US 7,732,190 B2Grant

Modified two-component gelation systems, methods of use and methods of manufacture

Issue Date:2010-06-08

•8 Claims

•7 Drawing Sheets

Abstract

Compositions, methods of manufacture and methods of treatment for post-myocardial infarction are herein disclosed. In some embodiments, the composition includes at least two components. In one embodiment, a first component can include a first functionalized polymer and a substance having at least one cell adhesion site combined in a first buffer at a pH of approximately 6.5. A second component can include a second buffer in a pH of between about 7.5 and 9.0. A second functionalized polymer can be included in the first or second component. In some embodiments, the composition can include at least one cell type and/or at least one growth factor. In some embodiments, the composition(s) of the present invention can be delivered by a dual bore injection device to a treatment area, such as a post-myocardial infarct region.

Metadata

Assignee

Advanced Cardiovascular Systems, Inc.

Inventors

Eugene Michal
Olof Mikael Trollsas
Shubhayu Basu

Application Information

Application Number:US 11/496,824

Filing Date:2006-07-31

Priority Date:2006-07-31

Art Unit:1651

Classifications

IPC:

A61K45/00C12M1/00A01N65/00A01N37/18A61K9/00A61K9/14A61K35/12A61F2/00

Patent Drawings (7 sheets)

Description

Field of Invention

[0001] Post-myocardial infarction treatments and compositions.

Background of Invention

[0002] Ischemic heart disease typically results from an imbalance between the myocardial blood flow and the metabolic demand of the myocardium. Progressive atherosclerosis with increasing occlusion of coronary arteries leads to a reduction in coronary blood flow, which creates ischemic heart tissue. “Atherosclerosis” is a type of arteriosclerosis in which cells including smooth muscle cells and macrophages, fatty substances, cholesterol, cellular waste product, calcium and fibrin build up in the inner lining of a body vessel. “Arteriosclerosis” refers to the thickening and hardening of arteries. Blood flow can be further decreased by additional events such as changes in circulation that lead to hypoperfusion, vasospasm or thrombosis.

[0003] Myocardial infarction (MI) is one form of heart disease that results from the sudden lack of supply of oxygen and other nutrients. The lack of blood supply is a result of a closure of the coronary artery (or any other artery feeding the heart) which nourishes a particular part of the heart muscle. The cause of this event is generally attributed to arteriosclerosis in coronary vessels.

[0004] Formerly, it was believed that an MI was caused from a slow progression of closure from, for example, 95% then to 100%. However, an MI can also be a result of minor blockages where, for example, there is a rupture of the cholesterol plaque resulting in blood clotting within the artery. Thus, the flow of blood is blocked and downstream cellular damage occurs. This damage can cause irregular rhythms that can be fatal, even though the remaining muscle is strong enough to pump a sufficient amount of blood. As a result of this insult to the heart tissue, scar tissue tends to naturally form.

[0005] Various procedures, including mechanical and therapeutic agent application procedures, are known for reopening blocked arteries. An example of a mechanical procedure includes balloon angioplasty with stenting, while an example of a therapeutic agent application includes administering a thrombolytic agent, such as urokinase. Such procedures do not, however, treat actual tissue damage to the heart. Other systemic drugs, such as ACE-inhibitors and Beta-blockers, may be effective in reducing cardiac load post-MI, although a significant portion of the population that experiences a major MI ultimately develop heart failure.

[0006] An important component in the progression to heart failure is remodeling of the heart due to mismatched mechanical forces between the infarcted region and the healthy tissue resulting in uneven stress and strain distribution in the left ventricle. Once an MI occurs, remodeling of the heart begins. The principle components of the remodeling event include myocyte death, edema and inflammation, followed by fibroblast infiltration and collagen deposition, and finally scar formation from extra-cellular matrix (ECM) deposition. The principle component of the scar is collagen which is non-contractile and causes strain on the heart with each beat. Non-contractility causes poor pump performance as seen by low ejection fraction (EF) and akinetic or diskinetic local wall motion. Low EF leads to high residual blood volume in the ventricle, causes additional wall stress and leads to eventual infarct expansion via scar stretching and thinning and border-zone cell apoptosis. In addition, the remote-zone thickens as a result of higher stress which impairs systolic pumping while the infarct region experiences significant thinning because mature myocytes of an adult are not regenerated. Myocyte loss is a major etiologic factor of wall thinning and chamber dilation that may ultimately lead to progression of cardiac myopathy. In other areas, remote regions experience hypertrophy (thickening) resulting in an overall enlargement of the left ventricle. This is the end result of the remodeling cascade. These changes also correlate with physiological changes that result in increase in blood pressure and worsening systolic and diastolic performance.

Summary of Invention

[0007] Compositions, methods of manufacture and methods of treatment for post-myocardial infarction are herein disclosed. In some embodiments, the composition includes at least two components. In one embodiment, a first component can include a first functionalized polymer and a substance having at least one cell adhesion site combined in a first buffer at a pH of approximately 6.5. A second component can include a second buffer in a pH of between about 7.5 and 9.0. A second functionalized polymer can be included in the first or second component. In some embodiments, the composition can include at least one cell type and/or at least one growth factor. In some embodiments, the composition(s) of the present invention can be delivered by a dual bore injection device to a treatment area, such as a post-myocardial infarct region.

Brief Description of Drawings

[0008] FIGS. 1A-1B illustrate the progression of heart damage once the build-up of plaque in an artery induces an infarct to occur.

[0009] FIGS. 2A-2G show examples of chemical structures of a functionalized polyethylene glycol.

[0010] FIG. 3 shows a general formula for the chemical structure of a functionalized polyethylene glycol.

[0011] FIG. 4 illustrates an embodiment of a dual bore delivery device.

[0012] FIGS. 5A-5B illustrate an alternative embodiment of a dual bore delivery device.

[0013] FIGS. 6A-6C illustrate a second alternative embodiment of a dual bore delivery device.

Detailed Description

[0014] FIGS. 1A-1B illustrate the progression of heart damage once the build-up of plaque induces an infarct to occur. FIG. 1A illustrates a site 10 where blockage and restricted blood flow can occur from, for example, a thrombus or embolus. FIG. 1B illustrates resultant damage area 20 to the left ventricle that can result from the lack of oxygen and nutrient flow carried by the blood to the inferior region left of the heart. Damage area 20 will likely undergo remodeling, and eventually scarring, resulting in a non-functional area.

[0015] Bioscaffoldings formed of two components and applied in situ to the left heart ventricle can be used to treat post-myocardial infarction tissue damage. “Bioscaffolding” and “two-component gelation system” and “gelation system” are hereinafter used interchangeably. Examples of two-component gelation systems include, but are not limited to, alginate construct systems, fibrin glues and fibrin glue-like systems, self-assembled peptides, synthetic polymer systems and combinations thereof. Each component of the two-component gelation system may be co-injected to an infarct region by a dual-lumen delivery device. Examples of dual-lumen delivery devices include, but are not limited to, dual-needle left-ventricle injection devices, dual-needle transvascular wall injection devices and the like.

