U.S. patent application number 14/200958 was filed with the patent office on 2014-07-03 for method for repairing or replacing damaged tissue.
The applicant listed for this patent is Ayman BOUTROS. Invention is credited to Ayman BOUTROS.
Application Number | 20140186416 14/200958 |
Document ID | / |
Family ID | 48669541 |
Filed Date | 2014-07-03 |
United States Patent
Application |
20140186416 |
Kind Code |
A1 |
BOUTROS; Ayman |
July 3, 2014 |
METHOD FOR REPAIRING OR REPLACING DAMAGED TISSUE
Abstract
A method for repairing or replacing damaged tissue, or for
providing post-surgical augmentation, comprising administering a
pliable biocompatible material and a physiologically acceptable
suspending agent to a patient is disclosed. Copolymers of
unsubstituted acrylate and substituted acrylate are disclosed as
pliable biocompatible materials.
Inventors: |
BOUTROS; Ayman; (Great
Falls, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BOUTROS; Ayman |
Great Falls |
VA |
US |
|
|
Family ID: |
48669541 |
Appl. No.: |
14/200958 |
Filed: |
March 7, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13336340 |
Dec 23, 2011 |
8709395 |
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14200958 |
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12741280 |
Sep 7, 2010 |
8475815 |
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PCT/US2008/081608 |
Oct 29, 2008 |
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13336340 |
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11926930 |
Oct 29, 2007 |
7910134 |
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12741280 |
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Current U.S.
Class: |
424/422 ;
424/489; 424/78.31 |
Current CPC
Class: |
A61L 27/48 20130101;
A61P 17/00 20180101; A61K 31/765 20130101; A61P 9/00 20180101; A61L
27/20 20130101; A61L 27/52 20130101; A61P 25/00 20180101; A61L
2300/41 20130101; A61P 29/00 20180101; A61L 27/34 20130101; A61P
1/00 20180101; A61L 2300/402 20130101; A61K 31/78 20130101; A61L
27/16 20130101; A61P 11/00 20180101; A61L 27/54 20130101; A61L
27/58 20130101; A61P 21/00 20180101; A61K 47/32 20130101; A61L
2400/06 20130101; A61P 19/00 20180101; A61K 45/06 20130101; A61L
27/20 20130101; C08L 5/08 20130101; A61L 27/48 20130101; C08L 5/08
20130101; A61L 27/16 20130101; C08L 33/06 20130101; A61L 27/34
20130101; C08L 33/06 20130101 |
Class at
Publication: |
424/422 ;
424/78.31; 424/489 |
International
Class: |
A61K 31/78 20060101
A61K031/78; A61L 27/34 20060101 A61L027/34; A61K 45/06 20060101
A61K045/06 |
Claims
1. A method for repairing or replacing damaged tissue comprising:
identifying a site of damaged tissue in a subject; and injecting
into the subject at or near the site of damaged tissue an
alloplastic and biocompatible composition comprising an
unsubstituted acrylate/substituted acrylate copolymer in an amount
sufficient to repair or replace the damaged tissue.
2. The method of claim 1, wherein the composition is a
solution.
3. The method of claim 1, wherein the composition is a
suspension.
4. The method of claim 3, wherein the suspension has a viscosity of
about 100 to about 1,000 mPa.S.
5. The method of claim 1, wherein the unsubstituted
acrylate/substituted acrylate copolymer comprises particles in a
suspension.
6. The method of claim 5, wherein the particles have a diameter of
less than about 100 .mu.m.
7. The method of claim 5, wherein the particles have a diameter of
less than about 10 .mu.m
8. The method of claim 5, wherein the particles have a diameter of
about 0.01 .mu.m to about 10 .mu.m.
9. The method of claim 5, wherein the particles have a diameter of
about 0.1 .mu.m to about 5 .mu.m.
10. The method of claim 1, wherein the substituted acrylate monomer
of the unsubstituted acrylate/substituted acrylate copolymer is
substituted with a methyl group.
11. The method of claim 1, wherein the substituted acrylate monomer
is substituted with a hydrocarbon chain of two, three, four or five
carbons.
12. The method of claim 1, wherein the substituted acrylate monomer
is substituted with a halogen group.
13. The method of claim 1, wherein the substituted acrylate monomer
is substituted with a nitrile group.
14. The method of claim 1, wherein the acrylate/methacrylate
copolymer is a finely ground solid.
15. The method of claim 14, wherein the finely ground solid is a
powder.
16. The method of claim 14, wherein the finely ground solid is a
non-porous microbead.
17. The method of claim 14, wherein the finely ground solid is a
microsphere.
18. The method of claim 14, wherein the finely ground solid has a
diameter of from about less than 0.1 .mu.m to about 10 .mu.m.
19. The method of claim 1, wherein the composition further
comprises a physiologically acceptable suspending agent.
20. The method of claim 19, wherein the physiologically acceptable
suspending agent is resorbable.
21. The method of claim 19, wherein the physiologically acceptable
suspending agent is a buffered physiological solution.
22. The method of claim 19, wherein the physiologically acceptable
suspending agent comprises cross-linked sodium hyaluronate.
23. The method of claim 19, wherein the physiologically acceptable
suspending agent comprises a non cross-linked sodium
hyaluronate.
24. The method of claim 19, wherein the physiologically acceptable
suspending agent comprises collagen.
25. The method of claim 24, wherein the collagen is derived from
natural sources or is synthetic tissue replacement
26. The method of claim 1, wherein the damaged tissue is the result
of an injury
27. The method of claim 1, wherein the damaged tissue is the result
of disease.
28. The method of claim 1, wherein the damaged tissue is the result
of a nutritional deficiency.
29. The method of claim 1, wherein the damaged tissue is the result
of a surgical procedure.
30. The method of claim 29, wherein the surgical procedure is
rhinoplasty.
31. The method of claim 1, wherein the damaged tissue is connective
tissue.
32. The method of claim 1, wherein the damaged tissue is skin,
muscle, ligament, cartilage, fat, or bone, or combinations
thereof.
33. The method of claim 1, wherein the damaged tissue is cardiac
tissue, aortic tissue, vascular tissue, pulmonary tissue,
gastrointestinal tissue, or neurosurgical tissue or any combination
thereof.
34. The method of claim 1, further comprising administering an
anti-inflammatory agent.
35. The method of claim 34, wherein said anti-inflammatory agent is
a non-steroidal anti-inflammatory drug (NSAID).
36. The method of claim 34, wherein said anti-inflammatory agent is
acetaminophen, azapropazone, diclofenac, diflunisal, etodolac,
fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, mefenamic, meloxicam, nabumetone, naproxen,
phenylbutazone, piroxicam, a salicylate, sulindac, tenoxicam,
tiaprofenic acid, or tolfenamic acid or any combination
thereof.
37. The method of claim 36, wherein said salicylate is
acetylsalicylic acid, amoxiprin, benorylate, choline magnesium
salicylate, ethenzamide, faislamine, methyl salicylate, magnesium
salicylate, salicyl salicylate, or salicylamide or any combination
thereof.
38. The method of claim 1, further comprising administering an
analgesic to the subject.
39. The method of claim 38, wherein said analgesic is
acetaminophen, amitriptyline, carbamazepine, codeine,
dihydromorphine, fentanyl patch, Flupirtine, fluriprofen,
gabapentin, hydrocodone APAP, hydromorphone, ibuprofen, ketoprofen,
morphine, oxycodone, pentazocine, pethidine, phenacetin,
pregabalin, propoeylphene, propoyl APA, salicylamide, tramadol,
tramadol APAP, or voltaren, or any combination thereof.
40. The method of claim 1, wherein said method further comprises
administering a local anesthetic to the subject.
41. The method of claim 40, wherein said local anesthetic is
amethocaine, articaine, benzocaine, bupivacaine, mepivacaine,
cocaine, cinchocaine, chloroprocaine, cyclomethycaine, dibucaine,
dimethocaine, EMLA.RTM. (eutectic mixture of lidocaine and
prilocalne), etidocaine, larocaine, levobupivacaine, lidocaine,
lignocaine, procaine, piperocaine, prilocalne, proparacaine,
propoxycaine, ropivacaine, saxitoxin, tetracaine, tetrodotoxin, or
trimecaine or any combination thereof.
42. A method for repairing or replacing damaged tissue comprising:
injecting into a subject at or near a site having damaged tissue an
effective amount of a composition comprising a copolymer of
phenylethyl acrylate and phenylethyl methacrylate.
43. The method of claim 42, wherein the copolymer of
phenylethylacrylate and phenylethylmethacrylate is a solid.
44. The method of claim 43, wherein the solid is selected from the
group consisting of a powder, a non-porous microbead, a microsphere
and combinations thereof.
45. The method of claim 43, wherein the solid comprises particles
each having a diameter of: about 10 .mu.m to about 100 .mu.m; about
0.01 .mu.m to about 10 about 0.01 .mu.m to about 5 .mu.m, or any
combination thereof.
46. The method of claim 42, wherein the composition further
comprises a physiologically acceptable suspending agent.
47. The method of claim 46, wherein the physiologically acceptable
suspending agent is resorbable.
48. The method of claim 46, wherein the physiologically acceptable
suspending agent is selected from the group consisting of a
buffered physiological solution, cross-linked sodium hyaluronate, a
non cross-linked sodium hyaluronate, collagen, and any combination
thereof.
49. The method of claim 42, wherein the molar ratio between the
phenylethyl acrylate and the phenylethyl methacrylate is selected
from the group consisting of: between about 1:1000 and about 1:1;
between about 1:10 and about 1:1; between about 1:1000 and about
1:10; about 1:1000; about 1:100; about 1:10; about 1:9; about 1:8;
about 1:7; about 1:6; about 1:5; about 1:4; about 1:3; about 1:2;
about 1:1; between about 1000:1 and about 1; between about 10:1 and
about 1:1; between about 1000:1 and about 10:1; about 1000; about
100:1; about 10:1; about 9:1; about 8:1; about 7:1; about 6:1;
about 5:1; about 4:1; about 3:1; about 2:1; about 1:2; about 3:2;
about 5:2; about 1:3; about 2:3; about 4:3; about 5:3; about 1:4;
about 3:4; about 5:4; about 1:5; about 2:5; about 3:5; about 4:5;
about 2:1; about 2:3; about 2:5; about 3:1; about 3:2; about 3:4;
about 3:5; about 4:1; about 4:3; about 4:5; about 5:1; about 5:2;
about 5:3; and about 5:4.
50. The method of claim 42, wherein the copolymer is cross-linked
with 1.4 butanediol diacrylate.
51. The method of claim 42, further comprising administering an
anti-inflammatory agent.
52. The method of claim 51, wherein said anti-inflammatory agent is
a non-steroidal anti-inflammatory drug (NSAID).
53. The method of claim 51, wherein said anti-inflammatory agent is
acetaminophen, azapropazone, diclofenac, diflunisal, etodolac,
fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, mefenamic, meloxicam, nabumetone, naproxen,
phenylbutazone, piroxicam, a salicylate, sulindac, tenoxicam,
tiaprofenic acid, or tolfenamic acid, or any combination
thereof.
54. The method of claim 53, wherein said salicylate is
acetylsalicylic acid, amoxiprin, benorylate, choline magnesium
salicylate, ethenzamide, faislamine, methyl salicylate, magnesium
salicylate, salicyl salicylate, or salicylamide or any combination
thereof.
55. The method of claim 42, further comprising administering an
analgesic.
56. The method of claim 55, wherein said analgesic is
acetaminophen, amitriptyline, carbamazepine, codeine,
dihydromorphine, fentanyl patch, Flupirtine, fluriprofen,
gabapentin, hydrocodone APAP, hydromorphone, ibuprofen, ketoprofen,
morphine, oxycodone, pentazocine, pethidine, phenacetin,
pregabalin, propoeylphene, propoyl APA, salicylamide, tramadol,
tramadol APAP, or voltaren, or any combination thereof.
57. The method of claim 42, wherein said method further comprises
administering a local anesthetic.
58. The method of claim 57, wherein said local anesthetic is
amethocaine, articaine, benzocaine, bupivacaine, mepivacaine,
cocaine, cinchocaine, chloroprocaine, cyclomethycaine, dibucaine,
dimethocaine, EMLA.RTM. (eutectic mixture of lidocaine and
prilocalne), etidocaine, larocaine, levobupivacaine, lidocaine,
lignocaine, procaine, piperocaine, prilocalne, proparacaine,
propoxycaine, ropivacaine, saxitoxin, tetracaine, tetrodotoxin, or
trimecaine, or any combination thereof.
59. A method of preparing a composition for repairing or replacing
tissue comprising admixing a finely ground copolymer of phenylethyl
acrylate and phenylethyl methacrylate with a physiologically
acceptable suspending agent to form an injectable, biocompatible
material.
60. The method of claim 59, wherein the copolymer is a solid.
61. The method of claim 60, wherein the solid selected from the
group consisting of: a powder, a non-porous microbead, and a
microsphere.
62. The method of claim 60, wherein the solid comprises particles
each having a diameter selected from the group consisting of: about
10 .mu.m to about 100 .mu.m; about 0.01 .mu.m to about 10 .mu.m,
and about 0.01 vm to about 5 .mu.m.
63. The method of claim 59, wherein the physiologically acceptable
suspending agent is resorbable.
64. The method of claim 59, wherein the physiologically acceptable
suspending agent is selected from the group consisting of a
buffered physiological solution, cross-linked sodium hyaluronate, a
non cross-linked sodium hyaluronate, collagen, and any combination
thereof.
65. The method of claim 59, wherein the molar ratio between the
phenylethyl acrylate and the phenylethyl methacrylate is selected
from the group consisting of: between about 1:1000 and about 1:1;
between about 1:10 and about 1:1; between about 1:1000 and about
1:10; about 1:1000; about 1:100; about 1:10; about 1:9; about 1:8;
about 1:7; about 1:6; about 1:5; about 1:4; about 1:3; about 1:2;
about 1:1; between about 1000:1 and about 1; between about 10:1 and
about 1:1; between about 1000:1 and about 10:1; about 1000; about
100:1; about 10:1; about 9:1; about 8:1; about 7:1; about 6:1;
about 5:1; about 4:1; about 3:1; about 2:1; about 1:2; about 3:2;
about 5:2; about 1:3; about 2:3; about 4:3; about 5:3; about 1:4;
about 3:4; about 5:4; about 1:5; about 2:5; about 3:5; about 4:5;
about 2:1; about 2:3; about 2:5; about 3:1; about 3:2; about 3:4;
about 3:5; about 4:1; about 4:3; about 4:5; about 5:1; about 5:2;
about 5:3; and about 5:4.
66. The method of claim 59, wherein said copolymer is cross-linked
with 1.4 butanediol diacrylate.
67. A method of preparing a soft tissue filler for repairing or
replacing tissue comprising admixing an acrylate/methacrylate
copolymer with a physiologically acceptable suspending agent to
form an injectable, biocompatible material.
68. The method of claim 67, wherein the acrylate/methacrylate
copolymer is a finely ground solid.
69. The method of claim 68, wherein the finely ground solid is a
powder.
70. The method of claim 68, wherein the finely ground solid is a
non-porous microbead.
71. The method of claim 68, wherein the finely ground solid is a
microsphere.
72. The method of claim 68, wherein the finely ground solid has a
diameter of from about less than 0.1 .mu.m to about 10 .mu.m.
73. The method of claim 68, wherein the physiologically acceptable
suspending agent is resorbable.
74. The method of claim 68, wherein the physiologically acceptable
suspending agent is a buffered physiological solution.
75. The method of claim 68, wherein the physiologically acceptable
suspending agent comprises cross-linked sodium hyaluronate.
76. The method of claim 68, wherein the physiologically acceptable
suspending agent comprises a non cross-linked sodium
hyaluronate.
77. The method of claim 68, wherein the physiologically acceptable
suspending agent comprises collagen.
78. The method of claim 77, wherein the collagen is derived from
natural sources or is synthetic.
79. A method for repairing or replacing damaged tissue in a subject
comprising: performing a surgical incision; and injecting at or
near the site of the surgical incision a composition comprising an
unsubstituted acrylate/substituted acrylate copolymer in an amount
sufficient to repair or replace the damaged tissue.
80. A method for repairing or replacing damaged tissue in a subject
comprising: injecting at or near a site of tissue damage a
composition comprising an unsubstituted acrylate/substituted
acrylate copolymer and a substance that promotes regeneration of
tissue.
81. Use of a composition to repair or replace damaged tissue in a
subject, said composition comprising an effective amount of an
unsubstituted acrylate/substituted acrylate copolymer and a
physiologically acceptable suspending agent.
82. An apparatus for tissue repair or replacement comprising: an
implantable device comprising an unsubstituted acrylate/substituted
acrylate copolymer.
83. The apparatus of claim 82, wherein the composition further
comprises a proteoglycan.
84. The apparatus of claim 83, wherein said proteoglycan is
aggrecan, decorin, biglycan, fibromodulin, lumican, keratocan,
epiphycan, or osteoglycin.
85. The apparatus of claim 82, further comprising an
anti-inflammatory agent.
86. The apparatus of claim 85, wherein said anti-inflammatory agent
is a non-steroidal anti-inflammatory drug (NSAID).
