft material, and wherein the method is
conducted so as to form a plurality of discrete drug depots from
the flowable material, wherein the drug depots have top surfaces
that, taken together, define a surface area that is less than 50%
of the surface area defined by the top surface of the of the sheet
graft material.
47. An implantable device, comprising: a graft material having a
porous matrix formed by a network of fibers, the porous matrix
having pores formed between the fibers of the network; and one or
more drug depots including a polymeric carrier and a drug, the one
or more drug depots including a first portion infiltrating pores of
the porous matrix and a second portion external of the porous
matrix.
48. The implantable device of claim 47, wherein the graft material
comprises an extracellular matrix material.
49. The implantable device of claim 47 or 48, wherein the drug is
an antibiotic agent.
50. The implantable device of any one of claims 47 to 49, wherein
the drug is gentamycin.
51. The implantable device of any one of claims 47 to 50, wherein
the one or more drug depots are capable of eluting the drug over a
period of time of at least about 72 hours when the device is
immersed in aqueous phosphate buffered saline at 37.degree. C.
52. The implantable device of any one of claims 47 to 51, wherein
the one or more drug depots are attached to a top side of the graft
material, and wherein the depots in combination cover less than
about 50% of the surface area of the top side of the graft
material.
53. The implantable device of any one of claims 47 to 51, wherein
from 2 to no more than 100 of said drug depots incorporate at least
50% of a total dose of the drug on the device.
53. The implantable device of any one of claims 47 to 51, wherein
from 5 to about 80 of said drug depots incorporate at least 80% of
a total dose of the drug on the device.
54. The implantable device of any one of claims 47 to 51, wherein
from 10 to about 60 of said drug depots incorporate at least 99% of
a total dose of the drug on the device.
55. The implantable device of any one of claims 47 to 54, wherein:
said first portion of the one or more drug depots extends only
partially through a thickness of the graft material.
56. The implantable device of any one of claims 47 to 55, wherein
said sheet graft comprises a laminate of a plurality of
extracellular matrix layers.
57. The implantable device of claim 56, wherein said extracellular
matrix layers have a native collagen architecture retained from an
animal source tissue for the extracellular matrix layers.
58. The implantable device of claim 56 or 57, wherein said
extracellular matrix layers retain at least one native growth
factor from an animal source tissue for the extracellular matrix
layers.
59. The implantable device of any one of claims 1 to 28 or 47 to
58, wherein the graft material includes a synthetic polymeric mesh
and at least one extracellular matrix sheet.
60. The implantable device of claim 59, wherein the graft material
includes the synthetic polymeric mesh sandwiched between a first
extracellular matrix sheet and a second extracellular matrix
sheet.
61. A method for treating a patient, comprising implanting in the
patient an implantable device according to any one of claims 1 to
28 or 47 to 60.
62. The method of claim 61, wherein said implanting comprises
implanting the device so as to support soft tissue of the
patient.
63. The method of claim 62, wherein said implanting is to repair a
hernia.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/210,903 filed Mar. 14, 2014 which claims
the benefit of U.S. Provisional Application Ser. No. 61/799,080,
filed on Mar. 15, 2013, which is incorporated herein by reference
in its entirety.
BACKGROUND
[0002] The present invention relates generally to medical
technology and in particular aspects to medical graft constructs
with the capacity to elute a drug.
[0003] As further background, a variety of materials have been used
to form implants, grafts and other medical constructs. These
materials include both naturally derived and non-naturally derived
materials. In some cases, bioremodelable materials including
remodelable extracellular matrix (ECM) materials have been used.
Remodelable ECM materials can be provided, for example, by
materials isolated from a suitable tissue source from a
warm-blooded vertebrate, e.g., from the submucosal, dermal or other
tissue of a mammal. Such isolated tissue, for example, small
intestinal submucosa (SIS), can be processed so as to have
bioremodelable properties and promote cellular invasion and
ingrowth. Illustratively, sheet-form SIS material has been
suggested and used to form hernia repair grafts and other medical
products. Some of these grafts exhibit a multiple layer
configuration to provide strength and/or reinforcement.
[0004] There remain needs for improved and/or alternative medical
materials and constructs, as well as methods for preparing and
utilizing the same. The present invention is addressed to those
needs.
SUMMARY
[0005] The present invention provides, in certain aspects, products
that include drug depots carried by a sheet material. The drug
depots can, in embodiments herein, include a limited number of
depots that incorporate a substantial percentage, for example at
least 50% by weight, of the total dose of the drug applied to the
product.
[0006] In certain embodiments, provided is an implantable device
that includes a sheet graft material having a top side and a bottom
side, and a plurality of drug depots attached to the sheet graft
material. The sheet graft material can include an extracellular
matrix sheet material, and/or can have a porous matrix formed by a
network of fibers, the porous matrix having pores formed between
the fibers of the network. The drug depots can comprise solid
deposits including a polymeric carrier and a drug. When the sheet
graft material has a porous matrix, such solid deposits can include
a first portion infiltrating pores of the porous matrix and a
second portion external of the porous matrix, and/or the porous
matrix can facilitate the distribution of the drug into depot-free
regions of the graft material by diffusion of dissolved, eluted
amounts of the drug through the porous matrix. The drug can be an
antibiotic agent, for example gentamycin. The drug depots can be
constructed and arranged so as to have the capacity to elute the
drug over a time period of at least about 72 hours, or at least
about 96 hours, when the implantable device is immersed in an
aqueous medium such as an aqueous phosphate buffered saline (PBS)
solution at 37.degree. C. The PBS can be a 66.7 mM phosphate buffer
saline solution, prepared for example as described in Example 1
below. The implantable device can incorporate at least 50%, at
least 70%, at least 80%, at least 90%, or essentially all (at least
99%), of the total dose of the drug on the device within 2 to about
120 depots attached to the sheet graft material, preferably about 5
to about 80 depots, and more preferably about 10 to about 60
depots. These specified depots can each be constituted of a wafer
or other material layer, which can in some forms have at least one
width dimension exceeding about 2 mm and/or occupy a surface area
of at least about 10 mm.sup.2.
[0007] Additional sheet graft embodiments of the invention are
provided wherein the features of an embodiment as discussed in the
paragraph immediately above are combined with one or more features
described in the Detailed Description found below. It is to be
understood that the features described in connection with specific
embodiments set forth in the Detailed Description are contemplated
as being capable of generalization to other embodiments unless
clearly indicated otherwise.
[0008] Additional embodiments herein relate to methods for
preparing one or more depots on a graft material. In certain
aspects, such methods comprise depositing on a graft material at
least one volume, and in some modes a plurality of volumes, of a
flowable material including a drug, and causing the flowable
material to harden. In preferred aspects, the sheet graft material
includes a porous matrix, and a portion of the flowable material
infiltrates the porous matrix, more preferably only partially
through the thickness of the sheet graft material. The infiltrated
material is hardened during the hardening step, and forms a hybrid
matrix with the porous matrix of the sheet material, which can
facilitate an attachment of the drug depot to the sheet graft
material. Such an attached drug depot can include, in addition to
the infiltrated depot material, additional depot material residing
outside of the porous matrix, e.g. extending above a surface of the
region of the sheet graft material occupied by the depot.
[0009] Still further embodiments herein relate to methods for
treating a patient, comprising implanting in the patient an
implantable sheet graft device as described herein. In certain
modes, the sheet graft device is configured to support soft tissue
of the patient, and is implanted to as to support soft tissue. In
some preferred methods, the sheet graft device is implanted to
support tissue adjacent a body wall defect, such as a hernia in an
abdominal wall or other location in the patient.
[0010] Additional objects, embodiments, forms, features,
advantages, aspects, and benefits of the present invention shall
become apparent from the detailed description and drawings included
herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a top view of a medical sheet graft device
according to one embodiment of the invention.
[0012] FIG. 2 is a side view of the device of FIG. 1.
[0013] FIG. 3 is an enlarged cross-sectional view of a region of
the device of FIGS. 1 and 2 including a drug depot.
[0014] FIG. 3A is an enlarged cross-sectional view of a region of
the device of FIGS. 1 and 2 including a drug depot in another
embodiment.
[0015] FIG. 4 is a partial side view of a sheet graft device during
one stage of its manufacture.
[0016] FIG. 5 is a partial, side view of the medical product of
FIG. 4 at a subsequent stage of manufacture.
