U.S. patent application number 15/144902 was filed with the patent office on 2016-08-25 for tissue prostheses for repairing, reconstructing and replacing damaged or diseased biological structures and associated tissue.
The applicant listed for this patent is CorMatrix Cardiovascular, Inc.. Invention is credited to Robert G. Matheny.
Application Number | 20160242895 15/144902 |
Document ID | / |
Family ID | 55163486 |
Filed Date | 2016-08-25 |
United States Patent
Application |
20160242895 |
Kind Code |
A1 |
Matheny; Robert G. |
August 25, 2016 |
Tissue Prostheses for Repairing, Reconstructing and Replacing
Damaged or Diseased Biological Structures and Associated Tissue
Abstract
Non-antigenic, bioremodelable tissue prostheses that can be
engineered into a variety of shapes and used to repair, augment,
reconstruct or replace damaged or diseased biological structures
and associated tissue.
Inventors: |
Matheny; Robert G.;
(Norcross, GA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CorMatrix Cardiovascular, Inc. |
Roswell |
GA |
US |
|
|
Family ID: |
55163486 |
Appl. No.: |
15/144902 |
Filed: |
May 3, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14635118 |
Mar 2, 2015 |
9352070 |
|
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15144902 |
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14337863 |
Jul 22, 2014 |
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14635118 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 2002/048 20130101;
A61F 2002/046 20130101; A61L 27/28 20130101; A61F 2002/047
20130101; A61L 27/34 20130101; A61F 2002/044 20130101; A61F 2/04
20130101; A61L 27/3625 20130101; A61L 2300/64 20130101; A61F
2002/045 20130101; A61L 2300/40 20130101; A61L 2300/414 20130101;
A61F 2002/043 20130101; A61L 27/3629 20130101; A61L 27/54 20130101;
A61F 2/06 20130101; A61L 27/58 20130101; A61L 2430/20 20130101;
A61F 2002/041 20130101; A61L 27/3834 20130101; C08L 67/04 20130101;
A61L 2300/606 20130101; A61L 27/36 20130101; A61L 27/38 20130101;
A61L 27/34 20130101; A61L 2300/41 20130101; A61F 2/24 20130101;
A61L 27/3633 20130101 |
International
Class: |
A61F 2/04 20060101
A61F002/04; A61F 2/06 20060101 A61F002/06; A61L 27/54 20060101
A61L027/54; A61L 27/36 20060101 A61L027/36; A61L 27/34 20060101
A61L027/34 |
Claims
1. A method for reconstructing and replacing damaged biological
structures and tissue, comprising the steps of: providing a tissue
prosthesis comprising a seamless tubular member, said seamless
tubular member comprising a decellularized mammalian tubular
structure, said tubular structure having a first length, proximal
and distal ends, an outer surface and a lumen that extends
therethrough, said mammalian tubular structure further comprising
at least one coating, said coating comprising poly(glycerol
sebacate) (PGS), said PGS coating being disposed on at least a
portion of said tubular structure outer surface, said coated
mammalian tubular structure being configured to induce modulated
healing when said tubular member is disposed proximate damaged
biological tissue of a biological structure, said modulated healing
comprising modulation of inflammation of said damaged tissue, host
tissue proliferation, bioremodeling of said damaged tissue, and
regeneration of new tissue and tissue structures with site-specific
structural and functional properties; and disposing said tissue
prosthesis proximate said damaged biological tissue of said
biological structure, wherein said tubular member induces modulated
healing of said damaged biological tissue and biological
structure.
2. The method of claim 1, wherein said mammalian tubular structure
comprises a segment of a mammalian structure selected from the
group consisting of mammalian intestine, umbilical artery and vein,
ureter, mesenteric vessel and jugular vein.
3. The method of claim 1, wherein said mammalian tubular structure
comprises a segment of adolescent small intestine.
4. The method of claim 1, wherein said mammalian tubular structure
further comprises at least a first exogenously added biologically
active agent.
5. The method of claim 4, wherein said first biologically active
agent comprises a growth factor selected from the group consisting
of transforming growth factor-beta (TGF-.beta.), and basic
fibroblast growth factor (bFGF).
6. The method of claim 1, wherein said mammalian tubular structure
further comprises a statin selected from the group consisting of
atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,
pitavastatin, pravastatin, rosuvastatin and simvastatin.
7. The method of claim 1, wherein said coating comprises an
extracellular matrix (ECM) composition comprising an ECM material
selected from the group consisting of small intestine submucosa
(SIS), urinary bladder submucosa (UBS), stomach submucosa (SS),
liver basement membrane (LBM), intact basement membrane, placental
extracellular matrix, omentum extracellular matrix, cardiac
extracellular matrix, kidney extracellular matrix, pancreas
extracellular matrix, lung extracellular matrix, and combinations
thereof.
8. The method of claim 1, wherein said mammalian tubular structure
further comprises reinforcement means.
9. The method of claim 1, wherein said mammalian tubular structure
further comprises at least one anchoring mechanism.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a division of U.S. application Ser. No.
14/635,118, filed on Mar. 2, 2015, which is a continuation-in-part
of U.S. application Ser. No. 14/337,863, filed on Jul. 22,
2014.
FIELD OF THE INVENTION
[0002] The present invention relates to methods and apparatus for
reconstructing or replacing damaged or diseased cardiovascular
vessels. More particularly, the present invention relates to tissue
prostheses in the form of seamless tubular members or grafts for
repairing, augmenting, reconstructing or replacing damaged or
diseased biological structures and associated tissue.
BACKGROUND OF THE INVENTION
[0003] As is well known in the art, various prostheses are often
employed to reconstruct or replace damaged or diseased
cardiovascular vessels.
[0004] Currently, the prostheses often employed to reconstruct or
replace damaged or diseased cardiovascular vessels are autologous
arteries and veins, e.g., internal mammary artery or saphenous
vein; particularly, in situations where small diameter (i.e. 3-4
mm) vessels are required, such as below the knee and coronary
artery bypass grafting.
[0005] Autologous arteries and veins are, however, often
unavailable, due to prior harvest, or unsuitable, due to arterial
disease.
[0006] When autologous arteries and veins are unavailable or
unsuitable, synthetic polytatrafluoroethylene (PTFE) or Dacron.RTM.
grafts are often employed to reconstruct or replace damaged or
diseased cardiovascular vessels; particularly, in situations where
large diameter (i.e. .gtoreq.6 mm) vessels are required.
[0007] There are, however, numerous drawbacks and disadvantages
associated with synthetic prostheses. A major drawback is the poor
median patency exhibited by synthetic prostheses, due to stenosis,
thromboembolization, calcium deposition and infection. Indeed, it
has been found that patency is >25% @ 3 years using synthetic
and cryopreserved prostheses in peripheral and coronary bypass
surgeries, compared to >70% for autologous vascular conduits.
See Chard, et al., Aorta-Coronary Bypass Grafting with
Polytetrafluoroehtylene Conduits: Early and Late Outcome in Eight
Patients, j Thorac Cardiovasc Surg, vol. 94, pp. 312-134
(1987).
[0008] Decellularized bovine internal jugular xenografts and human
allograft vessels from cadavers have also employed to reconstruct
or replace damaged or diseased cardiovascular vessels. Such
materials and structures are, however, prone to calcification and
thrombosis and, thus, have not gained significant clinical
acceptance.