[0016] In some applications, the two-component gelation system includes fibrin glue. Fibrin glue consists of two main components, fibrinogen and thrombin. Fibrinogen is a plasma glycoprotein of about 340 kiloDaltons (kDa) in its endogenous state. Fibrinogen is a symmetrical dimer comprised of six paired polypeptide chains, alpha, beta and gamma chains. On the alpha and beta chains, there is a small peptide sequence called a fibrinopeptide which prevents fibrinogen from spontaneously forming polymers with itself. In some embodiments, fibrinogen is modified with proteins. Thrombin is a coagulation protein. When combined in equal volumes, thrombin converts the fibrinogen to fibrin by enzymatic action at a rate determined by the concentration of thrombin. The result is a biocompatible gel which gelates when combined at the infarct region. Fibrin glue can undergo gelation between about 5 to about 60 seconds. Examples of fibrin glue-like systems include, but are not limited to, Tisseel™ (Baxter), Beriplast P™ (Aventis Behring), Biocol® (LFB, France), Crosseal™ (Omrix Biopharmaceuticals, Ltd.), Hemaseel HMN® (Haemacure Corp.), Bolheal (Kaketsuken Pharma, Japan) and CoStasis® (Angiotech Pharmaceuticals).

[0017] In some embodiments, the two-component gel comprises self-assembled peptides. Self-assembled peptides generally include repeat sequences of alternating hydrophobic and hydrophilic amino acid chains. The hydrophilic amino acids are generally charge-bearing and can be anionic, cationic, or both. Examples of cationic amino acids are lysine and arginine. Examples of anionic amino acids are aspartic acid and glutamic acid. Examples of hydrophobic amino acids are alanine, valine, leucine, isoleucine, or phenylalanine. Self-assembled peptides can range from 8 to about 40 amino acids in length and can assemble into nanoscale fibers under conditions of physiological pH and osmolarity. In sufficient concentration and over time, the fibers can assemble into an interconnected structure that appears macroscopically as a gel. Self-assembled peptides typically undergo gelation between several minutes to several hours. Examples of self-assembled peptides include, but are not limited to: AcN-RARADADARARADADA-CNH₂(RAD 16-II), containing the sequence RARADADARARADADA (SEQ ID NO: 1); VKVKVKVKVPPTKVKVKVKV-NH₂(MAX-1), containing the sequence VKVKVKVKVPPTKVKVKVKV (SEQ ID NO: 2); and AcN-AEAEAKAKAEAEAKAK-CNH2 (EAK16-II), containing the sequence AEAEAKAKAEAEAKAK (SEQ ID NO: 3); wherein Ac indicates acetylation, R is arginine, A is alanine, D is aspartic acid, V is valine, K is lysine, P is proline, and E is glutamic acid.

[0018] In some applications, the two-component gelation system is an alginate construct system. One component may be an alginate conjugate (or alginate alone) which can include alginate and a protein constituent. The second component may be a salt. Examples of alginate conjugates can include, but are not limited to, alginate-collagen, alginate-laminin, alginate-elastin, alginate-collagen-laminin and alginate-hyaluronic acid in which the collagen, laminin, elastin, collagen-laminin or hyaluronic acid is covalently bonded (or not bonded) to alginate. Examples of salts which can be used to gel the alginate constructs include, but are not limited to, calcium chloride (CaCl₂), barium chloride (BaCl₂) or strontium chloride (SrCl₂).

[0019] In one embodiment, the alginate construct is alginate-gelatin. The molecular weight of the gelatin may be in the approximate range of 5 kDa to 100 kDa. The relatively low molecular weight of gelatin offers processing advantages in that it is more soluble and has lower viscosity than hydrogels of higher molecular weight. Another advantage of gelatin is that it contains from 1 to 4 RGD (arginine-glycine-aspartic acid peptide sequence) sites per molecule. RGD is a common cell adhesion ligand and would increase the retention of cells within the infarct zone where the bioscaffolding is formed. The cells retained by the RGD sites may be cells co-injected with the bioscaffolding components or dispersed throughout a component of the system.

[0020] The gelatin may be a porcine gelatin or a recombinant human gelatin. The porcine gelatin is a hydrolyzed type 1 collagen extracted from porcine skin. In one embodiment, the molecular weight of the porcine gelatin is approximately 20 kDa. The human gelatin is produced by bacteria using human genetic material. The human recombinant gelatin is equivalent to the porcine gelatin but may reduce the likelihood of an immune response when injected into an infarct region of a human subject.

[0021] Alginate is a linear polysaccharide derived from seaweed and contains mannuronic (M) and guluronic acid (G), presented in both alternating blocks and alternating individual residues. It is possible to use some of the carboxyl groups of the alginate as sites to graft useful cell adhesion ligands, such as collagen, laminin, elastin and other peptide fragments of the ECM matrix, forming an alginate conjugate, because alginate does not have RGD groups for cell attachment.

[0022] The alginate-gelatin conjugate can be formed of approximately 1% to 30% and more particularly approximately 10% to 20% gelatin (either porcine or human recombinant) and approximately 80% to 90% alginate. A relatively lower proportion of gelatin is used in the conjugate to retain gelation capacity of native alginate because the carboxyl groups of alginate that cause the gelation may be bound up in the alginate-gelatin conjugate.

[0023] In some embodiments, the two-component gelation system includes polyethylene glycols. PEG is a synthetic polymer having the repeating structure (OCH₂CH₂)_n. A first component may be a polyethylene glycol (PEG) polymer functionalized with at least two nucleophilic groups. Examples of nucleophilic groups include, but are not limited to, thiol (—SH), thiol anion (—S⁻), and amine (—NH₂). A “nucleophile” is a reagent which is attracted to centers of positive charge. A nucleophile participates in a chemical reaction by donating electrons to an electrophile in order to form a chemical bond. A second component may be a PEG polymer functionalized with at least two electrophilic groups. Examples of electrophilic groups include, but are not limited to, N-hydroxy succinimide ester (—NHS), acrylate, vinyl sulfone, and maleimide. —NHS, or succinimidyl, is a five-member ring structure represented by the chemical formula —N(COCH₂)₂. An “electrophile” is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. The total number of electrophilic and nucleophilic groups should be greater than 4.

[0024] In some embodiments, two functionalized PEGs comprising a PEG functionalized with at least two nucleophilic groups and a PEG functionalized with at least two electrophilic groups can be combined in a 1:1 ratio. The PEGs can be stored in a 0.01M acidic solution at a pH below about 4.0. At room temperature and standard concentration, reaction and cross-linking between the two functionalized PEGs occurs beginning at approximately pH greater than 6.5. Under these conditions, reaction kinetics are slow. When 0.3 M basic buffer solution at pH about 9.0 is added to the PEGs, gelation occurs in less than 1 minute. This system exhibits poor cytocompatibility due to the low pH of the functionalized PEG solution and the high osmolality pH 9.0 buffer. “Cytocompatibility” refers to the ability of media to provide an environment conducive to cell growth. Additionally, this system does not include any cell adhesion sites.

Modified Polyethylene Glycol Gelation Systems

[0025] In some embodiments, a bioscaffolding is formed from combining functionalized polymers (bioscaffolding precursors) with an extra-cellular matrix (ECM) protein at physiological osmolality. The resulting bioscaffolding can be in a pH range of between about 6.5 and about 7.5. Examples of ECM proteins include, but are not limited to, collagen, laminin, elastin and fragments thereof, in addition to, proteins, protein fragments and peptides with cell adhesion ligands such as RGD groups. In some embodiments, cells can be added to the bioscaffolding precursors. Examples of cell types include, but are not limited to, localized cardiac progenitor cells, mesenchymal stem cells (osteoblasts, chondrocytes and fibroblasts), bone marrow derived mononuclear cells, adipose tissue derived stem cells, embryonic stem cells, umbilical-cord-blood-derived stem cells, smooth muscle cells or skeletal myoblasts. In some embodiments, growth factors can be added to the system. Examples of growth factors include, but are not limited to, isoforms of vasoendothelial growth factor (VEGF), fibroblast growth factor (FGF, e.g. beta-FGF), Del 1, hypoxia inducing factor (HIF I-alpha), monocyte chemoattractant protein (MCP-1), nicotine, platelet derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), transforming growth factor (TGF alpha), hepatocyte growth factor (HGF), estrogens, follistatin, proliferin, prostaglandin E1 and E2, tumor necrosis factor (TNF-alpha), interleukin 8 (Il-8), hematopoietic growth factors, erythropoietin, granulocyte-colony stimulating factors (G-CSF) and platelet-derived endothelial growth factor (PD-ECGF).