[0017] FIG. 6 is a perspective view of a medical product according
to one embodiment of the present invention;
[0018] FIG. 7 is a cross-sectional view of the product of FIG. 6
along the view line 7-7 shown in FIG. 6.
[0019] FIG. 8 is a top view of another sheet graft device
embodiment.
[0020] FIG. 9 is a partial cross-sectional view of the product of
FIG. 8 along the view line 9-9 shown in FIG. 8.
[0021] FIG. 10 is an exploded, side view of another sheet graft
device embodiment.
[0022] FIG. 11 is an exploded, side view of another sheet graft
device embodiment.
[0023] FIG. 12 is an exploded, side view of another sheet graft
device embodiment.
[0024] FIG. 13 is a top view of another sheet graft device
embodiment.
[0025] FIG. 14 is a partial, cross-sectional view of the embodiment
of FIG. 13 along the view line 14-14 shown in FIG. 13.
[0026] FIG. 15 is a partial cutaway top view of another sheet graft
device embodiment.
DETAILED DESCRIPTION
[0027] While the present invention may be embodied in many
different forms, for the purpose of promoting an understanding of
the principles of the present invention, reference will now be made
to the embodiments illustrated in the drawings, and specific
language will be used to describe the same. It will nevertheless be
understood that no limitation of the scope of the invention is
thereby intended. Any alterations and further modifications in the
described embodiments and any further applications of the
principles of the present invention as described herein are
contemplated as would normally occur to one skilled in the art to
which the invention relates.
[0028] As disclosed above, certain aspects of the present invention
are directed to graft products that incorporate multiple drug
depots in and/or on the products. These products, in some forms,
include a sheet graft material, e.g., an absorbable or remodelable
sheet material such as extracellular matrix sheet. The sheet graft
material can have a plurality of drug depots distributed along an
outer surface of the sheet. In certain preferred embodiments, the
drug depots are hardened deposits that have been created in situ
onto the top and/or bottom side of the sheet, and that can
infiltrate at least a portion of the thickness, and preferably only
a portion of the thickness, of the sheet. The drug depots
incorporate a (at least one) drug and can be capable of eluting the
drug. The drug depots are desirably layer bodies or regular or
irregular shapes, for example in the form of circular, ovoid or
polygonal wafers. Desirably, the drug depots are constructed and
arranged to elute the drug over an extended period of time. The
depots can be constructed and arranged to elute the drug over a
period of time of at least 72 hours, or at least 96 hours, or at
least 168 hours, when the device is immersed in an aqueous
phosphate buffered saline solution (e.g. as described in Example
1). These same minimum elution times may also be achieved in the
target implant site for the graft device, e.g. a subcutaneous
implant site or when implanted in a body wall, such as the
abdominal wall, to repair damaged tissue such as herniated tissue.
Elution can occur for example when bodily fluids contact the drug
depots so as to dissolve amounts of the drug, which are then eluted
from the depots. When taking the form of hardened deposits, the
drug depots can be a dried composition including a bioabsorbable
polymeric material and the drug. In some preferred aspects, the
drug depots are positioned on the top surface of the sheet graft
material, and taken all together occupy less than about 50% of the
sheet's top surface, e.g., in some preferred forms occupying at
least about 5% but less than about 30% of the top surface. In some
forms, the drug depots will be regularly situated, e.g., in a
repeating pattern, along the top surface of the sheet. In these and
other forms, a plurality of thru-openings such as holes or slits
can be made through the sheet graft material in regions which are
unoccupied by the drug depots. Such thru-openings can allow fluid
to pass through the sheet graft material from one side to the
other. As well, other aspects of the present invention provides
methods for preparing and using depot-bearing graft constructs, and
medical products that include constructs as described herein
enclosed within packaging in a sterile condition.
[0029] With reference now to FIGS. 1 to 3, an inventive sheet graft
construct 20 is depicted. Construct 20 includes a sheet graft
material 21 having a top surface 22 and a bottom surface 23.
Construct 20 also includes a plurality of drug depots 24 attached
to corresponding depot-bearing regions 25 of the sheet graft
material 21, which are surrounded by depot-free regions 26 of the
sheet graft material 21. In the depicted construct 20, a portion of
the material of the drug depots 24 is located infiltrated within
pores between fibers of a porous fibrous matrix of the sheet graft
material 21, forming a hybrid matrix region 27 including fibers of
the porous fibrous matrix entrained within material of the drug
depots 24. In this fashion, an attachment is created between the
drug depots 24 and the sheet graft material 21. Construct 20 as
depicted is generally rectangular in shape having a first edge 28
and a corresponding second, opposite edge 29, and a third edge 30
and a corresponding fourth, opposite edge 31. It will be understood
that other shapes for the construct will also be suitable within
the invention. Construct 20 also includes a plurality of
thru-openings 32 in the form of perforations of generally circular
cross-section, to allow fluid passage through the construct 20 from
one side to the other. As shown, in the preferred device
thru-openings 32 are located in depot-free regions of the sheet
graft material 21.
[0030] Construct 20 also includes a perimeter weaving element 33,
such as a suture, extending along the path defined by the outer
edges of sheet graft material 21 and spaced inwardly from the
edges, for example by a distance of about 0.1 to about 1 cm.
Construct 20 also has an interior weaving element or elements 34,
such as a suture(s), that provide a pattern of intersecting weave
lines, which in the depicted embodiment form generally rectangular
(and particularly here square) shapes across the sheet graft
material 21. Where sheet graft material 21 is composed of a
laminate including multiple layers, weaving elements 33 and 34 can
be provided and distributed across the graft material 21 to provide
resistance to delamination of the layers. The sutures or other
weaving elements 33 and 34 can, for example, provide lock stitches
that stitch the layers together for these purposes. A drug depot 24
is located within each rectangular shape provide by weaving
element(s) 34.
[0031] In certain preferred aspects, the sheet graft material of
construct 20 includes multiple ECM layers (e.g., 2 to 10 layers or
more), desirably laminated together as described herein, more
desirably by dehydrothermal bonding between ECM layers of the
laminate, for example using any of the dehydrothermal bonding
techniques described herein. The weaving component(s) are desirably
bioabsorbable sutures. Additionally, such constructs 20 can
incorporate one or more synthetic mesh layers above or below any of
the ECM layers as described elsewhere herein, e.g., between any two
ECM layers of the laminate or other multiple layer construct.
[0032] Generally, the total surface area defined by the top
surfaces of the drug depots 24, taken together, will be less than
the total surface area of the top surface of the of the sheet graft
material 21. In preferred embodiments, the total surface area
defined by the top surfaces of the drug depots, taken together,
will be less than 50% of the total surface area of the top surface
of the of the sheet graft material 24, more preferably less than
about 35%, and even more preferably less than about 25%. In certain
embodiments, the total surface area defined by the top surfaces of
the drug depots, taken together, will be in the range of about 3%
to about 50% of the total surface area of the top surface of the of
the sheet graft material, more preferably in the range of about 5%
to about 35%, and even more preferably in the range of about 8%, to
about 25%. Again, when drug depots are associated with a sheet
graft material, they can be positioned along the top and/or bottom
side of the sheet graft material, and/or embedded within the sheet
graft material (e.g. between layers of a laminated construct).
Thus, in some embodiments, some of the depots can be located on the
top and/or bottom of the sheet material while some are embedded
within the sheet graft material, and in other embodiments all of
the depots can be on an outer exposed surface of the sheet graft
material (i.e. top and/or bottom). Sheet graft embodiments having
attached depots in accordance of the invention will thus include
depot-free areas or regions between the depots, which can
advantageously present the unmodified sheet graft material to the
body of a subject when implanted. Where sheet graft materials
comprise or are constituted of ECM material or another porous
material receptive to cellular invasion, such invasion can occur in
the depot-free areas unaffected by the solid depot material.
[0033] The total number of drug depots attached to the sheet graft
material can vary. It is preferred that at least a substantial
proportion of the total dose of drug on the sheet graft device be
carried by relatively few drug depots. In some aspects, at least
50%, at least 70%, at least 80%, at least 90%, at least 95%, at
least 99%, or all or essentially all of the total dose of the drug
on the device, will be incorporated within 2 to about 120 drug
depots, preferably about 5 to about 80 drug depots, more preferably
about 10 to about 60 drug depots, and even more preferably about 20
to about 50 drug depots. In some embodiments, these numbers of drug
depots constitute the total number of drug depots on the
device.