87. The apparatus of claim 82, wherein said anti-inflammatory agent
is acetaminophen, azapropazone, diclofenac, diflunisal, etodolac,
fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, mefenamic, meloxicam, nabumetone, naproxen,
phenylbutazone, piroxicam, a salicylate, sulindac, tenoxicam,
tiaprofenic acid, or tolfenamic acid.
88. The apparatus of claim 87, wherein said salicylate is
acetylsalicylic acid, amoxiprin, benorylate, choline magnesium
salicylate, ethenzamide, faislamine, methyl salicylate, magnesium
salicylate, salicyl salicylate, or salicylamide.
89. The apparatus of claim 82, further comprising administering an
analgesic.
90. The apparatus of claim 89, wherein said analgesic is
acetaminophen, amitriptyline, carbamazepine, codeine,
dihydromorphine, fentanyl patch, Flupirtine, fluriprofen,
gabapentin, hydrocodone APAP, hydromorphone, ibuprofen, ketoprofen,
morphine, oxycodone, pentazocine, pethidine, phenacetin,
pregabalin, propoeylphene, propoyl APA, salicylamide, tramadol,
tramadol APAP, or voltaren.
91. The apparatus of claim 82, further comprising a local
anesthetic.
92. The apparatus of claim 91, wherein said local anesthetic is
amethocaine, articaine, benzocaine, bupivacaine, mepivacaine,
cocaine, cinchocaine, chloroprocaine, cyclomethycaine, dibucaine,
dimethocaine, EMLA.RTM. (eutectic mixture of lidocaine and
prilocalne), etidocaine, larocaine, levobupivacaine, lidocaine,
lignocaine, procaine, piperocaine, prilocalne, proparacaine,
propoxycaine, ropivacaine, saxitoxin, tetracaine, tetrodotoxin, or
trimecaine.
93. The apparatus of claim 82, wherein the copolymer is a
phenylethyl acrylate/phenylethyl methacrylate copolymer.
94. The apparatus of claim 82, wherein the copolymer forms the
structure of the implantable device.
95. The apparatus of claim 82, wherein the copolymer is embedded
into the implantable device.
96. The apparatus of claim 82, wherein the copolymer forms a
coating on the implantable device.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compositions comprising a
pliable biocompatible material and a physiological acceptable
substance for use in repairing or replacing damaged tissue and/or
post-operatively augmenting tissue, and uses thereof and methods of
manufacture. This application is a continuation-in-part of U.S.
patent application Ser. No. 12/741,280, filed Sep. 7, 2010, which
is a continuation-in-part of U.S. patent application Ser. No.
11/926,930, filed Oct. 29, 2007.
BACKGROUND OF THE INVENTION
[0002] The soft tissues of our bodies connect, support and surround
other structures and organs and include connective tissue such as
skin, tendons, ligaments, fibrous tissue, fascia, fat and synovial
membranes, and non-connective tissue such as muscles, nerves, and
blood vessels. Over the course of a person's lifetime, their soft
tissues may suffer damage as the result of injury, disease,
nutritional deficiencies, toxins, pollutants and other
environmental factors, surgical intervention, or simply from wear
and tear. Tissue damage can result from many causes, including
natural and man-made. A few examples of the common causes of
significant tissue damage include traumatic injuries (including
lacertations, contusions, abrasions, penetrations, blunt injury or
combinations of the foregoing); surgical incisions (such as
internal and epidermal surgical incisions); implantation of devices
(such as prosthetics and other medical devices); and a variety of
other injuries and illnesses.
[0003] Injuries to the soft tissue may effect virtually any area of
anatomy. For instance, injuries to the soft tissues of the face are
particularly conspicuous and include eyelid injuries, ear injuries,
nasal injuries, scalp injuries, and lip injuries. Facial and other
soft tissue injuries may occur as the result of a wide variety of
incidents including motor vehicle accidents, domestic violence,
sports, animal bites, self-inflicted wounds, and on-the-job
accidents. Injuries to the soft tissue of other areas of the body,
though not as conspicuous as those to the face, can cause
functional impairment ranging from minor to severe. Tissue damage
may result from a variety of surgical techniques including plastic,
reconstructive and cosmetic surgery.
[0004] Soft tissue damage in human and other mammalian tissue leads
to tissue disruption and the coagulation of vasculature at the site
of the wound. Our bodies generally react to such tissue damage with
a natural cellular response to repair the tissue damage. Soft
tissue damage heals in a similar manner regardless of the extent of
the damage. Tissue growth and repair involve processes of cellular
proliferation and angiogenesis that occurs in the presence of an
oxygen gradient. Some of the morphological changes that occur
during tissue repair have been characterized. See Hunt, T. K., et
al., "Coagulation and macrophage stimulation of angiogenesis and
wound healing," The Surgical Wound, pp. 1-18, (Lea & Febiger,
Philadelphia 1981). Tissue regeneration in various organs, such as,
for example, the skin or the heart relies upon restoring blood
supply to the tissue and allowing cells (for example, keratinocytes
or muscle cells) to facilitate organ vitality. One function of
mesenchymal cells, such as the fibroblasts or endothelial cells of
the vasculature, is secretion of factors enhancing the healing
process, such as factors promoting angiogenesis (blood vessel
growth) or re-epithelialization.
[0005] Skin wounds that do not readily heal can cause the subject
considerable physical, emotional, and social distress as well as
great financial expense. See e.g., Richey et al., Annals of Plastic
Surgery 23(2):159-65 (1989). Wounds that fail to heal properly may
require aggressive surgical intervention, such as autologous skin
grafting. Even where a wound heals, the anatomy may suffer
aesthetically or functionally.
[0006] Various materials have been proposed for repairing or
replacing damaged tissue. For instance, various biomedical
applications of collagen, including its use in tissue engineering
as a skin replacement, bone substitute, or as artificial blood
vessels and valves, are described by Lee et al., "Biomedical
applications of collagen", Intl Journal of Pharmaceutics, 221
(2001) 1-22. The potential use of a polymer material as a patch for
rotator cuff repairs is described by Cole et al., "Biocompatibility
of a polymer patch for rotator cuff repair", Knee Surg Sports
Traumatol Arthrosc, May 10, 2006.
[0007] U.S. Pat. No. 5,922,025 discusses examples of biocompatible
materials that have been proposed for use in augmenting soft tissue
in the practice of plastic and reconstructive surgery, including
collagen, gelatin beads, beads of natural or synthetic polymers
such as polytetrafluoroethylene, silicone rubber and various
hydrogel polymers, such as polyacrylonitrile-polyacrylamide
hydrogels.
[0008] Similarly, according to U.S. Pat. No. 4,595,713, a large
number of tissue augmentation compositions are proposed, that
comprise soft or moldable polymeric materials, which are designed
to occupy the space where tissue regeneration is desired, and
eventually be replaced by the hard or soft regenerated tissue, such
as cartilage or bone. Among the references directed to such
invention are U.S. Pat. Nos. 4,424,208 and 4,347,234. The latter,
in particular, describes a collagen-based shaped mass which may
include osteogenic material, such as tricalcium phosphate. The
implant material of both U.S. Pat. Nos. 4,424,208 and 4,347,234 is
based on collagen in a binder to form a polymeric mass. U.S. Pat.
No. 4,440,750, describes a wide number of compounds found to be
osteogenic, and describes a method and preparation for introducing
such osteogenic materials where it is necessary to enhance or
promote bone regeneration, such as in the case, of genetic
disorders and traumatic injury.
[0009] A similar material is provided through an alternative
approach in U.S. Pat. No. 3,949,073. That patent describes a
collagen-based solution which may be injected or implanted into the
desired location, and immediately polymerized into a stable mass
upon injection. The reference also suggests the use of tissue
augmentation materials in addition to the collagen polymer.
[0010] A different approach is taken in U.S. Pat. No. 3,919,773,
which is directed to a bone replacement, or implant, particularly
designed for use in dental or oral surgery, where a socket is
exposed after tooth extraction, or an similar void is formed in
dental bone. A polymerizable material, comprised, in contrast to
U.S. Pat. No. 3,949,073, of synthetic polymers, is injected into
the socket and rapidly polymerizes therein, to form a hardened,
permanent fixture. To enhance subsequent tissue connection, but not
replacement, to the implant, the material, prior to polymerization,
is provided with discrete particles that are soluble in body fluids
commonly encountered in the oral cavity. When the particles are
dissolved, the implant is made porous, which enhances the
connection of connective tissue thereto.
[0011] Also known in the art are synthetic polymers useful, in
general, as surgical articles or devices, owing to their complete
bioabsorbability. U.S. Pat. No. 4,243,775 describes a polymer based
on lactide and glycolide, which, when polymerized, is designed as a
medical suture, or similar sterile surgical article. However, the
polymer of the reference is not moldable, and is not suggested as
being suitable for the enhancement of, or replacement by,
connective tissue.
[0012] Other related art also includes a variety of hemostatic
materials, designed to control osseous hemorrhage, particularly in
the case of orthopedic surgery or the like. Several different
compositions are generally described in U.S. Pat. Nos. 4,439,420;
4,440,789 and 4,443,430. Although these compositions may be useful
in the healing process, and as an adjunct to surgical or traumatic
injury to bone and similar connective tissue, they do not serve as
"scaffolds" or similar basis for the replacement of the implant by
regenerated tissue, nor do they substantially promote to the
regeneration of that tissue.
[0013] Most often, the biomaterials are delivered to the tissue
site where augmentation is desired by means of an injectable
composition which comprises the biomaterial and a biocompatible
fluid that acts as a lubricant to improve the injectability of the
biomaterial suspension. The injectable biomaterial compositions can
be introduced into the tissue site by injection from a syringe
intradermally or subcutaneously into humans or other mammals to
augment soft tissue, to correct congenital anomalies, acquired
defects or cosmetic defects. They may also be injected into
internal tissues such as tissue defining sphincters to augment such
tissue in the treatment of incontinence, and for the treatment of
unilateral vocal cord paralysis.
[0014] U.K. Patent Application No. 2,227,176 to Ersek et al,
relates to a microimplantation method for filling depressed scars,
unsymmetrical orbital floors and superficial bone defects in
reconstructive surgery procedures using microparticles of about 20
to 3,000 microns that may be injected with an appropriate
physiologic vehicle and hypodermic needle and syringe in a
predetermined locus such as the base of depressed scars, beneath
skin areas of depression and beneath perichondrium or periosteum in
surface irregularities of bone and cartilage. Textured
microparticles can be used, including silicone,
polytetrafluoroethylene, ceramics or other inert substances. In
those instances wherein the requirement is for hard substances,
biocompatible material such as calcium salts including
hydroxyapatite or crystalline materials, biocompatible ceramics,
biocompatible metals such as stainless steel particles or glass may
be utilized. Appropriate physiological vehicles have been
suggested, including saline, various starches, polysaccharides, and
organic oils or fluids.
[0015] U.S. Pat. No. 4,803,075 to Wallace et al, relates to an
injectable implant composition for soft tissue augmentation
comprising an aqueous suspension of a particulate biocompatible
natural or synthetic polymer and a lubricant to improve the
injectability of the biomaterial suspension. U.S. Pat. No.
4,837,285 to Berg et al, elates to a collagen-based composition for
augmenting soft tissue repair, wherein the collagen s in the form
of resorbable matrix beads having an average pore size of about 50
to 350 microns, with the collagen comprising up to about 10% by
volume of the beads. U.S. Pat. No. 4,280,954 to Yannas et al,
relates to a collagen-based composition for surgical use formed by
contacting collagen with a mucopolysaccharide under conditions at
which they form a reaction product and subsequently covalently
crosslinking the reaction product. U.S. Pat. No. 4,352,883 to Lim
discloses a method for encapsulating a core material, in the form
of living tissue or individual cells, by forming a capsule of
polysaccharide gums which can be gelled to form a shape retaining
mass by being exposed to a change in conditions such as a pH change
or by being exposed to multivalent cations such as calcium. Namiki,
"Application of Teflon Paste for Urinary Incontinence-Report of Two
Cases", Urol. Int., Vol. 39, pp. 280-282, (1984), discloses the use
of a polytetrafluoroethylene paste injection in the subdermal area
to treat urinary incontinence. Drobeck et al, "Histologic
Observation of Soft Tissue Responses to Implanted, Multifaceted
Particles and Discs of Hydroxylapatite", Journal of Oral
Maxillofacial Surgery, Vol. 42, pp. 143-149, (1984), discloses that
the effects on soft tissue of long and short term implants of
ceramic hydroxylapatite implanted subcutaneously in rats and
subcutaneously and subperiosteally in dogs. The process consisted
of implanting hydroxylapatite in various sizes and shapes for time
periods ranging from seven days to six years to determine whether
migration and/or inflammation occurred. Misiek et al., "Soft Tissue
Responses to Hydroxylapatite Particles of Different Shapes",
Journal of oral Maxillofacial Surgery, Vol. 42, pp. 150-160,
(1984), discloses that the implantation of hydroxylapatite in the
form of sharp edged particles or rounded particles in the buccal
soft tissue pouches produced inflammatory response at the implant
sites with both particle shapes. Each of the particles weighed 0.5
grams. However, inflammation resolved at a faster rate at the sites
implanted with the rounded hydroxylapatite particles. Shimizu,
"Subcutaneous Tissue Responses in Rats to Injection of Fine
Particles of Synthetic Hydroxyapatite Ceramic", Biomedical
Research, Vol. 9, No. 2, pp. 95-111 (1988), discloses that
subcutaneous injections of fine particles of hydroxyapatite ranging
in diameter from about 0.65 to a few microns and scattered in the
tissue were phagocytized by macrophages in extremely early stages.
In contrast, larger particles measuring several microns in diameter
were not phagocytized, but were surrounded by numerous macrophages
and multinucleated giant cells. It was also observed that the small
tissue responses to hydroxyapatite particles were essentially a
non-specific foreign body reaction without any cell or tissue
damage. R. A. Appell, "The Artificial urinary Sphincter and
Periurethral Injections", Obstetrics and Gynecology Report. Vol. 2,
No. 3, pp. 334-342, (1990), is a survey article disclosing various
means of treating urethral sphincteric incompetence, including the
use of injectables such as polytetrafluoroethylene micropolymer
particles of about 4 to 100 microns in size in irregular shapes,
with glycerin and polysorbate. Another periurethral injectable
means consists of highly purified bovine dermal collagen that is
crosslinked with glutaraldehyde and dispersed in phosphate-buffered
physiologic saline. Politano et al., "Periurethral Teflon Injection
for Urinary Incontinence", The Journal of Urology, Vol. 111, pp.
180-183 (1974), discloses the use of polytetrafluoroethylene paste
injected into the urethra and the periurethral tissues to add bulk
to these tissues to restore urinary control in both female and male
patients having urinary incontinence. Malizia et al, "Migration and
Granulomatous Reaction After Periurethral Injection of Polytef
(Teflon)", Journal of the American Medical Association, Vol. 251,
No. 24, pp. 3277-3281, Jun. 22-29 (1984), discloses that although
patients with urinary incontinence have been treated successfully
by periurethral injection of polytetrafluoroethylene paste, a study
in continent animals demonstrates migration of the
polytetrafluoroethylene particles from the inspection site. Claes
et al, "Pulmonary Migration Following Periurethral
Polytetrafluoroethylene Injection for Urinary Incontinence", The
Journal of Urology, Vol. 142, pp. 821-2, (September 1989), confirms
the finding of Malizia in reporting a case of clinically
significant migration of polytetrafluoroethylene paste particles to
the lungs after periurethral injection. Ersek et al, "Bioplastique:
A New Textured Copolymer Microparticle Promises Permanence in
Soft-Tissue Augmentation", Plastic and Reconstructive Surgery, Vol.
87, No. 4, pp. 693-702, (April 1991), discloses the use of a
biphasic copolymer made of fully polymerized and vulcanized
methylmethylpoly-siloxane mixed with a plasdore hydrogel, and used
in reconstructing cleft lips, depressed scars of chicken pox and
indentations resulting from liposuction, glabella frown wrinkles
and soft tissue augmentation of thin lips. The biphasic copolymer
particles were found to neither migrate nor become absorbed by the
body were textured and had particle sizes varying from 100 to 600
microns. Lemperle et al. "PMMA Microspheres for Intradermal
Implantation: Part I. Animal Research", Annals of Plastic Surgery,
Vol. 26, No. 1, pp. 57-63, (1991), discloses the use of
polymethylmethacrylate microspheres having particle sizes of 10 to
63 microns in diameter used for correction of small deficiencies
within the dermal corium to treat wrinkles and acne scars. Kresa et
al, "Hydron Gel Implants in Vocal Cords", Otolaryngology Head and
Neck Surgery, Vol. 98. No. 3, pp. 242-245, (March 1988), discloses
a method for treating vocal cord adjustment where there is
insufficient closure of the glottis which comprises introducing a
shaped implant of a hydrophilic gel that has been previously dried
to a glassy, hard state, into the vocal cord. Hirano et al,
"Transcutaneous Intrafold Injection for Unilateral Vocal Cord
Paralysis: Functional Results", Ann Otol. Rhinol. Laryngol., Vol.
99, pp. 598-604 (1990), discloses the technique of transcutaneous
intrafold silicone injection in treating glottic incompetence
caused by unilateral vocal fold paralysis. The silicone injection
is given under a local anesthetic with the patient in a supine
position, wherein the needle is inserted through the cricothyroid
space. Hill et al, "Autologous Fat Injection for Vocal Cord
Medialization in the Canine Larynx", Laryngoscope, Vol. 101, pp.
