U.S. patent application number 14/899570 was filed with the patent office on 2016-05-26 for films and methods of manufacture.
The applicant listed for this patent is DEPUY SYNTHES PRODUCTS, INC.. Invention is credited to David ARMBRUSTER, Jeffrey CHOMYN, James DWYER (Deceased), Sean H. KERR.
Application Number | 20160144067 14/899570 |
Document ID | / |
Family ID | 51179149 |
Filed Date | 2016-05-26 |
United States Patent
Application |
20160144067 |
Kind Code |
A1 |
ARMBRUSTER; David ; et
al. |
May 26, 2016 |
FILMS AND METHODS OF MANUFACTURE
Abstract
Embodiments of the present disclosure are directed to perforated
polymer films and methods of making the same. In some embodiments,
the films are for use with implantable medical devices. In one
embodiment there is a flexible body including a polymer film having
a first surface and an opposing second surface, the film having a
plurality of apertures extending from the first surface to the
second surface and a plurality of raised lips protruding from the
first surface such that each of the plurality of apertures is
surrounded by a one of the plurality of raised lips. In one
embodiment, the film comprises a single layer, and in another
embodiment, the film can comprise a plurality of layers. In certain
embodiments, the film can comprise an adhesive layer. In another
embodiment, one or more of the layers may be a drug containing
layer and/or a rate controlling layer for drug release.
Inventors: |
ARMBRUSTER; David; (West
Chester, PA) ; DWYER (Deceased); James; (US) ;
CHOMYN; Jeffrey; (Maurrieta, CA) ; KERR; Sean H.;
(West Chester, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DEPUY SYNTHES PRODUCTS, INC. |
Raynham |
MA |
US |
|
|
Family ID: |
51179149 |
Appl. No.: |
14/899570 |
Filed: |
June 10, 2014 |
PCT Filed: |
June 10, 2014 |
PCT NO: |
PCT/US2014/041662 |
371 Date: |
December 18, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61837716 |
Jun 21, 2013 |
|
|
|
Current U.S.
Class: |
604/307 ;
424/400; 606/71 |
Current CPC
Class: |
A61L 31/06 20130101;
A61F 2310/0097 20130101; A61B 17/80 20130101; A61F 2002/30677
20130101; A61F 2310/00389 20130101; A61L 31/14 20130101; A61F
2/30907 20130101; A61B 17/8057 20130101; A61L 2430/02 20130101;
A61L 24/0015 20130101; A61B 2017/00526 20130101; A61K 9/7007
20130101; A61L 31/16 20130101; B32B 3/266 20130101; B32B 2535/00
20130101; A61B 17/8085 20130101; A61L 31/06 20130101; C08L 67/04
20130101 |
International
Class: |
A61L 24/00 20060101
A61L024/00; A61K 9/70 20060101 A61K009/70; A61B 17/80 20060101
A61B017/80; B32B 3/26 20060101 B32B003/26 |
Claims
1. A flexible body comprising: a film having a first surface and an
opposing second surface, the film having a plurality of apertures
extending from the first surface to the second surface and a
plurality of raised lips protruding from the first surface such
that each of the plurality of apertures is surrounded by a one of
the plurality of raised lips; wherein the film comprises a
plurality of layers, wherein at least one of the plurality of
layers includes a drug containing layer containing a drug, and,
wherein at least one of the plurality of layers includes an
adhesive layer.
2. The flexible body of claim 1, wherein the adhesive layer defines
one of the first surface and the second surface.
3. The flexible body of claim 1, wherein at least one of the
plurality of layers includes a rate controlling layer configured to
control a rate release of the drug.
4. The flexible body of claim 1, wherein the film comprises a
biodegradable polymer.
5. The flexible body of claim 4, wherein the drug is at least
partially insoluble in the polymer.
6. The flexible body of claim 1, wherein the film further comprises
one or more biocompatible particles.
7. The flexible body of claim 6, wherein the particles comprise
calcium-containing salt particles.
8. The flexible body of claim 1, wherein the film defines a first
region having the apertures and a second region devoid of the
apertures.
9. A method of forming a multi-layered film comprising: placing a
first polymer solution into a mold having a plurality of
protrusions extending from a bottom of the mold; urging the polymer
solution around each of the plurality of protrusions; placing one
or more additional polymer solutions into the mold; and,
solidifying the polymer solution; wherein a multi-layer film having
a plurality of apertures is formed.
10. The method according to claim 9, wherein the step of placing
one or more additional polymer solutions into the mold occurs prior
to the step of urging, such that urging the polymer solution
includes urging the first polymer solution and the one or more
polymer solutions.
11. The method according to claim 9, wherein the step of
solidifying the polymer solution occurs both prior to and after the
step of placing one or more additional polymer solutions into the
mold.
12. The method according to claim 9, wherein at least one of the
first polymer solution or the one or more additional polymer
solutions comprises a drug.
13. The method according to claim 9, wherein at least one of the
first polymer solution or the one or more additional polymer
solutions comprises an adhesive layer when solidified.
14. The method according to claim 9, wherein at least one of the
first polymer solution, or the one or more additional polymer
solutions comprises a rate controlling layer for drug release when
solidified.
15. A film storage system, for the storage, packaging and/or
shipment of a film comprising: the flexible body of claim 1; and a
removable non-adhesive backing material placed over the adhesive
layer.
16. A film storage system, for the storage, packaging and/or
shipment of a film comprising: the flexible body of claim 1; and a
collector configured to collect the film, wherein the film is
separable from the collector.
17. A system for orthopedic treatment comprising: an orthopedic
medical device; and, a film fixation system including the flexible
body of claim 1 and a film fixation element.
18. The system for orthopedic treatment according to claim 17,
wherein the orthopedic medical device is a bone plate having a bone
fixation hole.
19. The system for orthopedic treatment according to claim 18,
further comprising a bone having a threaded shaft configured to
align with the bone fixation hole.
20. The system for orthopedic treatment according to claim 19,
wherein a diameter of the threaded shaft of the bone screw is
greater than both a cross-sectional dimension of at least two
adjacent apertures and a gap between the at least two adjacent
apertures such that the screw shaft is configured to be driven
through a region of the film aligned with the bone fixation hole
that includes more than one aperture.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/837,716, filed Jun. 21, 2013, titled
"Films and Methods of Manufacture," which is hereby incorporated by
reference in its entirety.
INCORPORATIONS BY REFERENCE
[0002] U.S. patent application Ser. No. 12/089,574, filed on Apr.
8, 2008, is a national stage application of PCT/US2006/040038,
filed Oct. 12, 2006, and both applications are hereby incorporated
by reference in their entirety. U.S. patent application Ser. No.
13/727,682, filed on Dec. 27, 2012, claims the benefit of U.S.
Provisional Patent Application No. 61/580,679 filed Dec. 28, 2011
entitled "Films and Methods of Manufacture," and both applications
are hereby incorporated by reference in their entirety.
FIELD OF THE DISCLOSURE
[0003] The present disclosure generally relates to films (e.g.,
polymer films) and methods of manufacture, and in at least some
embodiments, perforated films and methods of medical use.
BACKGROUND
[0004] High-energy lower extremity fractures have been associated
with surgical site infection (SSI) and osteomyelitis rates ranging
from approximately 14% to 60% in both military and civilian
settings. The current standard for treatment of such fractures
typically includes using metal implants (plates and screws or
nails) for fracture fixation, which have the potential disadvantage
of placing metal within a fracture site. These metal implants can
serve as sites for bacterial adhesion and formation of a bacterial
biofilm, where bacteria can remain sequestered from the body's
immune system, resulting in surgical site infections.
[0005] Although the use of intravenous (IV) antibiotics as a
prophylaxis against wound infection has become standard, infection
rates in certain types of orthopedic trauma remain high. Systemic
antibiotics may not reach the implant surface in sufficient
concentration due to locally impaired circulation at the wound
site, and bacterial biofilm formation can be very rapid. Biofilm
based infections are not only resistant to systemic antibiotic
therapy and the host immune system, they typically require
additional surgery to remove the infected implant.
[0006] Locally delivered antibiotics hold promise for reducing
SSIs, particularly those associated with high-energy fractures, as
they can be used to deliver high concentrations of antibiotics
where needed and prevent the development of biofilms on the implant
surface. Multiple studies in animals have demonstrated that if an
implant surface can be protected from colonization by bacteria for
a period of time immediately after surgery, the rate of subsequent
infection can be significantly reduced.
[0007] Surgeons have used a variety of products for local delivery
of antibiotics, typically aminoglycosides and/or vancomycin,
including polymethyl methacrylate (PMMA) cements, beads, gels, and
collagen sponges. However, in certain situations, these antibiotic
treatments are not practical, for example where they take up space
at the site making wound closure difficult, and in other situations
may also require a separate surgery for their removal.
[0008] Infections represent a major challenge in orthopedic or
trauma surgery. Despite prophylactic measures like asepsis and
antisepsis, the surgery site is still a site of access for local
pathogens to become virulent and cause infections.
[0009] Coating an implantable device with a drug, such as an
antibiotic, has been effective to reduce infection. However, given
the large number, sizes, and shapes of implants and other medical
devices, the regulatory, financial, and logistical burden of
providing a coating for each device is enormous. The problem is
amplified if one considers additional drugs to use in coatings such
as analgesics, antineoplastic agents and growth promoting
substances.
SUMMARY
[0010] Embodiments of the present disclosure are directed to
polymer films, and in some embodiments, perforated polymer films
and novel casting methods of making the same. In some embodiments,
the films are for use with implantable medical devices though the
films may be used in any application.
[0011] Commercial methods of forming a perforated film currently
existing generally involve forming a solid film as a first step,
then punching or cutting holes into the film as a second step. An
advantage of at least some of the embodiments described herein is
that the holes or apertures of the film are formed at the same time
that the film is formed. This may be useful when the polymer film
to be formed is very thin and at risk for damage due to subsequent
handling or processing or when the thickness and/or strength of the
film makes it difficult to punch or cut by traditional methods
without damaging the film. Such a process may also be advantageous
when the polymer solution contains an active agent that may be
damaged by subsequent hole-punching steps. The active agent may be
a drug, such as an anti-microbial agent, including one or more of
an anti-bacterial agent, an anti-viral agent, and anti-parasitic
agent of the type known to one having ordinary skill in the art, or
any suitable alternative active agent, such as an
anti-inflammatory, a steroid, an analgesic, an opioid, a growth
factor, or the like,
[0012] Embodiments of the present disclosure may also be useful for
making quantities of cast film such as those which are considered
too small to make economically by traditional methods which are
typically continuous processes designed for high volume production.
An additional advantage of at least some embodiments of the present
disclosure is that apertures (or perforations) formed in the cast
sheet can have complex shapes. A further advantage of certain
embodiments of the disclosure is that at least one side of the film
may be formed to have a non-planar surface which in some
embodiments increases (or reduces) friction and gives an improved
tactile feel. These advantages of the present disclosure, as well
as others, are described in further detail below.
[0013] In one embodiment there is a flexible body comprising a film
(e.g., a polymer film) having a first surface and an opposing
second surface, the film having a plurality of apertures extending
from the first surface to the second surface and a plurality of
raised lips protruding from the first surface such that each of the
plurality of apertures is surrounded by a one of the plurality of
raised lips. In a preferred embodiment, the film is comprised of a
polymeric material (i.e., a polymer film). In one embodiment, the
film comprises a single layer, and in another embodiment, the film
can comprise a plurality of layers, for example, two or more
layers, such as two layers, three layers, four layers, up to and
including seven layers. In certain embodiments, the film can
comprise an adhesive layer, for example, the first surface or the
second surface of the film, or both, can comprise an adhesive
layer. In another embodiment, one or more of the layers may be a
drug containing layer and/or a rate controlling layer for drug
release (with or without a drug contained therein).
[0014] In one embodiment, the polymer material comprises a
bioresorbable polymer. In one embodiment, the bioresorbable polymer
comprises a polyester or blend of polyesters (collectively
"polyesters") and their co-polymers and derivatives. In certain
preferred embodiments the polyester(s) is hydrolyzable. Suitable
polyesters can include, for example, polyglycolic acid, polylactic
acid and polycaprolactone. In one embodiment, the bioresorbable
polymer is a copolymer of glycolide, trimethylene carbonate,
lactide and caprolactone.
[0015] In one embodiment, the first surface includes a contiguous
planar portion extending between the plurality of raised protruding
lips. In one embodiment, the plurality of raised protruding lips
each have an outer edge that is raised above the contiguous planar
portion by approximately 0.1 mm to approximately 1.0 mm. In one
embodiment, the polymer film comprises a plurality of discrete
eluting drug components and wherein the polymer film is configured
to elute the plurality of discrete drug components at different
time periods following implantation of the flexible body. In a
further embodiment, the flexible body comprises at least one
attachment configured to form the polymer film into a sleeve. In
one embodiment, the polymer film has a first tensile strength in a
first planar direction and a second tensile strength in a second
planar direction that is perpendicular to the first planar
direction, wherein the first tensile strength is substantially
equal to the second tensile strength. In one embodiment, the
polymer film has a nominal thickness of no greater than 0.06 mm. In
one embodiment, the first surface has a first tactile feel that is
different from a second tactile feel of the second surface.
[0016] In another embodiment there is a method of producing a
polymer film comprising: placing a polymer solution into a one
sided mold having a plurality of protrusions extending from a
bottom of the mold. In certain embodiments, the polymer solution is
characterized by a viscosity that inhibits the unaided flow of the
polymer throughout the mold. The process further includes urging
the polymer solution around each of the plurality of protrusions;
and solidifying the polymer solution. In one embodiment, the mold
includes a perimeter form extending to an elevation that is
substantially equal to an elevation of each of the plurality of
protrusions. In one embodiment, the urging comprises drawing an
urging instrument such as a blade, bar, squeegee or roller across
the perimeter form and the plurality of protrusions to force the
polymer solution to flow around the plurality of protrusions and
throughout the mold such that the polymer solution has a
substantially uniform thickness. In one embodiment, at least a
portion of an outer surface of a protrusion, for example an upper
portion of a protrusion, is substantially free of polymer solution
after the drawing. In one embodiment, the placing step includes
depositing the polymer solution in the mold such that a portion of
the polymer solution is above the elevation of the perimeter form
and the protrusions. In a still further embodiment, one or more of
the method steps can be repeated such that a film comprising a
plurality of layers may be produced, for example, two or more
layers, such as two layers, three layers, four layers, up to and
including seven layers. In certain embodiments, the method
additionally includes the steps of placing one or more additional
polymer solutions in the mold over a first polymer solution, and
urging the one or more polymer solutions around each of the
plurality of protrusions. These steps can occur prior to, during,
or after the step of solidifying the polymer solution. Thus,
according to one embodiment of the method, each of the one or more
polymer solutions placed in the mold can solidify prior to, during,
or after, the step of placing the next or subsequent additional
polymer solution into the mold. According to one embodiment, the
one or more polymer solutions comprises a polymer solution that can
solidify into an adhesive layer, and according to another
embodiment, the one or more polymer solutions comprises a rate
controlling layer for drug release.