[0026] The polymers can include synthetic polymers, such as polyamino acids, polysaccharides, polyalkylene oxide or polyethylene glycol (PEG). The molecular weight of the compounds can vary depending on the desired application. In most instances, the molecular weight (mol. wt.) is about 100 to about 100,000 mol. wt., and more preferably about 1,000 to about 20,000 mol. wt.

[0027] In some embodiments, the polymer is polyethylene glycol. As used herein, the term “polyethylene glycol(s)” includes modified and/or derivatized polyethylene glycols. According to some embodiments, a first functionalized PEG can be functionalized by at least two reactive groups, such as electrophilic groups. Examples of reactive groups include, but are not limited to, a succinimidyl group (—NHS), a vinyl group, such as acrylate, vinylsulfone, vinyl ether, allyl ether, vinyl ester, vinyl ketone or maleimide, and nitrophenolate or similar leaving group. According to some embodiments, a second functionalized PEG can be functionalized by at least two reactive groups, such as nucleophilic groups. Examples of reactive groups include, but are not limited to, a thiol group, an amino group, a hydroxyl group, phospine radical (PH₂) and —CO—NH—NH₂. Representative functionalized PEGs with electrophilic groups are shown in FIGS. 2A through 2G. A general representative formula for functionalized PEGs with nucleophilic groups are shown in FIG. 3. In some embodiments a PEG functionalized with electrophilic groups is combined with a PEG functionalized with nucleophilic groups to form a bioscaffolding gel. The total number of electrophilic and nucleophilic groups should be greater than 4.

[0028] The branched conformation of the PEGs represented in FIGS. 2A-2G & 3 is not limiting. In some embodiments, the combined functionality of the PEGs can be greater than four. “Functionality” refers to the number of electrophilic or nucleophilic groups on the polymer core that are capable of reacting with other nucleophilic or electrophilic groups, respectively, to form a gel. That is, as long as the PEGs to be combined are at least difunctional, i.e., each PEG contains at least two nucleophilic or electrophilic groups, the functionalized PEGs can be combined to form a bioscaffolding gel. The total number of electrophilic and nucleophilic groups should therefore be greater than 4.

[0029] In some embodiments, a bioscaffolding can include a first component with at least one functionalized PEG and an ECM protein, and a second component of buffer. “Component” hereinafter refers to one part of a two-part system and can include multiple constituents (e.g., a mixture). In one embodiment, the first component can include a mixture of a first functionalized PEG, such as —NHS PEG (or other functionalized PEG with at least two reactive groups), a second functionalized PEG, such as —SH PEG (or other functionalized PEG with at least two reactive groups), and an ECM protein. In some embodiments, the first component can include first functionalized polymer only, such as —NHS PEG (or other functionalized PEG with at least two reactive groups) and an ECM protein.

[0030] In some embodiments, the first functionalized PEG can be combined with the second functionalized PEG in a 1:1 ratio. In some embodiments, e.g., the functionalized PEGs can be combined in a ratio less than 1:1. For example, the two PEGs can have different number of functional groups and, as a result, the PEG stoichiometry could be altered. Alternatively, the crosslinking density may be altered by varying the polymer ratio. In some embodiments, the functionalized PEGs are combined in the solid phase. When preparing to deliver to a treatment site, the mixture can be suspended in a pH 6.5 buffer at approximately physiological osmolality, i.e., 280-300 mOsm/kg H₂O. Examples of buffers include, but are not limited to dilute hydrogen chloride and citrate buffers.

[0031] The second component can include a buffer in a pH range from approximately 7.5 to 9.5 at a concentration from about 140 mM to about 150 mM. Examples of buffers include sodium phosphate and sodium carbonate buffers. The buffer can be at approximately physiological osmolality, i.e., 280-300 mOsm/kg H₂O. In some embodiments, the second component can include an —SH PEG and the buffer (or other functionalized PEG with at least two reactive groups).

[0032] In some embodiments, a cell type can be added to the first component. Examples of cell types include, but are not limited to, localized cardiac progenitor cells, mesenchymal stem cells (osteoblasts, chondrocytes and fibroblasts), bone marrow derived mononuclear cells, adipose tissue derived stem cells, embryonic stem cells, umbilical-cord-blood-derived stem cells, smooth muscle cells or skeletal myoblasts. For example, human mesenchymal stem cells (hMSC) can be added to the first component. In some embodiments, a growth factor can be added to the first component. In some applications, the functionalized PEGs can react with the growth factors which could stabilize the growth factors, extend their half-life or provide a mode for controlled release of the growth factors. The growth factors can act to help survival of injected hMSC or endogenous progenitor cells at the infarct region. In addition, the growth factors can aid direct endogenous progenitor cells to the injury site.

[0033] In general, cells do not attach to PEG surfaces or gels formed from PEG polymers. That is, PEG polymers do not provide a cytocompatible environment for cells. Collagen or gelatin or any other ECM protein such as fibronectin, may be added to improve cytocompatibility. However, in the case of collagen, for example, the collagen added to the mixture of PEGs can make the mixture very viscous and therefore not conducive with catheter delivery systems. It is anticipated that the pH of the first component and the concentration of the second component, as described in embodiments of the invention, will increase the cytocompatibility of the cell types even with an ECM protein present.

[0034] In some embodiments, the first component can be combined with the second component to produce a bioscaffolding at an infarct region. When combined, the resulting bioscaffolding gel can be at a pH of between 6.8 and 7.4. Although the low buffer concentration of the second component may slow the reaction down, the resulting gel can enable improved cytocompatibility. The ECM protein can provide cell adhesion cites to enable cell spreading and migration. “Cell spreading” refers to the naturally occurring morphology that some cells attain when they are allowed to grow on cytocompatible surfaces. In the case of hMSC, the natural morphology is a flattened, spindle-shaped morphology. In some embodiments, the N-terminus and lysine and arginine side groups of the ECM may react with the —NHS PEG. This may provide better mechanical stability of the gel and reduce the tendency of the gel to swell. This reaction is what forms the gel.

[0035] In some embodiments, the —NHS group of the —NHS PEG can be replaced with a vinyl constituent such as acrylate, vinylsulfone, vinyl ketone, allyl ester, allyl ketone or maleimide group(s). When mixed with an —SH PEG at appropriate conditions, these groups can react with the thiol group(s) of the —SH PEG through a Michael type reaction. Michael type reactions are well known by those skilled in the art. In some embodiments, the reaction could be activated with a buffer in a pH range of between about 6.0 and about 9.0, by a catalytic amount of various amines or a combination thereof. It is anticipated that a Michael type reaction would contribute to the long term stability of the resulting gel since thioether bonds are formed as compared to the more hydrolytically labile thioester bonds formed from the reaction of thiols with activated esters. In some embodiments, the —NHS group of the —NHS PEG can be replaced with a leaving group such as a nitrophenolate.

[0036] In some embodiments, the —SH group of the —SH PEG can be replaced with an amino group to form an amide bond when combined with an —NHS or alternatively functionalized PEG.