344-348 (April 1991), discloses the use of autologous fat as an
alternative to TEFLON. collagen as the implantable material in
vocal cord medialization, with a view to its use as an alternative
to non-autologous injectable material in vocal cord augmentation.
Mikaelian et al, "Lipoinjection for Unilateral Vocal Cord
Paralysis", Laryngoscope, Vol. 101, pp. 4654-68 (May 1991),
discloses that the commonly used procedure of injecting TEFLON
paste to improve the caliber of voice in unilateral vocal cord
paralysis has a number of drawbacks, including respiratory
obstruction from overinjected TEFLON and unsatisfactory voice
quality. In this procedure, lipoinjection of fat commonly obtained
from the abdominal wall appears to impart a soft bulkiness to the
injected cord while allowing it to retain its vibratory qualities.
The injected fat is an autologous material which can be retrieved
if excessively overinjected. Strasnick et al, "Transcutaneous
Teflon Injection for Unilateral Vocal Cord Paralysis: An Update",
Laryngoscope, Vol. 101, pp. 785-787 (July 1991), discloses the
procedure of TEFLON injection to restore glottic competence in
cases of paralytic dysphonia.
[0016] Many previously attempted materials for tissue augmentation,
repair or replacement are unsuitable for a variety of reasons
including efficacy, lack of biocompatibility, expense, and ease of
use. For example, collagen, being an organic substance principally
derived from bovines, presents potentially serious allergenic
reaction problems, and general difficulties with a patient's immune
system. Further, it is difficult to insure the sterility of
collagen, and the storage requirements associated with it are quite
extensive, and expensive. Many previously used materials lack the
mechanical strength and/or flexibility to be useful in tissue
repair and/or replacement. Many materials also deteriorate fairly
quickly and therefore do not present a viable long term treatment
option.
[0017] There remains an ongoing need for treatments and materials
to repair and/or replace tissue that is damaged (for aesthetic,
structural and/or functional purposes), or provide post-surgical
augmentation of tissue, including treatments in which the damaged
tissue is supplemented, partially replaced or entirely replaced.
Further, there is a demand for a durable, long-lasting,
biocompatible approach that restores the aesthetic appearance of
the tissue and/or restores the normal physiological function of the
tissue including providing or improving function, movement, balance
and support.
SUMMARY OF THE INVENTION
[0018] An embodiment of the present invention provides a method for
repairing or replacing damaged tissue comprising: identifying a
site of damaged tissue in a subject; and injecting into the subject
at or near the site of damaged tissue an alloplastic and
biocompatible composition comprising an unsubstituted
acrylate/substituted acrylate copolymer in an amount sufficient to
repair or replace the damaged tissue.
[0019] A further embodiment of the present invention provides a
method for repairing or replacing damaged tissue comprising:
injecting into a subject at or near a site having damaged tissue an
effective amount of a composition comprising a copolymer of
phenylethyl acrylate and phenylethyl methacrylate.
[0020] Another embodiment of the present invention provides a
method of preparing a composition for repairing or replacing tissue
comprising admixing a finely ground copolymer of phenylethyl
acrylate and phenylethyl methacrylate with a physiologically
acceptable suspending agent to form an injectable, biocompatible
material.
[0021] Yet another embodiment of the present invention provides a
method of preparing a soft tissue filler for repairing or replacing
tissue comprising admixing an acrylate/methacrylate copolymer with
a physiologically acceptable suspending agent to form an
injectable, biocompatible material.
[0022] A further embodiment of the present invention provides a
method for repairing or replacing damaged tissue in a subject
comprising: performing a surgical incision; and injecting at or
near the site of the surgical incision a composition comprising an
unsubstituted acrylate/substituted acrylate copolymer in an amount
sufficient to repair or replace the damaged tissue.
[0023] Another embodiment of the present invention provides a
method for repairing or replacing damaged tissue in a subject
comprising: injecting at or near a site of tissue damage a
composition comprising an unsubstituted acrylate/substituted
acrylate copolymer and a substance that promotes regeneration of
tissue.
[0024] Yet another embodiment of the present invention provides use
of a composition to repair or replace damaged tissue in a subject,
said composition comprising an effective amount of an unsubstituted
acrylate/substituted acrylate copolymer and a physiologically
acceptable suspending agent.
[0025] A further embodiment of the present invention provides an
apparatus for tissue repair or replacement comprising: an
implantable device comprising an unsubstituted acrylate/substituted
acrylate copolymer.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The foregoing and other aspects of the present invention
will now be described in more detail with respect to embodiments
described herein. It should be appreciated that the invention can
be embodied in different forms and should not be construed as
limited to the embodiments set forth herein. Rather, these
embodiments are provided so that this disclosure will be thorough
and complete, and will fully convey the scope of the invention to
those skilled in the art.
[0027] The terminology used in the description of the invention
herein is for the purpose of describing particular embodiments only
and is not intended to be limiting of the invention. As used in the
description of the embodiments of the invention and the appended
claims, the singular forms "a," "an" and "the" are intended to
include the plural forms as well, unless the context clearly
indicates otherwise. Also, as used herein, "and/or" refers to and
encompasses any and all possible combinations of one or more of the
associated listed items. Furthermore, "about," as used herein when
referring to a measurable value such as an amount of a compound,
dose, time, temperature is meant to encompass variations of 5%, 1%,
0.5%, or even 0.1% of the specified amount. Unless otherwise
defined, all terms, including technical and scientific terms used
in the description, have the same meaning as commonly understood by
one of ordinary skill in the art to which this invention
belongs.
[0028] "Administration" as used herein, refers broadly to any means
by which a composition is given to a patient. A preferred route of
administration is by injection and unless otherwise indicated, any
reference herein to "administration" includes "administration by
injection."
[0029] An "aqueous medium," as the term is used herein, refers to a
liquid medium composed largely, but not necessarily exclusively, of
water. Other components may also be present, such as salts,
co-solvents, buffers, stabilizers, dispersants, colorants and the
like.
[0030] "Autologous solution," as used herein, refers broadly to any
liquid that is autologous to a patient to be treated, or that
originates from the patient to be treated.
[0031] "Biocompatible," as used herein, refers broadly to the
quality of a material to be compatible with biological tissues,
that is not toxic to biological tissues, and that is tolerated by
the biological tissues.
[0032] "Biocompatible polymer," as used herein refers broadly to a
polymer that is substantially non-toxic and does not tend to
produce substantial immune responses, clotting, or other
undesirable effects.
[0033] "Composition" as used herein, refers broadly to any
composition containing an agent or agents. The composition may
comprise a dry formulation, an aqueous solution, a paste
formulation, an organic solution formulation, a gel formulation, a
jelly formulation, or a sterile composition. Compositions
comprising the molecules described herein can be stored in
freeze-dried form and can be associated with a stabilizing agent
such as a carbohydrate. Composition, as used herein, includes
"pharmaceutical compositions" which refers broadly to a chemical or
biological composition suitable for administration to a subject
(e.g., mammal). Such compositions may be specifically formulated
for administration via one or more of a number of routes, including
but not limited to cutaneous, epicutaneous, infusion, intradermal,
intrathecal, subcutaneous, subdermal, and transdermal. In addition,
the composition may be in the form of a capsule, drops, foams, gel,
gum, injection, liquid, patch, pill, porous pouch, powder, or
tablet.
[0034] "Copolymer," as used herein, refers broadly to a polymer
comprising more than one different monomer in the polymer chain
(e.g., heteropolymer). The constituent monomers may be arranged in
various ways, including alternating copolymers, periodic
copolymers, statistical copolymers, random copolymers, graft
copolymers, block copolymers, stereoblock copolymers, and other
arrangements known in the art. Copolymers may be linear or
branched, which includes star copolymers, brush copolymers, and
comb copolymers, and other branched copolymer structures that are
known in the art. For example, without limitation, the molar ratio
between the substituent monomers in a copolymer may be about
1:1000, 1:100, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1:1
according to various embodiments.
[0035] "Effective amount" or "effective," as used herein, refers
broadly to a dose that causes a relief of symptoms of a disease or
disorder as noted through clinical testing and evaluation, or
patient observation. "Effective amount" or "effective" further can
further designate a dose that causes a detectable change in
biological or chemical activity. The detectable changes may be
detected and/or further quantified by one skilled in the art for
the relevant mechanism or process. Moreover, "effective amount" or
"effective" may designate an amount that maintains a desired
physiological state, i.e., reduces or prevents significant decline
and/or promotes improvement in the condition of interest (e.g.,
relief of symptoms). As is generally understood in the art, the
dosage will vary depending on the administration routes, symptoms,
age, and body weight of the patient but also depending upon the
composition being administered
[0036] "Gelatin," as the term is used herein, is a collagen-derived
material that is about 98-99% protein by dry weight. The
approximate amino acid composition of gelatin is: glycine 21%,
proline 12%, hydroxyproline 12%, glutamate 10%, alanine 9%,
arginine 8%, aspartate 6%, lysine 4%, serine 4%, leucine 3%, valine
2%, phenylalanine 2%, threonine 2%, isoleucine 1%, hydroxylysine
1%, methionine and histidine <1% and tyrosine <0.5%.
[0037] "Homopolymer," as used herein, refers broadly to a polymer
constructed of the same monomers.
[0038] "Increased" or "increase" as used herein, refers broadly to
a quantified change in a measurable quality that is larger than the
margin of error inherent in the measurement technique, preferably
an increase by about 2-fold or greater relative to a control
measurement, more preferably an increase by about 5-fold or
greater, and most preferably an increase by about 10-fold or
greater. In particular, the term "increase," as used herein, refers
broadly to make greater, as in number, size, strength, or quality;
add to; and/or augment. "Increase," as used herein, also
encompasses expand, extend, prolong, augment, and/or enlarge.
"Increase," as used herein, additionally encompasses where a given
parameter (e.g., level, amount, size, scope, duration, weight) is
greater, as in number, size, strength, or quality, than it once
was. Furthermore, the "increase" in any number, size, strength, or
quality of a given parameter may be determined as between to two or
more time points, especially if before or after a treatment, event,
or administration of an agent or composition. Further, "increase"
refers broadly to significant or detectable, functionally,
analytically, and/or clinically, changes in the number, size,
strength, or quality of a given parameter in question.
[0039] "Mammal" as used herein, refers broadly to any and all
warm-blooded vertebrate animals of the class Mammalia, including
humans, characterized by a covering of hair on the skin and, in the
female, milk-producing mammary glands for nourishing the young.
Examples of mammals include but are not limited to humans,
non-human primates, alpacas, camels, capybaras, cats, chimpanzees,
chinchillas, cows, dogs, goats, gorillas, horses, llamas, mice,
pigs, rats, sheep, and tapirs. Mammals include but are not limited
to bovine, canine, equine, feline, murine, ovine, porcine, primate,
and rodent species. Mammal also includes but is not limited to
those listed on the Mammal Species of the World maintained by the
National Museum of Natural History, Smithsonian Institution in
Washington, D.C.
[0040] As used herein, the act of "mixing between mutually coupled
syringes" refers to a procedure wherein one syringe is partially
filled with one ingredient, a second syringe is partially filled
with a second ingredient, and the two syringes are coupled together
as with a luer connector such that the contents of the syringes are
mixed by drawing the contents of one syringe through the connector
into the second syringe, then reciprocally expelling the contents
of the second syringe back into the first syringe. This process may
be repeated until adequate mixing is achieved.
[0041] "Patient" as used herein, refers broadly to any animal who
is in need of treatment either to alleviate a disease state or to
prevent the occurrence or reoccurrence of a disease state. Also,
"Patient" as used herein, refers broadly to any animal who has a
history of disease, symptoms, signs, was previously diagnosed, or
is a member of a patient population for a disease. The patient may
be a clinical patient such as a human or a veterinary patient such
as a companion, domesticated, livestock, exotic, or zoo animal.
[0042] "Physiologically acceptable suspending agent" or
"pharmaceutically acceptable suspending agent," as used herein,
refers broadly to physiologically inert substances (e.g., solvent
or dispersion media) that acts to reduce the sedimentation rate of
particles (e.g., pliable biocompatible material) in suspension or
increases the viscosity of the suspension. Physiologically
acceptable suspending agent includes aqueous solutions, dispersions
and polymers. The use of such media and agents for physiologically
acceptable suspending agents is well known in the art.
[0043] "Restoring," as used herein, refers broadly to the action of
bringing back, totally or partly, specific normal physiological
properties such as the physico-chemical, the physical (e.g.,
thickness), the mechanical (e.g., absorbing) or the physiological
functions.
[0044] "Self-gelling," as used herein, refers broadly to the
ability of turning into gels under specific conditions such as the
internal composition or/and the action of external stimuli.
Self-gelling encompasses pH-triggered or pH-controlled gelling,
thermo-gelling, and ionic gelling.
[0045] "Signs" of disease, as used herein, refers broadly to any
abnormality indicative of disease, discoverable on examination of
the patient; an objective indication of disease, in contrast to a
symptom, which is a subjective indication of disease.
[0046] "Solution," as used herein, refers broadly to any liquid,
organic or aqueous, low to high viscosity systems, to any
dispersions of solids into liquid, organic or aqueous, low to high
viscosity systems, and to any gelled, organic or aqueous,
extrudable or injectable, systems. Such solutions may comprise
soluble small-size molecules, soluble monomers, soluble oligomers,
soluble polymers and copolymers as well as nonsoluble solid organic
or mineral entities such as microparticles or nanoparticles.
[0047] "Subjects" as used herein, refers broadly to anyone suitable
to be treated according to the present invention include, but are
not limited to and mammalian subjects (e.g., humans). The present
invention can also be carried out on animal subjects, particularly
mammalian subjects such as mice, rats, dogs, cats, cattle, goats,
sheep, and horses for veterinary purposes, and for screening,
testing, and development purposes. "Subjects" is used
interchangeably with "patients."
[0048] A "suture" or the act of "suturing" refers to the physical
joining of two separate masses of tissue with thread or fiber, or
alternatively with solid materials such as fabrics or plastic films
on which an adhesive is disposed, whereby the physical joining
serves to hold the separate tissue masses in close physical
proximity at least temporarily, such as for the period of time
required for biological healing to occur. A "suture line" is a line
of, for example, stitches of thread as is used to close an incision
at the end of a surgical procedure.
[0049] "Swellable" microspheres, as used in the present invention,
refers to microspheres that are capable of being enlarged in size,
yet still retain substantially the same shape, upon certain
conditions such as contacting physiological fluids.
[0050] "Symptoms" of disease as used herein, refers broadly to any
morbid phenomenon or departure from the normal in structure,
function, or sensation, experienced by the patient and indicative
of disease.
[0051] "Therapy" or "therapeutic," as used herein, refers broadly
to treating a disease, arresting, or reducing the development of
the disease or its clinical symptoms, and/or relieving the disease,
causing regression of the disease or its clinical symptoms. Therapy
encompasses treatment, cure, remedy, minimization, reduction,
alleviation, and/or providing relief from a disease, signs, and/or
symptoms. Therapy encompasses an alleviation of signs and/or
symptoms in patients with ongoing disease signs and/or symptoms
(e.g., pain, inflammation.) The term "reduced," for purpose of
therapy, refers broadly to the clinical significant reduction in
signs and/or symptoms. Therapy includes treating chronic disease
("maintenance") and acute disease.
[0052] "Tissue," as used herein, refers to any material that forms
solid or semi-solid structures that are found in any of the
components of a living organism, including, for example, membrane,
skin, muscle, bone, cartilage, ligament, nerves and nerve sheathes,
meninges, connective tissue, blood vessels, the sclera or iris of
the eye, the solid materials constituting internal organs such as
liver, stomach, pancreas, intestine, kidney, thymus, uterus,
testes, bladder, lung, heart and any other internal structures that
are solid or semi-solid in texture, and the like, without
limitation.
[0053] "Treating" or "treatment," as used herein, refers broadly to
a course of therapy where signs and/or symptoms are present in the
patient. The term "reduced," for purpose of therapy, refers broadly
to clinically significant reduction in signs and/or symptoms.
Treatment can alleviate, decrease, lessen, relieve, remedy, repair,
and/or soothe a disease, signs, and/or symptoms. By the terms
"treating" or "treatment" of a condition, it is intended that the
severity of the disorder or the symptoms of the condition are
reduced, or the condition is partially or entirely eliminated, as
compared to that which would occur in the absence of treatment.
Treatment does not require the achievement of a complete cure of
the condition. Treatment includes treating chronic disease
("maintenance") and acute disease.
[0054] Tissue repair and/or replacement involves administration of
a pliable biocompatible material and a physiologically acceptable
suspending agent according to various embodiment of the present
invention. The pliable biocompatible material may be a polymer
(including copolymers), calcium hydroxylapatite, or autologous fat,
and the physiologically acceptable suspending agent may be any
solvent, suspension, colloid, gel, foam, macromolecules, polymers
(including copolymers), or solution. Supplementary active compounds
may be incorporated into the tissue repair and/or replacement
compositions (e.g., analgesics, anti-inflammatory agents). Various
embodiments of the present invention are directed to methods for
effecting tissue repair. Specifically, embodiments present
invention can be used to provide for the repair and restoration of
tissue in a minimally invasive fashion. Certain embodiments of the
present invention are directed to implants constructed of,
partially constructed of, coated with, or embedded with a
composition in accordance with the present invention or their
progenitors as a means of reducing unfavorable host response to the
implant. Specifically implants according to certain embodiments of
the present invention are resistant to encapsulation and
inflammatory response.