[0017] In one embodiment, solidifying the polymer solution includes
reducing a thickness of the polymer solution. In one embodiment,
solidifying the polymer solution includes forming a meniscus of
solidified polymer around each of the plurality of protrusions. In
one embodiment, distance from the bottom of the mold to a top of
each of the plurality of protrusions is less than approximately 0.3
mm. In one embodiment, the polymer solution contains a drug. In one
embodiment, the polymer solution is formed by combining a solvent,
a polymer, and the drug at a temperature below 90.degree. C. In one
embodiment, the perimeter form defines a total mold area and the
plurality of protrusions defines an area that is at least about 15%
of the total mold area. In a further embodiment, the method
comprises peeling, or otherwise removing, the drug eluting film
from the mold.
[0018] In one embodiment, the polymer solution comprises a
cross-linkable pre-polymer solution. In one embodiment, the
solidifying step includes cross-linking the polymer by applying UV
radiation, temperature change, polymerization catalysts, soluble
crosslinking agents or combinations thereof to the polymer
solution. In one embodiment, the polymer solution includes discrete
drug units. In one embodiment, the polymer solution comprises a
first solvent and a polymer and the solidifying step includes
exposing the polymer solution to a second solvent in which the
first solvent is soluble and in which the polymer and the drug are
not soluble such that the first solvent is at least substantially
removed from the polymer solution and the polymer solidifies to
contain the drug.
[0019] The polymer films disclosed herein may be used to inhibit
microbial infection at a surgical site, including bacterial
colonization of a medical implant implanted at the surgical site.
Typically, the methods comprise identifying a surgical site in need
of microbial inhibition and contacting the surgical site with a
polymer film comprising an active agent (e.g., drug). The methods
may also involve identifying a zone at a surgical site or on a
medical implant needing microbial inhibition, contacting the
medical implant with the polymer film, e.g., by affixing the
polymer film to the implant, and implanting the medical implant at
the surgical site. Because the contacting of the polymer film and
the medical implant are done at or near the time of surgery, i.e.,
intraoperatively, the surgeon can match the polymer film with the
medical implant to be contacted based on the size and shape of the
medical implant and the drug requirements for the subject
patient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The foregoing summary, as well as the following detailed
description of embodiments of the polymer films and methods of
manufacture, will be better understood when read in conjunction
with the appended drawings of exemplary embodiments. It should be
understood, however, that the invention is not limited to the
precise arrangements and instrumentalities shown.
[0021] In the drawings:
[0022] FIG. 1A is an enlarged perspective schematic view of a
portion of a film (in this instance a polymer film) in accordance
with an exemplary embodiment of the present disclosure;
[0023] FIG. 1B is a 60.times. magnified photo of an aperture of a
polymer film in accordance with an exemplary embodiment of the
present disclosure;
[0024] FIG. 2 is a top view of three exemplary sleeves formed from
the polymer film of FIG. 1B in combination with a respective
implantable medical device;
[0025] FIG. 3A is a perspective view of a portion of a mold in
accordance with an exemplary embodiment of the present
disclosure;
[0026] FIG. 3B is a top plan view of the mold of FIG. 3A;
[0027] FIG. 3C is a cross-sectional side view of the mold of FIG.
3B taken about line C-C in FIG. 3B;
[0028] FIG. 3D is an enlarged corner section of the mold shown in
FIG. 3B;
[0029] FIG. 3E is an enlarged cross section of the mold shown in
FIG. 3D taken along line 3E-3E;
[0030] FIG. 3F is an enlarged perspective photograph of a section
of the mold of FIG. 3A;
[0031] FIG. 3G is an enlarged perspective photograph of a section
of the mold in accordance with another exemplary embodiment of the
present disclosure;
[0032] FIG. 4A is a schematic side cross-sectional view of the mold
of FIG. 3A with the polymer added;
[0033] FIG. 4B is a schematic side cross-sectional view of the mold
shown in FIG. 4A showing the drawing device drawing the polymer
across the mold;
[0034] FIG. 4C is a schematic side cross-sectional view of the mold
shown in FIG. 4A showing the polymer after being drawn across the
mold and solidified to form a polymer film;
[0035] FIG. 4D is a schematic side cross-sectional view of the mold
shown in FIG. 4C showing the polymer after being drawn across the
mold and solidified to form a polymer film in accordance with
another embodiment;
[0036] FIG. 4E is a schematic side cross-sectional view of the mold
shown in FIG. 4C showing the polymer after being drawn across the
mold and solidified to form a polymer film in accordance with yet
another embodiment;
[0037] FIG. 5 is a perspective view of an automated casting
apparatus in accordance with an exemplary embodiment of the present
disclosure;
[0038] FIG. 6 is a perspective view of the automated casting
apparatus of FIG. 5 showing the polymer being added to the
mold;
[0039] FIG. 7 is a perspective view of the automated casting
apparatus of FIG. 5 showing the drawing device drawing the polymer
across the mold;
[0040] FIG. 8 is a perspective view of polymer being added to a
mold in accordance with another exemplary embodiment of the present
disclosure;
[0041] FIG. 9 is a perspective view of the mold of FIG. 8 showing
the drawing device drawing the polymer across the mold;
[0042] FIG. 10 is a perspective view of the mold of FIG. 8 showing
the polymer film being removed from the mold;
[0043] FIG. 11A is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1 shown in
one configuration;
[0044] FIG. 11B is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1 shown in
another configuration;
[0045] FIG. 11C is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1, shown in
another configuration;
[0046] FIG. 11D is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1, shown in
another configuration;
[0047] FIG. 11E is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1, shown in
another configuration;
[0048] FIG. 11F is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1, shown in
another configuration;
[0049] FIG. 11G is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1, shown in
another configuration;
[0050] FIG. 11H is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1, shown in
another configuration;
[0051] FIG. 11I is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1, shown in
another configuration;
[0052] FIG. 11J is a top plan view of a sleeve that comprises at
least one polymer film of the type illustrated in FIG. 1, shown in
another configuration;
[0053] FIG. 11K is an enlarged perspective view of a portion of the
film of each of the sleeves as illustrated in FIGS. 11A-J in
accordance with one embodiment;
[0054] FIG. 11L is an enlarged top plan view of a portion of each
of the sleeves as illustrated in FIGS. 11A-J, such as a top plan
view of the area within region 11E in FIG. 11E;
[0055] FIG. 11M is an enlarged view of a seam of a sleeve such as
those shown in FIGS. 11A-11J;
[0056] FIG. 12 is a yield stress graph of a polymer film in
accordance with an exemplary embodiment of the present
disclosure;
[0057] FIG. 13 is a strain at yield graph of a polymer film in
accordance with an exemplary embodiment of the present
disclosure;
[0058] FIG. 14 is a graph illustrating the rate of drug release
over time when a sleeve in accordance with an exemplary embodiment
of the present disclosure is placed into saline solution;
[0059] FIG. 15 is an in-vitro mass loss graph of a polymer film in
accordance with an exemplary embodiment of the present
disclosure;
[0060] FIG. 16 is an in-vitro molecular weight loss graph of a
polymer film in accordance with an exemplary embodiment of the
present disclosure;
[0061] FIG. 17A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11A, including a pair of films shown in
a closed configuration;
[0062] FIG. 17B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 17A taken at line 17B-17B of FIG. 17A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0063] FIG. 17C is a top plan view of the sleeve illustrated in
FIG. 17A;
[0064] FIG. 17D is a bottom plan view of the sleeve illustrated in
FIG. 17A;
[0065] FIG. 17E is a rear elevation view of the sleeve illustrated
in FIG. 17A;
[0066] FIG. 17F is a front elevation view of the sleeve illustrated
in FIG. 17A;
[0067] FIG. 17G is a right side elevation view of the sleeve
illustrated in FIG. 17A;
[0068] FIG. 17H is a left side elevation view of the sleeve
illustrated in FIG. 17A;
[0069] FIG. 18A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11B, including a pair of films shown in
a closed configuration;
[0070] FIG. 18B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 18A taken at line 18B-18B of FIG. 18A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0071] FIG. 18C is a top plan view of the sleeve illustrated in
FIG. 18A;
[0072] FIG. 18D is a bottom plan view of the sleeve illustrated in
FIG. 18A;
[0073] FIG. 18E is a rear elevation view of the sleeve illustrated
in FIG. 18A;
[0074] FIG. 18F is a front elevation view of the sleeve illustrated
in FIG. 18A;
[0075] FIG. 18G is a right side elevation view of the sleeve
illustrated in FIG. 18A;
[0076] FIG. 18H is a left side elevation view of the sleeve
illustrated in FIG. 18A;
[0077] FIG. 19A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11C, including a pair of films shown in
a closed configuration;
[0078] FIG. 19B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 19A taken at line 19B-19B of FIG. 19A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0079] FIG. 19C is a top plan view of the sleeve illustrated in
FIG. 19A;
[0080] FIG. 19D is a bottom plan view of the sleeve illustrated in
FIG. 19A;
[0081] FIG. 19E is a rear elevation view of the sleeve illustrated
in FIG. 19A;
[0082] FIG. 19F is a front elevation view of the sleeve illustrated
in FIG. 19A;
[0083] FIG. 19G is a right side elevation view of the sleeve
illustrated in FIG. 19A;
[0084] FIG. 19H is a left side elevation view of the sleeve
illustrated in FIG. 19A;
[0085] FIG. 20A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11D, including a pair of films shown in
a closed configuration;
[0086] FIG. 20B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 20A taken at line 20B-20B of FIG. 20A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0087] FIG. 20C is a top plan view of the sleeve illustrated in
FIG. 20A;
[0088] FIG. 20D is a bottom plan view of the sleeve illustrated in
FIG. 20A;
[0089] FIG. 20E is a rear elevation view of the sleeve illustrated
in FIG. 20A;
[0090] FIG. 20F is a front elevation view of the sleeve illustrated
in FIG. 20A;
[0091] FIG. 20G is a right side elevation view of the sleeve
illustrated in FIG. 20A;
[0092] FIG. 20H is a left side elevation view of the sleeve
illustrated in FIG. 20A;
[0093] FIG. 21A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11E, including a pair of films shown in
a closed configuration;
[0094] FIG. 21B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 21A taken at line 21B-21B of FIG. 21A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0095] FIG. 21C is a top plan view of the sleeve illustrated in
FIG. 21A;
[0096] FIG. 21D is a bottom plan view of the sleeve illustrated in
FIG. 21A;
[0097] FIG. 21E is a rear elevation view of the sleeve illustrated
in FIG. 21A;
[0098] FIG. 21F is a front elevation view of the sleeve illustrated
in FIG. 21A;
[0099] FIG. 21G is a right side elevation view of the sleeve
illustrated in FIG. 21A;
[0100] FIG. 21H is a left side elevation view of the sleeve
illustrated in FIG. 21A;
[0101] FIG. 22A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11F, including a pair of films shown in
a closed configuration;
[0102] FIG. 22B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 22A taken at line 22B-22B of FIG. 22A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0103] FIG. 22C is a top plan view of the sleeve illustrated in
FIG. 22A;
[0104] FIG. 22D is a bottom plan view of the sleeve illustrated in
FIG. 22A;
[0105] FIG. 22E is a rear elevation view of the sleeve illustrated
in FIG. 22A;
[0106] FIG. 22F is a front elevation view of the sleeve illustrated
in FIG. 22A;
[0107] FIG. 22G is a right side elevation view of the sleeve
illustrated in FIG. 22A;
[0108] FIG. 22H is a left side elevation view of the sleeve
illustrated in FIG. 22A;
[0109] FIG. 23A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11G, including a pair of films shown in
a closed configuration;
[0110] FIG. 23B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 23A taken at line 23B-23B of FIG. 23A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0111] FIG. 23C is a top plan view of the sleeve illustrated in
FIG. 23A;
[0112] FIG. 23D is a bottom plan view of the sleeve illustrated in
FIG. 23A;
[0113] FIG. 23E is a rear elevation view of the sleeve illustrated
in FIG. 23A;
[0114] FIG. 23F is a front elevation view of the sleeve illustrated
in FIG. 23A;
[0115] FIG. 23G is a right side elevation view of the sleeve
illustrated in FIG. 23A;
[0116] FIG. 23H is a left side elevation view of the sleeve
illustrated in FIG. 23A;
[0117] FIG. 24A is a top, front, right perspective view of a
portion of the sleeve illustrated in FIG. 11H, including a pair of
films shown in a closed configuration;
[0118] FIG. 24B is a sectional elevation view of the sleeve
illustrated in FIG. 23A taken at line 24B-24B of FIG. 24A, showing
the sleeve in an open configuration whereby the films are partially
separated from each other;
[0119] FIG. 24C is a top plan view of the sleeve illustrated in
FIG. 24A;
[0120] FIG. 24D is a bottom plan view of the sleeve illustrated in
FIG. 24A;
[0121] FIG. 24E is a rear elevation view of the sleeve illustrated
in FIG. 24A;
[0122] FIG. 24F is a front elevation view of the sleeve illustrated
in FIG. 24A;
[0123] FIG. 24G is a right side elevation view of the sleeve
illustrated in FIG. 24A;
[0124] FIG. 24H is a left side elevation view of the sleeve
illustrated in FIG. 24A;
[0125] FIG. 25A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11I, including a pair of films shown in
a closed configuration;
[0126] FIG. 25B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 25A taken at line 25B-25B of FIG. 25A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0127] FIG. 25C is a top plan view of the sleeve illustrated in
FIG. 25A;
[0128] FIG. 25D is a bottom plan view of the sleeve illustrated in
FIG. 25A;
[0129] FIG. 25E is a rear elevation view of the sleeve illustrated
in FIG. 25A;
[0130] FIG. 25F is a front elevation view of the sleeve illustrated
in FIG. 25A;
[0131] FIG. 25G is a right side elevation view of the sleeve
illustrated in FIG. 25A;
[0132] FIG. 25H is a left side elevation view of the sleeve
illustrated in FIG. 25A;
[0133] FIG. 26A is a top, front, right perspective view of the
sleeve illustrated in FIG. 11J, including a pair of films shown in
a closed configuration;
[0134] FIG. 26B is a sectional elevation view of a portion of the
sleeve illustrated in FIG. 26A taken at line 26B-26B of FIG. 26A,
showing the sleeve in an open configuration whereby the films are
partially separated from each other;
[0135] FIG. 26C is a top plan view of the sleeve illustrated in
FIG. 26A;
[0136] FIG. 26D is a bottom plan view of the sleeve illustrated in
FIG. 26A;
[0137] FIG. 26E is a rear elevation view of the sleeve illustrated
in FIG. 26A;
[0138] FIG. 26F is a front elevation view of the sleeve illustrated
in FIG. 26A;
[0139] FIG. 26G is a right side elevation view of the sleeve
illustrated in FIG. 26A; and
[0140] FIG. 26H is a left side elevation view of the sleeve
illustrated in FIG. 26A;
[0141] FIG. 27 is graph showing a log reduction in CFUs for a
variety of bacteria in the presence of a drug-containing polymer
film according to one embodiment of the present disclosure;
[0142] FIG. 28 is a graph showing a minimum effective concentration
and zone of inhibition in the presence of drug-containing polymer
films according to embodiments of the present disclosure; and;
[0143] FIG. 29 is a graph showing a zone of inhibition against
several bacteria in the presence of a drug-containing polymer film
according to an embodiment of the present disclosure.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0144] Referring to the drawings in detail, wherein like reference
numerals indicate like elements throughout, there is shown in FIGS.