[0009] Vascular prostheses constructed of various biodegradable
materials, such as poly (trimethylene carbonate), have also been
developed to reconstruct or replace damaged or diseased
cardiovascular vessels. There are, however, several drawbacks and
disadvantages associated with such prostheses.
[0010] One major disadvantage is that the biodegradable materials
and, hence, prostheses formed therefrom, often break down at a
faster rate than is desirable for the application. A further
disadvantage is that the materials can, and in many instances will,
break down into large, rigid fragments that can cause obstructions
in the interior of the vessel and cause inflammation.
[0011] More recently, prostheses comprising various remodelable
materials, such as extracellular matrix (ECM.RTM.) sheets, have
been developed to reconstruct or replace damaged or diseased
cardiovascular vessels. Illustrative are the ECM.RTM. prostheses
disclosed in Applicant's Co-Pending application Ser. No.
13/573,226.
[0012] Although such materials and prostheses formed therewith have
garnered overwhelming success and, henc.sup.e, gained significant
clinical acceptance, there are a few drawbacks associated with such
grafts. Among the drawbacks are the construction and, hence,
configuration of the noted prostheses.
[0013] As discussed in detail in Co-Pending application Ser. No.
13/573,226, such prostheses typically comprise one or more sheets
of ECM tissue, e.g., small intestine submucosa, which is secured at
one edge to form a tubular structure. The secured edge or seam can,
and in many instances will, disrupt blood flow through the graft. A
poorly secured edge also poses a significant risk of thrombosis and
cause turbulent flow.
[0014] Further, in some instances, wherein the ECM prostheses
comprise two or more sheets, i.e. a multi-sheet laminate, the
laminate structure may delaminate.
[0015] Thus, readily available, versatile tissue prostheses that
are not prone to calcification, thrombosis and intimal hyperplasia
would fill a substantial and growing clinical need.
[0016] It is therefore an object of the present invention to
provide tissue prostheses in the form of seamless tubular members
(or structures) or graft structures that substantially reduce or
eliminate (i) the risk of thrombosis, (ii) intimal hyperplasia
after intervention in a vessel, (iii) the harsh biological
responses associated with conventional polymeric and metal
prostheses, and (iv) the formation of biofilm, inflammation and
infection.
[0017] It is another object of the present invention to provide
tissue prostheses that can effectively replace or improve
biological functions or promote the growth of new tissue in a
subject.
[0018] It is another object of the present invention to provide
tissue prostheses that induce "modulated healing" of damaged
biological structures and/or damaged tissue associated therewith,
including modulation of inflammation, and host tissue
proliferation, bioremodeling and regeneration of new tissue and
tissue structures with site-specific structural and functional
properties.
[0019] It is another object of the present invention to provide
tissue prostheses that are capable of administering a biologically
active and/or pharmacological agent to host tissue and, thereby,
produce a desired biological and/or therapeutic effect.
SUMMARY OF THE INVENTION
[0020] The present invention is directed to non-antigenic,
resilient, bioremodelable, biocompatible tissue prostheses that can
be engineered into a variety of shapes and used to repair, augment,
reconstruct or replace damaged or diseased biological structures
and associated tissue, including a pericardium, myocardium, heart
valve, an aorta, artery, vein and vena cava, and other biological
structures, including, without limitation, an esophagus, trachea,
bronchus, ureter, urethra, bile duct, and small and large
intestine. The tissue prostheses can also be readily employed to
reconstruct or replace damaged or diseased dura around a spinal
cord.
[0021] In a preferred embodiment of the invention, the tissue
prostheses comprise seamless tubular members or conduits and graft
structures.
[0022] As discussed in detail herein, in a preferred embodiment,
the seamless tubular members (or conduits) comprise seamless
tubular structures having first (or proximal) and second (or
distal) ends.
[0023] According to the invention, the seamless tubular structures
can comprise any mammalian tubular structure, including, without
limitation, a segment of a large or small intestine, umbilical
artery or vein, ureter, mesenteric vessel and jugular vein.
[0024] In a preferred embodiment of the invention, the seamless
tubular structures comprise a decellularized segment of fetal small
intestine, i.e. small intestine derived from an adolescent mammal,
such as a piglet.
[0025] In some embodiments of the invention, the seamless tubular
structures and/or graft structures include at least one additional
biologically active agent or composition, i.e. an agent that
induces or modulates a physiological or biological process, or
cellular activity, e.g., induces proliferation, and/or growth
and/or regeneration of tissue.
[0026] In some embodiments, the biologically active agent comprises
a cell, such as a human embryonic stem cell, cardiac stem cell,
fetal cardiomyocyte, myofibroblast, mesenchymal stem cell, etc.
[0027] In some embodiments, the biologically active agent comprises
a growth factor, such as a transforming growth factor-alpha
(TGF-.alpha.), transforming growth factor-beta (TGF-.beta.),
fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor
(bFGF), and vascular epithelial growth factor (VEGF).
[0028] In some embodiments, the seamless tubular structures and/or
graft structures include at least one pharmacological agent or
composition (or drug), i.e. an agent or composition that is capable
of producing a desired biological effect in vivo, e.g., stimulation
or suppression of apoptosis, stimulation or suppression of an
immune response, etc.
[0029] Suitable pharmacological agents and compositions include any
of the aforementioned agents, including, without limitation,
antibiotics, anti-viral agents, analgesics, steroidal
anti-inflammatories, non-steroidal anti-inflammatories,
anti-neoplastics, anti-spasmodics, modulators of cell-extracellular
matrix interactions, proteins, hormones, enzymes and enzyme
inhibitors, anticoagulants and/or antithrombic agents, DNA, RNA,
modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein
synthesis, polypeptides, oligonucleotides, polynucleotides,
nucleoproteins, compounds modulating cell migration, compounds
modulating proliferation and growth of tissue, and vasodilating
agents.
[0030] In some embodiments of the invention, the pharmacological
agent comprises a statin, i.e. a HMG-CoA reductase inhibitor, such
as cerivastatin.
[0031] In some embodiments of the invention, the seamless tubular
structures and/or graft structures include at least one outer
coating.
[0032] In some embodiments, the outer coating comprises a
biodegradable polymeric composition coating.
[0033] In some embodiments of the invention, the seamless tubular
structures and/or graft structures further comprise reinforcement
means, i.e. reinforced vascular grafts.
[0034] In some embodiments, the reinforcement means comprises a
thin strand or thread of reinforcing material that is wound around
the tubular graft.
[0035] In some embodiments, the reinforcing strand comprises a
biocompatible and biodegradable polymeric material.
[0036] In some embodiments, the reinforcing strand comprises an ECM
strand or thread.
[0037] In some embodiments, the reinforcing strand comprises a
biocompatible metal, such as stainless steel or Nitinol.RTM., or a
biocompatible and biodegradable metal, such as magnesium.
[0038] In some embodiments, the reinforcement means comprises a
braided or mesh configuration.