[0055] Polymers acceptable for use in the present invention include
but are not limited to alginate, cellulose (including substituted
cellulose), chitosan, chondrotin sulfate, fatty acids, gelatin,
glycol, glycosaminoglycans, hyaluronic acid, polyacrylamide,
polyethylene glycol, polylysine, polypeptides, polysaccharides,
proteoglycans, and silicone.
[0056] The pliable biocompatible material is not absorbable or
degradable by the body and is inert. The material may be pliable
because it is a characteristic that is important for tissue repair
and/or replacement applications. The material may also be
hydrophobic because it is beneficial for expansion of the tissue
repair and/or replacement filler. The material may comprise a
colorant agent (e.g., dye, contrast agent, tint) for easier
administration, monitoring, or removal. The material may produce
little or no immunological response in the host tissue or no
immunological response in the host tissue. For example, the
administration of the material should not lead to the formation of
inflammatory granuloma and scarring.
[0057] The materials described herein may be purified from cells
that naturally express it, purified from cells (e.g., bacteria,
plant, insect, mammal) that have been altered to express it (e.g.,
recombinant), or synthesized using standard methods known in the
art. The pliable biocompatible materials described herein may also
be obtained from commercial sources as a purified or isolated form
(e.g., natural, recombinant, or synthetic sources).
[0058] The solid particles may be a dust, powder, non-porous
microspheres, nanoparticles, granules, grains, or microbeads. The
solid particles may easily administered (e.g., injected), remain
immobilised at the administration site, and be tolerated by the
tissue (e.g., little or no side effects). Generally, the solid
particles may be small enough to be injected through a cannula of
an injection syringe to the desired site and not be identified by
human touch as a single foreign body under the skin. The material
may be a solid particle with a diameter such that it is not washed
away through lymph tracts or other tissue tracts from the site to
which they have administered.
[0059] According to certain embodiments, the solid particles have a
spherical form or a spherical like form. Spherical formed particles
have an advantage in that they form a closely packed arrangement at
the site where they are administered.
[0060] According to an embodiment, the particles have an average
diameter of less than about 100 .mu.m. According to a further
embodiment, the particles have a average diameter of less than
about 10 .mu.m. According to a further embodiment, the particles
have an average diameter of about 0.01 .mu.m to about 10 .mu.m.
According to a further embodiment, the particles have an average
diameter of about 0.1 .mu.m to about 5 .mu.m.
[0061] The solid particles may be swellable microspheres which are
highly water absorbing microspheres capable of swelling to many
times of their original sizes under certain conditions. Swellable
microspheres are capable of swelling upon contacting with medium
resembling the properties of physiological fluids, thus allowing
the microspheres to secure themselves into position after injection
into the body. Furthermore, the microspheres are substantially
spherical and can be easily calibrated so that their sizes can be
accurately determined.
[0062] The swellable microspheres can be enlarged to about four (4)
times their original diameter or fifteen (15) times their original
volume. The degree of swelling can be controlled by controlling
factors such as the solvents in which they are suspended, specific
polymers used to make the microspheres and degree of crosslinking.
This property enables the microspheres to be easily injected
through needles of 30 gauge or smaller, yet be enlarged and secured
at the injection site and of sufficient size to avoid or reduce the
chance of being eliminated by the immune system of the mammal.
[0063] The fabrication of and application of microspheres is known
and as such the following examples are included herein as
reference. U.S. Pat. No. 3,887,699 describes a solid biodegradable
polymer spheroid implants which incorporate a drug for sustained
release as the polymer naturally degrades in the human body. Many
different methods of constructing this type of controlled release
system have been developed. Although the uniform matrix of a
polymer provides a simple and efficient structure for the
controlled release of agents with microspheres, many advanced
methods of containing and releasing the therapeutic agents have
been developed. U.S. Pat. No. 4,637,905 (Gardner) discloses a
method for encapsulating a therapeutic agent within a biodegradable
polymer microsphere. U.S. Pat. No. 4,652,441 (Okada et al.)
discloses a method of utilizing a water-in-oil emulsion to give
prolonged release of a water-soluble drug. The patent describes a
wide variety of drugs that can be delivered via prolonged release
micro-capsules as well as suitable polymeric materials and drug
retaining substances. It is conceived that the system of this
invention could incorporate any of the drugs described to in this
patent to generate a beneficial effect in the cardiac tissue. U.S.
Pat. No. 5,718,921 (Mathiowitz et al.) discloses a method for
constructing a multiple layer microsphere which can release two
different drugs at controlled rates or a singe drug at two
different rates. U.S. Pat. No. 5,912,017 (Mathiowitz et al.) also
discloses a method of forming two layered microspheres by using an
organic solvent or melting two different polymers, combining them
with a desired substance and cooling. Microspheres are not limited
to just water-soluble therapeutic agents. See, for example, U.S.
Pat. No. 5,288,502 (McGinity et al.) which discloses a multi-phase
microsphere which is capable of incorporating water-soluble and
water-insoluble drugs.
[0064] The polymer is administered in any manner as would be well
known to persons of ordinary skill in the art. According to certain
embodiments, the polymer may be administered in a volume at least
about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10
.mu.L, as well as at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,
0.8, 0.9, or 1.0 .mu.L, as well as at least about 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10 .mu.L. The polymer may be administered in a volume
of at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 .mu.L
in certain embodiments. The volume of the composition administered
to the patient may be about 1-5, 5-10, or 1-100 .mu.L in certain
embodiments.
[0065] According to certain embodiments, the polymer may be
administered in a volume at least about 0.01, 0.02, 0.03, 0.04,
0.05, 0.06, 0.07, 0.08, 0.09, or 0.10 mL (cc), as well as at least
about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mL, as
well as at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mL (cc).
The volume of the composition administered to the patient may be
about 1-5, 5-10, or 1-10 mL (cc).
[0066] According to certain embodiments, the composition
administered may comprise a physiological acceptable suspending
agent of at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07,
0.08, 0.09, or 0.10% (w/w), as well as at least about 0.1, 0.2,
0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0% (w/w), as well as at
least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% (w/w). The
composition may comprise a physiological acceptable suspending
agent of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50,
60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 99.5% (w/w).
[0067] The composition administered may comprise a pliable
biocompatible material of at least about 0.01, 0.02, 0.03, 0.04,
0.05, 0.06, 0.07, 0.08, 0.09, or 0.10% (w/w), as well as at least
about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0% (w/w),
as well as at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% (w/w),
according to certain embodiments. The composition administered may
comprise a pliable biocompatible material of at least about 1, 5,
10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95,
96, 97, 98, 99, or 99.5% (w/w), according to certain
embodiments.
[0068] The composition administered may comprise a physiological
acceptable suspending agent of at least about 0.01, 0.02, 0.03,
0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10 .mu.g/mL, as well as at
least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0
.mu.g/mL, as well as at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10 .mu.g/mL, according to certain embodiments. The composition
administered may comprise a physiological acceptable suspending
agent at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30,
35, 40, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99,
99.5, or 100 .mu.g/mL, according to certain embodiments.
[0069] The composition administered may comprise about a
physiological acceptable suspending agent at least about 0.01,
0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10 mg/mL, as
well as at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,
or 1.0 mg/mL, as well as at least about 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10 mg/mL, according to certain embodiments. The composition
administered may comprise a physiological acceptable suspending
agent of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,
30, 35, 40, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99,
99.5, or 100 mg/mL, according to certain embodiments.
[0070] The composition administered may comprise a pliable
biocompatible material at least about 0.01, 0.02, 0.03, 0.04, 0.05,
0.06, 0.07, 0.08, 0.09, or 0.10 .mu.g/mL, as well as at least about
0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 .mu.g/mL, as
well as at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 .mu.g/mL,
according to certain embodiments. The composition may comprise a
pliable biocompatible material at least about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 65, 70, 75, 80, 85,
90, 95, 96, 97, 98, 99, 99.5, or 1001 .mu.g/mL, according to
certain embodiments.
[0071] According to embodiments of the invention, the composition
may comprise a pliable biocompatible material of at least about
0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10
mg/mL, as well as at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,
0.8, 0.9, or 1.0 mg/mL, as well as at least about 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10 mg/mL. According to embodiments of the invention,
the composition may comprise a pliable biocompatible material of at
least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40,
45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5, or
100 mg/mL.
[0072] According to embodiments of the invention, the composition
may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different
pliable biocompatible materials, without limitation. The
composition may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
different physiological acceptable suspending agents, for example,
without limitation. For example, the composition may comprise at
least one pliable biocompatible material and at least one
physiological acceptable suspending agent. Further, the
physiological acceptable suspending agent may comprise a mixture of
different components (e.g., mixture of fatty acids).
[0073] According to certain embodiments, the composition may be
under gel (or solid form) at low to room temperature, e.g., about
20.degree. C. and below, but may become more or less a viscous
liquid at higher temperatures, e.g., about above 35-40.degree.
C.
[0074] According to certain embodiments, the composition may become
highly viscous or turn into a gel after being injected by one of
the following processes: (a) Gelling: the solution is injected as a
liquid, and later turns in situ into a gel; (b) Polymerisation in
situ: the solution containing monomers and/or oligomers, or a
mixture of two or more different monomers, is injected as a liquid,
and later polymerises or co-polymerises in situ; (c) Concentration:
the solution contains a viscous component mixed with an appropriate
metabolically absorbable liquid vehicle, to reduce viscosity and to
allow injectability, the solvent or vehicle, after injection, being
absorbed by the patient, thus increasing the concentration and
hence the viscosity of the viscous component.
[0075] The viscosity (.eta.) may be determined using methods known
in the art (e.g., a rotating viscometer at 20.degree. C., Ostwald
viscometer). See, e.g., Akhare, et al. (2007) Indian Journal of
Pure & Applied Physics 45: 984-986. The viscosity of the tissue
repair and/or replacement filler composition may be at least about
100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 mPa.S.
(millipascal-second).
Acrylate Copolymers
[0076] A copolymer suitable for use in the present invention
comprises an unsubstituted acrylate monomer and a substituted
acrylate monomer (e.g., acrylate/methacrylate copolymer). Any
suitable acrylate/methacrylate copolymer as would be known to
persons skilled in the art based upon the guidance provided in the
present specification may be used in the present invention.
According to certain embodiments, the substituted acrylate monomer
is substituted with a methyl group. According to further
embodiments, other alkyl group derivatives, e.g., one, two, three,
four, five, or six carbons in length (e.g., methyl, ethyl, propyl,
isopropyl, butyl, tert-butyl, pentyl, hexyl) are used as a
substituent in the substituted acrylate monomer. Cyclic alkyl
groups with four, five, or six cabons are the substituent group on
the substituted acrylate monomer in further embodiments. The
substituent group for the substituted acrylate monomer is a halogen
group in further embodiments. For example, the halogen group may be
flourine (F), chlorine (Cl), bromine (Br), iodine (I), or astatine
(At). Additionally, a nitrile group is another possible substituent
for the substituted acrylate monomer in further embodiments. In a
further embodiment, the acrylate/methacrylate copolymer is the
copolymer used in AcryS of MA60BM intraocular lenses (Alcon
Laboratories).
[0077] The inventor surprisingly found that a copolymer comprising
an unsubstituted acrylate monomer and a substituted acrylate
monomer (e.g., acrylate/methacrylate copolymer) in a finely ground
powder form is a highly desirable copolymer for use in accordance
with embodiments of the present invention. For example, when
introduced into human tissue a copolymer comprising an
unsubstituted acrylate monomer and a substituted acrylate monomer
(e.g., acrylate/methacrylate copolymer) has few or no side-effects.
Further, the copolymers of the present invention tend not to form
granulomas when introduced into human tissue, in contrast with
other polymers.
Calcium Hydroxylapatite
[0078] In further embodiments, calcium hydroxylapatite may be used
as a pliable biocompatible material or in combination with the
copolymer described above. Calcium hydroxylapatite is a component
of bone and teeth may be used in the form of microspheres suspended
in an aqueous carrier (e.g., RADIESSE.RTM. (calcium
hydroxylaptite)). The host tissue reacts to the injected calcium
hydroxyapatite microspheres to stimulate collagen production to
encapsulate the microspheres. Calcium hydroxylapatite may be
admixed with a polymer to form a pliable composite.
Collagen
[0079] In further embodiments, collagen may be employed as a
pliable biocompatible material or in combination with the copolymer
described above to form the pliable biocompatible material.
Collagen is the major insoluble fibrous protein in the
extracellular matrix and in connective tissue. Collagen that may be
used including but not limited to autologous, synthetic,
recombinant, and natural collagen. See U.S. Pat. Nos. 4,544,516;
4,698,360; and 5,856,308 and WO 2006/098326. Collagen may be
isolated from cattle, pigs, or humans (e.g., autologous). Collagen
may also be made by recombinant means including transgenic animals,
bacteria, insect cells, and transgenic plants. See U.S. Pat. Nos.
6,111,165; 6,413,742; and 7,238,783; U.S. Patent Application
Publication No. 2009/0030184. For example, Autologen.RTM.
(collagen) is a collagen extracted from a patient, sterilized and
processed into injectable form. Alternatively, Isolagen.RTM.
(pharmaceutical composition of fibroblasts) a preparation of live
cloned fibroblasts, such as collagen-producing cells, which are
also derived from a patient's own tissue repair and/or replacement
and prepared into liquid form may be used to produce collagen in
situ. Collagen may be cross-linked with glutaraldehyde. Further
examples of commercially available collagen include but are not
limited to bovine, human, cross-linked porcine [EVOLENCE.RTM.]) and
synthetic (FG-5030 synthetic human collagen (type III))
COSMOPLAST.RTM. (highly purified human collagen), COSMODERM.RTM.
(highly purified human collagen).
Fatty Acids
[0080] In further embodiments, at least one fatty acid may be used
as a pliable biocompatible material or in combination with the
copolymer described above to form the pliable biocompatible
material. Fatty acids suitable for use in this invention include
but are not limited to natural or unnatural saturated and mono- or
poly-unsaturated fatty acids. Additionally, exemplary fatty acids
include but are not limited to palmitate, stearate, myristate,
palmitoleate, oleate, vaccenate, linoleate, and their acyclic,
cyclic, heterocyclic, aromatic ester derivatives thereof. The fatty
acid derivatives may comprise one or more groups including but not
limited to hydroxy, acyloxy, aryloxy, amino, sulfhydryl, sulfonate,
sulfate, phosphonate, phosphate, bis-, tris- and poly-phosphonates
and phosphates, phosphatidyl, nucleosides, oligosaccharides,
polysaccharides, polyols, and a mixture thereof. An exemplary fatty
acid mixture comprises oleoate and palmitate (e.g., 17% palmitic
acid and 83% oleic acid (w/w)). Another exemplary fatty acid
mixture comprise myristate, palmitate, stearate, palmitoleate,
vaccenate, oleate, and linoleate (e.g., myristate 1.9%, palmitate
15.9%, stearate 1.7%, palmitoleate 12.3%, vaccenate 4.8%, oleate
46.4% and linoleate 17.0% (w/w)).
Hyaluronic Acid
[0081] In further embodiments, hyaluronan (hyaluronic acid or
hyaluronate) may be used as a pliable biocompatible material
material or in combination with the copolymer described above to
form the pliable biocompatible material. Hyaluronan is an anionic,
nonsulfated glycosaminoglycan distributed widely throughout
connective, epithelial, and neural tissues. Exemplary hyaluronan
compositions include but are not limited to sodium hyaluronate,
JUVEDEM.RTM. (cross-linked hyaluronic acid), RESTYLANE.RTM.
(hyaluronic acid), and PERLANE.RTM. (hyaluronic acid). Hyaluronan
made be admixed with a another agent such as an analgesic (e.g.,
PREVELLE.RTM. SILK (hyaluronic acid with lidocaine)).
Polyacrylates
[0082] Polyacrylates that may be used include but are not limited
to polymethylacrylate and polymethylmethacrylate (PMMA).
ARTEFILL.RTM. (polymethylmethacrylate (PMMA) microspheres) is a
permanent microsphere-based injectable filler comprising
non-resorbable microspheres having a diameter of between 30-42
.mu.M and a smooth surface. Treatment with PMMA is considered
permanent, not only because of the volume increase under the
defect, but also because of the presumed life-long stimulation of
collagen deposition beneath the defect. The electrical charge of
filler microbeads appears to play a role in attracting and
activating macrophages, which promotes formation of foreign body
giant cells, then fibroblasts, and thereby increases the
composition of new connective tissue. Adverse side-effects may
include lumpiness and inflammatory granulomas. PMMA may be admixed
with another filler for use as a tissue repair and/or replacement
filler composition. For example, collagen, may be combined with
PMMA in a ratio of 20% PMMA to 80% collagen. This collagen/PMMA
mixture may further comprise an anesthetic, such as lidocaine
(e.g., 3% lidocaine anesthetic solution). See, e.g., U.S. Pat. No.
5,344,452.