[0034] The drug depots can be substantially the same size as each
other (e.g. having top surfaces that have surface areas within
about 20% of one another) or may vary in size, and the drug depots
in some embodiments can be completely discrete from one another. It
will be understood that while completely discrete depots,
unconnected to one another by the same material from which the
depots are formed, are preferred, in other forms, the depots might
be connected to one another by smaller volumes or masses of the
depot material such that the majority of the depot material mass on
the device is within the depots (e.g. greater than 80%, or 90% by
weight). For example, bands or threads of the depot material may
span between more compact or shaped depot wafers or layers as
described herein. These embodiments can nonetheless concentrate the
drug to be released in the depot regions, while the overall depot
material of the device still only occupies a percentage of the
surface area of the overall sheet graft device, e.g. those
percentages identified above.
[0035] At least some (e.g. two or more, five or more, or ten or
more) of the above-specified drug depots, or all of the
above-specified drug depots, can be material layers that have top
surfaces with a surface area of at least about 10 mm.sup.2, or at
least about 20 mm.sup.2, or at least about 50 mm.sup.2, and
typically in the range of about 10 mm.sup.2 to about 1000 mm.sup.2,
more typically in the range of about 50 mm.sup.2 to about 500
mm.sup.2. Additionally or alternatively, at least some (e.g. two or
more, five or more, or ten or more) of the above-specified drug
depots can be material layers with at least one width dimension of
at least about 2 mm, more preferably at least about 4 mm, and
typically in the range of about 4 mm to about 20 mm; and/or the
drug depots can be planar or substantially planar material layers,
for example wafers of circular, ovoid, polygonal or other shapes,
that when considered in the plane of the material layer have a
first, maximum width taken along a first axis which is no more than
about three times that a second width taken on an axis
perpendicular to and centered upon the first axis. Such
characteristics can contribute a preferred, relatively compact
shape of the depots.
[0036] As an addition or alternative to a consideration of the
total number of the above-specified drug depots on the sheet graft
construct (which specified drug depots may incorporate either all
or a substantial portion of the total dose of drug on the device,
as indicated), the percentage of the total dose of the drug on the
construct that is incorporated in each of the above-specified drug
depots can be a consideration. In certain embodiments, each of the
above-specified drug depots incorporates at least about 0.5% of the
total dose of drug on the construct, preferably at least about
1%.
[0037] The drug depots can be spatially arranged on the sheet graft
material in a variety of ways as needed for a particular medical
application. The drug depots can be arranged in a regular pattern,
for example as shown in FIG. 1, or a random or irregular pattern if
desired. Some embodiments will include rows or lines of drug
depots. Drug depots may or may not be located across all parts of a
surface, e.g., the top side of a sheet graft material.
Additionally, drug depots can be distributed on the sheet graft
material such that upon implantation, eluted drug from the drug
depots diffuses and impregnates the entire sheet graft material. A
substantially even distribution of the drug depots across the sheet
graft material can be used for these purposes, and/or a porous
matrix incorporated into the sheet graft material can facilitate
this distribution.
[0038] In some embodiments, the maximum thickness of at least some
of the drug depots, and potentially all of the depots, will be at
least about 25% of the maximum thickness of the sheet graft
material, or at least about 100% of the maximum thickness of the
sheet graft material, and typically in the range of about 25% to
about 500% of the maximum thickness of the sheet graft material.
Additionally or alternatively, the average thickness of at least
some of the drug depots, and potentially all of the depots, will be
at least about 25% of the average thickness of the sheet graft
material, or at least about 50% of the average thickness of the
sheet graft material, and typically in the range of about 25% to
about 500% of the average thickness of the sheet graft material. As
well, in certain embodiments, such as that depicted in FIGS. 1 to
3, the drug depots will exposed at the surface of the sheet graft
material and will be situated upon a depot-bearing portion of the
sheet graft material. In such embodiments, the drug depots can have
an average thickness (which includes the thickness of any
infiltrated portion of the depots) that is greater than the average
thickness of the corresponding depot-bearing portion of the sheet
graft material. For example, the drug depots can have an average
thickness that is at least 100% of the average thickness of the
corresponding depot-bearing portion, and typically in the range of
about 100% to 1000% of the average thickness of the corresponding
depot-bearing portion. Relatively thick drug depots, for example as
specified herein, facilitate the provision of a beneficial extended
release of the drug(s) from the depots.
[0039] FIG. 3A shows another drug depot construct that can be
incorporated into the depots of embodiments described herein. The
construct of FIG. 3A is similar to that shown in FIG. 3, only
having a top surface of the drug depot 24 in plane or at least
substantially in plane (e.g. varying by no more than about 2 mm, or
no more than about 1 mm, or no more than about 0.5 mm above or
below) with the top surface of the sheet graft material 21 adjacent
the drug depot 24. This preferred arrangement can in some
embodiments provide a substantially smooth top surface to the
overall graft device (e.g. device 20).
[0040] As shown particularly in FIGS. 3 and 3A, when the sheet
graft material has a porous matrix, material of the formed drug
depot can infiltrate and combine with the porous matrix to form a
hybrid matrix. With reference to FIGS. 4 and 5, illustrated is one
embodiment of a method by which such a structure can be prepared.
As shown in FIG. 4, a flowable material 40 has been ejected from a
dispensing nozzle 41 and formed a deposited volume of material 42
supported by the sheet graft material 21. Flowable material 40
incorporates one or more drugs for availability in the implantable
product, and typically a carrier material such as a synthetic
polymeric material. While still flowable, at least a portion of
flowable material 40 infiltrates into a porous matrix of the sheet
graft material 21. This can be under pressure caused by the force
of gravity, or other means of pressuring the material 40 may also
be used, potentially combined with a wicking action of the porous
matrix. However, as discussed above, in preferred embodiments the
infiltration of the material of the depot is only partially through
the thickness of the sheet graft material 21. Control of the level
of penetration can be achieved by consideration of various factors
including, for example, the viscosity of the deposited flowable
material, the extent of porosity of the depot-bearing region of the
sheet graft material upon which the flowable material is deposited,
the extent of pressure applied to the deposited material, the
residence time of the flowable material on the sheet graft material
before hardening, and the like. In some modes of practice of the
invention, the deposited flowable material can infiltrate into the
sheet graft material a distance that equals at least about 1%, or
at least about 2%, of the thickness of the corresponding
depot-bearing region of the sheet graft material, and typically in
the range of about 1% to about 75% of the thickness of the
corresponding depot-bearing region of the sheet, preferably in the
range of about 1% to about 50%, and more preferably in the range of
about 1% to about 20%. As well, as discussed above, in some forms
of the invention, the depot-bearing regions of the sheet graft
material are denser and/or less porous than adjacent regions of the
sheet graft material. This can help to prevent undesired levels of
penetration of the deposited flowable material through the sheet
graft material.
[0041] FIG. 5 shows an illustrative subsequent stage of manufacture
where the flowable material has hardened to a non-flowable solid
volume 43, a lower portion of which is infiltrated and combined
with the porous matrix of sheet 21. The hardening of the flowable
material can be caused by any suitable mechanism. In certain
embodiments, such hardening is caused at least in part, and
potentially completely by, removal of a liquid solvent material
from the flowable material, for example by evaporation. This can be
accomplished for example by any suitable drying technique or
techniques, including for example drying at atmospheric pressure
and/or under vacuum (subatmospheric pressure). Water and/or organic
solvent materials may be used for these purposes, with volatile
organic solvents, for example acetone, proving beneficial in some
methods. In some modes, a polymeric carrier used to form the depot
will be soluble in the liquid solvent selected while the drug is
not and thus exists in the flowable material as a suspended solid
particulate. Further, in some variants, the hardening of the
deposited flowable material will cause the formation of entrapped
gas bubbles within the hardened volume 43, forming pores therein.
Further, in some modes of practice, the manufacture of the depot
includes a further step of compressing the non-flowable solid
volume 43. This can deform and re-shape the volume 43. For example,
this can provide a smoother upper surface to the volume 43 and
formed depot, and/or reduce the thickness of the volume 43 and
formed depot, and/or where the volume 43 incorporates pores as
noted above, can collapse the pores and potentially densify the
volume 43 in the formation of the drug depot. As well, during or
after such compressing, the volume 43 can be further dried, for
example under a vacuum and/or with applied heat, to remove
additional amounts of solvent. Such processes can contribute to the
desired elution properties of the drug depot.