[0039] In some embodiments of the invention, the seamless tubular
structures and/or graft structures further comprise at least one
anchoring mechanism.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] Further features and advantages will become apparent from
the following and more particular description of the preferred
embodiments of the invention, as illustrated in the accompanying
drawings, and in which like referenced characters generally refer
to the same parts or elements throughout the views, and in
which:
[0041] FIG. 1A is a perspective view of one embodiment of a
seamless tubular structure, in accordance with the invention;
[0042] FIG. 1B is a side or edge plan view of the seamless tubular
structure shown in FIG. 1A, in accordance with the invention;
[0043] FIG. 2A is a perspective view of one embodiment of a coated
seamless tubular structure, in accordance with the invention;
[0044] FIG. 2B is a side or edge plan view of the coated tubular
structure shown in FIG. 2A, in accordance with the invention;
[0045] FIG. 3A is a perspective view of one embodiment of a
reinforced seamless tubular structure, in accordance with the
invention;
[0046] FIG. 3B is a side or edge plan view of the tubular structure
shown in FIG. 3A, in accordance with the invention;
[0047] FIG. 4A is a perspective view of another embodiment of a
reinforced seamless tubular structure, in accordance with the
invention; and
[0048] FIG. 4B is a side or edge plan view of the tubular structure
shown in FIG. 4A, in accordance with the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0049] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particularly
exemplified apparatus, systems, structures or methods as such may,
of course, vary. Thus, although a number of apparatus, systems and
methods similar or equivalent to those described herein can be used
in the practice of the present invention, the preferred apparatus,
systems, structures and methods are described herein.
[0050] It is also to be understood that the terminology used herein
is for the purpose of describing particular embodiments of the
invention only and is not intended to be limiting.
[0051] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one
having ordinary skill in the art to which the invention
pertains.
[0052] Further, all publications, patents and patent applications
cited herein, whether supra or infra, are hereby incorporated by
reference in their entirety.
[0053] As used in this specification and the appended claims, the
singular forms "a, "an" and "the" include plural referents unless
the content clearly dictates otherwise. Thus, for example,
reference to "a pharmacological agent" includes two or more such
agents and the like.
[0054] Further, ranges can be expressed herein as from "about" or
"approximately" one particular value, and/or to "about" or
"approximately" another particular value. When such a range is
expressed, another embodiment includes from the one particular
value and/or to the other particular value. Similarly, when values
are expressed as approximations, by use of the antecedent "about"
or "approximately", it will be understood that the particular value
forms another embodiment. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint.
[0055] It is also understood that there are a number of values
disclosed herein, and that each value is also herein disclosed as
"about" or "approximately" that particular value in addition to the
value itself. For example, if the value "10" is disclosed, then
"approximately 10" is also disclosed. It is also understood that
when a value is disclosed that "less than or equal to" the value,
"greater than or equal to the value" and possible ranges between
values are also disclosed, as appropriately understood by the
skilled artisan. For example, if the value "10" is disclosed then
"less than or equal to 10" as well as "greater than or equal to 10"
is also disclosed.
DEFINITIONS
[0056] The term "fetal", as used herein, means and includes an
adolescent mammal, e.g., a piglet, preferably, less than three (3)
years of age.
[0057] The terms "extracellular matrix", "ECM" and "ECM material"
are used interchangeably herein, and mean and include a
collagen-rich substance that is found in between cells in mammalian
tissue, and any material processed therefrom, e.g. decellularized
ECM. According to the invention, the ECM material can be derived
from a variety of mammalian tissue sources, including, without
limitation, small intestine submucosa (SIS), urinary bladder
submucosa (UBS), stomach submucosa (SS), liver basement membrane
(LBM), intact basement membrane, central nervous system tissue,
dermal extracellular matrix, subcutaneous extracellular matrix,
gastrointestinal extracellular matrix, i.e. large and small
intestines, tissue surrounding growing bone, placental
extracellular matrix, omentum extracellular matrix, cardiac
extracellular matrix, e.g., pericardium and/or myocardium, kidney
extracellular matrix, pancreas extracellular matrix, lung
extracellular matrix, and combinations thereof. The ECM material
can also comprise collagen from mammalian sources.
[0058] The terms "urinary bladder submucosa (UBS)", "small
intestine submucosa (SIS)" and "stomach submucosa (SS)" also mean
and include any UBS and/or SIS and/or SS material that includes the
tunica mucosa (which includes the transitional epithelial layer and
the tunica propria), submucosal layer, one or more layers of
muscularis, and adventitia (a loose connective tissue layer)
associated therewith.
[0059] The term "mesothelial tissue", as used herein, means and
includes epithelium of mesodermal origin. As is well known in the
art, mesothelial tissue includes many of the seminal components,
e.g., GAGs, growth factors, etc, that are contained in ECM.
[0060] The term "angiogenesis", as used herein, means a physiologic
process involving the growth of new blood vessels from pre-existing
blood vessels.
[0061] The term "neovascularization", as used herein, means and
includes the formation of functional vascular networks that can be
perfused by blood or blood components. Neovascularization includes
angiogenesis, budding angiogenesis, intussuception, sprouting
angiogenesis, therapeutic angiogenesis and vasculogenesis.
[0062] The terms "biologically active agent" and "biologically
active composition" are used interchangeably herein, and mean and
include agent that induces or modulates a physiological or
biological process, or cellular activity, e.g., induces
proliferation, and/or growth and/or regeneration of tissue.
[0063] The terms "biologically active agent" and "biologically
active composition" thus mean and include, without limitation, the
following growth factors: platelet derived growth factor (PDGF),
epidermal growth factor (EGF), transforming growth factor-alpha
(TGF-.alpha.), transforming growth factor-beta (TGF-.beta.),
fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor
(bFGF), vascular epithelial growth factor (VEGF), hepatocyte growth
factor (HGF), insulin-like growth factor (IGF), nerve growth factor
(NGF), platlet derived growth factor (PDGF), tumor necrosis
factor-alpha (TNA-.alpha.), and placental growth factor (PLGF).
[0064] The terms "biologically active agent" and "biologically
active composition" also mean and include, without limitation,
human embryonic stem cells, fetal cardiomyocytes, myofibroblasts,
mesenchymal stem cells, autotransplated expanded cardiomyocytes,
adipocytes, totipotent cells, pluripotent cells, blood stem cells,
myoblasts, adult stem cells, bone marrow cells, mesenchymal cells,
embryonic stem cells, parenchymal cells, epithelial cells,
endothelial cells, mesothelial cells, fibroblasts, osteoblasts,
chondrocytes, exogenous cells, endogenous cells, stem cells,
hematopoietic stem cells, bone-marrow derived progenitor cells,
myocardial cells, skeletal cells, fetal cells, undifferentiated
cells, multi-potent progenitor cells, unipotent progenitor cells,
monocytes, cardiac myoblasts, skeletal myoblasts, macrophages,
capillary endothelial cells, xenogenic cells, allogenic cells, and
post-natal stem cells.
[0065] The terms "biologically active agent" and "biologically
active composition" also mean and include, without limitation, the
following biologically active agents (referred to interchangeably
herein as a "protein", "peptide" and "polypeptide"): collagen
(types I-V), proteoglycans, glycosaminoglycans (GAGs),
glycoproteins, cytokines, cell-surface associated proteins, cell
adhesion molecules (CAM), angiogenic growth factors, endothelial
ligands, matrikines, cadherins, immuoglobins, fibril collagens,
non-fibrallar collagens, basement membrane collagens, multiplexins,
small-leucine rich proteoglycans, decorins, biglycans,
fibromodulins, keratocans, lumicans, epiphycans, heparin sulfate
proteoglycans, perlecans, agrins, testicans, syndecans, glypicans,
serglycins, selectins, lecticans, aggrecans, versicans, neurocans,
brevicans, cytoplasmic domain-44 (CD-44), macrophage stimulating
factors, amyloid precursor proteins, heparins, chondroitin sulfate
B (dennatan sulfate), chondroitin sulfate A, heparin sulfates,
hyaluronic acids, fibronectins, tenascins, elastins, fibrillins,
laminins, nidogen/enactins, fibulin I, finulin II, integrins,
transmembrane molecules, thrombospondins, ostepontins, and
angiotensin converting enzymes (ACE).