Polyacrylamide
[0083] In further embodiments, polyacrylamide (IUPAC
poly(2-propenamide) or poly(1-carbamoylethylene)) is a polymer
(--CH.sub.2CHCONH.sub.2--) formed from acrylamide. Polyacrylamide
may be admixed with another compound to form a composite. For
example, AQUAMID.RTM. (hydrophilic polyacrylamide) is a composition
currently used in tissue augmentation. See U.S. Patent Application
Publication Nos. 2006/0115457 and 2008/0292706.
Polyalkylene Glycol
[0084] In further embodiments, polyalkylene glycol polymers may be
used as a pliable biocompatible material may be used in the present
invention or in combination with the copolymer described above to
form the pliable biocompatible material. Polyalkylene glycol
polymers include but are not limited to straight or branched
polyalkylene glycol polymers such as polyethylene glycol,
polypropylene glycol, and polybutylene glycol, and further includes
the monoalkylether of the polyalkylene glycol. The polyalkylene
glycol polymer may be a lower alkyl polyalkylene glycol moiety such
as a polyethylene glycol moiety (PEG), a polypropylene glycol
moiety, or a polybutylene glycol moiety. PEG has the formula
--HO(CH.sub.2CH.sub.2O).sub.nH, where n can range from about 1-100,
5-30, or 1-4000. The PEG moiety can be linear or branched. PEG may
be attached to groups such as hydroxyl, alkyl, aryl, acyl, or
ester. For example, PEG may be an alkoxy PEG, such as methoxy-PEG
(or mPEG), where one terminus is a relatively inert alkoxy group,
while the other terminus is a hydroxyl group. Further polyalkylene
glycol polymers include but are not limited to poly(ethylene
glycol), poly(propylene glycol), and its copolymers, poly(ethylene
glycol) copolymers with other synthetics such as poly(hydroxy
acids), poly(vinyl alcohol), poly(vinyl pyrrolidone), and mixture
thereof.
Polylactic Acid
[0085] In further embodiments, polylactic acid microspheres may be
used as a pliable biocompatible material or in combination with the
copolymer described above to form the pliable biocompatible
material. The microspheres may have a diameter of about 2-50 .mu.m.
The polylactic acid microspheres become porous after a first phase
of moderate inflammation in the host tissue, followed by a second
stronger inflammation in which foreign body giant cells phagocytose
the microspheres and accelerate the implant's degradation. The
improvement of defects is immediate and has been reported to last
up to two years. The non-resorbable microspheres add permanent
volume under the treated defect, as well as stimulate the host to
produce collagen fibers around the implant. An example of
polylactic acid which may be used is SCULPTRA.RTM. (injectable
polylactic acid).
Proteoglycans
[0086] In further embodiments, proteoglycans may be used as a
pliable biocompatible material or in combination with the copolymer
described above to form the pliable biocompatible material.
Proteoglycans are glycoproteins in connective tissue comprising a
core protein and one or more covalently attached glycosaminoglycan
(GAG) chain(s). Proteoglycans can be categorized depending upon the
nature of their glycosaminoglycan chains and include but are not
limited to chondroitin sulfate, dermatan sulfate, heparin, heparan
sulfate, and keratan sulfate.
Cross-Linking Agents
[0087] The pliable biocompatible materials (including polymers)
described herein may be cross-linked using any suitable
cross-linking agent as would be known to persons skilled in the
art, for example, 1.4 butanediol diacrylate. Exemplary
cross-linking agents may be any terminally ethylenically
unsaturated compound having more than one unsaturated group (i.e.,
a multiplicity of unsaturated groups.) See U.S. Pat. No. 5,741,923.
Other exemplary cross-linking agents include, but are not limited
to ethylene glycol diacrylate or dimethacrylate, diethylene glycol
diacrylate or dimethacrylate, triethylene glycol diacrylate or
dimethacrylate, tetraethylene glycol diacrylate or dimethacrylate,
polyethylene glycol diacrylate or dimethacrylate,
trimethylolpropane triacrylate or trimethacrylate, bisphenol A
diacrylate or dimethacrylate, ethoxylated bisphenol A diacrylate or
dimethacrylate, pentaerythritol tri- and tetra-acrylate or
methacrylate, tetramethylene diacrylate or dimethacrylate,
methylene bisacrylamide or methacrylamide, dimethylene
bisacrylamide or methacrylamide, N,N'-dihydroxyethylene
bisacrylamide or methacrylamide, hexamethylene bisacrylamide or
methacrylamide, decamethylene bisacrylamide or methacrylamide,
divinyl benzene, vinyl methacrylate, and allyl methacrylate.
Additional exemplary cross-linking agents include
1,3-bis(4-methacryloyl oxyalkyl)tetra disiloxane and similar
poly(organo-siloxane) monomers. See U.S. Pat. No. 4,153,641.
Another group of exemplary cross-linking agents are the
resonance-free di(alkylene tertiary amine) cyclic compounds (e.g.,
N,N'-divinyl ethylene urea). See U.S. Pat. No. 4,436,887. Further
exemplary cross-linking agents include di- or polyvinyl ethers of
di- or polyvalent alcohols such as ethylene glycol divinyl
ether.
[0088] Physiologically Acceptable Suspending Agent
[0089] The physiologically acceptable suspending agent generally
acts to the reduce viscosity, reduce the sedimentation rate of
particles in suspension, and/or allow injectability at room
temperature. When admixed with a pliable biocompatible material it
forms a composition that may be a suspension, colloid, gel, or
solution. The physiologically acceptable suspending agent may be
resorbable.
[0090] The physiologically acceptable suspending agent may be a
solution comprising an aqueous liquid or a non-aqueous liquid such
as water-soluble and water-insoluble solvents or liquid chemicals
(e.g., alcoholic solvents, alkylene glycols (ethylene glycol),
dimethyl sulfoxide, ethanol, ethyl acetate, ethylene glycol,
glycerol, isopropyl alcohol, N-methyl-pyrrolidone, physiological
buffers, poly-alcohols, propylene carbonate, triacetin, water, and
mixtures thereof).
[0091] The physiologically acceptable suspending agent may be a
buffered physiological solution (e.g., normal saline, Ringer's
solution, phosphate buffered saline (PBS), TRIS-buffered saline
(TBS), HEPES-buffered saline (HBS)). The buffered physiological
solution may have a pH or about 7.0 to about 8.0 including a pH of
about 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or 7.9.
[0092] The physiologically acceptable suspending agent may be a
polymer including copolymers as described herein. For example,
hyaluronan, collagen, or fatty acids may used as physiological
acceptable suspending agents.
[0093] The physiologically acceptable suspending agent may be
stored in one form (e.g., gel) and then prepared (e.g., heated) to
change into an injectable form (e.g., solution) prior to
administration. For example, the solution may be stored as a gel at
a temperature below the physiological temperature and heated above
the physiological temperature prior to use in order for the
solution to be injectable. The suspending agents may contain a
tenside (surfactant), for instance Tween 80.RTM.
(polyethoxysorbitanoleate) because surfactants change the surface
tension of water so that the solid particles and in particular the
polymer particles float better.
[0094] The solution may be a self-gelling solution such as a
stimuli-triggered self-gelling polymeric solution, and preferably a
thermo-gelling solution. This thermo-gelling solution may be a
thermo-gelling chitosan-based aqueous. WO 99/07416. Self-gelling
solutions may be liquid at low to room temperature (e.g., about
25.degree. C. or below) and may form a solid gel at a higher
temperature, e.g., above 30.degree. C. Inversely, such self-gelling
solutions may be liquid at high temperatures, e.g., above
40.degree. C., but may form a gel at a lower temperature, e.g.,
below 40.degree. C. Typical thermo-gelling polymeric solutions may
be designed with polymers selected among poly(acrylic acid), methyl
cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose,
poly(ethylene oxide)-based triblock copolymers, or chitosan. Other
injectable self-forming systems, e.g., Lower critical solution
temperature (LCST), liquid crystalline, polymer precipitation
(solid), precipitation in situ, coagulation may also be used.
Pharmaceutical Compositions
[0095] The preferred forms of administration in the present
invention are injectable forms known in the art of pharmaceutics.
The formulations may be conveniently prepared by any of the methods
well-known in the art. The pharmaceutical compositions of the
present invention may include one or more suitable production aids
or excipients including fillers, binders, disintegrants,
lubricants, diluents, flow agents, buffering agents, moistening
agents, preservatives, colorants, and pharmaceutically compatible
carriers.
[0096] For each of the recited embodiments, the composition can be
administered by a variety of dosage forms as known in the art. Any
biologically-acceptable dosage form known to persons of ordinary
skill in the art, and combinations thereof, are contemplated.
Examples of such dosage forms include, without limitation, elixirs,
emulsions, liquids, solutions, suspensions, syrups, emulsions,
beads, powders, gum, granules, particles, microparticles,
dispersible granules, topicals, patches, implants, depot implants,
injectables, infusions, and combinations thereof.
[0097] According to certain embodiments of the invention, a
therapeutic agent may be included in the composition to be
administered or in another composition administered to the patient.
A "therapeutic agent" is any agent which serves to repair damage to
a living organism to heal the organism, to cure a malcondition, to
combat an infection by a microorganism or a virus, to assist the
body of the living mammal to return to a healthy state. A
"protective agent" is any agent which serves to prevent the
occurrence of damage to an organism, such as by preventing the
establishment of an infection by a microorganism, to prevent the
establishment of a malcondition, to preserve an otherwise healthy
body in the state of health. Therapeutic and protective agents
comprise pharmaceuticals, radiopharmaceuticals, hormones or their
analogs, enzymes, materials for genetic therapy such as antisense
nucleotides or their analogs, macroscopic ingredients such as bone
powder as is used to induce bone growth, growth factors as may be
used to stimulate tissue growth such as by angiogenesis, or any
other such agents as are medically advantageous for use to treat a
pathological condition. As used herein, "treating" or "treat"
includes (i) preventing a pathologic condition from occurring (e.g.
prophylaxis); (ii) inhibiting the pathologic condition or arresting
its development; (iii) relieving the pathologic condition; and/or
(iv) diminishing symptoms associated with the pathologic
condition.
[0098] A therapeutic agent or a protective agent may comprise a
"drug." As used herein, a "drug" refers to a therapeutic agent or a
diagnostic agent and includes any substance, other than food, used
in the prevention, diagnosis, alleviation, treatment, or cure of a
disease. Stedman's Medical Dictionary, 25.sup.th Edition (1990).
The drug can include any substance disclosed in at least one of:
The Merck Index, 12.sup.th Edition (1996); Pei-Show Juo, Concise
Dictionary of Biomedicine and Molecular Biology, (1996); U.S.
Pharmacopeia Dictionary, 2000 Edition; and Physician's Desk
Reference, 2001 Edition.
[0099] Specifically, the drug can include, but is not limited to,
one or more polynucleotides, polypeptides, oligonucleotides, gene
therapy agents, nucleotide analogs, nucleoside analogs, polynucleic
acid decoys, therapeutic antibodies, anti-inflammatory agents,
blood modifiers, anti-platelet agents, anti-coagulation agents,
immune suppressive agents, anti-neoplastic agents, anti-cancer
agents, anti-cell proliferation agents, and nitric oxide releasing
agents.
[0100] The polynucleotide can include deoxyribonucleic acid (DNA),
ribonucleic acid (RNA), double stranded DNA, double stranded RNA,
duplex DNA/RNA, antisense polynucleotides, functional RNA or a
combination thereof. In one embodiment, the polynucleotide can be
RNA. In another embodiment, the polynucleotide can be DNA. In
another embodiment, the polynucleotide can be an antisense
polynucleotide.
[0101] The polynucleotide can be a single-stranded polynucleotide
or a double-stranded polynucleotide. The polynucleotide can have
any suitable length. Specifically, the polynucleotide can be about
2 to about 5,000 nucleotides in length, inclusive; about 2 to about
1000 nucleotides in length, inclusive; about 2 to about 100
nucleotides in length, inclusive; or about 2 to about 10
nucleotides in length, inclusive.
[0102] An antisense polynucleotide is typically a polynucleotide
that is complimentary to an mRNA, which encodes a target protein.
For example, the mRNA can encode a cancer promoting protein i.e.,
the product of an oncogene. The antisense polynucleotide is
complimentary to the single stranded mRNA and will form a duplex
and thereby inhibit expression of the target gene, i.e., will
inhibit expression of the oncogene. The antisense polynucleotides
of the invention can form a duplex with the mRNA encoding a target
protein and will disallow expression of the target protein.
[0103] A "gene therapy agent" refers to an agent that causes
expression of a gene product in a target cell through introduction
of a gene into the target cell followed by expression. An example
of such a gene therapy agent would be a genetic construct that
causes expression of a protein, such as insulin, when introduced
into a cell. Alternatively, a gene therapy agent can decrease
expression of a gene in a target cell. An example of such a gene
therapy agent would be the introduction of a polynucleic acid
segment into a cell that would integrate into a target gene and
disrupt expression of the gene. Examples of such agents include
viruses and polynucleotides that are able to disrupt a gene through
homologous recombination. Methods of introducing and disrupting
genes within cells are well known to those of skill in the art.
[0104] Nucleotide and nucleoside analogues are well known on the
art. Examples of such nucleoside analogs include, but are not
limited to, CYTOVENE (Roche Laboratories), EPIVIR (Glaxo Wellcome),
GEMZAR (Lilly), HIVID (Roche Laboratories), REBETRON (Schering),
VIDEX (Bristol-Myers Squibb), ZERIT (Bristol-Myers Squibb), and
ZOVIRAX (Glaxo Wellcome). See Physician's Desk Reference, 2001
Edition.
[0105] As used herein, a "peptide" and a "protein" refer to
polypeptides, linear polymers of amino acids, the difference
between the terms "peptide" and "protein" largely being in the
length of the polymer. In one embodiment, the polypeptide can be an
antibody. Examples of such antibodies include single-chain
antibodies, chimeric antibodies, monoclonal antibodies, polyclonal
antibodies, antibody fragments, Fab fragments, IgA, IgG, IgM, IgD,
IgE and humanized antibodies. In one embodiment, the antibody can
bind to a cell adhesion molecule, such as a cadherin, integrin or
selectin. In another embodiment, the antibody can bind to an
extracellular matrix molecule, such as collagen, elastin,
fibronectin or laminin. In still another embodiment, the antibody
can bind to a receptor, such as an adrenergic receptor, B-cell
receptor, complement receptor, cholinergic receptor, estrogen
receptor, insulin receptor, low-density lipoprotein receptor,
growth factor receptor or T-cell receptor. Antibodies of the
invention can also bind to platelet aggregation factors (e.g.,
fibrinogen), cell proliferation factors (e.g., growth factors and
cytokines), and blood clotting factors (e.g., fibrinogen). In
another embodiment, an antibody can be conjugated to an active
agent, such as a toxin or a radionuclide.
[0106] An "anti-cancer agent" means an agent that either inhibits
the growth of cancerous cells, or causes the death of cancerous
cells. Anti-cancer agents include, e.g., nucleotide and nucleoside
analogs, such as 2-chloro-deoxyadenosine, adjunct antineoplastic
agents, alkylating agents, nitrogen mustards, nitrosoureas,
antibiotics, antimetabolites, hormonal agonists/antagonists,
androgens, antiandrogens, antiestrogens, estrogen & nitrogen
mustard combinations, gonadotropin releasing hotmone (GNRH)
analogues, progestrins, immunomodulators, miscellaneous
antineoplastics, photosensitizing agents, and skin & mucous
membrane agents. See Physician's Desk Reference, 2001 Edition.
[0107] An "antimicrobial," as used herein, refers to a molecular
entity that is effective as a therapeutic agent or as a protective
agent against an infection by a microorganism, which could be a
bacterium, a protozoan, a fungus, a virus, or another pathogenic
living organism. An antimicrobial may be an antibiotic, effective
against bacteria, including aminoglycoside antibiotics such as
gentamicin or streptomycin, a cephalosporin such as cephalexin or
cephtriaxone, a carbacephem such as loracarbef, a glycopeptide such
as vancomycin, a macrolide such as erythromycin, a penicillin such
as amoxicillin or ampicillin, a polypeptide such as bacitracin or
polymyxin B, a quinolone such as ciprofloxacin, a tetracycline such
as oxytetracycline, a sulfonamide, or any other medically approved
agent for treatment of bacterial infections. Alternatively the
antimicrobial may be an antifungal agent such as ketoconazole,
miconazole or amphotericin B, or an antiviral agent such as
acyclovir or AZT.
[0108] Moreover, the compounds (e.g., analgesics, anti-inflammatory
agents) described herein can be formulated in a time release
formulation, for example in a composition that includes a slow
release polymer. The tissue repair and/or replacement filler may be
prepared with carriers that will protect the compound against rapid
release, such as a controlled release formulation, including
implants and microencapsulated delivery systems. Biodegradable,
biocompatible polymers may be used (e.g., ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters,
polylactic acid and polylactic, and polyglycolic copolymers (PLG)).
Many methods for the preparation of such formulations are known to
those skilled in the art.