[0042] With continued reference to FIG. 5, while amounts of the
drug depot material can infiltrate at least partially into the
depot-bearing region of the sheet graft material as discussed
above, in preferred embodiments the formed drug depots also include
an amount of drug depot material external of and extending beyond
the depot-bearing region of the sheet graft material.
[0043] While the depot formation can include solvent evaporation or
other removal, as noted above, still other methods for forming the
depots either in situ on the graft material or separately can be
used. For example, these other methods include deposition of molten
mixtures which harden upon cooling, heated compression casting of
dry powder materials, or other suitable methods.
[0044] In certain advantageous embodiments, the sheet graft
material will have reservoirs into which the flowable,
drug-containing material will be deposited to form the depots.
These reservoirs can be formed in the sheet graft material as it is
being initially prepared, or can be formed in the sheet graft
material after it is prepared, or both, and can have depths of at
least about 0.5 mm, or at least about 1 mm. The thus-formed
reservoirs can have a bottom wall and sidewalls. In some forms, a
sheet graft material having a porous matrix is processed to
compress selected regions of the sheet graft material to form these
reservoirs. Such compression can densify the sheet graft material
underlying and forming the bottom surface of the reservoirs,
reducing its porosity. This reduced porosity can in certain
embodiments at least partially control the depth of infiltration of
a flowable drug-containing material deposited onto the sheet graft
material to form a depot, as described elsewhere herein. In one
illustrative reservoir-forming process, a mold piece having
protrusions corresponding to the reservoirs can be compressed into
the porous matrix of the sheet graft material, desirably when the
sheet graft material is in a wetted state. With continued
compression with the mold piece the sheet graft material can be
dried. The reservoirs are thus stably imprinted into the sheet
graft material, and remain after the mold or form is removed. Such
processing to form reservoirs has been conducted to particular
advantage using extracellular matrix sheet graft material as
described herein.
[0045] After formation of the reservoirs as noted above,
depot-forming material can be deposited into the reservoirs. The
depot-forming material can at least partially fill the reservoir,
and in some embodiments will completely fill the reservoir,
potentially with some material provided beyond that necessary to
fill the reservoir. The deposited material can contact the bottom
wall and sidewalls of the reservoir, which will tend to retain the
deposited material in the shape of the reservoir. As well, where
the sheet graft material includes a porous matrix, due to
infiltration of the depot-forming material into the porous matrix,
hybrid matrices including the porous matrix and the depot material
can in some embodiments be formed not only in regions adjacent the
bottom walls of the reservoirs as discussed above, but also in
regions adjacent the sidewalls. After deposit of the depot-forming
material in the reservoirs, the depot-forming material can be
suitably processed, e.g. as described herein, to form a hardened
drug depot.
[0046] While products with outwardly exposed drug depots like those
shown in FIGS. 1 to 3 are highly useful in certain aspects of the
present invention, it will be understood that such products can in
other embodiments be incorporated into or provide building blocks
for other medical products. For example, a multilayered construct
could include multiple drug-eluting depots on any outer surface of
the construct and/or embed multiple depots between any two layers
of the construct. Illustratively, a product incorporating the
construct in FIGS. 1 to 3 could include one or more additional
layers, e.g. of a tissue-ingrowth receptive material, over the top
side of sheet material 21 and over drug depots 24 so as to cover
the bodies. The added layer(s) could then be adhered or otherwise
anchored to the drug depots 24 and/or the sheet graft material
21.
[0047] While the product of FIGS. 1 to 3 described in relation with
FIGS. 4 and 5 is illustrative of embodiments in which drug depots
are formed as solid deposits of material onto the sheet graft
material, in other embodiments, a drug depot can be created as a
separate article and then attached to the sheet graft material.
Depots 24 shown in FIGS. 1 to 3 could be separately created and
attached to the sheet graft material, to create a sheet graft
embodiment herein. As another example, FIGS. 6 and 7 illustrate
another sheet graft medical product 50 according to one embodiment
of the present invention. This particular product includes a sheet
graft material 51 with a plurality of discrete drug depots 52
situated along the sheet's top side 53. Sheet graft material 51 can
be made of any suitable material, with materials that are receptive
to tissue ingrowth upon implantation in or on the body of a patient
being preferred, e.g. those described herein. In some particularly
preferred embodiments, the sheet graft material will be or
incorporate a remodelable material such as a remodelable
extracellular matrix material, including any of those described
herein.
[0048] With continued reference to FIGS. 6 and 7, drug depots 52,
in this illustrative embodiment, are generally disk members with a
circular cross-sectional shape, although drug depots can exhibit a
variety of shapes and configurations for example, even including
bodies that are randomly shaped. The depots can be created
separately from the sheet material and then subsequently adhered to
or otherwise anchored upon the sheet, for example, with an
adhesive, preferably a biodegradable adhesive, which adhesive can
itself optionally be drug-loaded. The drug depots can be
essentially identical to each other in terms of size, shape, and
composition, although this kind of uniformity is certainly not
required in all embodiments herein.
[0049] Drug depots 52 or other drug depots to be used herein can be
formed with one or more biocompatible materials, including for
example bioabsorbable and/or non-bioabsorbable materials, and they
can be constructed in any suitable manner. Suitable formation
techniques include but are not limited to extrusion, hand
formation, deposition on a removable backing layer or other
substrate, formation in or on a mold or form and/or combinations or
variations thereof, just to give a few examples. One or more drugs
can be incorporated into such bodies in any suitable manner
including, for example, by surface treatment (e.g., spraying, dip
coating, etc.) and/or by impregnation (e.g., soaking) of an
already-formed body, or in some cases by mixing one or more drugs
into a depot-forming material during a manufacturing step, which
can thereafter be hardened by drying, curing, crosslinking,
polymerization or other means.
[0050] Sheet graft device 50 also includes a plurality of slits 55
formed into the sheet, although these slits may be absent in other
embodiments. The slits 55 are arranged in a repeating pattern on
the sheet graft material 51 and are offset from the drug depots 52,
i.e., so as to reside in areas unoccupied by the depots. As
discussed herein, in addition to these particular slits, a variety
of other slit and non-slit thru-openings can be formed in the sheet
graft material.
[0051] In some embodiments, a sheet graft material herein will
include an extracellular matrix sheet material and a resorbable or
non-resorbable synthetic polymer sheet graft material, for example
a synthetic polymer mesh or other synthetic polymer layer. FIGS. 8
and 9 illustrate an embodiment combining a synthetic polymer mesh
sheet with multiple extracellular matrix layers in accordance with
certain aspects of the present invention. Sheet graft construct 60
includes a first sheet 61 and a second sheet 62 of a
collagen-containing extracellular matrix material. A portion of the
first or top sheet 61 has been cut away in FIG. 8 to reveal a
synthetic mesh material 63 (e.g., polypropylene mesh) disposed
between the two sheets 60 and 61. The synthetic mesh includes a
plurality of mesh openings 64, and as seen in FIG. 9, the top and
bottom sheets 61 and 62 contact one another through the plurality
of mesh openings 64 so as to provide a corresponding plurality of
contacting regions 65 between the apposed faces of sheets 61 and
62.
[0052] While not necessary to broader aspects of this embodiment,
in this illustrative construction, the top and bottom sheets 61 and
62 are also bonded to one another in regions 65 to provide a
plurality of bonded regions 66. By bonding the top and bottom
sheets in this manner and around the peripheral edges of the mesh
material, the synthetic mesh becomes sealed within the surrounding
ECM sheets. Either ECM sheet, top or bottom, might be formed with a
single ECM layer or a multilayered ECM construct, for example, a
sheet incorporating two, three, four, five, six, seven, eight or
more individual ECM layers. Additionally or alternatively, an
adhesive (e.g., a drug-loaded adhesive) could be used to bond the
top and bottom sheets together through the mesh openings and/or to
bond the top and/or bottom sheets directly to the synthetic polymer
mesh.
[0053] Suitable mesh materials include a large variety of mesh or
mesh-like structures. Thus, relative to what is shown in FIG. 8, a
suitable mesh can have, among other things, a different number of
openings than mesh 63 and/or the shape, size and relative spacing
of the openings can be adjusted as desired to suit a particular
medical application. Such features can be used to alter the overall
percentage of void space in a mesh structure. Illustratively, a
mesh opening might be circular, oval, square, rectangular or any
other suitable shape.