[0066] The terms "pharmacological agent", "active agent", "drug"
and "active agent formulation" are used interchangeably herein, and
mean and include an agent, drug, compound, composition of matter or
mixture thereof, including its formulation, which provides some
therapeutic, often beneficial, effect. This includes any
physiologically or pharmacologically active substance that produces
a localized or systemic effect or effects in animals, including
warm blooded mammals, humans and primates; avians; domestic
household or farm animals, such as cats, dogs, sheep, goats,
cattle, horses and pigs; laboratory animals, such as mice, rats and
guinea pigs; fish; reptiles; zoo and wild animals; and the
like.
[0067] The terms "pharmacological agent", "active agent", "drug"
and "active agent formulation" thus mean and include, without
limitation, antibiotics, anti-arrhythmic agents, anti-viral agents,
analgesics, steroidal anti-inflammatories, non-steroidal
anti-inflammatories, anti-neoplastics, anti-spasmodics, modulators
of cell-extracellular matrix interactions, proteins, hormones,
growth factors, matrix metalloproteinases (MMPS), enzymes and
enzyme inhibitors, anticoagulants and/or antithrombic agents, DNA,
RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or
protein synthesis, polypeptides, oligonucleotides, polynucleotides,
nucleoproteins, compounds modulating cell migration, compounds
modulating proliferation and growth of tissue, and vasodilating
agents.
[0068] The terms "pharmacological agent", "active agent", "drug"
and "active agent formulation" thus include, without limitation,
atropine, tropicamide, dexamethasone, dexamethasone phosphate,
betamethasone, betamethasone phosphate, prednisolone,
triamcinolone, triamcinolone acetonide, fluocinolone acetonide,
anecortave acetate, budesonide, cyclosporine, FK-506, rapamycin,
ruboxistaurin, midostaurin, flurbiprofen, suprofen, ketoprofen,
diclofenac, ketorolac, nepafenac, lidocaine, neomycin, polymyxin b,
bacitracin, gramicidin, gentamicin, oyxtetracycline, ciprofloxacin,
ofloxacin, tobramycin, amikacin, vancomycin, cefazolin,
ticarcillin, chloramphenicol, miconazole, itraconazole,
trifluridine, vidarabine, ganciclovir, acyclovir, cidofovir,
ara-amp, foscarnet, idoxuridine, adefovir dipivoxil, methotrexate,
carboplatin, phenylephrine, epinephrine, dipivefrin, timolol,
6-hydroxydopamine, betaxolol, pilocarpine, carbachol,
physostigmine, demecarium, dorzolamide, brinzolamide, latanoprost,
sodium hyaluronate, insulin, verteporfin, pegaptanib, ranibizumab,
and other antibodies, antineoplastics, anti VGEFs, ciliary
neurotrophic factor, brain-derived neurotrophic factor, bFGF,
Caspase-1 inhibitors, Caspase-3 inhibitors, .alpha.-Adrenoceptors
agonists, NMDA antagonists, Glial cell line-derived neurotrophic
factors (GDNF), pigment epithelium-derived factor (PEDF), and NT-3,
NT-4, NGF, IGF-2.
[0069] The terms "pharmacological agent", "active agent", "drug"
and "active agent formulation" further mean and include the
following Class I-Class V anti-arrhythmic agents: (Class Ia)
quinidine, procainamide and disopyramide; (Class Ib) lidocaine,
phenytoin and mexiletine; (Class Ic) flecainide, propafenone and
moricizine; (Class II) propranolol, esmolol, timolol, metoprolol
and atenolol; (Class III) amiodarone, sotalol, ibutilide and
dofetilide; (Class IV) verapamil and diltiazem) and (Class V)
adenosine and digoxin.
[0070] The terms "pharmacological agent", "active agent", "drug"
and "active agent formulation" further mean and include, without
limitation, the following antiobiotics: aminoglycosides,
cephalosporins, chloramphenicol, clindamycin, erythromycins,
fluoroquinolones, macrolides, azolides, metronidazole, penicillins,
tetracyclines, trimethoprim-sulfamethoxazole and vancomycin.
[0071] The terms "pharmacological agent", "active agent", "drug"
and "active agent formulation" further include, without limitation,
the following steroids: andranes (e.g., testosterone), cholestanes,
cholic acids, corticosteroids (e.g., dexamethasone), estraenes
(e.g., estradiol) and pregnanes (e.g., progesterone).
[0072] The terms "anti-inflammatory" and "anti-inflammatory agent"
are also used interchangeably herein, and mean and include a
"pharmacological agent" and/or "active agent formulation", which,
when a therapeutically effective amount is administered to a
subject, prevents or treats bodily tissue inflammation i.e. the
protective tissue response to injury or destruction of tissues,
which serves to destroy, dilute, or wall off both the injurious
agent and the injured tissues.
[0073] Anti-inflammatory agents thus include, without limitation,
alclofenac, alclometasone dipropionate, algestone acetonide, alpha
amylase, amcinafal, amcinafide, amfenac sodium, amiprilose
hydrochloride, anakinra, anirolac, anitrazafen, apazone,
balsalazide disodium, bendazac, benoxaprofen, benzydamine
hydrochloride, bromelains, broperamole, budesonide, carprofen,
cicloprofen, cintazone, cliprofen, clobetasol propionate,
clobetasone butyrate, clopirac, cloticasone propionate,
cormethasone acetate, cortodoxone, decanoate, deflazacort,
delatestryl, depo-testosterone, desonide, desoximetasone,
dexamethasone dipropionate, diclofenac potassium, diclofenac
sodium, diflorasone diacetate, diflumidone sodium, diflunisal,
difluprednate, diftalone, dimethyl sulfoxide, drocinonide,
endrysone, enlimomab, enolicam sodium, epirizole, etodolac,
etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac,
fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic
acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine,
fluocortin butyl, fluorometholone acetate, fluquazone,
flurbiprofen, fluretofen, fluticasone propionate, furaprofen,
furobufen, halcinonide, halobetasol propionate, halopredone
acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen
piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen,
indoxole, intrazole, isofiupredone acetate, isoxepac, isoxicam,
ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol
etabonate, meclofenamate sodium, meclofenamic acid, meclorisone
dibutyrate, mefenamic acid, mesalamine, meseclazone, mesterolone,
methandrostenolone, methenolone, methenolone acetate,
methylprednisolone suleptanate, momiflumate, nabumetone,
nandrolone, naproxen, naproxen sodium, naproxol, nimazone,
olsalazine sodium, orgotein, orpanoxin, oxandrolane, oxaprozin,
oxyphenbutazone, oxymetholone, paranyline hydrochloride, pentosan
polysulfate sodium, phenbutazone sodium glycerate, pirfenidone,
piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen,
prednazate, prifelone, prodolic acid, proquazone, proxazole,
proxazole citrate, rimexolone, romazarit, salcolex, salnacedin,
salsalate, sanguinarium chloride, seclazone, sermetacin,
stanozolol, sudoxicam, sulindac, suprofen, talmetacin,
talniflumate, talosalate, tebufelone, tenidap, tenidap sodium,
tenoxicam, tesicam, tesimide, testosterone, testosterone blends,
tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin
sodium, triclonide, triflumidate, zidometacin, and zomepirac
sodium.