Methods of Treatment

[0037] Devices which can be used to deliver each component of the gel include, but are not limited to, dual-needle left-ventricle injection devices, dual-needle transvascular wall injection and dual syringes. Methods of access to use the minimally invasive (i.e., percutaneous or endoscopic) injection devices include access via the femoral artery or the sub-xiphoid. “Xiphoid” or “xiphoid process” is a pointed cartilage attached to the lower end of the breastbone or sternum, the smallest and lowest division of the sternum. Both methods are known by those skilled in the art.

[0038] FIG. 4 illustrates an embodiment of a dual syringe device which can be used to deliver the compositions of the present invention. Dual syringe 400 can include first barrel 410 and second barrel 420 adjacent to one another and connected at a proximal end 455, distal end 460 and middle region 465 by plates 440, 445 and 450, respectively. In some embodiments, barrels 410 and 420 can be connected by less than three plates. Each barrel 410 and 420 includes plunger 415 and plunger 425, respectively. Barrels 410 and 420 can terminate at a distal end into needles 430 and 435, respectively, for extruding a substance. In some embodiments, barrels 410 and 420 can terminate into cannula protrusions for extruding a substance. Barrels 410 and 420 should be in close enough proximity to each other such that the substances in each respective barrel are capable of mixing with one another to form a bioscaffolding in the treatment area, e.g., a post-infarct myocardial region. Dual syringe 400 can be constructed of any metal or plastic which is minimally reactive or completely unreactive with the formulations described in the present invention. In some embodiments, dual syringe 400 includes a pre-mixing chamber attached to distal end 465.

[0039] In some applications, first barrel 410 can include a first component of a two-component polyethylene glycol gelation system and second barrel 420 can include a second component of the system according to any of the embodiments described previously. A therapeutic amount of the resulting gel is between about 25 μL to about 200 μL, preferably about 50 μL. Dual syringe 400 can be used during, for example, an open chest surgical procedure.

[0040] FIGS. 5A-5B illustrate an embodiment of a dual-needle injection device which can be used to deliver the compositions of the present invention. Delivery assembly 500 includes lumen 510 which may house delivery lumens, guidewire lumens and/or other lumens. Lumen 510, in this example, extends between distal portion 505 and proximal end 515 of delivery assembly 500.

[0041] In one embodiment, delivery assembly 500 includes first needle 520 movably disposed within delivery lumen 530. Delivery lumen 530 is, for example, a polymer tubing of a suitable material (e.g., polyamides, polyolefins, polyurethanes, etc.). First needle 520 is, for example, a stainless steel hypotube that extends a length of the delivery assembly. First needle 520 includes a lumen with an inside diameter of, for example, 0.08 inches (0.20 centimeters). In one example for a retractable needle catheter, first needle 520 has a needle length on the order of about 40 inches (about 1.6 meters) from distal portion 505 to proximal portion 515. Lumen 510 also includes auxiliary lumen 540 extending, in this example, co-linearly along the length of the catheter (from a distal portion 505 to proximal portion 515). Auxiliary lumen 540 is, for example, a polymer tubing of a suitable material (e.g., polyamides, polyolefins, polyurethanes, etc.). At distal portion 505, auxiliary lumen 540 is terminated at a delivery end of second needle 550 and co-linearly aligned with a delivery end of needle 520. Auxiliary lumen 540 may be terminated to a delivery end of second needle 550 with a radiation-curable adhesive, such as an ultraviolet curable adhesive. Second needle 550 is, for example, a stainless steel hypotube that is joined co-linearly to the end of main needle 520 by, for example, solder (illustrated as joint 555). Second needle 550 has a length on the order of about 0.08 inches (0.20 centimeters). FIG. 5B shows a cross-sectional front view through line A-A′ of delivery assembly 500. FIG. 5B shows main needle 520 and second needle 550 in a co-linear alignment.

[0042] Referring to FIG. 5A, at proximal portion 515, auxiliary lumen 540 is terminated to auxiliary side arm 460. Auxiliary side arm 560 includes a portion extending co-linearly with main needle 520. Auxiliary side arm 560 is, for example, a stainless steel hypotube material that may be soldered to main needle 520 (illustrated as joint 565). Auxiliary side arm 560 has a co-linear length on the order of about, in one example, 1.2 inches (3 centimeters).

[0043] The proximal end of main needle 520 includes adaptor 570 for accommodating a substance delivery device (e.g., a component of a two-component bioerodable gel material). Adaptor 570 is, for example, a molded female luer housing. Similarly, a proximal end of auxiliary side arm 560 includes adaptor 580 to accommodate a substance delivery device (e.g., a female luer housing).

[0044] The design configuration described above with respect to FIGS. 5A-5B is suitable for introducing two-component gel compositions of the present invention. For example, a gel may be formed by a combination (mixing, contact, etc.) of a first component and a second component. Representatively, a first component may be introduced by a one cubic centimeters syringe at adaptor 570 through main needle 520. At the same time or shortly before or after, second component including a silk protein and optionally a least one cell type may be introduced with a one cubic centimeter syringe at adaptor 580. When the first and second components combine at the exit of delivery assembly 500 (at an infarct region), the materials combine (mix, contact) to form a bioerodable gel.

[0045] FIGS. 6A-6C illustrate an alternative embodiment of a dual-needle injection device which can be used to deliver two-component gel compositions of the present invention. In general, the catheter assembly 600 provides a system for delivering substances, such as two-component gel compositions, to or through a desired area of a blood vessel (a physiological lumen) or tissue in order to treat a myocardial infarct region. The catheter assembly 600 is similar to the catheter assembly 600 described in commonly-owned, U.S. patent application Ser. No. 6,554,801, titled “Directional Needle Injection Drug Delivery Device”, which is incorporated herein by reference.

[0046] In one embodiment, catheter assembly 600 is defined by elongated catheter body 650 having proximal portion 620 and distal portion 610. Guidewire cannula 670 is formed within catheter body (from proximal portion 610 to distal portion 620) for allowing catheter assembly 600 to be fed and maneuvered over guidewire 680. Balloon 630 is incorporated at distal portion 610 of catheter assembly 600 and is in fluid communication with inflation cannula 660 of catheter assembly 600.

[0047] Balloon 630 can be formed from balloon wall or membrane 635 which is selectively inflatable to dilate from a collapsed configuration to a desired and controlled expanded configuration. Balloon 630 can be selectively dilated (inflated) by supplying a fluid into inflation cannula 660 at a predetermined rate of pressure through inflation port 665 (located at proximal end 620). Balloon wall 635 is selectively deflatable, after inflation, to return to the collapsed configuration or a deflated profile. Balloon 630 may be dilated (inflated) by the introduction of a liquid into inflation cannula 660. Liquids containing treatment and/or diagnostic agents may also be used to inflate balloon 630. In one embodiment, balloon 630 may be made of a material that is permeable to such treatment and/or diagnostic liquids. To inflate balloon 630, the fluid can be supplied into inflation cannula 660 at a predetermined pressure, for example, between about one and 20 atmospheres. The specific pressure depends on various factors, such as the thickness of balloon wall 635, the material from which balloon wall 635 is made, the type of substance employed and the flow-rate that is desired.