[0054] When incorporated into an inventive graft, a mesh structure,
in some embodiments, will be made up of many small filaments,
strands or other smaller pieces of material that are interconnected
or otherwise associated with one another to form a substantially
unitary structure with mesh openings, e.g., like openings 64. When
utilized, these smaller pieces may or may not be bonded or directly
connected to one another. In alternative forms, a mesh may be or
include a material that is manufactured (e.g., by extrusion, in a
mold or form, etc.) so as to exhibit essentially a unitary
structure. Mesh structures can exhibit a flexibility or compliancy
or they can be essentially non-flexible or non-compliant, in whole
or in part. Mesh structures can be essentially flat in a relaxed
condition, or they can exhibit curvature and/or other non-planar
features, for example, exhibiting a convexo-concavo or other
three-dimensional shape. A mesh structure, in some aspects, will
include multiple layers of material. When a mesh structure is
multi-layered, the individual layers may or may not be bonded or
otherwise connected to one another. In some embodiments, an
inventive graft will incorporate a coated mesh structure (e.g.,
coated with a composition comprising a drug and a polymeric
material, or coated with a drug and subsequently coated with a
separate polymer layer, just to give a few examples).
[0055] Continuing with FIG. 9, as occurs in contacting regions 65,
when opposing collagen-containing surfaces are in contact with one
another certain types of advantageous bonding or fusing can occur
between those surfaces. While the extent and types of contact
between such surfaces can vary, for example, depending on the
overall number, sizing and relative spacing of openings in the mesh
material, in certain forms, it will be desirable to fuse or bond
the surfaces together to form a more interconnected graft body.
[0056] In certain embodiments, these contacting collagenous
surfaces will desirably be of a character so as to form an
attachment to one another by virtue of being dried while compressed
against each other. For example, dehydration of these surfaces in
forced contact with one another can effectively bond the surfaces
to one another, even in the absence of other agents for achieving a
bond, although such agents can be used while also taking advantage
at least in part on the dehydration-induced bonding. With
sufficient compression and dehydration, two collagenous surfaces
can be caused to form a generally unitary collagenous structure.
Vacuum pressing operations, and the closely bonded nature that they
can characteristically impart to the collagen-containing materials,
are highly advantageous and preferred in these aspects of the
invention. Some particularly useful methods of dehydration bonding
ECM materials include lyophilization, e.g. freeze-drying or
evaporative cooling conditions.
[0057] Drug depots can be incorporated into sheet graft construct
50. For example, such depots can be any of those disclosed herein,
e.g., independently formed bodies such as those described in
conjunction with FIGS. 6 and 7, and/or drug depots formed in situ
on the sheet graft material as described in conjunction with FIGS.
1 to 3 and 4-5. Such drug depots can be placed or formed between
the extracellular matrix sheets 61 and 62, potentially in contact
with the synthetic mesh material 63, and/or by situating one or
more depots along the top and/or bottom surface of the construct
50.
[0058] Thus, products with sandwiched or embedded meshes like that
shown in FIGS. 8 and 9 can be incorporated into or provide
components of other medical products of the present invention.
Illustratively, FIG. 10 shows an exploded, side view of a medical
product 70 according to another embodiment of the invention. A
resorbable or non-resorbable synthetic polymer mesh 63 (e.g., a
polypropylene mesh) is situated between a first extracellular
matrix sheet 61 and a second extracellular matrix sheet 62 with an
optional drug-containing adhesive layer 71 occurring between mesh
63 and the second extracellular matrix sheet 62. A plurality of
drug depots 72 are situated above the first extracellular matrix
sheet 61, i.e., opposite the synthetic polymer mesh 63, so that the
depots 72 are not covered by any other sheet or layer and are
therefore left exposed to the exterior of the product 70. As noted,
the drug depots 72 can be created separately from the sheet
material and then subsequently anchored to it, e.g., with a
drug-containing or other adhesive, or may be formed in situ on the
extracellular matrix sheet 61 as and including the features
described herein, either before or after sheet 61 is incorporated
into the overall sheet of product 70.
[0059] Continuing with FIG. 10, in embodiments where the optional
adhesive layer 71 is omitted, dehydration bonding and/or other
bonding techniques as discussed elsewhere herein can be used to
bond the ECM sheets 61 and 62 together through openings in the
polymer mesh 63 and/or to bond the ECM sheets directly to the
polymer mesh 63. When an adhesive layer such as layer 71 is
present, it can provide some or all of the bonding between the
various layers. In respect of the embodiment shown in FIG. 10 and
all other embodiments disclosed herein made from multiple
constituent pieces, it will be understood that the various pieces
can be put together in any suitable order or fashion. In an
illustrative method of manufacture for product 70, the polymer mesh
and adhesive layer are placed between opposing hydrated ECM layers,
and this entire structure is then subjected to compression under
dehydration conditions. Subsequently, the drug-eluting bodies are
adhered to or formed in situ onto the top surface of the dried
hybrid structure. Optionally, product 70 itself can be incorporated
into or provide a building block for other medical products of the
present invention. For example, in an alternative embodiment, a
second synthetic polymer layer (e.g., a resorbable or
non-resorbable polymer mesh) can be positioned between the first
ECM sheet 61 and the drug depots 72 and/or a third ECM sheet could
be positioned over the drug-eluting bodies 72. Optionally, in any
of these embodiments, a second group of drug-eluting bodies could
be situated below and attached to the second ECM sheet 62.
[0060] FIG. 11 shows an exploded, side view of a sheet graft
medical product 80 according to another embodiment of the
invention. A synthetic polymer mesh 63 is situated between a first
extracellular matrix sheet 61 and a second extracellular matrix
sheet 62. Additionally, a first group of drug-eluting bodies 81 is
situated between the first extracellular matrix sheet 61 and a
third extracellular matrix sheet 82, while a second group of
drug-eluting bodies 83 is situated between the second extracellular
matrix sheet 62 and a fourth extracellular matrix sheet 84. Again,
the various illustrative components can be bonded or otherwise
affixed together in any suitable manner including those described
herein, and product 80 itself can be incorporated into or provide a
component for other medical products of the present invention.
[0061] FIG. 12 shows an exploded, side view of a medical product 90
according to another embodiment of the invention. A distinct
drug-containing adhesive layer 91 is situated between a synthetic
polymer mesh 63 and an extracellular matrix sheet 62. Additionally,
a plurality of drug-eluting bodies 92 are situated above the
synthetic polymer mesh 63, i.e., opposite the extracellular matrix
sheet 62, so that the bodies are not covered by any other sheet or
layer and are therefore left exposed to the exterior of the
product. Optionally, product 90 itself can be incorporated into or
provide a building block for many other medical products of the
present invention. In an alternative embodiment, a second group of
drug-eluting bodies could be situated below the ECM sheet 62 and/or
a second ECM sheet could be positioned over the drug-eluting bodies
92.
[0062] FIGS. 13 and 14 depict an illustrative graft construct 100
that incorporates a synthetic mesh material 63, for instance
similar to that shown in FIG. 9. In this embodiment, the synthetic
mesh 63 is totally encapsulated between and within a top ECM layer
61 and a bottom ECM layer 62. While the actual material of the
encapsulated mesh is hidden from view in the completed construct,
the contour of the external surface of the construct forms
depressions within the openings and protuberances over the mesh
elements. This makes it possible to discern the location of the
mesh openings, through which the opposing ECM layers have been
bonded together to form bonded regions 66. It should be understood
however that the shape of a bonded region need not correspond to
the shape of an underlying synthetic mesh opening, although this
will generally be the case where ECM sheets are pressed in close
proximity around a synthetic mesh and bonded together through
openings in the mesh. Also, because the synthetic mesh is slightly
smaller in area than the ECM sheets, the full bonding together of
the opposing ECM layers produces a band 101 of bonded material
around the entire periphery of the synthetic mesh. This band is a
multilayered bonded ECM region devoid of synthetic mesh
material.
[0063] A plurality of discrete drug depots 102 have been formed
directly onto the top of the graft. While not necessary to broader
aspects of the invention, in this embodiment, each depot 102 is
positioned over one of the bonded regions 66. Additionally, with
this particular design, a single passageway 103 extends through all
of the bonded regions except those covered by a depot 102 although
passageways could be placed at those locations as well. Passageways
103 include a passageway wall 104 that traverses the entire
thickness of the ECM-synthetic mesh combination. As can be seen in
FIG. 13, each passageway is generally centered within a
corresponding bonded region 66, and the area of the bonded region
66 is considerably larger than the diameter of the passageway 103
such that, when viewed from the top, the bonded region area extends
laterally beyond and fully around the passageway. Each generally
cylindrical passageway extends through a corresponding opening of
the mesh although a 1:1 ratio of passageways to synthetic mesh
openings is not required. A particular synthetic mesh opening or
bonded region might have two or more passageways associated with
it, or it might have none associated with it.