1A and 3A polymer films, generally designated 10, and molds,
generally designated 18, in accordance with exemplary embodiments
of the present disclosure.
[0145] Referring to the embodiment of FIG. 1A, the film 10 (e.g., a
polymer film) is a flexible body 11 having a first surface 10a and
a second surface 10b that is opposite the first surface along a
transverse direction T. As also illustrated in FIG. 2, the flexible
body 11, and thus the film 10, defines first and second opposed
sides 10c and 10d that are spaced from each other along a lateral
direction A that is perpendicular to the transverse direction T,
and first and second opposed ends 10e and 10f that are spaced from
each other along a longitudinal direction L that is perpendicular
to both the transverse direction T and the lateral direction A. In
accordance with one embodiment, the film 10 is elongate along the
longitudinal direction L so as to define a length along the
longitudinal direction L, defines a thickness along the transverse
direction T, and defines a width along the lateral direction A. The
sides 10c and 10d and the ends 10e and 10f can define edges, and in
combination can define an outer periphery 13 of the film 10.
[0146] The film may define at least one layer of a biologically
compatible material. such as a polymeric material. In one
embodiment, the film 10 may be formed from a single thin layer of a
biologically compatible material. In one embodiment, film 10 is
comprised of two or more layers of biologically compatible
material, such as two layers, three layers, four layers, up to and
including seven layers. In certain embodiments, the film 10 can
comprise an adhesive layer. For example, the first surface 10a or
the second 10b surface of the film 10, or both the first surface
10a and the second surface 10b, can comprise an adhesive layer,
such that the adhesive layer defines one or both of the first
surface 10a and the second surface 10b. For instance, when the film
10 is formed from a single layer, the single layer of the film 10
can have adhesive properties, such that the layer of adhesive is
defined by the single layer of the film 10 and one or both of the
first and second surfaces can comprise an adhesive layer.
Alternatively, when the film 10 comprises a plurality (e.g., at
least two) layers, at least one of the two or more layers of film
10 can include a layer of adhesive that is applied to one or both
of the first and second surfaces 10a and 10b of the film. In
certain embodiments, one or more of the layers of the film 10 may
be a drug containing layer and/or a rate controlling layer for drug
release (with or without a drug contained therein). Unless
otherwise indicated, reference herein to one or more layers of the
film 10 includes both embodiments where the film 10 is formed of a
single layer, and embodiments where the film comprises a plurality
of layers.
[0147] In a preferred embodiment, the biologically-compatible
material is a polymeric material and in a further preferred
embodiment, the polymeric material is bioresorbable. In embodiments
used with a medical device, such as a bone plate 12 (see FIG. 2),
for instance where the film covers at least a portion of the bone
plate 12, the film 10, in some embodiments, will dissolve away over
time when implanted in vivo and be absorbed into a patient, leaving
only the bone plate 12 behind (such as if bone plate 12 is not also
made of a bioresorbable material). The bone plate 12 may also be
made of a bioresorbable material in other embodiments in which case
both the bone plate 12 and the film 10 will eventually dissolve. In
some embodiments, the film 10 may be configured to absorb at a
different rate from an absorbable bone plate 12 (e.g., a faster or
a slower rate). It should be appreciated in certain embodiments
that the first surface 10a of the film 10 can face the bone plate
12 and the second surface 10b can face away from the bone plate 12
during use, and in other embodiments the second surface 10b of the
film 10 can face the bone plate 12 and the first surface 10a can
face away from the bone plate 12 during use. While reference is
made herein to a bone plate 12, it should be appreciated that the
film 10 is configured for use in combination with any suitable
medical implants as desired, such as any suitable orthopedic
implant used in musculoskeletal repair, and that unless otherwise
indicated herein, reference to a bone plate 12 applies with equal
weight to other medical implants.
[0148] In some embodiments, a bioresorbable film 10 has advantages
over non-resorbable meshes which, for example, can become encased
with or embedded in dense fibrous tissue or present other issues
associated with long term foreign body exposure. In some
embodiments, the film 10 is only partially bioresorbable.
[0149] A bioresorbable polymer may be used in order to provide a
controlled release of a drug such as an antibiotic, with a definite
end point. Continuous, long term presence of an antibiotic is often
undesirable, since this can create conditions for development of
antibiotic resistant bacteria. In one embodiment, complete
degradation of the film 10 ensures that the drug will be completely
released in a pre-determined and/or selectable time. In one
embodiment, the drug release can be completely released or
substantially completely released even where the film 10 is not
fully absorbed.
[0150] The absorption of the film 10 may also impact and/or control
the release of the antibiotic in the continuous release phase. As
the film 10 degrades, for example, the permeability of the film may
increase, and more drugs may be released. In some embodiments, the
polymer defines a film that is flexible, has a sufficiently high
tensile strength, and can be processed by solution casting.
[0151] One particular class of preferred bioresorbable polymers are
those containing aliphatic polyesters. Examples of such polyesters
include polyglycolic acid (PGA), polylactic acid (PLA),
polycaprolactone (PCL), polydioxanone, poly(trimethylene carbonate)
(TMC), polyhydroxyalkanoates, and copolymers, derivatives, and
blends of the same. Bioresorbable polymer materials can differ in
their molecular weight, polydispersity, crystallinity, glass
transition temperatures, and degradation rates, which can
ultimately alter the mechanical properties of the film.
[0152] Particularly preferred bioresorbable polymers include
co-polymer compositions containing PGA, PLA and PCL. According to
one embodiment, film 10 is comprised of co-polymer having about 40%
to about 95% glycolide content by weight; for example about 60% to
about 75%, about 60% to about 70%, about 65% to about 75%, and
about 68% to about 72%. According to another embodiment, film 10 is
comprised of co-polymer having about less than 1% (including 0%) to
about 50% caprolactone content by weight; for example about 5%
percent to about 30%, about 10% to about 40%, about 10% to about
22%, about 14% to about 18%, and about 30% to about 40%. According
to a further embodiment, film 10 is comprised of about less than 1%
(including 0%) to about 15% lactide content by weight; for example
less than about 1% to about 10%, less than about 1% to about 7.5%,
about 3% to about 7.5%, about less than 1% to about 5%, and about
4% to about 7%.
[0153] In one embodiment, the film 10 is comprised of a co-polymer
that includes one or more of four monomers; glycolide, lactide,
caprolactone, and trimethylene carbonate. Glycolide may be included
and may have the effect of speeding up degradation of the film 10.
Lactide may also be included and may have the effect of increasing
mechanical strength of film 10. Caprolactone and trimethylene
carbonate may be used and may have the effect of increasing
flexibility of film 10.
[0154] In one embodiment, the bioresorbable polymer includes one or
more of PLA, PGA, PCL, polydioxanone, TMC and copolymers of these.
In one embodiment, the bioresorbable polymer is produced from a
copolymer of glycolic acid, caprolactone, lactic acid, and
trimethylene carbonate. In one embodiment, the bioresorbable
polymer is produced from a copolymer of approximately 60-70%
glycolic acid, approximately 17-20% caprolactone, approximately
5-10% lactic acid and approximately 8-10% trimethylene carbonate.
In one embodiment, the bioresorbable polymer contains repeat units
selected from the group consisting of: L-lactic acid, D-lactic
acid, L-lactide, D-lactide, D,L-lactide, glycolide, a lactone, a
lactam, trimethylene carbonate, a cyclic carbonate, a cyclic ether,
para-dioxanone, beta-hydroxybutyric acid, beta-hydroxypropionic
acid, beta-hydroxyvaleric acid, and a combination thereof. In one
embodiment, the bioresorbable polymer contains repeat units
selected from the group consisting of: L-lactic acid, D-lactic
acid. L-lactide; D-lactide, D,L-lactide, .epsilon.-caprolactone,
trimethylene carbonate, para-dioxanone, and a combination thereof.
Film 10 may also or alternatively include natural biopolymers such
as alginate, chitosan, collagen, gelatin, hyaluronate, zein and
others.
[0155] Still referring to FIG. 1A, the film 10 may be configured to
have any preferred dimensions including a thickness h.sub.3
measured along the transverse direction T between first surface 10a
and second surface 10b not inclusive of the raised lips 14a that
are illustrated in FIGS. 1A and 1B as surrounding apertures 14. In
one embodiment, film 10 is sufficiently thin such that it does not
interfere with the mechanical interlocking between the bone plate
12 and the screws that are driven through the film 10 and the bone
plate 12 and into an underlying bone during fixation (such as where
if the film is trapped between the plate and screw). In some
embodiments, thickness h.sub.3 is minimized as much as possible. In
one embodiment, the thickness of film 10 is selected such that
degradation of film 10 does not cause significant loosening of a
connection to bone plate 12 such as a plate-screw construct.
[0156] In some embodiments, the thickness h.sub.3 of film 10 is
approximately 0.05 mm. In some embodiments, the thickness h.sub.3
of film 10 is approximately no greater than 0.05 mm. In some
embodiments, thickness h.sub.3 of film 10 is less than
approximately 0.05 mm, for example approximately 0.04 mm. In some
embodiments, thickness h.sub.3 of film 10 is approximately 0.06 mm.
In some embodiments, thickness h.sub.3 of film 10 is approximately
0.07 mm. In some embodiments, thickness h3 of film 10 is
approximately 0.08 mm. In some embodiments, thickness h.sub.3 of
film 10 is approximately 0.09 mm. In some embodiments, thickness
h.sub.3 of film 10 is approximately 0.1 mm. In some embodiments,
thickness h.sub.3 of film 10 is approximately 0.2 mm. In some
embodiments, thickness h.sub.3 of film 10 is approximately 0.3 mm.
In some embodiments, thickness h.sub.3 of film 10 is approximately
0.4 mm. In some embodiments, thickness h.sub.3 of film 10 is
approximately 0.5 mm.
[0157] In one embodiment, the thickness h.sub.3 of the film 10 is
approximately uniform throughout film body 11. In some embodiments,
the film 10 is tapered toward one or more edges along the outer
periphery 13. In some embodiments, thickness h.sub.3 of film 10
differs in two or more sections of the film body 11 to control
strength or drug delivery of each area.
[0158] In some embodiments, the film 10 is of sufficient strength
to withstand mechanical forces such as implantation, drilling and
screw placement. In other embodiments, the film 10 has tensile
properties that permit a region of the film to tear upon
penetration of a screw or other fixation element through that
region. This has the advantage of preventing the film from becoming
entangled with or otherwise wrapped around the fixation element,
which can potentially cause damage to the film and inhibit the
correct placement of the fixation element. In one embodiment, film
10 has a first tensile strength in a first planar direction and a
second tensile strength in a second planar direction that is
perpendicular to the first planar direction, where the first
tensile strength is substantially equal to the second tensile
strength. In one embodiment, film 10 has the strength
characteristics as listed in tables 1-3 below. Each of the six
samples listed in the Tables below were films comprised of a
copolymer containing approximately 70% glycolide, 17% caprolactone,
8% trimethylene carbonate, and 5% lactide by weight.
TABLE-US-00001 TABLE 1 Tensile strain at Film Specimen Length Width
Thickness Yield (Offset Sample Start Date label (mm) (mm) (mm)
0.2%) (%) 1 07/02/2009 Day 0 50.00 10.510 0.059 2.44051 9:02 AM
Sample 1 2 07/02/2009 Day 0 50.00 11.160 0.063 3.43452 9:05 AM
Sample 2 3 07/02/2009 Day 0 50.00 11.230 0.062 2.04468 9:07 AM
Sample 3 4 07/02/2009 Day 0 50.00 10.740 0.057 2.81023 9:09 AM
Sample 4 5 07/02/2009 Day 0 50.00 11.180 0.066 3.06678 9:13 AM
Sample 5 6 07/02/2009 Day 0 50.00 10.920 0.058 3.65944 9:15 AM
Sample 6 Mean 50.00 10.957 0.061 2.90936 Standard 0.000 0.288 0.003
0.607 Deviation Coefficient 0.000 2.625 5.639 20.854 of
Variation
TABLE-US-00002 TABLE 2 Tensile Tensile Tensile Tensile stress at
strain at stress at strain at Yield Maximum Maximum Break Film
(Offset 0.2%) Load Load (Standard) Sample (MPa) (%) (MPa) (%) 1
13.75364 22.50031 26.31165 31.66499 2 14.00508 31.66468 27.57964
49.99874 3 9.25147 32.49843 26.60082 149.99967 4 12.82553 26.66562
28.46340 55.83280 5 13.53060 23.33406 26.59371 36.66562 6 12.60631
35.83187 26.79990 212.49840 Mean 12.66211 28.74916 27.05819
89.44337 Standard 1.756 5.393 0.812 74.322 Deviation Coefficient
13.865 18.760 3.000 83.094 of Variation
TABLE-US-00003 TABLE 3 Tensile stress at Break Film (Standard)
Modulus (Automatic Sample (MPa) Young's) (MPa) 1 15.20147 749.15765
2 21.71590 504.50877 3 19.08817 657.83084 4 18.08469 574.31825 5
18.71550 618.69300 6 21.75346 436.82724 Mean 19.09320 590.22262
Standard 2.460 111.150 Deviation Coefficient 12.885 18.832 of
Variation
[0159] In one embodiment, film 10 has a tensile strain at yield
(Offset 0.2%) of approximately 2% to approximately 4% and/or a mean
tensile strain of approximately 3%. In one embodiment, film 10 has
a tensile stress at yield (Offset 0.2%) of approximately 9 MPa to
approximately 14 MPa, and/or a mean tensile stress at yield of
approximately 12.5 MPa. In one embodiment, film 10 has a tensile
stress at maximum load of approximately 25 MPa to approximately 30
MPa, and/or a mean tensile stress at maximum load of approximately
27 MPa. In one embodiment, film 10 has a tensile strain at break
(standard) of approximately 30% to approximately 215%, and/or a
mean tensile strain at break of approximately 89%. In one
embodiment, film 10 has an automatic Young's modulus of
approximately 430 MPa to approximately 750 MPa, and/or a mean
automatic Young's modulus of approximately 590 MPa. Film 10 may be
characterized by combination of one or more of the foregoing
properties.
[0160] Referring to FIGS. 1A, 1B, 2, 11K and 11L, in some
embodiments, film 10 includes a plurality of apertures or apertures
14. In one embodiment, the apertures 14 allow the passage or
transport of fluids through film 10 (e.g., when implanted near
living tissue). In some embodiments, it may be important to allow
for fluid flow from one side of the sleeve to the other (inside to
outside) in order, for example, to avoid creating a "dead space"
between the film 10 and the bone plate 12. Additionally, the
apertures 14 may advantageously provide more even distribution of
the drug or biological agent to adjacent tissue and bone as the
material leaches out of the polymer than a sleeve without such
apertures.