[0048] Catheter assembly 600 also includes at least two substance delivery assemblies 605a and 605b (not shown; see FIGS. 6B-6C) for injecting a substance into a myocardial infarct region. In one embodiment, substance delivery assembly 605a includes needle 615a movably disposed within hollow delivery lumen 625a. Delivery assembly 605b includes needle 615b movably disposed within hollow delivery lumen 625b (not shown; see FIGS. 6B-6C). Delivery lumen 625a and delivery lumen 625b each extend between distal portion 610 and proximal portion 620. Delivery lumen 625a and delivery lumen 625b can be made from any suitable material, such as polymers and copolymers of polyamides, polyolefins, polyurethanes and the like. Access to the proximal end of delivery lumen 625a or delivery lumen 625b for insertion of needle 615a or 615b, respectively is provided through hub 635 (located at proximal end 620). Delivery lumens 625a and 625b may be used to deliver first and second components of a two-component gel composition to a post-myocardial infarct region.

[0049] FIG. 6B shows a cross-section of catheter assembly 600 through line A-A′ of FIG. 6A (at distal portion 610). FIG. 6C shows a cross-section of catheter assembly 600 through line B-B′ of FIG. 6A. In some embodiments, delivery assemblies 605a and 605b are adjacent to each other. The proximity of delivery assemblies 605a and 605b allows each component of the two-component gelation system to rapidly gel when delivered to a treatment site, such as a post-myocardial infarct region.

[0050] From the foregoing detailed description, it will be evident that there are a number of changes, adaptations and modifications of the present invention which come within the province of those skilled in the part. The scope of the invention includes any combination of the elements from the different species and embodiments disclosed herein, as well as subassemblies, assemblies and methods thereof. However, it is intended that all such variations not departing from the spirit of the invention be considered as within the scope thereof.

Claims

What is claimed is:

1. A kit for a post-myocardial infarct bioscaffolding gel, the kit separately comprising the following components:

(a) a first mixture comprising a first functionalized polymer in a first buffer, the first buffer having a physiological osmolality;

(b) a second buffer having a concentration of 140 mM to 150 mM and a pH between 7.5 and 9;

(c) a second functionalized polymer different from the first functionalized polymer, the second functionalized polymer capable of being combined with the first mixture or the second buffer; and

(d) a proteinaceous or peptide substance having at least one cell-adhesion site, the substance capable of being combined with the first mixture,

wherein the first functionalized polymer is a functionalized polyethylene glycol selected from the group consisting of an activated ester-terminated polyethylene glycol or a vinyl-terminated polyethylene glycol; wherein the second functionalized polymer is selected from the group consisting of a thiol-terminated polyethylene glycol or an amino-terminated polyethylene glycol; and wherein the components, when combined, form a gel having a pH of 7.2.

2. The kit of claim 1, wherein the first mixture has a pH of less than 6.5.

3. The kit of claim 1, wherein the physiological osmolality of the first buffer is from 280 mOsm/kg H₂O to 300 mOsm/kg H₂O.

4. The kit of claim 1, wherein the substance having at least one cell-adhesion site is a protein selected from the group consisting of gelatin, laminin, and elastin or an arginine-glycine-aspartic acid (RGD) peptide sequence.

5. The kit of claim 1, wherein the first mixture further comprises a cell, a growth factor, or a combination thereof.

6. The kit of claim 5, wherein the growth factor is selected from the group consisting of vasoendothelial growth factor (VEGF), fibroblast growth factor (FGF), Del 1, hypoxia inducing factor (HIF), monocyte chemoattractant protein (MCP), nicotine, platelet derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), transforming growth factor (TGF), hepatocyte growth factor (HGF), estrogens, follistatin, proliferin, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), tumor necrosis factor (TNF), interleukin-8 (IL-8), hematopoietic growth factors, erythropoietin (EPO), granulocyte-colony stimulating factors (G-CSF), and platelet-derived endothelial growth factor (PD-ECGF).

7. The kit of claim 5, wherein the cell is selected from the group consisting of localized cardiac progenitor cells, mesenchymal stem cells, bone marrow derived mononuclear cells, adipose tissue derived stem cells, embryonic stem cells, umbilical-cord-blood-derived stem cells, smooth muscle cells and skeletal myoblasts.

8. The kit of claim 1, wherein the first functionalized polymer and the second functionalized polymer have a combined functionality greater than four.

Patent Citations (234)