[0064] With sufficient bonding between the top and bottom ECM
sheets where these sheets meet along the passageway wall 104, the
passageway can be substantially isolated from the material of the
synthetic mesh 63. This can allow, for example, bodily fluid and
other substances to more easily pass from one side of the graft to
the other without being able to directly contact the synthetic
material 63, or at least not for some period of time following
implantation. By using various bonding techniques as discussed
herein, the ECM sheets can be bonded together to the point of
essentially sealing off the passageway from the synthetic mesh.
Additionally, the passageway wall 104 can be lined or coated with a
variety of substances, e.g., waxes, oils or absorbable polymers
such as PLGA to help further separate or block the passageway from
the synthetic mesh 63 if desired.
[0065] FIG. 15 depicts an inventive graft construct 110 that
incorporates an optional synthetic polymer mesh 63 disposed between
a top sheet 61 and bottom sheet 61. The top and bottom sheets 61
and 62 are each constructed of multiple ECM layers, e.g., 2-10 or
more individual ECM layers. A drug depot 111 has been formed in
situ or otherwise attached onto top sheet 61. A plurality of such
drug depots can be attached to the top and/or bottom of the graft
constructs in a variety of locations as discussed elsewhere herein.
An optional interweaving member 112 (e.g., bioabsorbable suture)
affixes the top and bottom sheets together, and in instances where
the top and bottom sheets are laminated together, can provide the
function of helping to prevent their premature delamination. One or
more interweaving members of this sort can be incorporated into any
of embodiments disclosed herein. For example, interweaving members
such as those illustrated in International Application No.
PCT/US2011/063588 (Cook Biotech Incorporated), filed Dec. 6, 2011,
which is hereby incorporated by reference in its entirety, can be
incorporated into any of the inventive product disclosed herein to
provide some level of fixation between any two or more components
in the product. Also, as described elsewhere herein, any suitable
number and type of slit and non-slit openings can be formed into
the product extending fully or partially through any layer of the
product.
[0066] Continuing with FIG. 15, in one illustrative method of
manufacturing this particular embodiment, the synthetic mesh 63 is
sandwiched between the top and bottom sheets 61 and 62 (e.g.,
before any lamination occurs between the top and bottom sheets
and/or between the individual ECM layers within each of the top and
bottom sheets), and then all of the individual ECM layers are
laminated together with the synthetic mesh 63 inside. When
included, the interweaving member 112 provides further fixation of
the laminated ECM layers. Alternatively, the top and bottom sheets
61 and 62 could be prepared separately by dehydrothermally bonding
or otherwise laminating their individual ECM layers together, and
when included, the mesh 63 could then be inserted between the
previously-prepared sheets. Subsequent bonding of the top and
bottom sheets (e.g., with dehydrothermal bonding, use of adhesives
and other techniques) and/or installation of one or more
interweaving members could then be performed.
[0067] In preferred forms, sheet graft materials herein will
exhibit a compliancy, particularly when wet, so as to be
conformable to tissue structures or regions within a patient to be
treated. Sheets graft materials herein can be essentially planar in
a relaxed condition, or they can exhibit curvature and/or other
non-planar features, for example, exhibiting a curved, convex or
other three-dimensional configuration.
[0068] A sheet graft material, in some embodiments, will be a
laminate made from multiple layers of material, for instance 2 to
20 layers of material, or 2 to 10 layers of material in certain
forms. In a laminate sheet, the constituent layers may all be
identical, or any one layer may be the same or different than any
other layer in terms of its material(s) of construction and/or any
other characteristic. Illustratively, suitable laminate structures
can include a plurality of ECM layers bonded together, a plurality
of non-ECM layers (e.g., biodegradable or non-biodegradable
synthetic polymer layers) bonded together, or a combination of one
or more ECM layers and one or more non-ECM layers bonded together.
Illustratively, two or more ECM sheets can be bonded together using
a bonding technique, such as chemical cross-linking or vacuum
pressing under dehydrating conditions. An adhesive, glue or other
agent may also be used in achieving a bond between material layers.
Suitable bonding agents may include, for example, collagen gels or
pastes, gelatin, or other agents including reactive monomers or
polymers, for example cyanoacrylate adhesives. A combination of one
or more of these with dehydration-induced bonding may also be used
to bond ECM material layers to one another.
[0069] The drug or drugs incorporated in the drug depots can be any
of a wide variety of known useful drugs. The drug can be an
antimicrobial agent. Illustrative antimicrobial agents include, for
example, antibiotics such as penicillin, tetracycline,
chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin,
kanamycin, neomycin, gentamycin, erythromycin and cephalosporins.
Examples of cephalosporins include cephalothin, cephapirin,
cefazolin, cephalexin, cephradine, cefadroxil, cefamandole,
cefoxitin, cefaclor, cefuroxime, cefonicid, ceforanide, cefotaxime,
moxalactam, ceftizoxime, ceftriaxone, and cefoperazone, and
antiseptics (substances that prevent or arrest the growth or action
of microorganisms, generally in a nonspecific fashion) such as
silver sulfadiazine, chlorhexidine, sodium hypochlorite, phenols,
phenolic compounds, iodophor compounds, quaternary ammonium
compounds, and chlorine compounds. Still other drugs can be
incorporated in the drug depots, alone or in combination with an
antimicrobial agent or each other. Such other drugs may include,
for example, anti-clotting agents (e.g. heparin), anti-inflammatory
agents, anti-proliferative agents (e.g. taxol derivatives such as
paclitaxel), inhibitors of tissue adhesions, nonsteroidal
anti-inflammatory drugs (NSAIDs), and others.
[0070] Turning now to a more detailed discussion of materials that
can be utilized in the present invention, as discussed elsewhere
herein, inventive constructs can incorporate naturally derived
and/or non-naturally derived materials. In this regard, one or more
components of an inventive construct (e.g., a sheet, layer, mesh,
drug-eluting depot, just to name a few) may comprise one or more of
a variety of synthetic polymeric materials including but not
limited to bioresorbable and/or non-bioresorbable plastics.
Bioresorbable or bioabsorbable polymers that may be used include,
but are not limited to, poly(L-lactic acid), polycaprolactone,
poly(lactide-co-glycolide), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,
polyanhydride, poly(glycolic acid), poly(D,L-lactic acid),
poly(glycolic acid-co-trimethylene carbonate),
polyhydroxyalkanaates, polyphosphoester, polyphosphoester urethane,
poly(amino acids), cyanoacrylates, poly(trimethylene carbonate),
poly(iminocarbonate), copoly(ether-esters) (e.g., PEO/PLA),
polyalkylene oxalates, and polyphosphazenes. These or other
bioresorbable materials may be used, for example, where only a
temporary function or presence is desired, and/or in combination
with non-bioresorbable materials where only a temporary
participation by the bioresorable material is desired. Bioabsorable
polymers, such as those identified above, are preferred materials
to serve as carriers for drug depots herein, and/or in certain
embodiments may also be used to form bioabsorbable synthetic
polymer meshes used in embodiments herein.
[0071] Non-bioresorbable, or biostable polymers that may be used
include, but are not limited to, polytetrafluoroethylene (PTFE)
(including expanded PTFE), polyethylene terephthalate (PET),
polyurethanes, silicones, and polyesters and other polymers such
as, but not limited to, polyolefins, polyisobutylene and
ethylene-alphaolefin copolymers; acrylic polymers and copolymers,
vinyl halide polymers and copolymers, such as polyvinyl chloride;
polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene
halides, such as polyvinylidene fluoride and polyvinylidene
chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl
aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl
acetate; copolymers of vinyl monomers with each other and olefins,
such as ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl
acetate copolymers; polyamides, such as Nylon 66 and
polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes;
polyimides; polyethers; epoxy resins; polyurethanes; polypropylene;
rayon; and rayon-triacetate. In certain embodiments, biostable
polymers can be used as carriers in drug depots and/or meshes
incorporated in embodiments herein.
[0072] As disclosed above, in certain embodiments, the sheet graft
material will include a remodelable material. Particular advantage
can be provided by devices that incorporate a remodelable material.