[0161] The apertures 14 may be configured to be any size and shape,
including variations within the same polymer film. In one
embodiment, apertures 14 are defined by substantially cylindrical
sidewalls. In some embodiments, apertures 14 have sidewalls that
have segments that are inwardly facing convex surfaces. In some
embodiments, the inwardly facing convex surface is substantially
parabolic. Apertures 14 need not be perfectly round in cross
section, and in some embodiments, may be ovoid, elliptical, star or
diamond in shape. In some embodiments, apertures 14 extend to one
or more apexes. In one embodiment, such apexes promote tears in
film 10 during use (e.g., where a zone of weakness is created by
the aperture). In one embodiment, apertures 14 extend completely
through sheet 12 from the first surface 10a to the second surface
10b (see FIG. 4C). In one embodiment, one or more of the apertures
14 can extend only partially through film 10, for instance from the
second surface 10b toward but not to the first surface 10a, to
control drug release or increase the initial strength of the film
10. In certain embodiments, the film 10 may have a first one or
more regions having the apertures 14 and a second one or more
regions devoid of the apertures 14. A film region can be defined as
any single contiguous area, substantially either elliptical or
quadrangular, of at least 10% of the total surface area of film
surface 10a or 10b. According to one embodiment, one or more
regions having apertures 14 can be separated by one or more regions
having no apertures 14. According to another embodiment, a region
having apertures is contiguous, and in a further embodiment a
region having no apertures is contiguous. For example the periphery
of the film 10 can have apertures while the remainder of the film
is devoid of apertures, or alternatively a periphery of film 10 can
be devoid of apertures while the remainder of the film has
apertures. It should be appreciated that the distribution pattern
can be configured as desired to include more or less apertures in
any one region of the film, as well as permitting an even or
regular distribution of apertures throughout the film.
[0162] The apertures 14 may be configured to allow for any desired
porosity of film 10. In one embodiment, the porosity of the film 10
is the range of approximately 1% to approximately 30%, in another
embodiment approximately 5% to about 25%, in another embodiment
approximately 10% to about 20%, and in a preferred embodiment is
approximately 15%. In one embodiment, the porosity of film 10 is
greater than approximately 1%. In one embodiment, the porosity of
film 10 is greater than approximately 2%. In one embodiment, the
porosity of film 10 is greater than approximately 3%. In one
embodiment, the porosity of film 10 is greater than approximately
4%. In one embodiment, the porosity of film 10 is greater than
approximately 5%. In one embodiment, the porosity of film 10 is
greater than approximately 6%. In one embodiment, the porosity of
film 10 is greater than approximately 7%. In one embodiment, the
porosity of film 10 is greater than approximately 8%. In one
embodiment, the porosity of film 10 is greater than approximately
9%. In one embodiment, the porosity of film 10 is greater than
approximately 10%. In one embodiment, the porosity of film 10 is
greater than approximately 11%. In one embodiment, the porosity of
film 10 is greater than approximately 12%. In one embodiment, the
porosity of film 10 is greater than approximately 13%. In one
embodiment, the porosity of film 10 is greater than approximately
14%. In one embodiment, the porosity of film 10 is greater than
approximately 15%. In one embodiment, the porosity of film 10 is
greater than approximately 16%. In one embodiment, the porosity of
film 10 is greater than approximately 17%. In one embodiment, the
porosity of film 10 is greater than approximately 18%. In one
embodiment, the porosity of film 10 is greater than approximately
19%. In one embodiment, the porosity of film 10 is greater than
approximately 20%.
[0163] Referring to FIG. 11L, in one embodiment, the apertures 14
have an average maximum cross-sectional length (e.g., diameter) in
the range of approximately 0.1 mm to approximately 1.5 mm, such as
approximately 0.1 mm to 1.0 mm, 0.1 mm to 0.5 mm, 0.5 mm to 1.5 mm,
0.5 mm to 1.0 mm, 0.1 mm to 0.75 mm, 0.5 mm to 0.75 mm, 0.75 mm to
1.0 mm, and 0.75 mm to 1.5 mm. In a preferred embodiment apertures
14 have an average maximum cross-sectional length (e.g., diameter)
of about 0.75 mm. In one embodiment, apertures are spaced apart
from adjoining apertures in the range of approximately 0.5 mm to
about 5 mm. such as approximately 0.5 mm to approximately 2.5 mm,
2.5 mm to 5.0 mm, 1.0 mm to 2.0 mm, 1.5 mm to 2.0 mm, 0.5 mm to 1.0
mm, 0.5 mm to 1.75 mm, and 1.0 mm to 1.75 mm. In a particularly
preferred embodiment, apertures have an average maximum
cross-sectional length of 0.75 mm and a spaced apart approximately
1.75 mm. In a preferred embodiment, apertures 14 are spaced apart
approximately 1.75 mm. In one embodiment, the apertures 14 are
arranged in a regular array (e.g., aligned rows and columns as
illustrated in FIG. 11K). In one embodiment, the apertures 14 are
arranged in an irregular array. Thus, the apertures 14 can
generally be configured such that a diameter of the threaded shaft
of the bone screw that is driven through the film 10, an aligned
bone fixation hole of the bone implant, and the underlying bone, is
greater than both the cross-sectional dimensions of the apertures
14 and the gap between adjacent apertures 14, such that a given
screw shaft is configured to be driven through a region of the film
10 that includes more than one aperture 14. It should be
appreciated that the shaft of the bone fixation screw can be driven
through at least one of the apertures 14, such as a plurality of
the apertures 14, through the aligned bone implant hole, and into
the underlying bone. The step of driving the screw shaft through at
least one or more of the apertures 14 can decrease random
unpredictable tearing of the film compared to a step of driving the
screw shaft through a region of the film 10 that is devoid of
apertures 14.
[0164] Referring to FIGS. 1A, 1B and 4C, in some embodiments, the
first surface 10a can define a contiguous planar portion 15 and
interfaces, which can be configured as solidified meniscuses 17 as
described below, that adjoin the contiguous planar portion 15 and
one or more interior surfaces that define a respective one of the
apertures 14. In accordance with one embodiment, one or more of the
meniscuses 17 can be configured as a raised lip 14a that extends
out with respect to the contiguous planar portion 15 (e.g., along a
direction from the second surface 10b toward the first surface 10a)
along the transverse direction T, and thus extends out from the
first surface 10a. A benefit of the raised lip 14a around each
aperture 14 may include providing a reinforcement or grommet to
each aperture 14, effectively increasing the mechanical strength of
the film 10 relative to a similar perforated film that is devoid of
raised lips 14a. A further benefit of the raised lips 14a may
include a texture on the first surface 10a. Such a texture may be
an advantage for tactile feel or for the purpose of increasing (or
reducing) friction of the first surface 10a of the film 10 when,
for example, the first surface 10a is in contact with another
surface. In one embodiment, the raised lips 14a decrease the
tendency of the film 10 to adhere to a surface such as the metal
surface of an implant, making it easier to slide a sleeve made from
the film 10 onto the bone plate 12. In one embodiment, the lips 14a
provide stand-off between the bone plate 12 and the film 10,
thereby reducing the surface area of the film 10 that is in contact
with the bone plate 12.
[0165] In one embodiment, the contiguous planar portion 15 extends
between the plurality of raised protruding lips 14a, for instance
from each of the raised lips 14a to others of the raised lips 14a.
In one embodiment, the raised lips 14a are substantially in the
shape of the outer surface of an impact crater. In one embodiment,
the raised lips 14a define a continuous concave outer surface. In
one embodiment, the concave outer surface is a parabolic concave
surface. In one embodiment, one or more of lips 14a (or, in some
embodiments, each lip 14a) has a concave outer surface and an
opposed convex inner surface, either or both of which are parabolic
in shape. In one embodiment, the lips 14a can each have an edge
that is raised above the contiguous planar portion 15 of first
surface 10a by approximately 0.1 mm to approximately 1.0 mm. In one
embodiment, lips 14a each have an edge that is raised above the
contiguous planar portion 15 of first surface 10a by approximately
0.1 mm. In one embodiment, lips 14a each have an edge that is
raised above the contiguous planar portion 15 of first surface 10a
by approximately 0.2 mm. In one embodiment, lips 14a each have an
edge that is raised above the contiguous planar portion 15 of first
surface 10a by approximately 0.3 mm. In one embodiment, lips 14a
each have an edge that is raised above the contiguous planar
portion 15 of first surface 10a by approximately 0.4 mm. In one
embodiment, lips 14a each have an edge that is raised above the
contiguous planar portion 15 of first surface 10a by approximately
0.5 mm. In one embodiment, lips 14a each have an edge that is
raised above the contiguous planar portion 15 of first surface 10a
by approximately 0.6 mm. In one embodiment, lips 14a each have an
edge that is raised above the contiguous planar portion 15 of first
surface 10a by approximately 0.7 mm. In one embodiment, lips 14a
each have an edge that is raised above the contiguous planar
portion 15 of first surface 10a by approximately 0.8 mm. In one
embodiment, lips 14a each have an edge that is raised above the
contiguous planar portion 15 of first surface 10a by approximately
0.9 mm. In one embodiment, lips 14a each have an edge that is
raised above the contiguous planar portion 15 of first surface 10a
by approximately 1.0 mm.
[0166] In one embodiment, the lips 14a impart a first tactile feel
to the first surface 10a that is different (e.g., distinguishable
by a surgeon wearing a surgical glove) from a second tactile feel
of second surface 10b that is devoid of the lips 14a. In one
embodiment, apertures 14 in one or more areas on first surface 10a
each are bounded by a raised lip 14a and apertures 14 in one or
more other areas on first surface 10a are not so bounded. In one
embodiment, the solidified meniscus 17 can define a height h.sub.4
(see FIG. 4C) from the second surface 10b to the outermost end of
the raised lips 14a. The height h.sub.4 can be defined by the
raised lips 14a, and can be uniform across the first surface 10a in
accordance with one embodiment. In one embodiment, at least one of
the raised lips 14a has a height h.sub.4 that is different than the
height h.sub.4 of at least one other of the raised lips 14a. In one
embodiment, one or more apertures 14 are bounded by a lip 14a on
one or both first surface 10a and second surface 10b. An embodiment
such as the one illustrated in FIG. 1A, may include a single
continuous lip 14a that surrounds each aperture 14. The continuous
lip may be substantially uniform in thickness and/or substantially
uniform in height relative to any one aperture, or from aperture 14
to aperture 14. The apertures 14 may be evenly spaced apart across
all or at least a portion of the film 10. In other embodiments, at
least a portion of the film 10 is characterized by apertures 14
that are spaced apart in at least two different spacing
configurations, so as to define two different patterns of apertures
14.
[0167] In some embodiments, the film 10 includes one or more drugs
or other substance for delivery in the body. Such drugs include,
but are not limited to, antimicrobial agents, anti-fibrotic agents,
anesthetics and anti-inflammatory agents as well as other classes
of drugs, including biological agents such as proteins, growth
inhibitors and the like. In further embodiments, the film 10 can
include one or more biocompatible particles. The particles,
according to one embodiment, can assist in bone remodeling and
regrowth. For example, in certain embodiments, particles are
calcium-containing salt particles, such as calcium phosphate or
calcium sulfate particles. These calcium salts are well known for
use at bone remodeling and regrowth sites. Other potential
biocompatible particles can include salts or oxides containing, for
example, silicon, magnesium, strontium, and zinc. In certain
embodiments, the particles are at least partially insoluble and can
be substantially insoluble in the polymer film. In embodiments
where the particles are insoluble in the film, the particles
provide heterogeneous nucleation sites in the polymer film. Such
nucleation sites can increase the rate of crystallization of the
film as well as increasing the overall crystallinity of the film as
compared to the film without such nucleation sites. Altering the
crystallinity properties of a polymer film can be desired where a
decrease in elastic behavior is preferred. For example, FIGS. 12
and 13 (and explained more fully below) show the decrease in
elongation and yield properties of a plain polymer film upon the
incorporation of insoluble biocompatible particles (in this case,
5% and 10% addition of insoluble gentamicin sulfate particles).
Additionally, an increase in crystallinity can be a factor that
potentially slows the degradation rate of a biodegradable polymer
film.
[0168] In one embodiment, the film 10 includes an active agent,
such as a drug or drugs. The active agent may be an anti-microbial
agent, for instance an antibiotic, anti-viral agent, or
anti-parasitic agent, though as previously mentioned, it should be
appreciated that other active agents typically used in conjunction
with orthopedic surgery are also contemplated within the scope of
this disclosure, including, for example, anti-inflammatory drugs,
steroids, analgesics, opioids, growth factors, and the like. In
embodiments including an antibiotic, the antibiotic selected may be
active against the majority of bacteria found in orthopedic implant
related infections. These include primarily staphylococci, and Gram
negative bacilli.
[0169] In one embodiment, the drug selected is stable during the
manufacturing process that fabricates the film. Depending upon the
manufacturing processes utilized, the polymer formulation of the
film, the preferred drug, and the pharmaceutical formulation of the
preferred drug (e.g., the particular pharmaceutical salt utilized)
the drug can either be soluble or insoluble with the polymer
formulation. In embodiments where the drug is at least
partially--including being substantially--insoluble in the polymer,
the film can physically entrap the drug particles. In embodiments
where the drug is at least partially--including being
substantially--soluble with the polymer, the film can chemically
bond with and to the drug. In certain embodiments, the film can
both physically entrap and chemically bond with and to the drug
[0170] In one embodiment, film 10 includes gentamicin sulfate.
Gentamicin sulfate is thermally stable above 100.degree. C., and is
stable to organic solvents including DMSO, which is used in the
manufacturing process in some embodiments. Gentamicin sulfate is
active against many bacteria commonly associated with orthopedic
infection, such as Staphylococcus aureus including MRSA, coagulase
negative staphylococci, and Gram negative rods such as Pseudomonas
and Enterobacter species. Without being bound by any particular
theory, it is believed that local delivery of gentamicin to a
fracture site containing a metallic implant may be effective in
preventing infection by some bacteria which are intermediate or
resistant to systemic levels of gentamicin because of the locally
higher concentrations of gentamicin at the fracture site.
[0171] Referring to FIGS. 4A-4C, in one embodiment, film 10
comprises a drug that is at least partially insoluble and can be
substantially insoluble in the film, such that the drug can serve
as a biocompatible particle that provides a heterogeneous
nucleation site as previously mentioned. In a further embodiment,
film 10 comprises a plurality of discrete eluting drug components
30. In one embodiment, film 10 is configured to elute the plurality
of discrete drug components 30 at different time periods following
implantation. In one embodiment, the elution of drug components 30
(e.g., an antibiotic such as gentamicin) in vivo is a two-phase
process, with a burst release occurring as soon as film 10 contacts
water or body fluid, and a second phase which is controlled by the
degradation rate of the polymer. In some embodiments, it is
desirable to have an initial burst release of gentamicin to reduce
bacterial contamination of the wound site on initial implantation,
then a lower level release of gentamicin for a period of days to
weeks afterward, to prevent growth and/or biofilm formation of any
surviving bacteria. In one embodiment, film 10 is configured to
elute up to approximately 20 percent of the drug within the first
hour after implantation. In another embodiment, film 10 is
configured to elute up to approximately 60 percent of the drug
contained within film 10 approximately 1 week after film 10 has
been implanted in contact with living tissue. In another
embodiment, film 10 is configured to elute up to approximately 100%
of the drug within 10 days after implantation. In one embodiment,
the combination of particle size and polymer degradation rate
control the drug release profile, and create the desired 2-phase
release. In one embodiment, the drug is released over a 2 to 3 week
time period. In other embodiments, the drug is released over a
shorter or longer time frame.