[0109] In further embodiments, the agent may be any enzyme. The
agent may be a protein such as a degradation enzyme, cytokine or
cytokine inhibitor or a growth factor. As will be appreciated by
those skilled in the art, combinations of agents may be used and
these agents may be derived form a variety of sources, synthetic
and natural and may include recombinant methods of manufacture. The
amount of bioactive agent in an implant, in accordance with
embodiments of the invention, may be adjusted to achieve the
desired dosage. In further embodiments, the amount administered to
the patient or the amount in the implant is between about 0.01 ng
and about 300 mg of the active agent per milliliter of copolymer
material (or implant material). The composition or device could
contain more or less depending upon the application for which the
composition or device is intended and the required activity level
of the selected agent. The agent can be contained within the
composition to be administered or the implant in a number of
methods known to those skilled in the art.
[0110] In further embodiments, therapeutic agents include genetic
therapeutic agents, non-genetic therapeutic agents, and cells, and
can be negatively charged, positively charged, amphoteric, or
neutral. Therapeutic agents can be, for example, materials that are
biologically active to treat physiological conditions;
pharmaceutically active compounds; gene therapies; nucleic acids
with and without carrier vectors; oligonucleotides; gene/vector
systems; DNA chimeras; compacting agents (e.g., DNA compacting
agents); viruses; polymers; hyaluronic acid; proteins (e.g.,
enzymes such as ribozymes); immunologic species; nonsteroidal
anti-inflammatory medications; oral contraceptives; progestins;
gonadotrophin-releasing hormone agonists; chemotherapeutic agents;
and radioactive species (e.g., radioisotopes, radioactive
molecules). Non-limiting examples of therapeutic agents include
anti-thrombogenic agents; antioxidants; angiogenic and
anti-angiogenic agents and factors; anti-proliferative agents
(e.g., agents capable of blocking smooth muscle cell
proliferation); calcium entry blockers; and survival genes which
protect against cell death.
[0111] Exemplary non-genetic therapeutic agents include:
anti-thrombotic agents such as heparin, heparin derivatives,
urokinase, and PPack (dextrophenylalanine proline arginine
chloromethylketone); anti-inflammatory agents such as
dexamethasone, prednisolone, corticosterone, budesonide, estrogen,
sulfasalazine and mesalamine;
antineoplastic/antiproliferative/anti-mitotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, doxorubicin, vinblastine,
vincristine, epothilones, endostatin, angiostatin, angiopeptin,
monoclonal antibodies capable of blocking smooth muscle cell
proliferation, and thymidine kinase inhibitors; anesthetic agents
such as lidocaine, bupivacaine and ropivacaine; anti-coagulants
such as D-Phe-Pro-Arg chloromethyl ketone, an RGD
peptide-containing compound, heparin, hirudin, antithrombin
compounds, platelet receptor antagonists, anti-thrombin antibodies,
anti-platelet receptor antibodies, aspirin, prostaglandin
inhibitors, platelet inhibitors and tick antiplatelet peptides;
vascular cell growth promoters such as growth factors,
transcriptional activators, and translational promoters; vascular
cell growth inhibitors such as growth factor inhibitors, growth
factor receptor antagonists, transcriptional repressors,
translational repressors, replication inhibitors, inhibitory
antibodies, antibodies directed against growth factors,
bifunctional molecules consisting of a growth factor and a
cytotoxin, bifunctional molecules consisting of an antibody and a
cytotoxin; protein kinase and tyrosine kinase inhibitors (e.g.,
tyrphostins, genistein, quinoxalines); prostacyclin analogs;
cholesterol-lowering agents; angiopoietins; antimicrobial agents
such as triclosan, cephalosporins, aminoglycosides and
nitrofurantoin; cytotoxic agents, cytostatic agents and cell
proliferation affectors; vasodilating agents; and agents that
interfere with endogenous vasoactive mechanisms.
[0112] Exemplary genetic therapeutic agents include: anti-sense DNA
and RNA; DNA coding for anti-sense RNA, tRNA or rRNA to replace
defective or deficient endogenous molecules, angiogenic factors
including growth factors such as acidic and basic fibroblast growth
factors, vascular endothelial growth factor, epidermal growth
factor, transforming growth factor .alpha. and .beta.,
platelet-derived endothelial growth factor, platelet-derived growth
factor, tumor necrosis factor a, hepatocyte growth factor, and
insulin like growth factor, cell cycle inhibitors including CD
inhibitors, thymidine kinase ("TK") and other agents useful for
interfering with cell proliferation, and the family of bone
morphogenic proteins ("BMP's"), including BMP2, BMP3, BMP4, BMP5,
BMP6 (Vgr 1), BMP7 (OP1), BMP8, BMP9, BMP10, BM11, BMP12, BMP13,
BMP14, BMP15, and BMP16. Currently preferred BMP's are any of BMP2,
BMP3, BMP4, BMP5, BMP6 and BMP7. These dimeric proteins can be
provided as homodimers, heterodimers, or combinations thereof,
alone or together with other molecules. Alternatively or
additionally, molecules capable of inducing an upstream or
downstream effect of a BMP can be provided. Such molecules include
any of the "hedgehog" proteins, or the DNA's encoding them. Vectors
of interest for delivery of genetic therapeutic agents include:
plasmids; viral vectors such as adenovirus (AV), adenoassociated
virus (AAV) and lentivirus; and non-viral vectors such as lipids,
liposomes and cationic lipids.
[0113] Cells include cells of human origin (autologous or
allogeneic), including stem cells, or from an animal source
(xenogeneic), which can be genetically engineered if desired to
deliver proteins of interest.
[0114] In further embodiments, the invention relates to the
administration (or coadministration) of a cytokine. This cytokine
may be chosen from a group of cytokines, or may include
combinations of cytokines. Stem cell factor (SCF) and
granulocyte-colony stimulating factor (G-CSF) are known by those
skilled in the art as stimulating factors which cause the
mobilization of stem cells into the blood stream (Bianco et al,
2001, Clutterbuck, 1997, Kronenwett et al, 2000, Laluppa et al,
1997, Patchen et al, 1998). Stromal cell-derived factor-1 has been
shown to stimulate stem cell mobilization chemotactically, while
steel factor has both chemotactic and chemokinetic properties
(Caceres-Cortes et al, 2001, Jo et al, 2000, Kim and Broxmeyer,
1998, Ikuta et al, 1991). Vascular endothelial growth factor has
been surmised to engage a paracrine loop that helps facilitate
migration during mobilization (Bautz et al, 2000,
Janowska-Wieczorek et al, 2001). Macrophage colony stimulating
factor and granulocyte-macrophage stimulating factor have been
shown to function in the same manner of SCF and G-CSF, by
stimulating mobilization of stem cells. Interleukin-3 has also been
shown to stimulate mobilization of stem cells, and is especially
potent in combination with other cytokines.
[0115] The cytokine can be administered via a vector that expresses
the cytokine in vivo. A vector for in vivo expression can be a
vector or cells or an expression system as cited in any document
incorporated herein by reference or used in the art, such as a
viral vector, e.g., an adenovirus, poxvirus (such as vaccinia,
canarypox virus, MVA, NYVAC, ALVAC, and the like), lentivirus or a
DNA plasmid vector; and, the cytokine can also be from in vitro
expression via such a vector or cells or expression system or
others such as a baculovirus expression system, bacterial vectors
such as E. coli, and mammalian cells such as CHO cells. See, e.g.,
U.S. Pat. Nos. 6,265,189, 6,130,066, 6,004,777, 5,990,091,
5,942,235, 5,833,975. The cytokine compositions may lend themselves
to administration by routes outside of those stated to be
advantageous or preferred for stem cell preparations; but, cytokine
compositions may also be advantageously administered by routes
stated to be advantageous or preferred for stem cell
preparations.
[0116] Further embodiments of the invention involve administration
of a therapeutically effective dose or amount of a cytokine. An
effective dose is an amount sufficient to effect a beneficial or
desired clinical result. Said dose could be administered in one or
more administrations. In a further embodiment, the dose would be
given over the course of about two or three days following the
beginning of treatment. However, the precise determination of what
would be considered an effective dose may be based on factors
individual to each patient, including their size, age, size of the
infarct, the cytokine or combination of cytokines being
administered, and amount of time since damage. One skilled in the
art, specifically a physician or cardiologist, would be able to
determine a sufficient amount of cytokine that would constitute an
effective dose without being subjected to undue
experimentation.
[0117] The invention also involves the administration (or
coadministration) of the therapeutically effective dose or amount
of a cytokine being delivered by injection, specifically
subcutaneously or intravenously. A person skilled in the art will
be aware that subcutaneous injection or intravenous delivery are
extremely common and offer an effective method of delivering the
specific dose in a manner which allows for timely uptake and
circulation in the blood stream.
[0118] A further embodiment includes the administered cytokine
stimulating the patient's stem cells and causing mobilization into
the blood stream. As mentioned previously, the given cytokines are
well-known to one skilled in the art for their ability to promote
said mobilization. Advantageously, once the stem cells have
mobilized into the bloodstream, they home to the damaged area of
the heart, as will become clear through the following examples.
Further embodiments of the invention involve the stem cells
migrating into the infarcted region and differentiating into
myocytes, smooth muscle cells, and endothelial cells. It is known
in the art that these types of cells must be present to restore
both structural and functional integrity.
[0119] A further embodiment of the invention includes administering
an effective amount of one or more cytokines to the infarcted
region. An effective dose is an amount sufficient to effect a
beneficial or desired clinical result. Said dose could be
administered in one or more administrations. However, the precise
determination of what would be considered an effective dose may be
based on factors individual to each patient, including their size,
age, size of the infarct, the cytokine or combination of cytokines
being administered, and amount of time since damage. Persons
skilled in the art, specifically a physician or cardiologist, would
be able to determine a sufficient amount of cytokine that would
constitute an effective dose without being subjected to undue
experimentation.
[0120] A still further embodiment of the invention includes
administering (or coadministering) an effective amount of one or
more cytokines to the heart by injection. Preferably, the cytokines
are delivered to the infarcted region or to the area bordering the
infarcted region. As one skilled in the art would be aware, the
infarcted area is visible grossly, allowing this specific placement
of cytokines to be possible.
[0121] The cytokines are advantageously administered by injection,
for example by a intramyocardial injection. As a person skilled in
the art would be aware, this is a further method of delivery for
cytokines as the heart is a functioning muscle. Injection of the
cytokines into the heart ensures that they will not be lost due to
the contracting movements of the heart. In a further aspect of the
invention, the cytokines are administered by injection
trans-endocardially or trans-epicardially. This preferred
embodiment allows the cytokines to penetrate the protective
surrounding membrane, necessitated by the embodiment in which the
cytokines are injected intramyocardially. A further embodiment of
the invention includes use of a catheter-based approach to deliver
the trans-endocardial injection. The use of a catheter precludes
more invasive methods of delivery wherein the opening of the chest
cavity would be necessitated. As one skilled in the art is aware,
optimum time of recovery would be allowed by the more minimally
invasive procedure, which as outlined here, includes a catheter
approach.
[0122] A further embodiment of the invention includes the delivery
of the cytokines by a single administration. A still further
embodiment of the invention includes multiple administrations of
the same dosage of cytokines to the heart. A still further
embodiment of the invention includes administration of multiple
doses of the cytokines to the heart, such that a gradient is
formed.
[0123] A still further embodiment of the invention includes the
stimulation, migration, proliferation and/or differentiation of the
resident cardiac stem cells. Another embodiment of the invention
includes the proliferation of the differentiated cells and the
formation of the cells into cardiac structures including coronary
arteries, arterioles, capillaries, and myocardium. As one skilled
in the art is aware, all of these structures are important for
proper function in the heart. It has been shown in the literature
that implantation of cells including endothelial cells and smooth
muscle cells will allow for the implanted cells to live within the
infarcted region, however they do not form the necessary structures
to enable the heart to regain full functionality. The ability to
restore both functional and structural integrity or better
functional and structural integrity than previously achieved in the
art is yet another aspect of this invention.
[0124] It is a further embodiment in the practice of the invention
to utilize both the administration of stem cells and that of a
cytokine to ensure the most effective method of repairing damaged
myocardium.
[0125] Stem cells employed in the invention are advantageously
selected to be lineage negative. The term "lineage negative" is
known to one skilled in the art as meaning the cell does not
express antigens characteristic of specific cell lineages. And, it
is advantageous that the lineage negative stem cells are selected
to be c-kit positive. The term "c-kit" is known to one skilled in
the art as being a receptor which is known to be present on the
surface of stem cells, and which is routinely utilized in the
process of identifying and separating stem cells from other
surrounding cells.
[0126] In certain embodiments, a therapeutically effective dose of
stem cells is applied, delivered, or administered to the heart or
implanted into the heart. An effective dose or amount is an amount
sufficient to effect a beneficial or desired clinical result. Said
dose could be administered in one or more administrations. However,
the precise determination of what would be considered an effective
dose may be based on factors individual to each patient, including
their size, age, size of the infarct, and amount of time since
damage. Persons skilled in the art, specifically a physician or
cardiologist, would be able to determine the number and type (or
types) of stem cells that would constitute an effective dose
without being subjected to undue experimentation, from this
disclosure and the knowledge in the art; and, in this regard and in
general in regard to preparing formulations and administering
formulations or components thereof. The stem cells are
advantageously bone marrow or are cardiac stem cells; and even more
advantageously, the stem cells are adult bone marrow (hematopoietic
stem cells) or adult cardiac stem cells or a combination thereof or
a combination of cardiac stem cells such as adult cardiac stem
cells and another type of stem cell such as another type of adult
stem cells.
[0127] In another aspect of the invention, the stem cells are
delivered to the heart, specifically to the border area of the
infarct. As persons skilled in the art would be aware, the
infarcted area is visible grossly, allowing this specific placement
of stem cells to be possible.
[0128] The stem cells are advantageously administered by injection,
specifically an intramyocardial injection. As one skilled in the
art would be aware, this is the preferred method of delivery for
stem cells as the heart is a functioning muscle. Injection of the
stem cells into the heart ensures that they will not be lost due to
the contracting movements of the heart. In other aspects of the
invention, the stem cells are administered by injection
transendocardially or trans-epicardially. This further embodiment
allows the stem cells to penetrate the protective surrounding
membrane, necessitated by the embodiment in which the cells are
injected intramyocardially.
[0129] A further embodiment of the invention includes use of a
catheter-based approach to deliver the trans-endocardial injection.
The use of a catheter precludes more invasive methods of delivery
wherein the opening of the chest cavity would be necessitated. As
one skilled in the art is aware, optimum time of recovery would be
allowed by the more minimally invasive procedure, which as outlined
here, includes a catheter approach.
Analgesics
[0130] The composition may include or be administered in
conjunction with an analgesic. The analgesic may be included in the
tissue repair and/or replacement filler composition, or
administered sequentially, concurrently, or subsequently with the
administration of the tissue repair and/or replacement filler
composition. Analgesics that may be used in the present invention
include but are not limited to acetaminophen (Tylenol.RTM.),
amitriptyline, carbamazepine, codeine (Tylenol #2,3,4.RTM.),
dihydromorphine, fentanyl patch (Duragesic.RTM.), Flupirtine,
fluriprofen, gabapentin, hydrocodone APAP (Vicodin.RTM.),
hydromorphone
[0131] (Palladone.RTM.), ibuprofen, ketoprofen, morphine (MS
Contin.RTM.), oxycodone (Percocet.RTM., OxyContin.RTM.,
Percodan.RTM.), pentazocine (Talwin NX.RTM.), pethidine,
phenacetin, pregabalin, propoeylphene (Darvon.RTM.), propoyl APA
(Darvocet.RTM.), salicylamide (aspirin), tramadol (Ultram.RTM.),
tramadol APAP (Ultracet.RTM.), and voltaren.
Local Anesthetic
[0132] The composition may include or be administered in
conjunction with a local anesthetic. The local anesthetic may be
included in the composition, or administered sequentially,
concurrently, or subsequently with the administration of the tissue
repair and/or replacement filler composition. Local anesthetic that
may be used in the present invention include but are not limited to
amethocaine, articaine, benzocaine, bupivacaine, Carbocaine.RTM.
(mepivacaine), cocaine, cinchocaine, chloroprocaine,
cyclomethycaine, dibucaine, dimethocaine, EMLA.RTM. (eutectic
mixture of lidocaine and prilocalne), etidocaine, larocaine,
levobupivacaine, lidocaine, lignocaine, Novocaine.RTM. (procaine),
piperocaine, Polocalne.RTM. (mepivacaine), prilocalne,
proparacaine, propoxycaine, ropivacaine, saxitoxin, tetracaine,
tetrodotoxin, and trimecaine.
Anti-Inflammatory Agents
[0133] The composition may include or be administered in
conjunction with an anti-inflammatory agent. The anti-inflammatory
agent may be included in the composition, or administered
sequentially, concurrently, or subsequently with the administration
of the tissue repair and/or replacement filler composition.
Anti-inflammatory agents such as non-steroidal anti-inflammatory
drugs (NSAIDs) are classified into groups based on their chemical
structure: (1) propionic acid derivatives, (2) acetic acid
derivatives, (3) enolic acid derivatives, (4) fenamic acid
derivatives, and (5) selective COX-2 inhibitors. Any member of
these classes may be used as an anti-inflammatory agent. Exemplary
non-steroidal anti-inflammatory drugs (NSAIDs) that may be used in
the present invention include but are not limited to acetaminophen
(Tylenol.RTM.), azapropazone, diclofenac, diflunisal, etodolac,
fenbufen, fenoprofen, flurbiprofen, ibuprofen (Motrin.RTM.),
indomethacin (indometacin), ketoprofen, ketorolac, mefenamic,
meloxicam, nabumetone, naproxen, phenylbutazone, piroxicam,
salicylates (e.g., acetylsalicylic acid (Aspirin), amoxiprin,
benorylate/benorilate, choline magnesium salicylate,
Diflunisal.RTM., ethenzamide, faislamine, methyl salicylate,
magnesium salicylate, salicyl salicylate, and salicylamide),
sulindac, tenoxicam, tiaprofenic acid, and tolfenamic acid.