[0074] The term "pharmacological composition", as used herein,
means and includes a composition comprising a "pharmacological
agent" and/or a "biologically active agent" and/or any additional
agent or component identified herein.
[0075] The term "therapeutically effective", as used herein, means
that the amount of the "pharmacological agent" and/or "biologically
active agent" and/or "pharmacological composition" administered is
of sufficient quantity to ameliorate one or more causes, symptoms,
or sequelae of a disease or disorder. Such amelioration only
requires a reduction or alteration, not necessarily elimination, of
the cause, symptom, or sequelae of a disease or disorder.
[0076] The terms "patient" and "subject" are used interchangeably
herein, and mean and include warm blooded mammals, humans and
primates; avians; domestic household or farm animals, such as cats,
dogs, sheep, goats, cattle, horses and pigs; laboratory animals,
such as mice, rats and guinea pigs; fish; reptiles; zoo and wild
animals; and the like.
[0077] The term "comprise" and variations of the term, such as
"comprising" and "comprises," means "including, but not limited to"
and is not intended to exclude, for example, other additives,
components, integers or steps.
[0078] The following disclosure is provided to further explain in
an enabling fashion the best modes of performing one or more
embodiments of the present invention. The disclosure is further
offered to enhance an understanding and appreciation for the
inventive principles and advantages thereof, rather than to limit
in any manner the invention. The invention is defined solely by the
appended claims including any amendments made during the pendency
of this application and all equivalents of those claims as
issued.
[0079] As stated above, the present invention is directed to
non-antigenic, resilient, bioremodelable, biocompatible tissue
prostheses that can be engineered into a variety of shapes and used
to repair, augment, reconstruct or replace damaged or diseased
biological structures and associated tissue, including a
pericardium, myocardium, heart valve, an aorta, artery, vein and
vena cava, and other biological structures, including, without
limitation, an esophagus, trachea, bronchus, ureter, urethra, bile
duct, and small and large intestine. The tissue prostheses can also
be readily employed to reconstruct or replace damaged or diseased
dura around a spinal cord.
[0080] In a preferred embodiment of the invention, the tissue
prostheses comprise seamless tubular members or conduits and graft
structures.
[0081] As discussed in detail herein, in a preferred embodiment,
the seamless tubular members (or conduits) comprise seamless
tubular structures having first (or proximal) and second (or
distal) ends.
[0082] It is to be understood that, although the invention is
described in connection with seamless tubular structures, the
description, e.g., compositions, applications, etc., are equally
applicable to graft structures of the invention.
[0083] According to the invention, the seamless tubular structures
of the invention can comprise any mammalian tubular structure,
including, without limitation, a segment of a large or small
intestine, umbilical artery or vein, ureter, mesenteric vessel and
jugular vein.
[0084] In some embodiments, the seamless tubular structures of the
invention thus comprise a segment of mammalian small intestine.
[0085] In a preferred embodiment, the seamless tubular member(s) of
the invention comprises a segment of fetal or newborn small
intestine. As indicated above, fetal small intestine means that the
small intestine is derived from an adolescent mammal, such as a
piglet, which is preferably less than three (3) years of age.
[0086] In a preferred embodiment, the seamless tubular structures
are decellularized and, hence, remodelable. According to the
invention, the seamless tubular structures can be decellularized by
various conventional means.
[0087] In a preferred embodiment, the seamless tubular structures
are decellularized via one of the unique Novasterilis processes
disclosed in U.S. Pat. No. 7,108,832 and U.S. patent application
Ser. No. 13/480,204; which are incorporated by reference herein in
their entirety.
[0088] As set forth in U.S. application Ser. No. 13/480,204,
additional biologically active and pharmacological agents can be
disposed on and/or incorporated (or diffused) into the seamless
tubular structures (and graft structures) of the invention.
[0089] According to the invention, upon implanting a seamless
tubular structure (and/or graft structure) of the invention
proximate a damaged tissue of a biological structure, the seamless
tubular structure (and/or graft structure) induces "modulated
healing."
[0090] The term "modulated healing", as used herein, and variants
of this language generally refer to the modulation (e.g.,
alteration, delay, retardation, reduction, etc.) of a process
involving different cascades or sequences of naturally occurring
tissue repair in response to localized tissue damage or injury,
substantially reducing their inflammatory effect. Modulated
healing, as used herein, includes many different biologic
processes, including epithelial growth, fibrin deposition, platelet
activation and attachment, inhibition, proliferation and/or
differentiation, connective fibrous tissue production and function,
angiogenesis, and several stages of acute and/or chronic
inflammation, and their interplay with each other.
[0091] For example, in some embodiments, the seamless tubular
structures and/or graft structures are specifically formulated (or
designed) to alter, delay, retard, reduce, and/or detain one or
more of the phases associated with healing of damaged tissue,
including, but not limited to, the inflammatory phase (e.g.,
platelet or fibrin deposition), and the proliferative phase when in
contact with biological tissue.
[0092] In some embodiments of the invention, "modulated healing"
means and includes the ability of a seamless tubular structure
and/or graft structure to restrict the expression of inflammatory
components. By way of example, according to the invention, when a
seamless tubular structure and/or graft structure includes a
coating comprising a statin augmented ECM composition, i.e. a
composition comprising an ECM and a statin, and the seamless
tubular structure or graft structure is disposed proximate damaged
biological tissue, the seamless tubular structure and/or graft
structure restricts expression of monocyte chemoattractant
protein-1 (MCP-1) and chemokine (C--C) motif ligand 2 (CCR2).
[0093] In some embodiments, "modulated healing" means and includes
the ability of a seamless tubular structure and/or graft structure
to alter a substantial inflammatory phase (e.g., platelet or fibrin
deposition) at the beginning of the tissue healing process. As used
herein, the phrase "alter a substantial inflammatory phase" refers
to the ability of a seamless tubular structure or graft structure
to substantially reduce the inflammatory response at an injury site
when in contact with biological tissue.
[0094] In such an instance, a minor amount of inflammation may
ensue in response to tissue injury, but this level of inflammation
response, e.g., platelet and/or fibrin deposition, is substantially
reduced when compared to inflammation that takes place in the
absence of a seamless tubular structure or graft structure of the
invention.
[0095] The term "modulated healing" also refers to the ability of a
seamless tubular structure or graft structure to induce host tissue
proliferation, bioremodeling, including neovascularization, e.g.,
vasculogenesis, angiogenesis, and intussusception, and regeneration
of tissue structures with site-specific structural and functional
properties.
[0096] Thus, in some embodiments, the term "modulated healing"
means and includes the ability of a seamless tubular structure
and/or graft structure to modulate inflammation and/or induce host
tissue proliferation and remodeling. Again, by way of example,
according to the invention, when a seamless tubular structure or
graft structure includes a coating comprising a statin augmented
ECM composition, i.e. a composition comprising an ECM and a statin,
and the seamless tubular structure or graft structure is disposed
proximate damaged biological tissue, the seamless tubular structure
and/or graft structure modulates inflammation by, among other
actions, restricting expression of monocyte chemoattractant
protein-1 (MCP-1) and chemokine (C--C) motif ligand 2 (CCR2) and
induces tissue proliferation, bioremodeling and regeneration of
tissue structures with site-specific structural and functional
properties.