Such remodelable materials can be provided, for example, by
collagenous membrane layer materials isolated from a warm-blooded
vertebrate, and especially a mammal. Such isolated collagenous
membrane materials can be processed so as to have remodelable,
angiogenic properties and promote cellular invasion and ingrowth.
Remodelable materials may be used in this context to promote
cellular growth on, around, and/or in bodily regions in which
inventive devices are implanted or engrafted.
[0073] Suitable remodelable materials for incorporation in any of
the embodiments herein can be provided by collagenous extracellular
matrix (ECM) materials. For example, suitable collagenous materials
include ECM materials such as those comprising submucosa, renal
capsule membrane, dermal collagen, dura mater, pericardium, fascia
lata, serosa, peritoneum or basement membrane layers, including
liver basement membrane. Suitable submucosa materials for these
purposes include, for instance, intestinal submucosa including
small intestinal submucosa, stomach submucosa, urinary bladder
submucosa, and uterine submucosa. These or other ECM materials can
be characterized as membranous tissue layers harvested from a
source tissue and decellularized. These membranous tissue layers
can have a porous matrix comprised of a network of collagen fibers,
wherein the network of collagen fibers retains an inherent network
structure from the source tissue. In particular aspects,
collagenous matrices comprising submucosa (potentially along with
other associated tissues) useful in the present invention can be
obtained by harvesting such tissue sources and delaminating the
submucosa-containing matrix from smooth muscle layers, mucosal
layers, and/or other layers occurring in the tissue source, and
decellularizing the matrix before or after such delaminating. For
additional information as to some of the materials useful in the
present invention, and their isolation and treatment, reference can
be made, for example, to U.S. Pat. Nos. 4,902,508, 5,554,389,
5,993,844, 6,206,931, and 6,099,567.
[0074] Submucosa-containing or other ECM tissue, when used in the
invention, is preferably highly purified, for example, as described
in U.S. Pat. No. 6,206,931 to Cook et al. Thus, preferred ECM
material will exhibit an endotoxin level of less than about 12
endotoxin units (EU) per gram, more preferably less than about 5 EU
per gram, and most preferably less than about 1 EU per gram. As
additional preferences, the submucosa or other ECM material may
have a bioburden of less than about 1 colony forming units (CFU)
per gram, more preferably less than about 0.5 CFU per gram. Fungus
levels are desirably similarly low, for example less than about 1
CFU per gram, more preferably less than about 0.5 CFU per gram.
Nucleic acid levels are preferably less than about 5 .mu.g/mg, more
preferably less than about 2 .mu.g/mg, and virus levels are
preferably less than about 50 plaque forming units (PFU) per gram,
more preferably less than about 5 PFU per gram. These and
additional properties of submucosa or other ECM tissue taught in
U.S. Pat. No. 6,206,931 may be characteristic of any ECM tissue
used in the present invention.
[0075] Submucosa-containing or other remodelable ECM tissue
material may retain one or more growth factors native to the source
tissue for the tissue material, such as but not limited to basic
fibroblast growth factor (FGF-2), transforming growth factor beta
(TGF-beta), epidermal growth factor (EGF), cartilage derived growth
factor (CDGF), and/or platelet derived growth factor (PDGF). As
well, submucosa or other ECM materials when used in the invention
may retain other native bioactive agents such as but not limited to
proteins, glycoproteins, proteoglycans, and glycosaminoglycans. For
example, ECM materials may include native heparin, native heparin
sulfate, native hyaluronic acid, native fibronectin, native
cytokines, and the like. Thus, generally speaking, a submucosa or
other ECM material may retain one or more native bioactive
components that induce, directly or indirectly, a cellular response
such as a change in cell morphology, proliferation, growth, protein
or gene expression.
[0076] Submucosa-containing or other ECM materials can be derived
from any suitable organ or other tissue source, usually sources
containing connective tissues. The ECM materials processed for use
in the invention will typically be membranous tissue layers that
include abundant collagen, most commonly being constituted at least
about 80% by weight collagen on a dry weight basis. Such
naturally-derived ECM materials will for the most part include
collagen fibers that are non-randomly oriented, for instance
occurring as generally uniaxial or multi-axial but regularly
oriented fibers. When processed to retain native bioactive factors,
the ECM material can retain these factors interspersed as solids
between, upon and/or within the collagen fibers. Particularly
desirable naturally-derived ECM materials for use in the invention
will include significant amounts of such interspersed,
non-collagenous solids that are readily ascertainable under light
microscopic examination with appropriate staining. Such
non-collagenous solids can constitute a significant percentage of
the dry weight of the ECM material in certain inventive
embodiments, for example at least about 1%, at least about 3%, and
at least about 5% by weight in various embodiments of the
invention.
[0077] A submucosa-containing or other ECM material used in the
present invention may also exhibit an angiogenic character and thus
be effective to induce angiogenesis in a host engrafted with the
material. In this regard, angiogenesis is the process through which
the body makes new blood vessels to generate increased blood supply
to tissues. Thus, angiogenic materials, when contacted with host
tissues, promote or encourage the formation of new blood vessels
into the materials. Methods for measuring in vivo angiogenesis in
response to biomaterial implantation have recently been developed.
For example, one such method uses a subcutaneous implant model to
determine the angiogenic character of a material. See, C. Heeschen
et al., Nature Medicine 7 (2001), No. 7, 833-839. When combined
with a fluorescence microangiography technique, this model can
provide both quantitative and qualitative measures of angiogenesis
into biomaterials. C. Johnson et al., Circulation Research 94
(2004), No. 2, 262-268.
[0078] Further, in addition or as an alternative to the inclusion
of such native bioactive components, non-native bioactive
components such as those synthetically produced by recombinant
technology or other methods (e.g., genetic material such as DNA),
may be incorporated into an ECM material. These non-native
bioactive components may be naturally-derived or recombinantly
produced proteins that correspond to those natively occurring in an
ECM tissue, but perhaps of a different species. These non-native
bioactive components may also be drug substances. Illustrative drug
substances that may be added to materials include, for example,
anti-clotting agents, e.g. heparin, antibiotics, anti-inflammatory
agents, thrombus-promoting substances such as blood clotting
factors, e.g., thrombin, fibrinogen, and the like, and
anti-proliferative agents, e.g. taxol derivatives such as
paclitaxel. Such non-native bioactive components can be
incorporated into and/or onto ECM material in any suitable manner,
for example, by surface treatment (e.g., spraying) and/or
impregnation (e.g., soaking), just to name a few. Also, these
substances may be applied to the ECM material in a premanufacturing
step, immediately prior to the procedure (e.g., by soaking the
material in a solution containing a suitable antibiotic such as
cefazolin), or during or after engraftment of the material in the
patient.
[0079] In certain forms, inventive devices include a material
receptive to tissue ingrowth. Upon deployment of such devices in
accordance with the present invention, cells from the patient can
infiltrate the material, leading to, for example, new tissue growth
on, around, and/or within the device. In some embodiments, the
device comprises a remodelable material. In these embodiments, the
remodelable material promotes and/or facilitates the formation of
new tissue, and is capable of being broken down and replaced by new
tissue. Remodelable ECM materials having a relatively more open
matrix structure (i.e., higher porosity) are capable of exhibiting
different material properties than those having a relatively more
closed or collapsed matrix structure. For example, an ECM material
having a relatively more open matrix structure is generally softer
and more readily compliant to an implant site than one having a
relatively more closed matrix structure. Also, the rate and amount
of tissue growth in and/or around a remodelable material can be
influenced by a number of factors, including the amount of open
space available in the material's matrix structure for the infusion
and support of a patient's tissue-forming components, such as
fibroblasts. Therefore, a more open matrix structure can provide
for quicker, and potentially more, growth of patient tissue in
and/or around the remodelable material, which in turn, can lead to
quicker remodeling of the material by patient tissue. In certain
aspects, an extracellular matrix layer or multilayer sheet (e.g. a
laminate) includes an open matrix structure formed by
lyophilization drying of the layer or sheet.
[0080] In certain embodiments, the sheet graft material can include
two or more individual layers of ECM material (e.g., 2 or more
layers bonded together). The total thickness of such a sheet can be
in the range of about 200 microns to about 4,000 microns, e.g.,
more than about 400 microns, or more than about 600 microns, or
more than about 800 microns, or more than about 1,000 microns, or
more than about 1,200 microns, or more than about 1,500 microns but
typically less than about 2,000 microns. In certain aspects, 2 to
about 20 layers of ECM material are bonded in a laminate for use as
or in the sheet graft material, more preferably 2 to about 10
layers of ECM material.