Patent	Date	Inventor	Cited By
US3584624(A)	1971-06-01	de Ciutiis	Applicant
US3780733(A)	1973-12-01	Martinez-Manzor	Applicant
US3890976(A)	1975-06-01	Bazell et al.	Applicant
US4617186(A)	1986-10-01	Schafer et al.	Applicant
US4794931(A)	1989-01-01	Yock	Applicant
US4818291(A)	1989-04-01	Iwatsuki et al.	Applicant
US4842590(A)	1989-06-01	Tanabe et al.	Applicant
US5000185(A)	1991-03-01	Yock	Applicant
US5024234(A)	1991-06-01	Leary et al.	Applicant
US5049130(A)	1991-09-01	Powell	Applicant
US5092848(A)	1992-03-01	DeCiutiis	Applicant
US5100185(A)	1992-03-01	Menke et al.	Applicant
US5128326(A)	1992-07-01	Balazs et al.	Applicant
US5171217(A)	1992-12-01	March et al.	Applicant
US5202745(A)	1993-04-01	Sorin et al.	Applicant
US5203338(A)	1993-04-01	Jang	Applicant
US5270300(A)	1993-12-01	Hunziker	Applicant
US5291267(A)	1994-03-01	Sorin et al.	Applicant
US5306250(A)	1994-04-01	March et al.	Applicant
US5321501(A)	1994-06-01	Swanson et al.	Applicant
US5328955(A)	1994-07-01	Rhee et al.	Applicant
US5336252(A)	1994-08-01	Cohen	Applicant
US5354279(A)	1994-10-01	Hofling	Applicant
US5365325(A)	1994-11-01	Kumasaka et al.	Applicant
US5372138(A)	1994-12-01	Crowley et al.	Applicant
US5380292(A)	1995-01-01	Wilson	Applicant
US5437632(A)	1995-08-01	Engelson	Applicant
US5455039(A)	1995-10-01	Edelman et al.	Applicant
US5459570(A)	1995-10-01	Swanson et al.	Applicant
US5464395(A)	1995-11-01	Faxon et al.	Applicant
US5465147(A)	1995-11-01	Swanson	Applicant
US5485486(A)	1996-01-01	Gilhousen et al.	Applicant
US5499630(A)	1996-03-01	Hiki et al.	Applicant
US5540912(A)	1996-07-01	Roorda et al.	Applicant
US5546948(A)	1996-08-01	Hamm et al.	Applicant
US5575815(A)	1996-11-01	Slepian et al.	Applicant
US5580714(A)	1996-12-01	Polovina	Examiner
US5580856(A)	1996-12-01	Prestrelski et al.	Applicant
US5588432(A)	1996-12-01	Crowley	Applicant
US5621610(A)	1997-04-01	Moore et al.	Applicant
US5642234(A)	1997-06-01	Altman et al.	Applicant
US5655548(A)	1997-08-01	Nelson et al.	Applicant
US5667778(A)	1997-09-01	Atala	Applicant
US5693029(A)	1997-12-01	Leonhardt	Applicant
US5722403(A)	1998-03-01	McGee et al.	Applicant
US5730732(A)	1998-03-01	Sardelis et al.	Applicant
US5740808(A)	1998-04-01	Panescu et al.	Applicant
US5785689(A)	1998-07-01	De Toledo et al.	Applicant
US5811533(A)	1998-09-01	Gold et al.	Examiner
US5827313(A)	1998-10-01	Ream et al.	Applicant
US5843156(A)	1998-12-01	Slepian et al.	Applicant
US5874500(A)	1999-02-01	Rhee et al.	Applicant
US5879713(A)	1999-03-01	Roth et al.	Applicant
US5900433(A)	1999-05-01	Igo et al.	Applicant
US5919449(A)	1999-07-01	Dinsmore	Applicant
US5935160(A)	1999-08-01	Auricchio et al.	Applicant
US5939323(A)	1999-08-01	Valentini et al.	Applicant
US5941868(A)	1999-08-01	Kaplan et al.	Applicant
US5957941(A)	1999-09-01	Ream	Applicant
US5968064(A)	1999-10-01	Selmon	Applicant
US5979449(A)	1999-11-01	Steer	Applicant
US5981568(A)	1999-11-01	Kunz et al.	Applicant
US5997536(A)	1999-12-01	Osswald et al.	Applicant
US6022540(A)	2000-02-01	Bruder et al.	Applicant
US6045565(A)	2000-04-01	Ellis et al.	Applicant
US6051071(A)	2000-04-01	Charvet et al.	Applicant
US6051648(A)	2000-04-01	Rhee et al.	Applicant
US6056744(A)	2000-05-01	Edwards	Applicant
US6058329(A)	2000-05-01	Salo et al.	Applicant
US6060053(A)	2000-05-01	Atala	Applicant
US6071305(A)	2000-06-01	Brown et al.	Applicant
US6086582(A)	2000-07-01	Altman et al.	Applicant
US6093177(A)	2000-07-01	Javier, Jr. et al.	Applicant
US6099563(A)	2000-08-01	Zhong	Applicant
US6099864(A)	2000-08-01	Morrison et al.	Applicant
US6102887(A)	2000-08-01	Altman	Applicant
US6102904(A)	2000-08-01	Vigil et al.	Applicant
US6102926(A)	2000-08-01	Tartaglia et al.	Applicant
US6120520(A)	2000-09-01	Saadat et al.	Applicant
US6120904(A)	2000-09-01	Hostettler et al.	Applicant
US6127448(A)	2000-10-01	Domb	Examiner
US6133231(A)	2000-10-01	Ferrara et al.	Applicant
US6134003(A)	2000-10-01	Tearney et al.	Applicant
US6151525(A)	2000-11-01	Soykan	Applicant
US6152141(A)	2000-11-01	Stevens et al.	Applicant
US6153428(A)	2000-11-01	Gustafsson et al.	Applicant
US6159443(A)	2000-12-01	Hallahan et al.	Applicant
US6162202(A)	2000-12-01	Sicurelli et al.	Applicant
US6175669(B1)	2001-01-01	Colston et al.	Applicant
US6177407(B1)	2001-01-01	Rodgers et al.	Applicant
US6179809(B1)	2001-01-01	Khairkhahan et al.	Applicant
US6183432(B1)	2001-02-01	Milo	Applicant
US6183444(B1)	2001-02-01	Glines et al.	Applicant
US6187330(B1)	2001-02-01	Wang et al.	Applicant
US6190353(B1)	2001-02-01	Makower et al.	Applicant
US6191144(B1)	2001-02-01	Isner	Applicant
US6193763(B1)	2001-02-01	Mackin	Applicant
US6197324(B1)	2001-03-01	Crittenden	Applicant
US6201608(B1)	2001-03-01	Mandella et al.	Applicant
US6206893(B1)	2001-03-01	Klein et al.	Applicant
US6206914(B1)	2001-03-01	Soykan et al.	Applicant
US6207180(B1)	2001-03-01	Ottoboni et al.	Applicant
US6210392(B1)	2001-04-01	Vigil et al.	Applicant
US6217527(B1)	2001-04-01	Selmon et al.	Applicant
US6217554(B1)	2001-04-01	Green	Applicant
US6221049(B1)	2001-04-01	Selmon et al.	Applicant
US6231546(B1)	2001-05-01	Milo et al.	Applicant
US6235000(B1)	2001-05-01	Milo et al.	Applicant
US6241710(B1)	2001-06-01	Van Tassel et al.	Applicant
US6251104(B1)	2001-06-01	Kesten et al.	Applicant
US6283947(B1)	2001-09-01	Mirzaee	Applicant
US6287285(B1)	2001-09-01	Michal et al.	Applicant
US6290729(B1)	2001-09-01	Slepian et al.	Applicant
US6296602(B1)	2001-10-01	Headley	Applicant
US6299604(B1)	2001-10-01	Ragheb et al.	Applicant