[0097] In some embodiments, when a seamless tubular structure or
graft structure is in contact with damaged or diseased biological
tissue, modulated healing is effectuated through the structural
features of the seamless tubular structure or graft structure. The
structural features provide the spatial temporal and mechanical
cues to modulate cell polarity and alignment. The structural
features further modulate cell proliferation, migration and
differentiation thus modulating the healing process.
[0098] As stated above, in some embodiments of the invention, the
seamless tubular structures (and/or graft structures) of the
invention include at least one exogenously added biologically
active agent or composition, i.e. an agent that induces or
modulates a physiological or biological process, or cellular
activity, e.g., induces proliferation, and/or growth and/or
regeneration of tissue.
[0099] In a preferred embodiment of the invention, the biologically
active agent is similarly derived from an adolescent mammal;
preferably, a mammal less than three (3) years of age.
[0100] Suitable biologically active agents include any of the
aforementioned biologically active agents, including, without
limitation, the aforementioned cells and proteins.
[0101] In some embodiments of the invention, the biologically
active agent comprises a growth factor selected from the group
comprising transforming growth factor-alpha (TGF-.alpha.),
transforming growth factor-beta (TGF-.beta.), fibroblast growth
factor-2 (FGF-2), basic fibroblast growth factor (bFGF) and
vascular epithelial growth factor (VEGF).
[0102] According to the invention, upon implanting a seamless
tubular structure and/or graft structure of the invention proximate
damaged tissue of a biological structure, the exogenously added
growth factor(s) links to and interacts with at least one molecule
in the seamless tubular structure and/or graft structure, and
further induces modulated healing, including enhanced modulation of
inflammation, host tissue proliferation, bioremodeling, and
regeneration of new tissue structures.
[0103] In some embodiments of the invention, the biologically
active agent comprises a protein selected from the group comprising
proteoglycans, glycosaminoglycans (GAGS), glycoproteins, heparins,
chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A,
heparin sulfates, and hyaluronic acids.
[0104] In some embodiments of the invention, the protein comprises
a cytokine selected from the group comprising a stem cell factor
(SCF), stromal cell-derived factor-1 (SDF-1), granulocyte
macrophage colony-stimulating factor (GM-CSF), interferon gamma
(IFN-gamma), interleukin-3, interleukin-4, interleukin-10,
interleukin-13, leukemia inhibitory factor (LIF), amphiregulin,
thrombospondin 1, thrombospondin 2, thrombospondin 3,
thrombospondin 4, thrombospondin 5, and angiotensin converting
enzyme (ACE).
[0105] According to the invention, upon implanting a seamless
tubular structure and/or graft structure of the invention in a
cardiovascular system of a subject, the exogenously added
protein(s) similarly links to and interacts with at least one
molecule in the seamless tubular structure and/or graft structure
and similarly further induces modulated healing, including enhanced
modulation of inflammation, host tissue proliferation,
bioremodeling, and regeneration of new tissue structures.
[0106] In some embodiments, the seamless tubular structures (and/or
graft structures) of the invention include at least one
pharmacological agent or composition (or drug), i.e. an agent or
composition that is capable of producing a desired biological
effect in vivo, e.g., stimulation or suppression of apoptosis,
stimulation or suppression of an immune response, etc.
[0107] Suitable pharmacological agents and compositions include any
of the aforementioned agents, including, without limitation,
antibiotics, anti-viral agents, analgesics, steroidal
anti-inflammatories, non-steroidal anti-inflammatories,
anti-neoplastics, anti-spasmodics, modulators of cell-extracellular
matrix interactions, proteins, hormones, enzymes and enzyme
inhibitors, anticoagulants and/or antithrombic agents, DNA, RNA,
modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein
synthesis, polypeptides, oligonucleotides, polynucleotides,
nucleoproteins, compounds modulating cell migration, compounds
modulating proliferation and growth of tissue, and vasodilating
agents.
[0108] In some embodiments of the invention, the pharmacological
agent comprises one of the aforementioned anti-inflammatories.
[0109] In some embodiments of the invention, the pharmacological
agent comprises a statin, i.e. a HMG-CoA reductase inhibitor.
According to the invention, suitable statins include, without
limitation, atorvastatin (Lipitor.RTM.), cerivastatin, fluvastatin
(Lescol.RTM.), lovastatin (Mevacor.RTM., Altocor.RTM.,
Altoprev.RTM.), mevastatin, pitavastatin (Livalo.RTM.,
Pitava.RTM.), pravastatin (Pravachol.RTM., Selektine.RTM.,
Lipostat.RTM.), rosuvastatin (Crestor.RTM.), and simvastatin
(Zocor.RTM., Lipex.RTM.). Several actives comprising a combination
of a statin and another agent, such as ezetimbe/simvastatin
(Vytorin.RTM.), are also suitable.
[0110] Applicant has found that the noted statins exhibit numerous
beneficial properties that provide several beneficial biochemical
actions or activities. The properties and beneficial actions are
set forth in Applicant's Co-Pending application Ser. No.
13/373,569, filed on Sep. 24, 2012 and Ser. No. 13/782,024, filed
on Mar. 1, 2013; which are incorporated by reference herein in
their entirety.
[0111] In some embodiments of the invention, the seamless tubular
structures (and/or graft structures) of the invention include at
least one outer coating.
[0112] In some embodiments, the outer coating comprises a
biodegradable polymeric composition coating. According to the
invention, suitable biodegradable polymeric compositions comprise,
without limitation, formulations comprising polyurethane
derivatives, polyhydroxyalkonates (PHAs), polylactides (PLLA) and
polyglycolides (PLGA) and their copolymers, for example,
poly(.epsilon.-caprolactone-co-glycolide), polyanhydrides, and like
polymers.
[0113] Suitable polymeric composition coating formulations thus
include formulations comprising poly-beta-hydroxybutyrate,
poly(3-hydroybutyrate-co-3-hydroxyvalerate) (PHBV),
Poly(3-hydroxybutyrate) (PHB),
Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P3HB4HB),
Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), and
Poly(3-hydroxyoctanoate-co-3-hydroxyhexanoate) (PHoHHx).
[0114] In some embodiments of the invention, the biodegradable
polymeric composition coating comprises an ECM-mimicking
biomaterial composition. In some embodiments, the ECM-mimicking
biomaterial composition comprises poly(glycerol sebacate)
(PGS).
[0115] As discussed in detail below, PGS exhibits numerous
beneficial biochemical actions or activities. The properties and
beneficial actions resulting therefrom are discussed in detail
below.
PGS Physical Properties
[0116] PGS is a condensate of the non-immunogenic compositions
glycerol (a simple sugar alcohol) and sebacic acid (a naturally
occurring dicarboxylic acid), wherein, glycerol and sebacic acid
are readily metabolized when proximate mammalian tissue. The
non-immunogenic properties substantially limit the acute
inflammatory responses typically associated with other
"biocompatible" polymers, such as ePTFE (polytetrafluoroethylene),
that are detrimental to bioremodeling and tissue regeneration.
[0117] The mechanical properties of PGS are substantially similar
to that of biological tissue. Indeed, the value of the Young's
modulus of PGS is between that of a ligament (in KPa range) and
tendon (in GPa range). The strain to failure of PGS is also similar
to that of arteries and veins (i.e. over 260% elongation).