[0172] In one embodiment, where the drug is insoluble with the
film, the relative amounts of drug released during these two phases
are controlled by the particle size of the drug in the film. In one
embodiment, drug components 30 are evenly distributed throughout
film 10, and any drug components 30 in contact with a surface of
film 10 are dissolved more rapidly than a drug component 30 that is
not in contact with a surface of film 10. In one embodiment, a
quantity of drug components 30 that are in contact with a surface
of film 10 upon implantation are configured to release in a burst
upon implantation. In one embodiment, the larger the size of drug
components 30, the higher the proportion of drug components 30 in
contact with the surface, and the greater the burst release. For
this reason, the size of drug components 30, in one embodiment, is
kept under 10 microns in diameter which reduces the burst release
to approximately 20 to 35% of the total drug content. In one
embodiment, drug components 30 are under 20 microns in
diameter.
[0173] In one embodiment, film 10 is configured to deliver multiple
drugs from one or more independent layers, some of which may
contain no drug. In certain embodiments, one or more of the layers
may be a drug containing layer and/or a rate controlling layer for
drug release (with or without a drug contained therein). In another
embodiment, film 10 may include a plurality of drug components each
being characterized by a different release rate from film 10 such
that a first drug is associated with a first release profile that
is different from a second release profile of a second drug.
[0174] Where the film contains one or more antibiotics that can
release from the film into the surgical site environment over a
period a time, a Zone of Inhibition (ZOI) can be formed around the
film where certain bacterial growth cannot occur due to the
presence of the antibiotic containing film. Where the film defines
a central axis or center point, the ZOI is defined as the radial
distance extending in three dimensions from the central axis or
center point where bacteria will not colonize. According to one
embodiment, the film has a ZOI of at least 12 mm. According to one
embodiment, where the film includes the antibiotic gentamicin (13%
by weight), the film has a ZOI of at least 20 mm where the bacteria
are selected from S. aureus, S. epidermidis, Pseudomonas
aeruginosa, or Enterobacter cloacae, or combinations thereof
[0175] Accordingly, when the film 10 defines a cover suitable for
use in combination with a medical implant, the cover does not have
to overlay the entire surface area of an implant to be effective,
and can thus overlay at least a portion of the surface area of one
or both sides (e.g., the bone-facing side and the side opposite the
bone-facing side) of the implant up to an entirety of the surface
area of one or both sides of the implant. For example, in those
cases where at least one film 10 defines a cover configured as a
polymer film sleeve 31 (see, e.g., FIGS. 11A-J) designed to
completely cover an implant, such as the bone plate 12, the film 10
may be torn or damaged during fracture reduction and plating, or
otherwise does not cover the entire surface of the implant.
Alternatively, the sleeve can be designed to cover only a portion
of the implant. In this manner, a surgeon can determine an
appropriate zone of inhibition needed for a particular surgical
site and/or medical implant, and utilize the polymer film
accordingly, e.g., utilize the appropriate length and/or quantity
of polymer film.
[0176] Referring to FIGS. 3A-10, there are shown devices used in a
method of manufacturing films 10 in accordance with exemplary
embodiments of the present disclosure.
[0177] In one embodiment, a manufacturing method creates polymer
films 10 for drug delivery. In one embodiment, the film 10 is
solvent cast. In some embodiments, solvent casting methods are
advantageous in the fabrication of films 10 that contain a drug
component 30 that could be potentially damaged by the heat and
shear of melt processes such as blown film extrusion. Producing
films 10 using a punch press (e.g., with many hundreds or thousands
of holes or holes with complicated geometry) may also be time
consuming and expensive.
[0178] In some embodiments, methods described herein can create the
thin films 10 and the apertures 14 in a single step. In some
embodiments, methods described herein create the film 10 and
thousands of apertures 14 within the periphery of the film with
accurate predetermined control of geometry and placement of the
apertures 14 and accurate predetermined control of the thickness of
the film 10.
[0179] Referring to FIGS. 3A-3G, in some embodiments, the film 10
is cast in a mold 18. In one embodiment, mold 18 includes a
plurality of protrusions or posts 20 extending from a bottom 18a of
mold 18. When polymeric solution is deposited in the mold 18, the
posts 20 occupy space that defines the apertures 14 when the
polymeric solution solidifies into film 10. In one embodiment, the
mold 18 is comprised of injection molded polypropylene. The mold 18
may be manufactured from other materials, including polymers (see
FIG. 3F), glass, metals (see FIG. 3G) or ceramics. In one
embodiment, the mold 18 is comprised of two or more materials. For
example, the bottom 18a of the mold 18 may be made from metal with
a polymer coating to reduce adhesion of the cast film to the mold
and/or to form posts 20. The cavity in the mold may be formed by a
casting process, a compressing molding process, an injection
molding process, a chemical etching process or a machining
process.
[0180] In one embodiment, the mold 18 includes a cavity depth of
approximately 0.25 mm. In one embodiment, a distance from the
bottom of the mold 18 to a top of each of the plurality of the
posts 20 is equal to the cavity depth (i.e., the height of
peripheral wall 22) or vice versa. In one embodiment, the posts 20
are longer than the desired thickness of the film 10. In one
embodiment, the posts 20 extend 0.3 mm from the bottom 18a of the
mold 18. In one embodiment, posts 20 extend 0.2 mm from the bottom
18a of the mold 18. In one embodiment, the posts 20 extend 0.25 mm
from the bottom 18a of the mold 18. In one embodiment, the posts 20
extend 0.3 mm from the bottom 18a of the mold 18. In one
embodiment, the posts 20 extend 0.35 mm from the bottom 18a of the
mold 18. In one embodiment, the posts 20 extend 0.4 mm from the
bottom 18a of the mold 18. In one embodiment, the posts 20 extend
0.45 mm from the bottom 18a of the mold 18. In one embodiment, the
posts 20 extend 0.5 mm from the bottom 18a of the mold 18.
[0181] In one embodiment, the posts 20 are arranged to produce a
predetermined selected size, shape, pattern, and arrangement of the
apertures 14 described above. In one embodiment, a perimeter form
or peripheral wall 22 of the mold 18 defines a total mold area, and
the plurality of posts 20 define an area that is substantially
equal to or corresponding to the ultimate porosity of the film
10.
[0182] In one embodiment, the mold 18 includes a trough 24 that
extends at least partially around the peripheral wall 22 of mold
18. In one embodiment, the trough 24 extends around the entire
peripheral wall 22 of mold 18. In some embodiments, the trough 24
retains any excess polymer that flows or is urged from the cavity
of the mold over the peripheral wall 22. In one embodiment, the
mold 18 includes an extension 40, which can define a handle that
extends out from at least one outer edge of the mold 18. In one
embodiment, the extension 40 is provided for grasping and
manipulating the mold 18 without contacting the polymer solution
that is disposed within the mold 18.
[0183] According to the present disclosure, there is a method of
producing a polymer film comprising: placing a polymer solution
into a mold having a plurality of protrusions extending from a
bottom of the mold. In certain embodiments, the polymer solution is
characterized by a viscosity that inhibits the unaided flow of the
polymer throughout the mold. The process further includes urging
the polymer solution around each of the plurality of protrusions;
and solidifying the polymer solution. In one embodiment, the mold
includes a perimeter form extending to an elevation that is
substantially equal to an elevation of each of the plurality of
protrusions. In one embodiment, the urging comprises drawing an
urging instrument such as a blade, bar, squeegee or roller across
the perimeter form and the plurality of protrusions to force the
polymer solution to flow around the plurality of protrusions and
throughout the mold such that the polymer solution has a
substantially uniform thickness. In one embodiment, at least a
portion of an outer surface of a protrusion, for example an upper
portion of a protrusion, is substantially free of polymer solution
after the drawing. In one embodiment, the placing step includes
depositing the polymer solution in the mold such that a portion of
the polymer solution is above the elevation of the perimeter form
and the protrusions. In still further embodiments, one or more of
the method steps can be repeated such that the method can produce a
film comprising a plurality of layers, for example, two or more
layers, such as two layers, three layers, four layers, up to and
including seven layers. In certain embodiments the method
additionally includes the steps of placing one or more additional
polymer solutions (for example, placing an additional polymer
solution, placing a second additional polymer solution, placing a
third additional polymer solution, up to and including placing a
sixth additional polymer solution) in the mold over a first polymer
solution, and urging the one or more polymer solutions around each
of the plurality of protrusions. The step of placing one or more
polymer solutions in the mold can occur prior to, during, or after
the step of solidifying the polymer solution. Thus, according to
one embodiment of the method, each of the one or more polymer
solutions placed in the mold can solidify prior to, during, or
after, the step of placing the next or subsequent additional
polymer solution into the mold (e.g., placing a third additional
polymer solution into the mold prior to, during, or after,
solidifying the second additional solution; or placing an
additional polymer solution into the mold prior to, during, or
after solidifying a first polymer solution). According to another
embodiment, all of the polymer solutions placed into the mold can
solidify substantially simultaneously. According to one embodiment,
the one or more polymer solutions comprise a polymer solution that
can solidify into an adhesive layer, and according to another
embodiment, the one or more polymer solutions comprise a rate
controlling layer for drug release.
[0184] In one embodiment, a polymer solution 28 is formed. The
polymer solution 28 is placed in the cavity of the mold 18 so as to
create the film 10. In some embodiments where the drug is insoluble
in the polymer, a solvent and drug component 30 are first mixed to
form a well distributed suspension, and then polymer is added and
dissolved in the solvent/drug suspension. In other embodiments, the
polymer is dissolved in the solvent and then the insoluble drug is
added to the solution at the desired amount. In still other
embodiments, the drug is soluble in the polymer/solvent solution.
In embodiments where aliphatic polyesters comprise the polymer
formulation, typically a polar solvent will be used. Suitable polar
solvents can include dimethyl sulfoxide (DMSO), tetrahydrofuran
(THF), alcohols, acetone, ethyl acetate, acetonitrile,
dimethylformamide (DMF), and formic acid. In one embodiment, a
polymer material is dissolved at a 4:1 solvent to polymer ratio in
dimethyl sulfoxide (DMSO) at elevated temperature and the drug
gentamicin sulfate is added at 13% by weight. In one embodiment,
polymer solution 28 is formed by introducing drug units 30 to a
polymer/solvent blend at a temperature below 90.degree. C. In one
embodiment, polymer solution 28 comprises a cross-linkable
pre-polymer such as polyurethanes, polyfumarates,
polymethacrylates, etc.
[0185] Referring to FIGS. 4A, 6 and 8, once the polymer solution 28
is prepared, polymer solution 28 is placed into the mold 18, which
can be a one sided mold as illustrated. In some embodiments, the
viscosity of polymer solution 28 and/or the density of posts 20
substantially inhibits the unaided flow of the polymer 28
throughout the mold 18. In one embodiment, after adding polymer
solution 28 to mold 18, the top surface of polymer solution 28 is a
height h.sub.2 above the base 18a of mold 18 which is greater than
a height h.sub.1 of the mold cavity and posts 20.
[0186] Referring to FIGS. 4B, 7 and 9, after the polymer solution
28 has been added to the mold 18, in one embodiment, the polymer
solution 28 can be urged around each of the plurality of posts 20
in the cavity of the mold 18. For instance, any suitable urging
instrument 26 can urge the polymer solution around each of the
plurality of posts 20. In one embodiment, urging instrument 26 can
be, for example, a blade, bar, squeegee or roller that slides, or
the mold 18 is moved relative to urging instrument 26, across the
perimeter wall 22 and over the posts 20 to force polymer solution
28 to flow around posts 20 and throughout mold 18 such that polymer
solution 28 has a substantially uniform thickness. In one
embodiment, drawing the urging instrument 26 across mold 18 causes
the urging instrument 26 to remove excess polymeric film material
from the top surface of posts 20. In one embodiment, an outer
surface, such as an upper surface, of one or more posts 20 is
substantially free of polymer solution 28 after the drawing.
[0187] Referring to FIG. 4C, once the polymer solution 28 is drawn
or spread throughout mold 18, the polymer solution 28 is solidified
to form the film 10. In one embodiment, the mold 18 can be placed
into a solvent drying oven at an elevated temperature to remove the
solvent, leaving behind a thin cast film. In one embodiment, the
polymer solution 28 is solidified by cross-linking the polymer by
applying UV radiation, temperature change, polymerization
catalysts, soluble crosslinking agents or combinations thereof to
the polymer solution 28. In one embodiment, the solidifying step
includes exposing the mold 18 containing the polymer solution 28 to
a second solvent. In one embodiment where, for example, the polymer
solution 28 includes polymer, a drug and a first solvent, the first
solvent is soluble in the second solvent, but the polymer and drug
component are not soluble in the second solvent. Thus, by exposing
the polymer solution 28 to the second solvent, the first solvent is
removed from the polymer solution leaving the polymer and the drug
product to solidify to form, for example, the film.
[0188] In one embodiment, solidifying the polymer solution reduces
a thickness of the polymer solution from a first thickness h.sub.1
to a second thickness h.sub.3. In one embodiment, solidifying the
polymer solution reduces a thickness of the polymer solution
proximate to posts 20 from a first thickness h.sub.1 to a second
thickness h.sub.4. In one embodiment, the thickness h.sub.4 of the
film 10 proximate the posts 20 is greater than the thickness
h.sub.1 of the film 10 between the posts 20. In one embodiment, the
lips 14a can be created due to the polymer solution forming a
meniscus around each of posts 20 during solidifying of the polymer
solution 28 to form the film 10. In one embodiment, the meniscuses
formed about the posts 20 define the lips 14a when the polymer
solution 28 has solidified. In one embodiment, height h.sub.4 of
lips 14a may be controlled by careful selection of the material and
geometry of the posts 20 or by coating the posts 20 with, for
example, a lubricious material such as a fluoropolymer or silicone
mold release. In one embodiment, the height h.sub.4 of the lips 14a
is controlled by the concentration of the polymer solution.
[0189] Referring to FIGS. 4C-4E, the material that forms the posts
20 can affect the configuration of the solidified meniscus 17
between the apertures 14 and the contiguous planar portion 15, such
as the formation of lips 14a around apertures 14. The height of the
lips 14a relative to the contiguous planar portion 15 is the
difference between h.sub.4 and h.sub.3, and can be the result of a
meniscus of the polymer solution 28 solidifying around posts 20.
The meniscus can be defined by the curve in the upper surface of
the polymer solution near the posts 20 and is caused by surface
tension between the polymer solution 28 and the respective posts
20. The polymer solution 28 can have either a convex or concave
meniscus at posts 20. A concave meniscus, which creates the raised
lips 14a, can occur when the molecules of the polymer solution are
attracted to the material of the posts 20 (commonly known as
adhesion) such that the level of the polymer solution is higher
around the posts 20 than the solution generally. According to one
embodiment, as shown in FIG. 4C, the posts 20 comprise materials
configured to cause a concave meniscus in polymer solution, where
h.sub.4 is greater than h.sub.3. Conversely, a convex meniscus
occurs when the molecules of the polymer solution have a stronger
attraction to each other (commonly known as cohesion) than to the
material of the posts 20. According to one embodiment, as shown in
FIG. 4D, the posts 20 comprise materials configured to create a
convex meniscus in polymer solution where h.sub.3 is greater than
h.sub.4. Thus, it should be appreciated that the meniscuses 17
between the contiguous planar portion 15 and the apertures 14 can
be configured as raised lips 14a that extend out from the second
surface 10b in the manner described above, or can be configured as
depressions that are recessed into the second surface 10b along a
direction from the first surface 10a toward the second surface,
from the contiguous planar portion 15 to respective ones of the
apertures 14. According to a further embodiment as shown in FIG.