US6309370(B1)	2001-10-01	Haim et al.	Applicant
US6312725(B1)	2001-11-01	Wallace et al.	Applicant
US6315994(B2)	2001-11-01	Usala et al.	Applicant
US6323278(B2)	2001-11-01	Rhee et al.	Applicant
USRE37463(E)	2001-12-01	Altman	Applicant
US6328229(B1)	2001-12-01	Duronio et al.	Applicant
US6333194(B1)	2001-12-01	Levy et al.	Applicant
US6334872(B1)	2002-01-01	Termin et al.	Applicant
US6346098(B1)	2002-02-01	Yock et al.	Applicant
US6346099(B1)	2002-02-01	Altman	Applicant
US6346515(B1)	2002-02-01	Pitaru et al.	Applicant
US6358247(B1)	2002-03-01	Altman et al.	Applicant
US6358258(B1)	2002-03-01	Arcia et al.	Applicant
US6368285(B1)	2002-04-01	Osadchy et al.	Applicant
US6371935(B1)	2002-04-01	Macoviak et al.	Applicant
US6371992(B1)	2002-04-01	Tanagho et al.	Applicant
US6379379(B1)	2002-04-01	Wang	Applicant
US6385476(B1)	2002-05-01	Osadchy et al.	Applicant
US6391052(B2)	2002-05-01	Buirge et al.	Applicant
US6395023(B1)	2002-05-01	Summers	Applicant
US6409716(B1)	2002-06-01	Sahatjian et al.	Applicant
US6416510(B1)	2002-07-01	Altman et al.	Applicant
US6432119(B1)	2002-08-01	Saadat	Applicant
US6436135(B1)	2002-08-01	Goldfarb	Applicant
US6443941(B1)	2002-09-01	Slepian et al.	Applicant
US6443949(B2)	2002-09-01	Altman	Applicant
US6447504(B1)	2002-09-01	Ben-Haim et al.	Applicant
US6458095(B1)	2002-10-01	Wirt et al.	Applicant
US6458098(B1)	2002-10-01	Kanesaka	Applicant
US6464862(B2)	2002-10-01	Bennett et al.	Applicant
US6465001(B1)	2002-10-01	Hubbell et al.	Applicant
US6478776(B1)	2002-11-01	Rosenman et al.	Applicant
US6482231(B1)	2002-11-01	Abatangelo et al.	Applicant
US6485481(B1)	2002-11-01	Pfeiffer	Applicant
US6494862(B1)	2002-12-01	Ray et al.	Applicant
US6548081(B2)	2003-04-01	Sadozai et al.	Applicant
US6554801(B1)	2003-04-01	Steward et al.	Applicant
US6599267(B1)	2003-07-01	Ray et al.	Applicant
US6624245(B2)	2003-09-01	Wallace et al.	Applicant
US6628988(B2)	2003-09-01	Kramer et al.	Applicant
US6629947(B1)	2003-10-01	Sahatjian et al.	Applicant
US6632457(B1)	2003-10-01	Sawhney	Applicant
US6635267(B1)	2003-10-01	Miyoshi et al.	Applicant
US6660034(B1)	2003-12-01	Mandrusov et al.	Examiner
US6682730(B2)	2004-01-01	Mickle et al.	Applicant
US6689608(B1)	2004-02-01	Mikos et al.	Applicant
US6692466(B1)	2004-02-01	Chow et al.	Applicant
US6702744(B2)	2004-03-01	Mandrusov et al.	Applicant
US6706034(B1)	2004-03-01	Bhat	Applicant
US6737072(B1)	2004-05-01	Angele et al.	Applicant
US6748258(B1)	2004-06-01	Mueller et al.	Applicant
US6749617(B1)	2004-06-01	Palasis et al.	Applicant
US6777231(B1)	2004-08-01	Katz et al.	Applicant
US6790455(B2)	2004-09-01	Chu et al.	Applicant
US6858229(B1)	2005-02-01	Hubbell et al.	Applicant
US6992172(B1)	2006-01-01	Chang et al.	Applicant
US7035092(B2)	2006-04-01	Hillman et al.	Applicant
US7112587(B2)	2006-09-01	Timmer et al.	Applicant
US7129210(B2)	2006-10-01	Lowinger et al.	Applicant
US7438692(B2)	2008-10-01	Tsonton et al.	Applicant
US2001/0023349(A1)	2001-09-01	Van Tassel et al.	Applicant
US2002/0013408(A1)	2002-01-01	Rhee et al.	Applicant
US2002/0042473(A1)	2002-04-01	Trollsas et al.	Applicant
US2002/0072706(A1)	2002-06-01	Hiblar et al.	Applicant
US2002/0076441(A1)	2002-06-01	Shih et al.	Applicant
US2002/0090725(A1)	2002-07-01	Simpson et al.	Applicant
US2002/0124855(A1)	2002-09-01	Chachques	Applicant
US2002/0142458(A1)	2002-10-01	Williams et al.	Applicant
US2002/0146557(A1)	2002-10-01	Claude et al.	Applicant
US2002/0188170(A1)	2002-12-01	Santamore et al.	Applicant
US2003/0023202(A1)	2003-01-01	Nielson	Applicant
US2003/0040712(A1)	2003-02-01	Ray et al.	Applicant
US2003/0050597(A1)	2003-03-01	Dodge et al.	Applicant
US2003/0078671(A1)	2003-04-01	Lesniak et al.	Applicant
US2003/0105493(A1)	2003-06-01	Salo	Applicant
US2003/0175410(A1)	2003-09-01	Campbell et al.	Applicant
US2004/0181206(A1)	2004-09-01	Chiu et al.	Applicant
US2004/0185084(A1)	2004-09-01	Ree et al.	Applicant
US2004/0208845(A1)	2004-10-01	Michal et al.	Applicant
US2004/0213756(A1)	2004-10-01	Michal et al.	Applicant
US2005/0015048(A1)	2005-01-01	Chiu et al.	Applicant
US2005/0031874(A1)	2005-02-01	Michal et al.	Applicant
US2005/0042254(A1)	2005-02-01	Freyman et al.	Examiner
US2005/0070844(A1)	2005-03-01	Chow et al.	Applicant
US2005/0186240(A1)	2005-08-01	Ringeisen et al.	Applicant
US2005/0281883(A1)	2005-12-01	Daniloff et al.	Applicant
US2006/0149392(A1)	2006-07-01	Hsieh et al.	Applicant
US2006/0233850(A1)	2006-10-01	Michal	Applicant
US2007/0270948(A1)	2007-11-01	Wuh	Applicant
EP331584	1989-09-01		Applicant
EP861632	1998-09-01		Applicant
EP938871	1999-09-01		Applicant
GB2194144	1988-03-01		Applicant
JP61205446	1986-09-01		Applicant
WO-9210142	1992-06-01		Applicant
WO-9830207	1998-07-01		Applicant
WO-9854301	1998-12-01		Applicant
WO-0016818	2000-03-01		Applicant
WO-0071196	2000-11-01		Applicant
WO-0124775	2001-04-01		Applicant
WO-0145548	2001-06-01		Applicant
WO-0149357	2001-07-01		Applicant
WO-0228450	2002-04-01		Applicant
WO-0240070	2002-05-01		Applicant
WO-02072166	2002-09-01		Applicant
WO-02087623	2002-11-01		Applicant
WO-03022909	2003-03-01		Applicant
WO-03027234	2003-04-01		Applicant
WO-03064637	2003-08-01		Applicant
WO-2004000915	2003-12-01		Applicant
WO-2004050013	2004-06-01		Applicant
WO-2004066829	2004-08-01		Applicant
WO-2004091592	2004-10-01		Applicant
WO-2005061019	2005-07-01		Applicant
WO-2005067890	2005-07-01		Applicant
WO-2006039704	2006-04-01		Applicant
WO-2006113407	2006-10-01		Applicant
WO-2007048831	2007-03-01		Applicant
WO-2007145909	2007-12-01		Applicant