[0118] The tensile strength of the PGS is at least 0.28.+-.0.004
MPa. The Young's modulus and elongation are at least
0.122.+-.0.0003 and at least 237.8.+-.0.64%, respectively. For
applications requiring stronger mechanical properties and a slower
biodegradation rate, PGS can be blended with
poly(.epsilon.-caprolactone) PCL, i.e. a biodegradable
elastomer.
[0119] ECM Mimicking Properties/Actions
[0120] It has also been established that PGS induces tissue
remodeling and regeneration when administered proximate to damaged
tissue, thus, mimicking the seminal regenerative properties of ECM
and, hence, an ECM composition formed therefrom. The mechanism
underlying this behavior is deemed to be based on the mechanical
and biodegradation kinetics of the PGS. See Sant, et al., Effect of
Biodegradation and de novo Matrix Synthesis on the Mechanical
Properties of VIC-seeded PGS-PCL scaffolds, Acta. Biomater., vol.
9(4), pp. 5963-73 (2013).
[0121] In some embodiments of the invention, the ECM-mimicking
biomaterial composition further comprises one of the aforementioned
ECM materials.
[0122] In some embodiments of the invention, the ECM-mimicking
biomaterial composition comprises PGS and
poly(.epsilon.-caprolactone) (PCL). According to the invention, the
addition of PCL to the ECM-mimicking biomaterial composition
enhances the structural integrity and modulates the degradation of
the composition.
[0123] In some embodiments, the ECM-mimicking biomaterial
composition comprises poly(glycerol sebacate) acrylate (PGSA),
which, according to the invention, can be crosslinked and/or cured
via the combination of a photoinitiator and radiation.
[0124] According to the invention, suitable photoinitiators for
radiation induced crosslinking comprise, without limitation,
2-hydroxy-1-[4-hydroxyethoxy) phenyl]-2-methyl-1-propanone (D 2959,
Ciba Geigy), 2,2-dimethoxy-2-phenylacetophenone, titanocenes,
fluorinated diaryltitanocenes, iron arene complexes, manganese
decacarbonyl, methylcyclopentadienyl manganese tricarbonyl and any
organometallatic photoinitiator that produces free radicals or
cations.
[0125] According to the invention, suitable radiation wavelengths
for crosslinking and/or curing the ECM-mimicking biomaterial
composition comprise, without limitation, visible light;
particularly, radiation in the range of approximately 380-750 nm,
and ultraviolet (UV) light, particularly, radiation in the range of
10-400 nm, which includes extreme UV (10-121 nm), vacuum UV (10-200
nm), hydrogen lyman .alpha.-UV (121-122 nm), Far UV (122-200 nm),
Middle UV (200-300 nm), Near UV (300-400 nm), UV-C (100-280 nm),
UV-B (280-315 nm) and UV-A (315-400 nm) species of UV light.
[0126] In some embodiments, the ECM-mimicking biomaterial
composition comprises a co-polymer of PGSA and polyethylene glycol
(PEG) diacrylate.
[0127] Preferably, the ratio of PGSA to PEG diacrylate used when
developing the photocured PGSA is proportional to the physical
strength of the biomaterial composition, wherein a ratio of PGSA to
PEG diacrylate in the range of 95:05-50:50 comprises a Young's
modulus in the range of approximately 0.5-20 MPa respectively.
[0128] According to the invention, the Young's modulus will vary
based on the configuration of the multi-laminate structure.
[0129] In some embodiments of the invention, the outer coating
comprises an ECM composition comprising at least one of the
aforementioned ECM materials.
[0130] In some embodiments of the invention, the outer coating
comprises at least one of the aforementioned biologically active or
pharmacological agents.
[0131] In some embodiments, the seamless tubular structures and/or
graft structures comprise a combination of outer coatings having
varying biologically active and/or pharmacological agents and/or
properties, e.g. a first coating comprising a growth factor and a
second coating comprising pharmacological agent.
[0132] In some embodiments, the outer coating(s) comprises
modulated degradation kinetics, wherein the gradual degradation of
the coating provides a controlled release of biologically active
and/or pharmacological agents.
[0133] In some embodiments, the outer coating(s) is configured to
provide a delivery gradient of various biologically active and/or
pharmacological agent delivery profiles. By way of example, in some
embodiments, biologically active and/or pharmacological agents are
disposed throughout various depths or thickness ranges of the
coating.
[0134] In some embodiments, wherein a seamless tubular structure
and/or graft structure includes a plurality of outer coatings, the
plurality of coatings is configured to provide a plurality of
biologically active and/or pharmacological agent delivery profiles.
By way of example, in some embodiments, a seamless tubular member
can comprise a first coating comprising a growth factor augmented
ECM composition, and a second coating comprising an ECM composition
comprising a pharmacological agent, such as an anti-inflammatory or
antiviral.
[0135] According to the invention, the outer coating can be applied
to the seamless tubular structures and graft structures by any
conventional means, including, without limitation, spray, dip
coating, vapor deposition, etc.
[0136] In some embodiments of the invention, the seamless tubular
structures further comprise reinforcement means, i.e. reinforced
tubular members.
[0137] As discussed in detail below, in some embodiments, the
reinforcement means comprises a thin strand or thread of
reinforcing material that is wound around the tubular member.
According to the invention, the reinforcing strand can comprise
various biocompatible materials.
[0138] In a preferred embodiment, the reinforcing strand comprises
a biocompatible and biodegradable polymeric composition. According
to the invention, suitable biodegradable polymeric compositions can
comprise compositions that include at least one of the
aforementioned polymeric materials including, without limitation,
polyhydroxyalkonates (PHAs), polylactides (PLLA) and polyglycolides
(PLGA) and their copolymers, polyanhydrides, and like polymers.
[0139] A further suitable polymeric material comprises "Artelon",
i.e. a poly(capralactone urea) material distributed by Artimplant
AB in Goteborg, Sweden.
[0140] The polymeric composition can further comprise PGS and/or
one of the aforementioned ECM-mimicking biomaterial
compositions.
[0141] According to the invention, the reinforcing strand can also
comprise an ECM strand or thread, such as a small intestine or
urinary bladder submucosa suture.
[0142] According to the invention, the reinforcing strand can be
disposed on the outer surface of the graft manually or via an
electro-spin procedure.
[0143] According to the invention, the reinforcing strand can also
comprise a biocompatible metal, such as stainless steel or
Nitinol.RTM., or a biocompatible and biodegradable metal, such as
magnesium.
[0144] In some embodiments, the reinforcement means comprises a
braided or mesh configuration or other conventional stent
structure.
[0145] In some embodiments of the invention, the seamless tubular
structures and/or graft structures further comprise at least one
anchoring mechanism, such as disclosed in Co-pending application
Ser. Nos. 13/782,024 and 13/686,131; which are incorporated by
reference herein in their entirety.
[0146] Referring now to FIGS. 1A and 1B, there is shown one
embodiment of a seamless tubular structure of the invention. As
illustrated in FIG. 1A, the graft 10a comprises a continuous,
seamless tubular conduit 12 having proximal 14 and distal 16 ends,
and a lumen 18 that extends therethrough.
[0147] In a preferred embodiment of the invention, the seamless
tubular conduit 12 comprises a decellularized segment of fetal
small intestine.