4E, the posts 20 comprise materials configured to cause minimal to
no meniscus (e.g., substantially no meniscus) of the polymer
solution, such that where h.sub.4 is substantially equal to h.sub.3
at the meniscus 17.
[0190] Referring to FIG. 10, once the polymer solution 28 is
solidified, the film 10 is peeled out of the mold 18, such that the
meniscuses formed during the casting of the polymer solution 28
define the solidified meniscuses 17.
[0191] Referring to FIGS. 5-7, a method of producing film 10 may
include an automated or partially automated casting machine 42. In
one embodiment, the automated casting apparatus includes one or
more computers 44 having one or more processors and memory (e.g.,
one or more nonvolatile storage devices). In some embodiments,
memory or computer readable storage medium of memory stores
programs, modules and data structures, or a subset thereof for a
processor to control and run the various systems and methods
disclosed herein. In one embodiment, a computer readable storage
medium having stored thereon computer-executable instructions
which, when executed by a processor, perform one or more of the
methods disclosed herein.
[0192] The film 10 may be manufactured by alternative methods. In
one embodiment, the polymer solution 28 can be cast onto perforated
film material with a backing blotter layer, and then the perforated
film is removed from the blotter layer, removing the cast solution
where there were holes in the casting sheet. One difference with
such a process from the above described processes is that, in some
embodiments, it does not create a raised lip 14a and apertures
14.
[0193] In another embodiment, porous films 10 may also be formed by
a lyophilization or freeze-drying method. In one embodiment, a thin
solid film of polymer solution is cast in a mold, then the mold
chilled to a temperature below the freezing point of the solution,
then placed under vacuum to remove the solvent from the film. In
some embodiments, this process will also produce fine pores which
are much smaller than the apertures 14 described in some of the
embodiments above.
[0194] In one embodiment, the polymer material used for film 10 can
be a crosslinkable prepolymer liquid and urged or drawn to fill the
mold and remove excess material in the manner described above, then
crosslinked in place by UV radiation, temperature, a catalyst or
other means. In one embodiment, this process could produce a very
similar final product as described above, except that the final
thickness of the cast film 10 can be substantially equal to the
depth of the mold, and there would be little or no lip 14a around
the apertures 14.
[0195] In another embodiment, the film 10 can be produced as a thin
porous film in a screen printing process. In one embodiment, a
layer of solution is screen printed in the final pattern, then
dried. In one embodiment, this produces a much thinner layer,
however multiple layers of polymer can be screen printed and dried
one on top of the other to build up the desired thickness of film
10, which can define a multi-layered film.
[0196] In another embodiment, a similar casting process could be
performed as described above using a glass plate with a pattern
made from a hydrophobic polymer such as silicone, in the shape of
the desired apertures. In one embodiment, when a thin layer of
polymer solution is cast onto the plate, the surface tension
differences between the glass and the patterned polymer cause the
solution to concentrate on the glass surface, and pull away from
the patterned hydrophobic polymer surface. In one embodiment, the
solution is then dried to form a solid film with apertures in the
same pattern as the silicone polymer. In one embodiment, this
process could also be performed with a crosslinkable prepolymer
liquid as described above.
[0197] In another embodiment, a thin porous polymer film is made
using a two-sided mold, where the polymer solvent solution is
injected into the mold, and chilled to solidify the solution. In
one embodiment, the mold is then opened and one side removed,
leaving the chilled solution in the cavity side. In one embodiment,
the chilled solution side is placed into an oven to dry the polymer
solution and form a film 10.
[0198] According to one embodiment of the disclosure, the film
further comprises an adhesive layer, which is biocompatible, and
capable of adhesively fixing at least one surface of the film to
another surface (e.g. an outer surface of a medical device). In one
embodiment, substantially all of the first or second surface of the
film, or both has an adhesive layer. In another embodiment, only a
portion of the first or second surface of the film, or both has an
adhesive layer, for example along the periphery of the first or
second surface or both. The adhesive layer can be formed integrally
with the film during the solvent casting process. In such a process
the adhesive can be applied to the mold and the polymer solution
subsequently cast on top of the adhesive layer. Alternatively, the
polymer solution can be cast in the mold first and the adhesive
layer applied over the polymer. In certain embodiments, the polymer
solution itself can comprise the adhesive layer. Of course, where
it is desired to have the adhesive applied to both surfaces of the
film, the adhesive layer can be applied in both manners. In still
yet another embodiment, the film can be solution cast molded and
separately have the adhesive layer applied after removal from the
mold, for example by dipping, spraying, or coating the adhesive
onto the film.
[0199] According to one embodiment where the film contains a
surface adhesive layer as previously described, a film storage
system, for the storage, packaging and/or shipment of the film can
include 1) the film containing an surface adhesive layer, and 2) a
non-adhesive backing material (e.g., a strip) that can be placed
over the surface adhesive layer to protect and shield the adhesive
layer until such time as it is desired to adhesively affix the film
to the surface of another object, such as, for example, a surface
of a medical device or a tissue such as bone. At such time, a user,
preferably a surgeon or nurse, can remove the non-adhesive backing
material and apply the film as desired. According to another
embodiment where the film contains a surface adhesive layer, a film
storage system, for the storage, packaging and/or shipment of the
film can include 1) the film containing a surface adhesive layer,
and 2) a collector where the film can be collected. For example,
film 10 can be wound around a collector such as a cylinder and
collected and stored in a rolled configuration until such time as
it is desired to adhesively affix the film to the surface of a
medical device or surface of a tissue. At such time, a user,
preferably a surgeon or nurse, can unwind a length of film as
identified and cut or otherwise separate the desired length of film
from the cylinder and apply the film as desired.
[0200] In other embodiments, film 10 can be applied to a desired
anatomical site and secured at the site without the use of an
adhesive layer, or in conjunction with an adhesive layer. For
example in certain embodiments, a film fixation system for film
fixation at an anatomical site can include 1) a film and 2) a film
fixation element where the fixation element securely affixes the
film to the anatomical site, preferably securely affixes the film
to a medical device at the anatomical site or to a tissue such as a
bone or tendon at the anatomical site. According to one embodiment,
the fixation element is a screw, pin, wire, suture, staple, glue,
or combinations thereof. In addition, the polymer film (with or
without an adhesive layer) may be wrapped around the medical device
one or more times. It should be appreciated that in certain
embodiments as described above, the adhesive layer of the film can
function as the film fixation element. According to still another
embodiment, the system for film fixation can be further combined
with a medical device to provide a system for treatment, for
example a system for fracture fixation including 1) an orthopedic
medical device and 2) a film fixation system including a film and a
film fixation element.
[0201] The different possibilities for affixing the polymer film to
the medical device or tissue provides a user with flexibility. In
certain of these embodiments, the user can size and shape the
polymer as desired or needed and can cover all or part of the
medical device surface or tissue with the polymer film. For
example, one could selectively affix the polymer film to only a
bone-facing surface of the implant.
[0202] Referring to FIGS. 2 and 11A-11J, after creating the film
10, the film 10 can be formed into an active biocompatible implant
cover 25 configured for placement onto or over a surface of a
medical implant. The biocompatible implant cover 25 can be referred
to as active in that it includes one or more active agents of the
type described herein, alone or in combination, such that when
implanted, the active biocompatible implant cover 25 delivers the
one or more active agents. The medical implant can be a bone
implant, such as an intramedullary nail or a bone plate, or any
alternative medical implant (such as an implant for use in
orthopedic and/or musculoskeletal repair), the film 10 is shaped
and fashioned to generally correspond to conform to the shape of at
least a portion or substantially all of the bone plate 12. In some
embodiments, at least one film 10 is shaped and fashioned into a
cover 25 that can be configured as a sleeve 31 (see FIGS. 11A-I 1J
and 17A-26H) that is configured to receive at least a portion or an
entirety of the bone plate 12, or a strip that can be adhesively
attached to one or more surfaces of the bone plate 12. It should be
further appreciated that one or more surfaces of the sleeve 31 can
have adhesive properties so as to adhesively attach to one or more
surfaces of the bone plate 12.
[0203] Referring to FIGS. 11A-11J and 17A-26H in general, the
sleeve 31 includes at least one film 10 that defines a first sleeve
portion 31a and a second sleeve portion 31b that is spaced from the
first sleeve portion 31a along the transverse direction T. The
apertures 14 of the first sleeve portion 31a can be aligned with
the apertures 14 of the second sleeve portion 31b, or at least one
or more up to all of the apertures 14 of the first sleeve portion
31a can be offset with respect to all others of the apertures of
the second sleeve portion 31b along either or both of the lateral
and longitudinal directions. The first sleeve portion 31a defines
an inner surface 35a and an outer surface 37a opposite the inner
surface 35a. Similarly, the second sleeve portion 31b defines an
inner surface 35b and an outer surface 37b opposite the inner
surface 35b. The inner surfaces 35a and 35b face each other, and
the outer surfaces 37a and 37b face opposite each other.
[0204] Either or both of the inner surfaces 35a and 35b can be
defined by one of the first surface 10a or the second surface 10b,
and either or both of the outer surfaces 37a and 37b can be defined
by the other one of the first surface 10a or the second surface
10b. It should thus be appreciated that the meniscuses 17 (see,
e.g., FIG. 1A) can be disposed at either the inner surface 35a or
the outer surface 37a, and can further be disposed at the inner
surface 35b or the outer surface 37b. In one embodiment, the first
and second sleeve portions 31a and 31b are monolithic with each
other, such that the meniscuses 17 are disposed on either both
inner 35a and 35b or both outer surfaces 37a and 37b. Because the
at least one film 10 of the sleeve 31 is flexible, the sleeve 31
can be iterated between a first closed configuration whereby the
first and second sleeve portions 31a and 31b, and in particular the
inner surfaces 35a and 35b, are immediately adjacent each other
along the transverse direction T such that the sleeve 31 does not
define an opening between the first and second sleeve portions 31a
and 31b, and a second open configuration whereby the sleeve 31
defines an opening 33 between the first and second sleeve portions
31a and 31b, and in particular between the inner surfaces 35a and
35b. Thus, the inner surfaces 35a and 35b can be referred to as
implant facing, or bone plate facing, surfaces.
[0205] The opening 33 defined between the first and second sleeve
portions 31a and 31b. The opening 33 can be sized so as to define a
height in the transverse direction T and a width in the lateral
direction A that is at least equal to, and can be greater than, the
respective height and width of the bone plate 12 that is received
in the opening 33. The opening 33 can have a length along the
longitudinal direction L that can be equal to, less than, or
greater than, the length of the bone plate 12 such that the opening
33 is sized to receive at least a portion up to all of the bone
plate 12. Accordingly, each of the sleeve portions 31a and 31b is
configured to cover at least a portion, and up to all, of at least
one surface of the bone plate 12.
[0206] The sleeve 31 can be configured in any manner as desired.
For instance, the film 10 can be created in any manner described
herein, and shaped so as to define a shaped film that can
correspond to the shape of a preselected bone plate shape that is
to be received in the resulting sleeve 31. After the film 10 has
been molded, material of the resulting film 10 can be removed so as
to define a first shaped film that can correspond to the shape of a
preselected bone plate shape. A second shaped film substantially
identical to the first shaped film can be created from the same
film 10 that defined the first shaped film, or from a separate film
10. For instance, material can be removed from the respective film
10 so as to define the second shaped film. The first and second
shaped films 10 can be positioned adjacent each other such that
their respective outer peripheries are aligned along the transverse
direction T. At least a portion of the outer peripheries of the
first and second films can be attached to each other by any one of
the attachment methods of the type described herein so as to define
a closure 16, such as an attachment or an alternatively configured
closure, such that the first shaped film defines the first sleeve
portion 31a and the second shaped film defines the second sleeve
portion 31b.
[0207] The closure 16 can extend about a portion of the periphery
39 of the sleeve 31. For instance, the sleeve 31 can define a front
end 39a and a proximal portion 43a that is disposed proximate to
the front end 39a, and a rear end that is spaced from the front end
39b along at least the longitudinal direction L (which includes
embodiments in which at least a portion of the front and rear ends
39a and 39b can further be spaced from each other along the lateral
direction A) and defines a distal end 43b disposed proximate to the
rear end 39b. The sleeve 31 can further define first and second
sides 39c and 39d, respectively, that are spaced from each other
along at least the lateral direction A (which includes embodiments
in which at least a portion of the first and second sides 39c and
39d can further be spaced from each other along the longitudinal
direction L). The first and second sides 39c and 39d extend between
the front and rear ends 39a and 39b, for instance from the front
end 39a to the rear end 39b. The ends 39a and 39b in combination
with the sides 39c and 39d can define the outer periphery 39 of the
sleeve 31. The closure 16 can extend about a portion of the outer
periphery 39 so as to define at least one opening 41 at the outer
periphery 39 between the first sleeve portion 31a and the second
sleeve portion 31b. For instance, the closure 16 can extend along a
portion or an entirety of the rear end 39b, a portion or an
entirety of one or both of the first and second sides 39c and 39d,
and a portion or an entirety of the front end 39a, both alone or in
combination. For instance, in one embodiment, the first and second
sides 39c and 39d and the rear end 39b are attached, such that the
sleeve 31 defines the opening 41 at the front end 39a.
Alternatively or additionally, the sleeve 31 can define a second
open end at the rear end 39b. Alternatively or additionally, the
sleeve can define a third or fourth opening at one or both of the
sides 39c and 39d, respectively. One or more of the first, second,
third, and fourth openings can be continuous with each other.
[0208] When the sleeve 31 is in the open configuration, the opening
41 can be dimensioned such that the bone plate 12 can be inserted
into, and removed from if desired, the opening 41 and into and out
of the opening 33. Alternatively, the bone plate 12 can be placed
between the first and second sleeve portions 31a and 31b, and a
substantial entirety of the periphery of the sleeve 31 can define
the closure 16, such that the bone plate 12 is disposed in the
opening 33 and substantially encapsulated by the sleeve so as to be
non-removable from the film, meaning that the sleeve 31 does not
define an opening at the outer periphery 39 that is sized
sufficiently for the bone plate 12 to be removed from the sleeve 31
without breaching either of the sleeve portions 31a and 31b or the
closure 16. It should be appreciated that when the bone plate 12 is
disposed in the opening, the first and second sleeve portions 31a
and 31b cover at least a portion of respective opposed surfaces of
the bone plate 12.