Stem Cells
[0134] The present invention contemplates the use of stem cells in
combination with the copolymer of the invention. The stem cells may
be included in the composition, or administered sequentially,
concurrently, or subsequently with the administration of the
composition in accordance with embodiments of the present
invention. In further embodiments, methods and/or pharmaceutical
compositions use a therapeutically effective amount of somatic stem
cells alone or in combination with a cytokine such as a cytokine
selected from the group consisting of stem cell factor (SCF),
granulocyte-colony stimulating factor (G-CSF),
granulocyte-macrophage colony stimulating factor (GM-CSF), stromal
cell-derived factor-1, steel factor, vascular endothelial growth
factor, macrophage colony stimulating factor,
granulocyte-macrophage stimulating factor or Interleukin-3 or any
cytokine capable of the stimulating and/or mobilizing stem cells.
Cytokines may be administered alone or in combination of with any
other cytokine capable of: the stimulation and/or mobilization of
stem cells; the maintenance of early and late hematopoiesis (see
below); the activation of monocytes (see below),
macrophage/monocyte proliferation; differentiation, motility and
survival (see below) and a pharmaceutically acceptable carrier,
diluent or excipient (including combinations thereof). The stem
cells are advantageously adult stem cells, such as hematopoietic or
cardiac stem cells or a combination thereof or a combination of
cardiac stem cells and any other type of stem cells.
[0135] The implanting, depositing, administering or causing of
implanting or depositing or administering of stem cells, such as
adult stem cells, for instance hematopoietic or cardiac stem cells
or a combination thereof or any combination of cardiac stem cells
(e.g., adult cardiac stem cells) and stem cells of another type of
(e.g., adult stem cells of another type), alone or with a cytokine
such as a cytokine selected from the group consisting of stem cell
factor (SCF), granulocyte-colony stimulating factor (G-CSF),
granulocyte-macrophage colony stimulating factor (GM-CSF), stromal
cell-derived factor-1, steel factor, vascular endothelial growth
factor, macrophage colony stimulating factor,
granulocyte-macrophage stimulating factor or Interleukin-3 or any
cytokine capable of the stimulating and/or mobilizing stem cells
(wherein "with a cytokine . . . " can include sequential
implanting, depositing administering or causing of implanting or
depositing or administering of the stem cells and the cytokine or
the co-implanting co-depositing or co-administering or causing of
co-implanting or co-depositing or co-administering or the
simultaneous implanting, depositing administering or causing of
implanting or depositing or administering of the stem cells and the
cytokine), in circulatory tissue or muscle tissue or circulatory
muscle tissue, e.g., cardiac tissue, such as the heart or blood
vessels--e.g., veins, arteries, that go to or come from the heart
such as veins and arteries directly connected or attached or
flowing into the heart, for instance the aorta. This implanting,
depositing, or administering or causing of implanting, depositing
or administering can be in conjunction with grafts. Such
implanting, depositing or administering or causing of implanting,
depositing or administering is advantageously employed in the
treatment or therapy or prevention of cardiac conditions, such as
to treat areas of weakness or scarring in the heart or prevent the
occurrence or further occurrence of such areas or to treat
conditions which cause or irritate such areas, for instance
myocardial infarction or ischemia or other e.g., genetic,
conditions that impart weakness or scarring to the heart (see also
cardiac conditions mentioned infra).
[0136] Further embodiments include combinations with biocompatible
materials or polymers of the invention involving the use of such
stem cells alone or in combination with cytokine(s). Further
embodiments include medicaments for use in treatment, therapy or
prevention comprising the stem cells and optionally the
cytokine(s). Further embodiments include kits comprising the stem
cells and optionally the cytokine(s) for formulations for use in
such treatment, therapy or prevention. Further embodiments include
combinations with compositions comprising such stem cells and
optionally at least one cytokine and kits for preparing such
compositions. Further embodiments include methods of making the
kits and compositions described herein. Further embodiments include
methods of implanting or depositing stem cells or causing the
implanting or depositing of stem cells.
Methods of Manufacture
[0137] The composition may be produced by a method comprising
combining the components described herein. For example, the method
of manufacture may comprise admixing a pliable biocompatible
material with a physiologically acceptable suspending agent to form
a composition. The pliable biocompatible material may be admixed
with a physiologically acceptable suspending agent prior to
administration, including immediately prior to administration. For
example, the pliable biocompatible material may be admixed with a
physiologically acceptable suspending agent in a mixing vessel (or
even the syringe) and then immediately administered to the
patient.
[0138] The composition may be calibrated to approximate the
functional properties of the tissue that has been damaged. For
example, the relative proportion of a pliable biocompatible
material and the physiological acceptable suspending agent may be
determined to achieve mechanical properties similar to those of the
tissue that has been damaged.
[0139] The physiological acceptable suspending agent may be added
to a pliable biocompatible material until a desired thickness,
viscosity, or consistency is reached. The mixing ratio of the
components of the suspending agent may be chosen according to the
needs and in particular according to the size of the syringe used
for the injection. The solid particles used according to the
present invention, the particles may be suspended or slurried in a
physiological acceptable suspending agent.
Methods of Treatment
[0140] The present invention provides a variety techniques for
ameliorating the effects of tissue damage comprising administration
of an effective amount of a composition. It is intended that the
method described herein can be applied for restoring totally or
partly the physical functions of atrophic, damaged, deteriorated,
or degenerated tissue with an injectable composition, by injecting
the composition into the tissue.
[0141] The compositions described herein may be used in a method of
augmenting soft tissue, comprising administration of a tissue
repair and/or replacement filler composition. The compositions
described herein may also be used in a method for the stimulation
of collagen production, fibroblast production, fibrocyte
production, or any combination thereof, comprising administration
of a composition according to various embodiments of the present
invention. The stimulation of collagen production, fibroblast
production, fibrocyte production or any combination thereof, may be
beneath the tissue defect by administration of a composition.
[0142] The methods described herein provides long-term reduction of
a tissue repair and/or replacement condition of a duration of at
least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. The duration
may be at least about 1-5, 3-5, or 1-10 years. The duration may
also be at least about 10 years or longer.
[0143] The tissue repair and/or replacement filler composition may
be administered by injecting from a needle/syringe system. A 34-,
33-, 32-, 31-, 30-, 29-, 28-, 27-, 26-, 25-, 24-, 23-, 22-, 21-,
20-, 19-, 18-, 17-, 16-, 15-, 14-, 13-, 12-, 11-, 10-, 9-, 8-, or
7-gauge needle may be used. A standard length needle (2-3 cm) may
be used. For example, a 30-, 27-, or 26-gauge needle of 0.5 inch
length may be used. Any devices that enable one to percutaneously
administer the solution to the site of the damaged tissue may be
used. For example, the composition may be injected using any
devices designed for administering injectable fillers.
[0144] If required, a second injection of the composition may be
administered after a period of at least about 1-4 weeks to 1-4
months. This additive effect may be used to achieve the desired
result. More severely damaged tissue may require a second, third
and fourth injection of the composition.
[0145] Side-effects of superficial injection may be treated with
corticosteroid cream or intratissue repair and/or replacement
corticosteroid injections. Dermabrasion will remove granules of
microbeads or microspheres. If microbeads or microspheres are used,
the microbeads or microspheres can be spread around through massage
within a day or two after the injection to even the
distribution.
[0146] A colored dye may be included in the composition to allow a
clinician to monitor the spread of the composition and its
administration. Generally, the injection site may be evenly
massaged and slight pressure may be applied to smooth out any
detected lumps. Following massaging, this injection procedure
consistently resulted in having the dye spreading in the entire
tissue, without dispersing into the other tissues.
Tissue Repair and/or Replacement Conditions
[0147] Tissue repair and/or replacement must strike a balance
between achieving long-term results, minimizing side effects or
complications of the treatment procedure and the host tissue
reaction thereto, and decreasing the recurrence of treatment to
achieve the intended results.
[0148] The present invention provides methods for treating tissue
damage based on and/or resulting from a variety of conditions
including but not limited to birth defects, cosmetic surgical
procedures, skin conditions, orthopedic injuries, vocal cord
paralysis and urinary incontinence. The methods described herein
also may provide long-term tissue repair and/or replacement, and
provide relief from pain, inflammation, and other conditions.
[0149] The present invention provides methods for treating a
patient with pain including neuropathic pain. The neuropathic pain
may be due to a variety of etiologies include but are not limited
to diabetic neuropathy, nerve injury, nerve tract injury,
peripheral neuropathy, chemotherapy-induced neuropathy,
chemotherapy-induced peripheral neuropathy, HIV-treatment induced
neuropathy, 11W-treatment induced neuralgia, neuralgia,
polyneuropathy, mononeuropathy, mononeuritis multiplex, autonomic
neuropathy, symmetrical peripheral neuropathy, radiculopathy, large
fiber peripheral neuropathy, small fiber peripheral neuropathy, and
idiopathic neuropathic pain.
[0150] The present invention still further provides compositions
and methods for treating a tissue repair and/or replacement
deformity that requires re-contouring, such as a small tissue
defect (e.g., after animal bite(s)) or a deformity related to
trauma where the deformity is cosmetically unappealing. In a
further embodiment of the method of augmenting soft tissue, the
augmentation may be after plastic surgery to achieve symmetry or a
desired result. The methods described herein may also be used in
treating pain or discomfort that occurs after treatment, such as
surgery or physical therapy.
[0151] In accordance with further embodiments of the present
invention, the present invention contemplates the use of any of the
compositions described herein with other suitable compositions,
including as mixtures or as separately administered substances, as
would be recognized by persons skilled in the art based upon the
guidance provided herein.
Apparatus of the Present Invention
[0152] According to further embodiments, the present invention
provides medical devices or a materials for use in conjunction with
suitable medical devices, including implantable and non-implantable
medical devices as would be understood by persons skilled in the
art.
[0153] An embodiment of current invention provides an implantable
device or material comprising a tissue (e.g., bone, cartilage, soft
tissue, etc.) substitute material and a method and system for
deploying the implantable device or material. In general the
implantable device of this invention is generally fabricated from
one or more biocompatible materials (e.g. polymer, metal, ceramic)
that will act to treat the wound and serve as a scaffold for the
in-growth of tissue. According to certain embodiments of the
present invention, an apparatus for tissue repair or replacement
comprises an implantable device coated or embedded with a
composition comprising an unsubstituted acrylate/substituted
acrylate copolymer. According to a further embodiment, the
copolymer is a phenylethyl acrylate/phenylethyl methacrylate
copolymer.
[0154] The implant may contain other materials for assisting in the
growth of cells and act as a carrier for other constituents that
act to beneficially treat the patient in which it is implanted.
Some embodiments of the invention also incorporate cells or other
biological constituents for providing the basic building blocks for
tissue regeneration. Any suitable cells or other biological
constituents as would be known to persons skilled in the art may be
used or incorporated into embodiments of the present invention.
[0155] Any suitable material can be used to construct the implant,
or a portion thereof. Biocompatible polymers such as the copolymer
described herein alone or incombination with other polymers (for
example, collagen, chitosan, alginate, polylactide-co-glycolide,
polyurethane, polyethylene) are used in this invention in
accordance with various embodiments. Collagen, and most
specifically native fibrous collagen, may be used in combination
with the copolymer in accordance with an embodiment. Additionally,
biocompatible resorbable synthetic polymers may be used in
accordance with certain embodiments. However, virtually any
biodegradable and/or biocompatible material may be used in
combination according to various embodiments.
[0156] According to various embodiments, the medical implant
includes non-biological implant material which is coated with or
embedded with tissue producing cells, such as tissue-producing
cells. As used herein, the phrase "non-biological" refers to any
material which does not contain living cells. The tissue producing
cells function to reduce a physiological response to the implant in
the subject. The physiological response may be, for example, an
immune response, an inflammatory response, encapsulation,
ossification, calcification or infection. To reduce such a
physiological response, the tissue producing cells utilized by this
aspect of the present invention are preferably derived from the
subject or a tissue source which is syngeneic with respect to the
subject. It will be appreciated however, that other tissue sources
(allogeneic, xenogeneic) may also be used, provided measures are
taken to substantially reduce the immunogenicity of tissue
producing cells harvested from such sources.
[0157] In order to facilitate increased adherence of the tissue
producing cells to the device, an intermediate layer applied to the
device may be employed. Although many materials may be useful in
construction of this intermediate layer will be known to those of
ordinary skill in the art, fibronectin, silicone and combinations
thereof have been found to be especially well suited for use in the
context of the claimed device.
[0158] In further embodiments, the invention provides a medical
implant which does not elicit a physiological response following
implantation, thus traversing problems associated with rejection of
implants and as such prolonging the service life of such an implant
within the subject's body.
[0159] According to certain embodiments, the apparatus may further
comprise a proteoglycan. The proteoglycan may be aggrecan, decorin,
biglycan, fibromodulin, lumican, keratocan, epiphycan, or
osteoglycin, or combinations thereof. The apparatus may further
comprise an anti-inflammatory agent. The anti-inflammatory agent
may be a non-steroidal anti-inflammatory drug (NSAID). The
anti-inflammatory agent may be acetaminophen, azapropazone,
diclofenac, diflunisal, etodolac, fenbufen, fenoprofen,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
mefenamic, meloxicam, nabumetone, naproxen, phenylbutazone,
piroxicam, a salicylate, sulindac, tenoxicam, tiaprofenic acid, or
tolfenamic acid, or combinations thereof. The salicylate may be
acetylsalicylic acid, amoxiprin, benorylate, choline magnesium
salicylate, ethenzamide, faislamine, methyl salicylate, magnesium
salicylate, salicyl salicylate, or salicylamide. The apparatus may
further include administering an analgesic. The analgesic may be
acetaminophen, amitriptyline, carbamazepine, codeine,
dihydromorphine, fentanyl patch, Flupirtine, fluriprofen,
gabapentin, hydrocodone APAP, hydromorphone, ibuprofen, ketoprofen,
morphine, oxycodone, pentazocine, pethidine, phenacetin,
pregabalin, propoeylphene, propoyl APA, salicylamide, tramadol,
tramadol APAP, or voltaren. The apparatus may further involve the
use of a local anesthetic. The local anesthetic may be amethocaine,
articaine, benzocaine, bupivacaine, mepivacaine, cocaine,
cinchocaine, chloroprocaine, cyclomethycaine, dibucaine,
dimethocaine, EMLA.RTM. (eutectic mixture of lidocaine and
prilocalne), etidocaine, larocaine, levobupivacaine, lidocaine,
lignocaine, procaine, piperocaine, prilocalne, proparacaine,
propoxycaine, ropivacaine, saxitoxin, tetracaine, tetrodotoxin, or
trimecaine.
[0160] Further embodiments of the present invention will now be
described with reference to the following examples. The examples
contained herein are offered by way of illustration and not
intended in any way to limit the scope of the present invention.
Other suitable modifications and adaptations as would be known to
those skilled in the art, based upon the guidance provided herein,
are within the spirit and scope of the embodiments.
EXAMPLES
Example 1
Reduction of Horizontal Forehead Lines
[0161] Twenty patients presenting with deep horizontal forehead
lines, creases or wrinkles are treated with injections of
alloplastic injectable suspension for use as a dermal filler
comprising acrylate/methacrylate (A/M) copolymer powder (or
non-porous microbeads or microspheres) and a cross-linked sodium
hyaluronate, (or non-crosslinked sodium hyaluronate).
[0162] Light topical anesthetic is applied to the skin proximal to
the horizontal forehead lines, creases or wrinkles to alleviate any
discomfort during injection. A 30-, 27- or 26-gauge needle of a
0.5-inch length is used. The syringe contains 0.5 cc of the
suspended A/M copolymer. Needle patency is verified by gently
squeezing some of the suspended A/M copolymer out of the needle
tip. The needle is inserted into the skin beneath and along the
line of the forehead line, crease or wrinkle, with constant thumb
pressure applied on the syringe. The injection is places deep
intradermally into the reticular dermis just above the junction
between the dermis and the subcutaneous fat. Resistance from the
dermis will be experienced, however, if the needle is placed too
deep, there will be little resistance from the fatty tissue.
[0163] Injection occurs in a tunneling technique, wherein the
needle is moved back and forth horizontally just beneath the
forehead line, crease or wrinkle, such that the injection occurs
simultaneously with withdrawal of the needle. The gray needle
should not show through the skin of the line. If injected
superficially intradermally, the microbeads or microspheres will
form small granules in a line akin to a strand of pearls within the
line.
[0164] Evenly massage with a fingertip the injected and apply
slight pressure to smooth out any detected lumps. Vigorous massage
is not advisable, as it will spread the injected suspended A/M
copolymer deeper into the tissue and result in loss of the intended
effect.
[0165] In about three months, the diminished thickness of the
dermis recovers its previous thickness. The thickness recovery may
be determined mostly through the use of before and after photos,
thus, the time period may vary from patient to patient.