[0081] The constructs described herein have broad application. In
some aspects, inventive products will find use as precursor
materials for the later formation of a variety of other medical
products, or components thereof. Medical grafts and materials that
are already commercially available can be modified in accordance
with the present invention as well. In certain embodiments,
inventive products are useful in procedures to replace, augment,
support, repair, and/or otherwise suitably treat diseased or
otherwise damaged or defective patient tissue. Some of the
illustrative constructs described herein will be useful, for
example, in treating body wall defects such as herniated tissue in
an abdominal or other body wall, although inventive constructs and
materials can be developed and used in many other medical contexts.
In this regard, when used as a medical graft, inventive constructs
can be utilized in any procedure where the application of the graft
to a bodily structure provides benefit to the patient.
[0082] The present invention also provides, in certain aspects,
medical products that include a graft construct as described herein
in a sealed medical package. In some forms of the invention, such
medical products include the graft construct enclosed in sterile
condition within medical packaging. Illustratively, such a medical
product can have packaging including a backing layer and a front
film layer that are joined by a boundary of pressure-adhesive as is
conventional in medical packaging, wherein the contents of the
packaging are sealed between the backing layer and front film
layer. Sterilization of such a medical product may be achieved, for
example, by irradiation, ethylene oxide gas, or any other suitable
sterilization technique, and the materials and other properties of
the medical packaging will be selected accordingly. The medical
packaging in other aspects can include a further, outer package
containing a dessicant, which can act to maintain a dry condition
of the construct within the inner package when that inner package
is somewhat vapor permeable.
[0083] In order to promote a further understanding of aspects of
the present invention and features and advantages thereof, the
following specific Examples are provided. It will be understood
that these Examples are illustrative, and not limiting, of the
invention.
EXAMPLE 1
Preparation of Distributed Depot ECM Construct
[0084] A. Preparation of ECM Laminate With Reservoirs
[0085] An 8-ply layered lyophilized SIS sheet was prepared. The
sheet had approximately 12 mm diameter circular craters with raised
walls, formed by an embossing mold compressed against the 8 SIS
layer plies during lyophilization under conditions to bond the
layer plies to one another dehydrothermally. Each crater is formed
to have a diameter of 12 mm-13 mm with depth from bottom of the
crater to the top of the surrounding wall of about 1 to 2 mm. The
ECM material underlying the craters is denser and less porous than
the ECM material in surrounding regions due to the compression of
the material underlying the craters during drying. The formed SIS
laminate sheet is perforated (1.5 mm diameter open perforations)
and quilted with a 6-0 bioabsorable polyglycolic acid (PGA) thread,
with a 4 mm quilt spacing in a pattern generally as shown in FIG.
1, and cut to size with an appropriate templates or die.
[0086] B. In-Situ Formation of Depot Deposits
[0087] A 20% w/v solution of poly-DL-Lactide-Co-Glycolide (PLGA)
(50:50 PL:GA) in acetone is prepared and 15.68% w/w gentamicin
sulfate powder (equivalent to 10.232% w/w gentamicin freebase) to
the total solids (PLGA+gentamicin sulfate powder) is suspended in
the acetone solution. A controlled volume of the solution was
deposited into each crater on the SIS laminate sheet at a volume of
240 .mu.L per crater to form each depot. The depots are dried on
the SIS laminate sheet in a two stage process. The deposited
material was first dried using air drying at room temperature,
forming solidified depot material entraining air bubbles. In a
second drying step, the deposited material was further dried by
clamping the sheet between two porous inert polymeric sheets and
drying the clamped construct in a vacuum oven under vacuum and heat
(70.degree. C.) for 4 days. The clamping and drying process
compressed the depot material, collapsing the air bubbles and
reducing the thickness of the depots.
EXAMPLE 2
Gentamycin Depot Elution Testing
[0088] A. Collection of Test Articles
[0089] For this study, since it was difficult to implant multiple
of the whole 13.times.22 cm devices prepared as in Example 1 with
33 depots (as shown in FIG. 1) each into the peritoneal cavity of a
young 45 Kg domestic pig, the depot regions of the SIS laminate
sheet were cut out with a 15 mm diameter die. All such depot/ECM
samples were collected from prepared 6-7 laminate sheet devices and
pooled to randomize. These were the test articles. The test
articles were packaged in small groups, labeled and ETO
sterilized.
[0090] B. In Vitro Elution Study
[0091] An in vitro elution test was carried out by soaking each
test article in 5 mL of phosphate buffered saline (PBS) solution
(66.7 mM phosphate buffer prepared by dissolving 1.65 g potassium
phosphate monobasic and 14.63 g sodium phosphate dibasic
heptahydrate in 1000 mL of water) at 37.degree. C. for a specified
time period. Then the same test article was moved into a fresh vial
of PBS and soaked at 37.degree. C. for the next duration of time
point while maintaining traceability throughout. The soak solutions
thus collected were assayed for content of USP gentamicins using
known procedures, by colorimetric treatment followed by HPLC and UV
detection. The 3-4 major peaks representing the gentamicins were
integrated to estimate the total gentamicin present in the
solution. A five point calibration from 10 mcg/mL to 500 mcg/mL was
run with every batch made from the same lot of gentamicin from
vendor used to manufacture the devices. An elution profile graph
thus obtained is presented in FIG. 16.
[0092] C. In Vivo Elution Study
[0093] An in vivo elution study was conducted by implanting test
articles collected as described above intraperitoneally in a pig.
Test articles were implanted in the intraperitoneal abdominal space
of a domestic swine such that the total dose of gentamicin freebase
present in the implants was equal to or greater than 1.5 times the
highest documented intra venous dose of 7 mg/kg body weight in a
once-daily injection regime. The serum gentamicin levels were
tested at 0 (just pre-implant), 4 hr, 24 hr, 48 hr, 72 hr, 120 hr,
290 hr post implant using a validated LCMS assay. Gross necropsy
was conducted after 290 hours time point and what was left of the
implants was observed and collected. Un-implanted test articles
from the same lot were tested by using the above-noted colorimetric
USP content of gentamicins assay by HPLC/UV for determining average
gentamicin content and in vitro elution profile. Some of the
explanted test articles were also tested for average gentamicin
content left after 290 hours in vivo. Similar content of gentamicin
present in the un-implanted depots vs. the explanted test articles
was carried out using liquid chromatography-mass spectrometry
(LCMS).
[0094] More specifically, the test articles un-implanted were
soaked in vials containing high purity water (HPW) at the rate of 5
mL per article. The explanted test articles obtained were separated
if adhered to one another, rinsed quickly with 2-3 mL of HPW by
dropper to remove any gentamicin already eluted and any excess
blood present. The explanted samples were then placed in vials
containing HPW at 5 mL per article.
[0095] Vials containing test articles were closed and incubated at
80.degree. C. with 200 rpm orbital shaking for 46 hours to extract
most of the gentamicin entrapped in the PLGA by degrading the
polymer via accelerated hydrolysis. After cooling, the exhaustive
extraction solutions were assayed for content of gentamicins as
described above. An assessment of the data from these studies
showed that each test article was originally loaded with
4.522.+-.0.306 mg gentamicin freebase. Based on the number of test
articles implanted (110) in the pig the total dose of gentamicin
implanted was 497.42.+-.33.66 mg gentamicin freebase. This was
estimated as a dose of 11.05.+-.0.75 mg/Kg bw of the pig, which is
approximately 1.6 time greater than the maximum dose of gentamycin
given once-daily intravenously to humans.
[0096] The measured serum levels of gentamycin in the pig are shown
in FIG. 17. Also, based on an analysis of 12 randomly selected
un-implanted test articles and 12 randomly-selected explanted test
articles, an estimated 16% of the gentamycin originally present
remained in the explanted test articles (after 290 hours of
implantation in vivo).
[0097] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Further,
any theory, mechanism of operation, proof, or finding stated herein
is meant to further enhance understanding of the present invention,
and is not intended to limit the present invention in any way to
such theory, mechanism of operation, proof, or finding. While the
invention has been illustrated and described in detail in the
drawings and foregoing description, the same is to be considered as
illustrative and not restrictive in character, it being understood
that only selected embodiments have been shown and described and
that all equivalents, changes, and modifications that come within
the spirit of the inventions as defined herein or by the following
claims are desired to be protected.
* * * * *