[0209] In accordance with one embodiment, either or both of the
outer periphery 39 of the sleeve 31 and an outer periphery of the
opening 33, such as can be defined by the inner periphery of the
closure 16 or other closure, can extend parallel to an outer
periphery of the bone plate 12, such that the sleeve 31 can define
a sheath. Thus, it should be appreciated that the closure has an
inner boundary that defines an outer periphery of the opening 33,
and at least a portion up to all of the inner boundary can be
parallel to the outer periphery 39 of the sleeve 31. It should be
appreciated that the at least one film 10 can be shaped in any
suitable manner as desired so as to define the sleeve 31. For
instance, as described, two shaped films can be adjoined to define
the first and second portions of the sleeve 31a and 31b. The first
and second shaped films can be produced by cutting a respective one
or two molded films 10. Alternatively, the cavity of the mold can
be shaped so as to define the outer periphery 39 of the sleeve 31,
and the as-molded film can be removed from the mold and thus define
the shaped film. Alternatively still, the films 10 can be attached
in the manner described herein such that the inner periphery of the
closure 16 is sized and shaped such that the resulting opening 33
is sized to receive a plurality of differently shaped bone plates
12 and the inner periphery of the closure 16 does not extend
parallel to the outer periphery of the bone plate 12.
[0210] As described above, the sleeve 31 can include a closure 16,
such as an attachment or alternatively configured closure as
desired. For instance, a single film 10, which can be shaped as
desired, can be folded about itself along a fold, such that the
film defines the first and second portions 31a and 31b of the
sleeve 31 that are separated from each other by the fold. Thus, the
fold can be said to define a closure at a portion of the outer
periphery 39 of the sleeve 31. The fold can be disposed, for
instance at a midline of the film 10, such that the film 10 defines
two symmetrical regions separated from each other by the fold. The
fold can define a fold line, or the film 10 may be shaped into a
cylinder and the two opposed edges of the film that are opposite
the fold can, in combination, define one of the sides of the sleeve
31. Resulting open portions of the outer periphery 39 of the sleeve
31 can be left open as desired, or closed, for instance attached in
the manner disclosed above. Thus, the folded film 10 can be at
least partially attached to itself. For instance, the free ends of
the film 10 can be attached to each other so as to define an
attachment at one of the first and second sides 31c and 31d of the
sleeve 31, and the fold can define the other of the first and
second sides 31c and 31d. Thus, the sleeve 31 can include a closure
16 at both the first and second sides 31c and 31d. In one
embodiment, the second surface 10b overlaps the first surface 10a
at the opposed edges of the film 10 such that the first surface 10a
defines the inner sleeve surfaces 35a and 35b at the opposed edges
of the film 10 so as to define at a least a region of the closure
16 when the opposed edges of the film 10 are attached to each
other. Alternatively, the first surface 10a overlaps the second
surface 10b at the opposed edges of the film 10 such that the
second surface 10a defines the inner sleeve surfaces 35a and 35b at
the opposed edges of the film 10 so as to define a least a region
of the closure 16 when the opposed edges of the film 10 are
attached to each other. The two symmetrical regions of the film 10
can be shaped so as to correspond to the preselected bone plate
shape, for instance by removing material of the film 10 or by
contouring the mold cavity in the manner described above.
[0211] It should be appreciated that in some embodiments, the
closure 16, such as the attachment, can be visible through at least
one of the first and second sleeve portions 31a and 31b as
illustrated in FIGS. 11A, 11B, 11D, and 11E, or can be hidden by
the first and second sleeve portions 31a and 31b, for instance as
illustrated in FIGS. 11C and 11F-11J. Accordingly, those
embodiments in which the closure 16, such as the attachment, is
visible can be constructed such that the closure 16, such as the
attachment, is hidden, and thus the outer periphery can be
illustrated as shown in FIGS. 11C and 11F-11J. Conversely, those
embodiments in which the closure 16, such as the attachment, is
hidden can be constructed such that the closure, such as the
attachment, is visible, and thus the outer periphery 39 can be
illustrated as shown in FIGS. 11A, 11B, 11D, and 11E.
[0212] Referring now to FIGS. 11A-11J and FIGS. 17A-26H, the sleeve
31 can define any suitable size and shape as desired. For instance,
the sleeve 31 can be constructed as any suitable sized and shaped
sheath as desired that is configured to form fit the bone that is
to be received in the respective opening (such that the inner
periphery of the closure 16 is substantially parallel to the outer
periphery of the bone plate 12). As illustrated in FIGS. 11A-11C
and 17A-19H, the sleeve 31 can define a cross-sectional dimension
at the proximal portion 43a along the lateral direction A that is
greater than the cross-sectional dimension of the sleeve 31 at the
distal portion 43b along the lateral direction A. For instance, at
least one of the sides 31c and 31d can define a flared region 45
that extends laterally out from an adjacent region of the
respective side as it extends along a direction from the rear end
39b toward the front end 39a, and thus is flared along the lateral
direction A away from the opposed side with respect to the adjacent
region of the respective side as it extends along a direction from
the rear end 39b toward the front end 39a. The flared region 45 of
one of the sides 31c and 31d can extend laterally out further or an
equal amount (see FIGS. 11H, 11I and 24A-25H), with respect to the
flared region 45 of the opposed side. Further, the flared region 45
of one of the sides 31c and 31d can define the same shape (see
FIGS. 11H, 11I and 24A-25H) or a different shape with respect to
the flared region 45 of the opposed side. In accordance with the
illustrated embodiment at FIGS. 11A and 17A-H, the flared region 45
at the second side 39d extends laterally out further than the
flared region at the first side 39c. Thus, it should be appreciated
that a portion of the front end 39a is offset with respect to the
rear end 39b along the lateral direction. Either or both of the
front end 39a and the rear end 39b can be curved (e.g., convex as
illustrated or concave as desired) or straight as desired in all
embodiments, unless otherwise indicated. In accordance with the
illustrated embodiment at FIGS. 11B, 11C, 18A-18H, and 19A-19H, the
second side 39d includes the flared region 45 and the first side
39c is linear from the front end 39a to the rear end 39b. Referring
now to FIGS. 11D-11G and 20A-23H, both the first and second sides
39c and 39d can extend linearly and parallel to each other from the
front end 39a to the rear end 39b. The rear end 39b can be curved
or straight as desired. The length of the sleeve 31 can be any
dimension as desired from the front end 39a to the rear end 39b
along the longitudinal direction L. Similarly, the width of the
sleeve 31 can be any dimension as desired from the first side 39c
to the second side 39d along the lateral direction A. Referring to
FIGS. 11J and 26A-H, the flared region 45 at one of the sides 39c
and 39d can extend laterally inward toward the other one of the
sides 39c and 39d, and the flared region 45 at the other one of the
sides 39 can extend laterally outward. For instance, as
illustrated, the proximal end 43a of the first side 39c can extend
laterally inward toward the second side along a direction from the
rear end 39b toward the front end 39a. The proximal end 43a of the
second side 39d can extend laterally outward away from the first
side 39c along a direction from the rear end 39b toward the front
end 39a. Moreover, the flared region 45 can extend to a location
spaced from the front end 39a along a direction from the front end
39a toward the rear end 39b, such that a length of the proximal
portion 43a that extends between the flared region 43 and the front
end 39a extends parallel to an adjacent region of the respective
side, such as side 39d, that is disposed adjacent the flared region
45.
[0213] As described above, the active biocompatible implant cover
25 can be configured as a sleeve, such as any sized or shaped
sleeve 31 as desired, which can define a sheath, or the implant
cover 25 can be alternatively configured as desired. For instance,
the implant cover 25 can be configured as one or more strips of the
film 10 that are configured to overlay at least a portion of one or
more surfaces of the bone plate 12. The strips can be shaped as
described above such that the outer periphery of the strips is
substantially aligned with, or parallel to, the outer periphery of
the bone plate 12, or can be sized greater than the bone plate 12
or less than the bone plate 12. Thus, the strips can define any
size and shape as desired, for instance the shapes as illustrated
in FIGS. 11A-11J and FIGS. 17A-26H with respect to the sleeve 31,
or any alternative shape as desired. The strips can further be
sized greater than the sizes of the sleeves 31 illustrated in FIGS.
11A-11J and FIGS. 17A-26H, or less than the sizes of the sleeves 31
as illustrated in FIGS. 11A-11J and FIGS. 17A-26H. Thus, one or
more of the strips can be placed along a portion up to all of the
bone facing surface of the bone plate 12, a portion up to all of
the outer surface of the bone plate 12 that is opposite the bone
facing surface, or both. The strip can define an inner surface that
faces the bone plate 12, and an outer surface that faces away from
the bone plate 12. The inner surface of the strip can be defined by
the first surface 10a or the second surface 10b. Conversely, the
outer surface of the strip can be defined by the first surface 10a
or the second surface 10b.
[0214] In one embodiment, the strips can be sized so as to wrap
around the bone plate 12, for instance at least one-half of a
revolution about the bone plate 12 such that the strip overlays at
least a portion of the bone facing and outer surfaces of the bone
plate 12. The strip can be wrapped around the bone plate 12, as
many full revolutions as desired until the strip overlays a
sufficient area of one or both of the bone facing and outer
surfaces of the bone plate 12 as desired. The strip can be
dimensioned as desired, for instance by removing material from the
as-molded film 10, or by contouring the mold cavity to define a
desired size and shape of the strip.
[0215] As described herein, at least a portion of film 10 or films
10 can be attached to each other by attachment methods to define a
closure 16, such as an attachment. In certain embodiments, the
attachment can be defined by attachment components, such as a seam,
glue, sutures, staples, pins, wires, screws, heat, ultraviolet
light, or a combination thereof that attach a first region of film
to a second region of film that overlaps the first region of film,
for instance along the transverse direction T. Accordingly, two
regions of the same film or two separate films may be attached to
form a sleeve 31. For example, first and second films 10 can be
positioned adjacent each other such that a first region of film,
which can be defined by the first film 10, overlaps with a second
region of film, which can be defined by the second film 10. The
first and second regions of film can overlap along any direction as
desired, such as the transverse direction T. The overlapping first
and second regions of film can be attached to each other with one
of the attachment components. Alternatively, a single film 10 can
be formed into a sleeve by folding the film 10 so as to at least
partially define a closure 16, and contouring the single film such
that free ends overlap. Thus, the free ends of the single film 10
can define the first and second overlapping regions of film. The
overlapping first and second regions of film, whether monolithic
with each other and defined by the same film 10, or defined by
different films 10, can be attached to each other by applying any
of the above described attachment components to one or both of the
first and second overlapping regions of film so as to at least
partially define a closure 16. For instance, a glue can be applied
along one or both surfaces of the overlapping first and second
regions of film that face each other, and the surfaces can be
brought against each other and/or the glue. In another embodiment,
the attachment can be defined by applying heat and/or pressure to
the first and second overlapping regions until the regions of film
begin to soften (or melt) and integrate with one another, and
subsequently allowing the portions to re-solidify. In addition,
multi-film sleeves and strips may be prepared by attaching two
separate films that are immediately adjacent each other, for
instance in the transverse direction T.
[0216] In addition to sleeves 31, film 10 may be used, in some
embodiments, for other medical applications such as hernia repair
mesh, adhesion barrier, soft tissue augmentation, filtration
membranes, drug delivery membranes, bone graft containment (e.g.,
for maintaining bone graft in place for example in a spinal fusion
procedure, or segmental defect grafting in a long bone), or wound
care products such as bandages.
[0217] The polymer film may be used at any surgical site
susceptible to microbial infection. Such methods can be used with
any polymer film embodiment and/or combination of embodiments
disclosed herein. Typically, the methods comprise identifying a
surgical site in need of microbial inhibition and contacting the
surgical site with a polymer film comprising an active agent. The
methods may also involve identifying a zone at a surgical site or
on a medical implant needing microbial inhibition (zone of
inhibition), contacting the medical implant with the polymer film,
and implanting the medical implant at the surgical site. In certain
embodiments, the polymer film is used in conjunction with medical
implants comprised of material that is susceptible to bacterial
colonization, for example, implants comprising metal.
[0218] The polymer film may be used in conjunction with metal bone
plates to be implanted at fracture sites in the extremities,
particularly the lower extremities, such as fractures associated
with the femur, fibula, and tibia. Following implantation, the
bacterial growth at the surgical site may be monitored to determine
the effectiveness of the treatment.
[0219] The implant may be contacted with the film in any manner as
described herein. For example, the film may be in the form of an
implant cover configured for placement onto or over a surface of a
medical implant. In the case of a sleeve, the polymer film is
slipped over at least a portion of the implant. As described
herein, the sleeve can include at least one open end, and in
certain embodiments two open ends. Alternatively, the polymer film
may be adhered or affixed to the implant via adhesive or fixation
devices such as sutures, screws, or other types of fasteners.
Typically, a doctor will select an implant with the proper contour,
such as a bone plate, to treat the bone fracture at issue. In the
case of percutaneous procedures, and before implant fixation, a
cavity within the soft tissue may be prepared to reduce the
stresses on the polymer film during implant insertion.
[0220] The contacting of the polymer film and implant is typically
done at or near the time of surgery, i.e., intraoperatively, such
that the surgeon can match the polymer film with the medical
implant to be contacted based on size and shape and the drug
requirements for the subject patient. If the implant is in the form
of a sleeve, the sleeve may be applied by opening it and inserting
the implant, such as a bone plate, until the anatomic portion of
the plate is seated in the sleeve. The sleeve may cover the entire
implant or a portion of the implant. For example, the sleeve may be
trimmed and/or folded to conform to the implant as desired. Prior
to instrumentation attachment or screw/fastener insertion of the
medical implant at the surgical site, the polymer film may be
pierced through the holes in the implant that will be used during
final implant fixation. This will provide an unimpeded path for the
screw/fastener through the polymer film. The implant may then be
affixed using standard surgical procedures.
[0221] Total drug dosing of the polymer film is a function of the
size of the implant as well as surgical need. In one embodiment,
the polymer film contains approximately 0.6 mg of gentamicin
sulfate per square centimeter of surface area. The total dose of
drug delivered depends on the size of the polymer film and the
implant it is designed to contact. In certain embodiments, a
surgeon will determine the amount of antibiotic that is needed at a
surgical site of a particular patient. The polymer film may then be
manipulated to meet the delivery need. For example, if the patient
requires more antibiotic than is available in a single polymer
film, multiple polymer films may be used and/or longer or otherwise
larger films may be selected. To the extent the polymer film is in
the form of a sleeve, an implant may be fitted with multiple
sleeves. If the patient requires less antibiotic, the polymer film
may be reduced by, e.g., cutting or trimming. As indicated herein,
the surgeon may determine an appropriate zone of inhibition that
will prevent bacterial colonization on an implant even if the
polymer film is not contacting the entire surface area of the
implant, such that cutting or trimming the polymer film may reduce
the overall drug load, but not reduce the effectiveness of the
anti-microbial treatment.
[0222] In one embodiment, there is an initial release of 20% of the
drug content in the film within one hour of implantation. This is
followed by a sustained release of the remaining drug content for
approximately 7 to 10 days. The polymer film itself is completely
degraded by hydrolysis and absorbed by the body within 60-90 days
of implantation.