[0148] According to the invention, the tubular conduit 12, and,
hence seamless tubular structure 10a (and tubular structures
10b-10d, discussed below) formed therefrom, can be harvested from
an adolescent mammal, e.g. fetal pig or piglet, at various lengths
to accommodate specific applications.
[0149] According to the invention, the tubular conduit 12, and,
hence seamless tubular a (and tubular members 10b-10d, discussed
below) formed therefrom can have various diameters, e.g. 1.0 mm-5.0
cm.
[0150] In some embodiments of the invention, the seamless tubular
structure 10a (or decellularized fetal small intestine tubular
member 12) includes at least one additional biologically active
agent or composition, i.e. an agent that induces or modulates a
physiological or biological process, or cellular activity, e.g.,
induces proliferation, and/or growth and/or regeneration of
tissue.
[0151] Suitable biologically active agents include any of the
aforementioned biologically active agents, including, without
limitation, the aforementioned cells, growth factors and
proteins.
[0152] In some embodiments, the seamless tubular structure 10a (or
decellularized fetal small intestine tubular member 12) includes at
least one pharmacological agent or composition (or drug), i.e. an
agent or composition that is capable of producing a desired
biological effect in vivo, e.g., stimulation or suppression of
apoptosis, stimulation or suppression of an immune response,
etc.
[0153] Suitable pharmacological agents and compositions include any
of the aforementioned agents, including, without limitation,
antibiotics, anti-viral agents, analgesics, steroidal
anti-inflammatories, non-steroidal anti-inflammatories,
anti-neoplastics, anti-spasmodics, modulators of cell-extracellular
matrix interactions, proteins, hormones, enzymes and enzyme
inhibitors, anticoagulants and/or antithrombic agents, DNA, RNA,
modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein
synthesis, polypeptides, oligonucleotides, polynucleotides,
nucleoproteins, compounds modulating cell migration, compounds
modulating proliferation and growth of tissue, and vasodilating
agents.
[0154] In some embodiments of the invention, the pharmacological
agent comprises a statin, i.e. a HMG-CoA reductase inhibitor.
[0155] Referring now to FIGS. 2A and 2B, there is shown another
embodiment of a seamless tubular structure of the invention. As
illustrated in FIG. 2A, the seamless tubular structure 10b
similarly comprises a continuous, seamless tubular conduit 12
having proximal 14 and distal 16 ends, and a lumen 18 that extends
therethrough.
[0156] However, in this embodiment, the seamless tubular structure
10b further comprises at least one outer coating 20. In some
embodiments, the outer coating 20 comprises one of the
aforementioned outer coatings.
[0157] In some embodiments, the outer coating 20 comprises a
pharmacological composition.
[0158] In some embodiments, the outer coating 20 comprises a
biodegradable polymeric composition. As indicated above, suitable
biodegradable polymeric compositions comprise, without limitation,
formulations comprising polyurethane derivatives,
polyhydroxyalkonates (PHAs). polylactides (PLLA) and polyglycolides
(PLGA) and their copolymers, for example,
poly(.epsilon.-caprolactone-co-glycolide), polyanhydrides, and like
polymers.
[0159] In some embodiments of the invention, the biodegradable
polymeric composition comprises an ECM-mimicking biomaterial
composition. In some embodiments, the ECM-mimicking biomaterial
composition comprises poly(glycerol sebacate) (PGS) a biodegradable
polymeric coating.
[0160] As indicated above, in some embodiments of the invention,
the seamless tubular structures of the invention further comprise
reinforcement means, i.e. reinforced vascular grafts.
[0161] Referring now to FIGS. 3A and 3B there is shown one
embodiment of a reinforced seamless tubular structure of the
invention. As illustrated in FIG. 3A, the seamless tubular
structure 10c similarly comprises a continuous, seamless tubular
conduit 12 having proximal 14 and distal 16 ends, and a lumen 18
that extends therethrough.
[0162] The seamless tubular structure 10c further comprises
reinforcement means, which, in the illustrated embodiment,
comprises a thin strand or thread of reinforcing material 30, which
is wound around the tubular graft 10c, and, hence, disposed
proximate the outer surface 11 thereof. According to the invention,
the reinforcing strand 30 can comprise various biocompatible
materials.
[0163] As indicated above, in a preferred embodiment, the
reinforcing strand 30 comprises a biocompatible and biodegradable
polymeric material. Suitable biodegradable polymeric materials
similarly include, without limitation, PGS, polyhydroxyalkonates
(PHAs), polylactides (PLLA) and polyglycolides (PLGA) and their
copolymers, polyanhydrides, and like polymers.
[0164] In some embodiments, the reinforcing strand 30 can
alternatively comprise an ECM strand or thread, such as a small
intestine or urinary bladder submucosa suture. In a preferred
embodiment, the ECM strand comprises a cross-linked ECM
material.
[0165] According to the invention, the reinforcing strand 30 can
also comprise a biocompatible metal, such as stainless steel or
Nitinol.RTM., or a biocompatible and biodegradable metal, such as
magnesium.
[0166] As indicated above, in some embodiments, the reinforcement
means comprises a braided or mesh configuration.
[0167] Referring now to FIGS. 4A and 4B there is shown another
embodiment of a reinforced seamless tubular structure of the
invention (denoted "10d"), wherein the tubular structure 10d
includes a braided reinforcing structure 32.
[0168] According to the invention, the braided structure 32 can
comprise various configurations and can be formed by various
conventional means. The braided structure 32 can also comprise any
of the aforementioned biocompatible and biodegradable
materials.
[0169] In a preferred embodiment, the braided structure 32
comprises one of the aforementioned biodegradable polymeric
materials.
[0170] In some embodiments of the invention, the seamless tubular
structures 10a-10c1 further comprise at least one anchoring
mechanism, such as disclosed in Co-pending application Ser. Nos.
13/782,024 and 13/686,131.
[0171] As will readily be appreciated by one having ordinary skill
in the art, the present invention provides numerous advantages
compared to prior art tissue prostheses. Among the advantages are
the following: [0172] The provision of non-antigenic, resilient,
bioremodelable, biocompatible tissue prostheses that can be
engineered into a variety of shapes and used to repair, augment,
reconstruct or replace damaged or diseased biological structures
and associated tissue, including a pericardium, myocardium, heart
valve, an aorta, artery, vein and vena cava, and other biological
structures, including, without limitation, an esophagus, trachea,
bronchus, ureter, urethra, bile duct, and small and large
intestine. [0173] The provision of tissue prostheses, i.e. seamless
tubular structures and graft structures, that substantially reduce
or eliminate (i) the risk of thrombosis, (ii) intimal hyperplasia
after intervention in a vessel, (iii) the harsh biological
responses associated with conventional polymeric and metal
prostheses, and (iv) the formation of biofilm, inflammation and
infection. [0174] The provision of tissue prostheses that can
effectively replace or improve biological functions or promote the
growth of new tissue in a subject. [0175] The provision of tissue
prostheses that induce "modulated healing", including host tissue
proliferation, bioremodeling and regeneration of new tissue and
tissue structures with site-specific structural and functional
properties. [0176] The provision of tissue prostheses that are
capable of administering biologically active and pharmacological
agents to host tissue and, thereby produce a desired biological
and/or therapeutic effect.
[0177] Without departing from the spirit and scope of this
invention, one of ordinary skill can make various changes and
modifications to the invention to adapt it to various usages and
conditions. As such, these changes and modifications are properly,
equitably, and intended to be, within the full range of equivalence
of the following claims.
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