[0166] A second injection of the suspended A/M copolymer may be
placed on top of the first injection layer after a period of four
weeks to four months. This additive effect may be used to achieve
the desired result. Deeper forehead lines may require a second,
third and fourth injection of the suspended A/M copolymer.
[0167] An amount of 0.5 cc of the suspended A/M copolymer will
suffice for injection beneath a forehead line, crease or wrinkle,
for example, a frontal furrow. A second injection, if needed, for
example, to even the distribution of the first injected and
implanted microbeads or microspheres, will inject about the same
amount of the suspended A/M copolymer, or less, depending on the
tissue response and the patient's desired result.
[0168] Side-effects of superficial injection are treated with
corticosteroid cream or intradermal corticosteroid injections.
Dermabrasion will remove intradermal granules of microbeads or
microspheres. Because of the inert nature of the copolymer, it is
not expected to form granules in powder form. If microbeads or
microspheres are used, the microbeads or microspheres can be spread
around through massage within a day or two after the injection to
even the distribution. Therefore, clumping is not expected, since
it results if there is an inflammatory reaction which aggregates
the copolymer microbeads or microspheres together.
[0169] Within four weeks to four months of the last injection of
the suspended A/M copolymer the skin comprising the forehead line,
crease or wrinkle will be raised to the same level as the
surrounding skin, such that the appearance of the forehead line,
crease or wrinkle will be diminished or eliminated. The decrease of
appearance or removal forehead line, crease or wrinkle is expected
to be permanent, such as to last at least 18 months with no
palpability or visibility, and from about five to about ten years.
Muscle movement over a time period of from about five to about ten
years may cause the injected A/M copolymer to deepen by 1/10 of a
millimeter. If a line, crease or wrinkle appears during this time,
an injection of the suspended A/M copolymer is placed on top of the
original (or last, if more than one were injected) injection of
powder, microbeads or microspheres.
Example 2
Reduction of Glabellar Frown Lines
[0170] Glabellar frown lines form between the eyebrows in an almost
vertical position proximal to each eyebrow. To test the decrease of
the appearance of glabellar frown lines or eliminate them, twenty
patients presenting with moderate or deep frown lines between the
eyebrows are treated with an injection of alloplastic injectable
suspension for use as a dermal filler comprising
acrylate/methacrylate (A/M) copolymer powder (or non-porous
microbeads or microspheres) and a buffered physiological solution
(or cross-linked sodium hyaluronate, non-crosslinked sodium
hyaluronate or collagen), as the site of the glabellar frown lines
in accordance with the procedure described in Example 1.
[0171] An injection of 0.5 cc of the suspended A/M copolymer will
suffice to treat both glabellar frown lines. The dermis is
generally thick and the connective tissue beneath the glabellar
frown lines provides good support for the injected suspended A/M
copolymer. The injection should not be placed too far caudally,
such as not at the lower or tail end of the respective glabellar
frown line, as a lump may form. If deep lines exist at the
glabellar frown lines, treatment is repeated, as described above. A
thicker dermis beneath the glabellar frown line permits intradermal
injection without the above-described side-effects.
[0172] Within four weeks to four months of the last injection of
the suspended A/M copolymer the skin comprising glabellar frown
line will be raised to the same level as the surrounding skin, such
that the appearance of the previously existing glabellar frown
lines will be diminished or eliminated. The decrease of appearance
or removal of glabellar frown lines is expected to be permanent,
such as to last at least 18 months with no palpability or
visibility, and from about five to about ten years. Muscle movement
over a time period of from about five to about ten years may cause
the injected A/M copolymer to deepen by 1/10 of a millimeter. If a
glabellar frown line appears during this time, an injection of the
suspended A/M copolymer is placed on top of the original (or last,
if more than one were injected) injection of powder, microbeads or
microspheres.
Example 3
Reduction of Nasolabial Folds
[0173] Nasolabial folds, or smile lines, extend from the corners of
the nose, around the sides of mouth and down to the chin. To test
the decrease of the appearance of nasolabial folds or eliminate
them, twenty patients presenting with moderate to deep nasolabial
folds are treated by injection of alloplastic injectable suspension
for use as a dermal filler comprising acrylate/methacrylate (A/M)
copolymer powder (or non-porous microbeads or microspheres) and a
buffered physiological solution (or cross-linked sodium
hyaluronate, non-crosslinked sodium hyaluronate or collagen), as
the site of the nasolabial folds in accordance with the procedure
described in Example 1, except that the injections are administered
parallel and medially (at the middle) to the respective fold.
During the first three days, the injected A/M suspension may be
moved laterally (to the side) by movement of the facial muscles.
Accordingly, the injection is administered directly beneath and 1-2
mm medially to the crease.
[0174] In patients with thin skin, the injection of the suspended
A/M copolymer must not be too superficial. Otherwise, side-effects
such as erythema, such as reddening. will develop at the injection
site and the A/M microbeads or microspheres will be visible as
granules.
[0175] An injection of 0.5 cc of the suspended A/M copolymer will
suffice to treat one nasolabial fold. Therefore, treatment of both
nasolabial folds will require two syringes, each with 0.5 cc the
suspended A/M copolymer. Nasolabial folds generally will require a
second treatment with an injection of the alloplastic injectable
suspension for use as a dermal filler comprising A/M copolymer
powder (or non-porous microbeads or microspheres) and a buffered
physiological solution.
[0176] Within four weeks to four months of the last injection of
the suspended A/M copolymer the skin comprising the respective
nasolabial fold will be raised to the same level as the surrounding
skin, such that the appearance of the previously existing
nasolabial fold will be diminished or eliminated. The decrease of
appearance or removal of the nasolabial folds is expected to be
permanent, such as to last at least 18 months with no palpability
or visibility, and from about five to about ten years. Muscle
movement over a time period of from about five to about ten years
may cause the injected A/M copolymer to deepen by 1/10 of a
millimeter. If a nasolabial fold glabellar appears during this
time, an injection of the suspended A/M copolymer is placed on top
of the original (or last, if more than one were injected) injection
of powder, microbeads or microspheres, followed by a second
treatment three to four months after the first repeat
treatment.
Example 4
Reduction of Depressed ("Rolling") Acne Scars
[0177] Twenty patients presenting with either shallow, mildly
depressed or deep "rolling" scars, such as having smooth edges
which appear similar to "rolling hills," or "boxcar" scars, such as
having a cross-section akin to a box car, are treated by injection
of alloplastic injectable suspension for use as a dermal filler
comprising acrylate/methacrylate (A/M) copolymer powder (or
non-porous microbeads or microspheres) and a buffered physiological
solution (or cross-linked sodium hyaluronate, non-crosslinked
sodium hyaluronate or collagen), in accordance with the procedure
described in Example 1, except that the treatment of the "rolling"
acne scars is by injection of the suspension of the A/M copolymer
from a distance of 5 to 10 mm, such as such distance away from the
scar, and treatment of "boxcar" acne scars is by injection of the
suspension of the A/M copolymer perpendicularly downward into the
center of the scar.
[0178] The suspension of the A/M copolymer is implanted as
superficially as possible because blanching of the darkened scars
is desired. Blanching may be achieved by moving the injected
suspension of the A/M copolymer with the fingernail.
[0179] Fresh scars should never be treated because treatment will
be ineffective and the scar may exacerbated.
[0180] Scars which appear to look like "ice picks" may be treated
as the aforementioned scars, but must be pre-treated before
injection of the suspension of the A/M copolymer. Pre-treatment may
involve punching and suturing or subcising with an appropriate
blade or needle at a depth of about 1 mm. In contrast to the
"rolling" and "boxcar" scars, thusly pretreated "ice pick" scars
are filled with the suspension of the A/M copolymer within 3 to 8
days of pre-treatment upon decreased swelling and firm closing of
the incision wound.
[0181] An injection of less than 0.1 cc of the suspended A/M
copolymer will suffice to treat an acne scar. Acne scars may
require a second treatment with an injection of the alloplastic
injectable suspension for use as a dermal filler comprising A/M
copolymer powder (or non-porous microbeads or microspheres) and a
buffered physiological solution (or cross-linked sodium
hyaluronate, non-crosslinked sodium hyaluronate or collagen) may
achieve blanching of the scar in addition to the volume fill.
[0182] Within four weeks to four months of the last injection of
the suspended A/M copolymer the skin comprising the respective acne
scar will be raised to the same level as the surrounding skin, such
that the appearance of the previously existing acne scar will be
diminished or eliminated. The decrease of appearance or removal of
the acne scar is expected to be permanent, such as to last at least
18 months with no palpability or visibility, and from about five to
about ten years. If acne scars re-appear as darkened areas of the
skin with a depression of the skin of at least a shallow rolling
scar, the scar is treated with an injection of the suspended A/M
copolymer, administered in the same manner as described above for
the respective type of acne scar and placed on top of the original
(or last, if more than one were injected) injection of powder,
microbeads or microspheres. If the recurring appearance of the scar
is not aesthetically pleasing, a second treatment of the reappeared
scar, may follow three to four months after the first repeat
treatment.
Example 5
Reduction of Surgical Scars or Trauma Scars
[0183] Twenty patients presenting with either shallow, mildly
depressed or deep surgery scars or trauma scars, for example, from
a cut with a sharp object, either accidental or self-inflicted, are
treated by injection of alloplastic injectable suspension for use
as a dermal filler comprising acrylate/methacrylate (A/M) copolymer
powder (or non-porous microbeads or microspheres) and a buffered
physiological solution (or cross-linked sodium hyaluronate,
non-crosslinked sodium hyaluronate or collagen), as the site of the
surgery scars or trauma scars in accordance with the procedure
described in Example 1. Deeper injection site such as subcutaneous
tissue and periostial tissue may be needed, depending on the
severity of the scar. Larger amounts of the suspension will be
needed to ameliorate the cosmetic deformities in these cases. These
cases may require more injections than wrinkles to titrate the
desired effect.
[0184] An injection of 0.1 cc or more of the suspended A/M
copolymer will suffice to treat a surgical scar or trauma scar.
Such scars, especially deep ones, may require a second treatment
with an injection of the alloplastic injectable suspension for use
as a dermal filler comprising A/M copolymer powder (or non-porous
microbeads or microspheres) and a buffered physiological solution
to achieve filling (and possible blanching) of the scar.
[0185] Within four weeks to four months of the last injection of
the suspended A/M copolymer the skin comprising the surgical scar
or trauma scar will be raised to the same level as the surrounding
skin, such that the appearance of the previously existing surgical
scar or trauma scar will be diminished or eliminated. The decrease
of appearance or removal of the surgical scar or trauma scar is
expected to be permanent, such as to last at least 18 months with
no palpability or visibility, and from about five to about ten
years. If a surgical scar or trauma scar re-appears, the scar is
treated with an injection of the suspended A/M copolymer,
administered in the same manner as described above for the initial
treatment and is placed on top of the original (or last, if more
than one were injected) injection of powder, microbeads or
microspheres. If the recurring appearance of the scar is not
aesthetically pleasing, a second treatment of the reappeared scar,
may follow three to four months after the first repeat
treatment.
Example 6
Reduction of Single Crow's Feet
[0186] Twenty patients presenting with single crow's feet (one on
each sides, but not multiple crow's feet) are treated by injection
of alloplastic injectable suspension for use as a dermal filler
comprising acrylate/methacrylate (A/M) copolymer powder (or
non-porous microbeads or microspheres) and a buffered physiological
solution (or cross-linked sodium hyaluronate, non-crosslinked
sodium hyaluronate or collagen), as the site of the single crow's
feet in accordance with the procedure described in Example 1. The
area where crow's feet form has thinner epidermis and dermis.
Therefore, a smaller amount of the alloplastic injectable
suspension may be injected.
[0187] An injection of 0.05 cc to 0.2 cc of the suspended A/M
copolymer will suffice to treat a single crow's feet. Deep single
crow's feet may require a second treatment with an injection of the
alloplastic injectable suspension for use as a dermal filler
comprising A/M copolymer powder (or non-porous microbeads or
microspheres) and a buffered physiological solution to achieve
filling of the single crow's feet.
[0188] Within four weeks to four months of the last injection of
the suspended A/M copolymer the skin comprising the single crow's
feet will be raised to the same level as the surrounding skin, such
that the appearance of the previously existing single crow's feet
will be diminished or eliminated. The decrease of appearance or
removal of the single crow's feet is expected to be permanent, such
as to last at least 18 months with no palpability or visibility,
and from about five to about ten years. If a single crow's feet
re-appears, as a result of muscle movement over time, the single
crow's feet is treated with an injection of the suspended A/M
copolymer, administered in the same manner as described above for
the initial treatment and is placed on top of the original (or
last, if more than one were injected) injection of powder,
microbeads or microspheres. If the recurring appearance of the
single crow's feet is not aesthetically pleasing, a second
treatment of the reappeared scar, may follow three to four months
after the first repeat treatment.
Example 7
Treatment of Other Skin Defects and Medical Conditions
[0189] Skin defects besides the aforementioned conditions are
treated in accordance with the procedures described in Example 1
and modified, as needed, by one of skill, to effect the desired
treatment.
[0190] The described method of treatment may be used for
deformities that require re-contouring such as of a small tissue
defect (e.g., after animal bite(s)), deformities related to trauma
where the deformity is cosmetically unappealing, or for
augmentation after plastic surgery to achieve symmetry or a desired
result.
[0191] The patient is monitored for the development. If a pain
continues, or reoccurs, appears during this time, the patient may
be administered a subsequent effective amount of tissue repair
and/or replacement filler composition. The patient is monitored and
treated according to the lessening of the symptoms and/or the
development of side effects.
Example 8
Rotator Cuff Repair
[0192] Six male Sprague Dawley rats (250-275 g) (cared for in
accordance with the standards defined in "Principles of laboratory
animal care", NIH publication No. 86-23, revised 1985) are
anesthetized with intramuscular injections of Ketamine (100 mg/kg)
and Xylazine (5 mg/kg). Antibiotic prophylaxis is provided by
sucutaneious injection of Cefazolin (22 mg/kg) 30 minutes befroe
surgery, and then daily for a total of seven days. Then the upper
extremities are shaved, aseptically prepped and draped.
[0193] Surgical incisions of 2 cm are performed over the dorsal
aspects of the shoulder and scapula bilaterally. Bilateral full
thickness defects are created 1 mm proximal to the supraspinatus
tendon insertion with a no. 15 scalpel blade without removal of
tendon substance. The defects in both sides are then repaired to
the insertion site on the greater tuberosity with two 5-0 Prolene
(Ethicon Inc., Somerville, N.J., USA) sutures through transosseous
tunnels. On the control side, no further repair is made. On the
experimental side, the repair is additionally reinforced by
oversewing a patch comprising a copolymer of phenylethyl acrylate
and phenylethyl methacrylate to form a layered structure of patch
and tendon.
[0194] The deltoid muscle is re-approximated in both shoulders with
interrupted 4-0 Vicryl (Ethicon) suture, and the skin is closed
with 3-0 Monocryl (Ethicon).
[0195] Animals are sacrificed six weeks post-operatively by carbon
dioxide inhalation. Both shoulders are evaluated macroscopically
for gross evidence of healing, suture encapsulation, loose bodies
and inflammatory reactions. The supraspinatus tendon and proximal
humerus are removed and fixed in 10% neutral buffered formalin.
[0196] Specimens are decalcified before embedding in paraffin.
Slides are stained with hematoxylin and eosin. Sections are stained
for collagen and polarization microscopy. Slides containing
sections are placed in xylene at 37.degree. C. for 12 hours to
remove paraffin, hydrated in a series of ethanol of decreasing
concentration (btween 100 and 50%) and then finally placed in
water. Prior to staining with the Picrosirius red solution, dewaxed
and hydrated sections are treated at 37 C for 18 hours in 2 mg
bovine testicular hyaluronidase in 1 ml of 0.1 M phosphate fbuffer
at pH 6.0 to remove chondroitin sulfate molecules, which can mask
the cationic binding sites of the collagen for polyanionic Sirius
red molecules. Sections are then stained for 30 minutes in a
solution of 0.1% Sirius red F3B (Polysciences, Warringto, Pa., USA)
dissolved in saturated picric acid. Section are dehydrated in
absolute ethanol for 9 minutes (three changes of 3 minutes each),
cleared in a 1:1 mixture of absolute ethanol and xylene for 3
minutes, and in xylene for 9 minutes (3 changes for 3 minutes each)
before cover slips are mounted. Stained sections are analyzed with
a Nikon polarization microscope.
[0197] To quantify soft tissue ingrowth into the patch, microscopic
images are digitized for histomorphometric analysis.
[0198] Gross inspection at time of retrieval is expected to reveal
good integration of the patch into the tendon and bone with no
gross inflammatory changes.
[0199] Although the invention has been described in some detail by
way of illustration and example for purposes of clarity of
understanding, it will be obvious that certain changes and
modifications may be practiced within the scope of the appended
claims. Modifications of the above-described modes for carrying out
the invention that are obvious to persons of skill in medicine,
pharmacology, and/or related fields are intended to be within the
scope of the following claims. All patents (U.S. and foreign),
publications (e.g., Non-Patent Literature), patent application
publications, and patent applications cited herein are hereby
incorporated by reference in their entirety.
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