[0223] In the case of gentamicin, gentamicin-related nephrotoxicity
is related to duration of treatment, and is typically transient
although full functional recovery may not occur for several months
after therapy stops. Nephrotoxicity is also related to plasma
gentamicin levels, with recommended trough levels not to exceed 2.0
.mu.g/ml. Peak plasma gentamicin levels released from the polymer
film have been found to be well below this level in sheep studies,
including in the range of 0.1 .mu.g/ml. Local administration of
gentamicin may be particularly advantageous as compared to systemic
antibiotic treatments. According to one embodiment, local delivery
of gentamicin provides a higher concentration of antibiotic at a
surgical site than a comparable standard of care amount of systemic
antibiotic treatment, thus permitting a higher potential for
eliminating bacterial growth at the site. According to another
embodiment, local delivery of gentamicin provides a lower plasma
concentration than a comparable standard of care amount of systemic
antibiotic treatment, thus potentially reducing potential adverse
effects, for example nephrotoxicity, that can result from systemic
antibiotic treatments. Thus, local delivery provides an opportunity
to deliver higher concentration of antibiotics with an overall
smaller quantity than systemic treatments.
[0224] In one embodiment, the method of inhibiting microbial
infection at a surgical site comprises contacting a medical implant
with a polymer film of the present disclosure at or near the time
of surgery, wherein the film comprises a drug component having a
particle size of 10 microns or less, and implanting the medical
implant at the surgical site. As described herein, with respect to
bacteria, the polymer film is able to produce a 5 to 7-log
reduction of colony forming units.
[0225] In more particular embodiments of the method, the polymer
film is in the form of a sleeve and comprises a bioresorbable film
comprising a copolymer of glycolide, trimethylene carbonate,
lactide and caprolactone, the active agent is gentamicin sulfate,
and the surgical site is a bone fracture site of the lower
extremities, such as the tibia.
Example 1
[0226] Film preparation: Films were produced from a copolymer of
approximately: 70% glycolic acid, 17% caprolactone, 5% lactic acid
and 8% trimethylene carbonate (US Surgical, North Haven, Conn.).
This copolymer was dissolved in dimethyl sulfoxide (DMSO) at a
concentration of 20% by weight, and either cast as a thin film onto
a 20 cm.times.20 cm glass plate, or mixed with 5% or 10% gentamicin
sulfate and then cast. Cast films were dried in air at 60.degree.
C. for a minimum of 12 hours to remove solvent, then removed from
the glass plate and stored under vacuum for further testing.
Finished films had a thickness of 0.06.+-.0.01 mm.
[0227] Tensile testing: 10 mm.times.80 mm strips cut from the cast
films were tested in tension to failure on an Instron test stand
(model 3342) at 20 mm/sec, dry and at room temperature, per ASTM
D882. Initial yield stress of the films tested at t=0 are shown in
FIG. 12 and the elongation of the films at yield are shown in FIG.
13. Incorporation of gentamicin sulfate into the films results in a
minor decrease in tensile strength and elasticity.
[0228] Drug release testing: 19 mm diameter disk samples cut from
cast films (5% & 10% gentamicin) were placed in PBS at
37.degree. C. Concentration of gentamicin in solution was measured
at 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 1 d, 2 d, 4 d, 7 d and
weekly up to 12 weeks, using fluorescence polarization immunoassay
technique (TDxFLx, Abbott Laboratories). Results are shown in FIG.
14.
[0229] In-vitro degradation: 19 mm diameter disk samples cut from
cast films (plain, 5% gentamicin, 10% gentamicin) were weighed and
placed into vials containing phosphate buffered saline solution
(PBS) at 37.degree. C. for 1 d, 4 d, 7 d and weekly up to 10 weeks.
Fresh PBS was changed weekly and the pH was monitored. At test
times, the samples were removed from the solution, freeze dried,
and weighed. The inherent viscosity of each sample was also
measured by dilute solution viscosity (Cannon-Ubbelhode semi micro
viscometer, in HFIP at 25.degree. C.). In-vitro degradation of all
polymer films proceeded at a similar rate, regardless of the level
of incorporated gentamicin, as shown in FIG. 15. Molecular weight
of the polymer as measured by inherent viscosity dropped rapidly
within the first 7 days in-vitro, then at a slower rate, as shown
in FIG. 16.
Example 2
[0230] In one exemplary embodiment, implants were tested by
implantation in sheep. The implants were metal plates with tubular,
thin (0.05-0.08 mm), transparent polymer sleeves carefully slipped
over the metal plates just before they were surgically inserted and
attached to the bone. The sleeves had a tight fit, covered the
metal plates completely over the entire length, although they were
open at both ends of the plates. The sleeves were comprised of a
synthetic copolyester (glycolide, caprolactone,
trimethylenecarbonate, lactide) with aperture holes of 1.5 mm
diameter equally spaced throughout. One group of sleeves contained
triclosan
(2,4,4.quadrature.-trichloro-2.quadrature.-hydroxydiphenyl ether)
at a concentration of 1%, one group of sleeves contained gentamicin
at a concentration of 10%, and one group of sleeves contained a
combination of both triclosan (1%) and gentamicin (10%). The
concentration of gentamicin and Triclosan were chosen based on in
vitro testing to determine the therapeutic window for each
compound.
[0231] The hydrophobic triclosan was in complete solution within
the polymer, in contrast to the hydrophilic gentamicin, which
remained suspended as 10-20 .mu.m small particles. In vitro testing
has shown that due to its poor water solubility, triclosan is
released from these films only slowly over a to 3 weeks period,
with minimal initial burst release.
[0232] Approximately 50% of the more water soluble gentamicin which
is exposed to the surface of the sleeves was released into the
adjacent tissue within 24 hours after insertion. The remaining
gentamicin encapsulated in the depth of the polymer dissolves more
slowly and was released over a 2 to 3 week period after
implantation. The polymer was designed to degrade through
hydrolysis within 60 days after surgery.
[0233] The sleeves with or without antimicrobial agents were proven
biocompatible, with minimal effect on soft tissue and bone healing
and not corrosive to the metallic implants. Additional details of
the experiment can be found in Vet Surg. 2012 Jan. 12.
Biodegradable Sleeves for Metal Implants to Prevent
Implant-Associated Infection: An Experimental In Vivo Study in
Sheep. von Plocki S C, Armbruster D, Klein K, Kampf K, Zlinszky K,
Hilbe M, Kronen P, Gruskin E, von Rechenberg B., which is hereby
incorporated by reference in its entirety.
Example 3
[0234] In one exemplary embodiment, film 10 is manufactured by the
following method:
[0235] Determination of Gentamicin Moisture Content:
[0236] The moisture content of gentamicin sulfate powder is
measured by a loss on drying method. Approximately 0.5 grams of
gentamicin is weighed in a glass jar, then heated under vacuum to
110.degree. C. for 3 hours and weighed a second time. The weight
loss is recorded as the moisture content, which is used to
calculate the percent moisture.
[0237] Solution Mixing:
[0238] 14.69 grams of gentamicin sulfate powder is weighed,
compensating for the percent moisture content as calculated above.
This is mixed into 400 g of DMSO solvent in a 1 L vessel, using a
paddle mixer. The mixture is stirred for 30 minutes until the
gentamicin is uniformly distributed. 100 g of a copolymer
containing glycolic acid, caprolactone, lactic acid, and
trimethylene carbonate monomers is added to the suspension, and the
mixing vessel is heated to 65.degree. C. Mixing is continued for 2
hours until the polymer is completely dissolved into the solution,
then the solution temperature is reduced to 55.degree. C.
[0239] Film Casting & Solvent Drying:
[0240] A casting mold and drawing blade made from high density
polyethylene are used to cast thin perforated films from the
polymer solution. The casting mold and drawing blade are
pre-cleaned using an alkaline detergent solution and loaded into an
automated CNC casting fixture. 15 ml of the polymer solution are
drawn up in a polypropylene syringe, which is loaded into the
casting fixture. The casting fixture automatically dispenses the
solution onto the casting mold, and draws the blade across the
surface of the mold. The mold filled with polymer solution is
placed into a solvent drying oven at 85.degree. C. for
approximately 90 minutes to dry the film. The molds are removed
from the drying oven and the films are peeled from the molds within
2 minutes.
[0241] Sleeve Sealing:
[0242] An impulse heat sealing press with specially shaped dies is
used to seal and cut the cast film into the shape of a sleeve. Two
cast films are placed into the press, and the press is closed with
a pressure of 80 psi and heated to 200.degree. C. for 4 seconds.
The sleeves are removed from the excess film material and cut to
the appropriate length. Sealed sleeves can be dried under vacuum at
50.degree. C. and sealed in moisture barrier packaging to prevent
degradation of the bioresorbable polymer.
Example 4
[0243] In vitro studies have been conducted to evaluate the
effectiveness of a gentamicin containing resorbable polymer film to
prevent colonization of metal implants by common bacterial
pathogens. Colonization assays using agar to simulate soft tissue
coverage of stainless steel and titanium fracture fixation plates
have shown that the film is effective in preventing bacterial
colonization of the metallic implants by Staphylococcus aureus,
Staphylococcus epidermidis, Pseudomonas aeruginosa and Enterobacter
cloacae. These data represent at least a 5 to 6-log reduction in
bacterial counts compared to metallic implants with no film
(control).
[0244] In time to kill assays, stainless steel plates were
inoculated with bacteria. The gentamicin sulfate containing film
was then placed on the plate and the number of surviving bacteria
were measured at different time points. Time to kill data for
target bacteria are shown below. The gentamicin film was effective
to produce a 5 to 7-log reduction in bacterial
colonization--measured as "colony forming units" (CFU)--by all Gram
positive (shown in blue: Staphylococcus aureus (MSSA),
Staphylococcus aureus (MRSA), Staphylococcus aureus (MDR) and
Staphylococcus epidermidis) and Gram negative (shown in green:
Pseudomonas aeruginosa, Enterobacter cloacae, and Acinetobacter
baumannii) target bacteria, except for a multi-drug resistant
strain of S. aureus, and the anaerobe P. acnes, both of which are
typically gentamicin resistant. FIG. 27 illustrates the
effectiveness of the gentamicin sulfate containing film in
preventing colonization of stainless steel in vitro (various
bacteria per ISO 22916)
Example 5
[0245] The objective was to measure the zone of inhibition of a
gentamicin film. Testing was performed with 4 different species of
bacteria.
[0246] Samples
[0247] 6 mm punches of the gentamicin film (0.1%, 0.5%, 1.0%, 5.0%,
and 13% gentamicin sulfate, anhydrous) (the 13% gentamicin film was
tested separately from the other gentamicin films and the data was
separately collected and produced)
[0248] Controls
[0249] blank filter disk w/ 120 ug Gentamicin in 30 ul dPBS; blank
filter disk in 30 ul dPBS
[0250] Bacteria
[0251] S. aureus ATCC 25923; S. epidermidis ATCC 12228; Pseudomonas
aeruginosa ATCC 10145; Enterobacter cloacae ATCC 29941
[0252] Materials & Instrument
[0253] Glass culture tubes (VWR #: 89001-480); Blank Disks, 6.35 mm
diameter (VWR#: 90002-114); 6 mm Disposable Biopsy Punches (VWR#:
21909-144); Mueller Hinton agar dishes (VWR #: 100219-188); 0.5
McFarland turbidity standard (VWR #: 29447-318); dPBS (VWR #:
12001-664); Cotton swabs; Incubator; Thermometer; Bacterial
hood
[0254] Experimental Method
[0255] Add colonies from an agar dish which was incubated o/n at
36.degree. C. to dPBS.
[0256] Adjust turbidity with dPBS to 0.5 McFarland Standard
equivalent.
[0257] Within 15 minutes of adjusting turbidity, dip a sterile
cotton swab into the dPBS. Swirl the swab in this tube and when
removing the swab, press it into the side of the tube above the
liquid.
[0258] Inoculate Mueller-Hinton agar plates by streaking once down
the middle of the plate. Then streak the swab all over the plate;
rotate 2.times.'s.about.60.degree. each time. After streaking the
entire plate, streak the swab around the rim of the plate.
[0259] Place filter disks/punches onto the dish.
[0260] Place in the 36.degree. C. incubator within 15 minutes
inoculating dish.
[0261] Incubate 16-18 hours.
[0262] Measure ZOI in millimeters using slide caliper (ZOI was
measured a linear distance measured through the center point of the
disk). FIG. 28 illustrates the minimum effective concentration and
measured ZOI.
TABLE-US-00004 Avg. ZOI (mm) S. P. S. aureus E. cloacae epidermidis
aeruginosa Blank 0.00 0.00 0.00 0.00 120 ug gentamicin 30.5 22.4
34.9 26.7 5% gentamicin 21.2 17.4 27.2 12.9 1% gentamicin 15.1 12.3
19.8 0.0 0.5% gentamicin 13.4 10.0 15.7 0.0 0.1% gentamicin 0.0 0.0
6.7 0.0
TABLE-US-00005 Avg. ZOI (mm) S. P. S. aureus E. cloacae epidermidis
aeruginosa Blank 0.00 0.00 0.00 0.00 120 ug gentamicin 28.73 25.27
31.37 24.90 13% gentamicin 25.80 22.40 29.87 20.33
Example 6
[0263] In order to evaluate the effectiveness of a gentamicin
sulfate containing polymer film to prevent bacterial colonization,
stainless steel fracture fixation plates were covered with
gentamicin sulfate containing polymer films in the form of sleeves
or sleeves that were too short to cover the full plate, i.e., only
half of the plate (5.5 cm of the 11 cm long plate) was covered.
These plates were inoculated with bacteria and evaluated for
antimicrobial activity in a 3-dimensional agar assay which
simulates soft tissue coverage Four common pathogens (P.
aeruginosa, S. aureus, E. cloacae, and S. epidermidis) were
evaluated, and the gentamicin sulfate containing polymer film (13%
by weight gentamicin) effectively prevented colonization of the
steel plates, even those surfaces of the plates not covered by the
polymer film (5 to 6 log reduction in CFU relative to controls).
FIG. 29 illustrates the measured zone of inhibition for the various
bacteria.
[0264] It will be appreciated by those skilled in the art that
changes could be made to the exemplary embodiments shown and
described above without departing from the broad inventive concept
thereof. It is understood, therefore, that this disclosure is not
limited to the exemplary embodiments shown and described, but it is
intended to cover modifications within the spirit and scope of the
present disclosure as defined by the claims. For example, specific
features of the exemplary embodiments may or may not be part of the
claimed invention and features of the disclosed embodiments may be
combined. Unless specifically set forth herein, the terms "a". "an"
and "the" are not limited to one element but instead should be read
as meaning "at least one".
[0265] It is to be understood that at least some of the figures and
descriptions of the invention have been simplified to focus on
elements that are relevant for a clear understanding of the
disclosure, while eliminating, for purposes of clarity, other
elements that those of ordinary skill in the art will appreciate
may also comprise a portion of the invention. However, because such
elements are well known in the art, and because they do not
necessarily facilitate a better understanding of the invention, a
description of such elements is not provided herein.
[0266] Further, to the extent that the method does not rely on the
particular order of steps set forth herein, the particular order of
the steps should not be construed as limitation on the claims.
Further, it should be appreciated that method steps of all
embodiments can be incorporated into the method steps of any other
embodiment described herein unless otherwise indicated, and
structural features of all embodiments can be incorporated into all
other embodiments unless otherwise indicated. The claims directed
to the method of the present invention should not be limited to the
performance of their steps in the order written, and one skilled in
the art can readily appreciate that the steps may be varied and
still remain within the spirit and scope of the present
invention.
* * * * *