Non-Patent Literature (159)

Staatz, WD, et al “Identification of a tetrapeptide recognition sequence for the alpha 2 beta 1 integrin in collagen” Journal of Biological Chemistry, 1991, 266(12), pp. 7363-7367.Examiner
Abbott Cardiovascular Systems, Inc., “PCT Search Report and Written Opinion dated Aug. 26, 2008”, PCT Appln. No. PCT/US2007/016433, 14 pages.Applicant
Agocha, A., et al., “Hypoxia regulates basal and induced DNA synthesis and collagen type I production in human cardiac fibroblasts: effects of transforming growth factor-beta 1, thyroid hormone, angiotensin II and basic fibroblast growth factor”, J. Mol. Cell. Cardiol., 29(8), (Apr. 1997), pp. 2233-2244.Applicant
Allemann, E., et al., “Kinetics of Blood Component Adsorption on poly(D,L-lactic acid) Nanoparticles: Evidence of Complement C3 Component Involvement”, J. Biomed. Mater. Res., 37(2), Abstract downloaded from the Internet at: http://www.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed, (Nov. 1997), pp. 229-234.Applicant
Anderson, James M., et al., “Biodegradation and biocompatibility of PLA and PLGA microspheres”, Advanced Drug Delivery Reviews 28, (1997), 5-24.Applicant
Assmus, B., et al., “Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI)”, Circulation, 106, (2002), 3009-3017, first page only.Applicant
Baxter, “FloSeal Matrix Hemostatic Sealant”, downloaded from the Internet on Nov. 14, 2002, from: http://www.fusionmed.com/docs/surgeon/default.asp, 2 pages.Applicant
Berger, et al., “Poly-L-cysteine”, J. Am. Chem. Soc., 78(17), (Sep. 5, 1956), pp. 4483-4488.Applicant
Bernatowicz, M., et al., “Preparation of Boc-[S-(3-nitro-2-pyridinesulfenyl)]-cysteine and its use for Unsymmetrical Disulfide Bond Formation”, Int. J. Peptide Protein Res. 28(2), (Aug. 1996), pp. 107-112.Applicant
Boland, E. D., “Electrospinning Collagen and Elastin: Preliminary Vascular Tissue Engineering”, Frontiers in Bioscience, vol. 9, (May 1, 2004), pp. 1422-1432.Applicant
Brust, G., “Polyimides”, downloaded from the Internet at: http://www.pslc.ws/macrog/imide.htm, (2005), 4 pages.Applicant
Buschmann, I, et al., “Arteriogenesis versus angiogenesis: Two mechanisms of vessel growth”, News Physiol. Sci., vol. 14, (Jun. 1999), 121-125.Applicant
Canderm Pharma, “Technical Dossier: Artecoll”, downloaded from the Internet on Oct. 22, 2002 from: http://www.canderm.com/artecoll/tech.html, 3 pages.Applicant
Capan, Y., et al., “Preparation and Characterization of Poly(D,L-lactide-co-glycolide) Microspheres for Controlled Release of Human Growth Hormone”, AAPS PharmSciTech.; 4(2): article 28, Downloaded from the Internet at: http://www.aapspharmscitech.org/view.asp?art=pt040228&pdf=yes, (2003), 12 pages.Applicant
Caplan, Michael J., et al., “Dependence on pH of polarized sorting of secreted proteins”, Dept. of Cell Biology and Dept. of Pathology, Yale Universit School of Medicine, Nature vol. 329, (Oct. 15, 1987), 630.Applicant
Carpino, L., et al., “Tris(2-aminoethyl)amine as a Substitute for 4-(Aminomethyl)piperidine in the FMOC/Polyamine Approach to Rapid Peptide Synthesis”, J. Org. Chem., 55(5), (Mar. 1990), pp. 1673-1675.Applicant
Chandy, et al., “The development of porous alginate/elastin/PEG composite matrix for cardiovascular engineering”, Journal of Biomaterials Applications, vol. 17, (Apr. 2003), 287-301.Applicant
Choi, Young Seon, et al., “Study on gelatin-containing artificial skin: I. Preparation and characteristics of novel gelatin-alginate sponge”, Biomaterials, vol. 20, (1999), 409-417.Applicant
Corbett, S., et al., “Covalent Cross-linking of Fibronectin to Fibrin is Required for Maximal Cell Adhesion to a Fibronectin-Fibrin Matrix”, The Journal of Biological Chemistry, 272(40), (Oct. 3, 1997), pp. 24999-25005.Applicant
Creemers, E., et al., “Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure?”, Circ. Res., vol. 89, (2001), pp. 201-210.Applicant
Crivello, et al., “Synthesis and Photoinitiated Cationic Polymerization of Monomers with the Silsesquioxane Core”, J Polym Science: Part A: Polymer Chemistry 35, (1997), pp. 407-425.Applicant
Davis, M. E., et al., “Injectable Self-Assembling Peptide Nanofibers Create Intramyocardial Microenvironments for Endothelial Cells”, Circulation, 111, (Feb. 2005), pp. 442-450.Applicant
De Rosa, et al., “Biodegradable Microparticles for the Controlled Delivery of Oligonucleotides”, International Journal of Pharmaceutics, 242, (Aug. 21, 2002), pp. 225-228.Applicant
Desai, M., et al., “Polymer bound EDC (P-EDC): A convenient reagent for formation of an amide bond”, Tetrahedron Letters, 34(48), Abstract downloaded from the Internet at: http://www.sciencedirect.com, 1 page, (Nov. 1993), pp. 7685-7688.Applicant
Dinbergs, et al., “Cellular response to transforming growth factor-β1 and basic fibroblast growth factor depends on release kinetics and extracellular matrix interactions” The Journal of Biological Chemistry, vol. 271, No. 47, (Nov. 1996), 29822-29829.Applicant
Dong, Zhanfeng, et al., “Alginate/gelatin blend films and their properties for drug controlled release”, Journal of Membrane Science, vol. 280, (2006), 37-44.Applicant
Edelman, “Controlled and modulated release of basic fibroblast growth factor”, Biomaterials, vol. 12, (Sep. 1999), 619-626.Applicant
Etzion, S., et al., “Influence of Embryonic Cardiomyocyte Transplantation on the Progression of Heart Failure in a Rat Model of Extensive Myocardial Infarction”, J. Mol. Cell Cardiol., 33, (May 2001), pp. 1321-1330.Applicant
Ferrara, N., “Role of Vascular Endothelial Growth Factor in the Regulation of Angiogenesis” Kidney International, 56(3), Abstract downloaded from the Internet at: http://www.nature.com/ki/journal/v56/n3/abs/4490967a.html, 1 page, (1999), pp. 794-814.Applicant
Fuchs, S., et al., “Catheter-Based Autologous Bone Marrow Myocardial Injection in No-Option Patients with Advanced Coronary Artery Disease”, J. Am. Coll. Cardiol., 41(10), (2003), pp. 1721-1724.Applicant
Fukumoto, S., et al., “Protein Kinase C δ Inhibits the Proliferation of Vascular Smooth Muscle Cells by Suppressing G1 Cyclin Expression”, The Journal of Biological Chemistry, 272(21), (May 1997), pp. 13816-13822.Applicant
Giordano, F., et al., “Angiogenesis: The Role of the Microenvironment in Flipping the Switch”, Current Opinion in Genetics and Development, 11, (2001), pp. 35-40.Applicant
Gossler, et al., “Transgenesis by means of blastocyst-derived embryonic stem cell lines”, Proc. Natl. Acad. Sci. USA, 83, (Dec 1986), pp. 9065-9069.Applicant
Grafe, T. H., “Nanofiber Webs from Electrospinning”, Presented at the Nonwovens in Filtration—Fifth International Conference,, Stuttgart, Germany, (Mar. 2003), pp. 1-5.Applicant
Gref, R., et al., “Biodegradable Long-Circulating Polymeric Nanospheres”, Science, 263(5153), Abstract downloaded from the Internet at: http://www.sciencemag.org/cgi/content/abstract/263/5153/1600, 1 page, (Mar. 1994), pp. 1600-1603.Applicant
Grund, F., et al., “Microembolization in Pigs: Effects on Coronary Blood Flow and Myocardial Ischemic Tolerance”, Am. J. Physiol., 277 (Heart Circ. Physiol. 46), (1999), pp. H533-H542.Applicant
Gupta, et al., “Changes in Passive Mechanical Stiffness of Myocardial Tissue with Aneurysm Formation”, Circulation, 89(5), (May 1994), pp. 2315-2326.Applicant
Hashimoto, T., et al., “Development of Alginate Wound Dressings Linked with Hybrid Peptides Derived from Laminin and Elastin”, Biomaterials, 25, (2004), pp. 1407-1414.Applicant
Haugland, et al., “Dialkylcarbocyanine and Dialkylaminostryryl Probes”, Handbook of Fluorescent Probes and Research Products, Molecular Probes, Inc., (2002), 530-534.Applicant
Haugland, et al., “Membrane-permeant reactive tracers”, Handbook of Fluorescent Probes and Research Products, Molecular Probes, Inc., (2002), 458-553.Applicant
Heeschen, C., et al., “Nicotine Stimulates Tumor Angiogenesis”, American College of Cardiology, 37(2) Supplement A,, Abstract downloaded from the Internet at: http://24.132.160.238/ciw-01acc/abstract—search—author.cfm? SearchName=Heeschen, 1 page, (Feb. 2001), pp. 1A-648A.Applicant
Helisch, A, et al., “Angiogenesis and arteriogenesis—not yet for prescription”, NEUE Diagnostische Und Therap. Verfahren, Z Kardiol 89, (2000), 239-244.Applicant
Hendel, R. C., et al., “Effect of Intracoronary Recombinant Human Vascular Endothelial Growth Factor on Myocardial Perfusion: Evidence for a Dose-Dependent Effect”, Circulation, 101, (2000), pp. 118-121.Applicant
Henry, R. R., et al., “Insulin Action and Glucose Metabolism in Nondiabetic Control and NIDDM Subjects: Comparison Using Human Skeletal Muscle Cell Cultures”, Diabetes, 44(8), Abstract downloaded from the Internet at: http://diabetes.diabetesjournals.org/cgi/content/abstract/44/8/936, 1 page, (1995), pp. 936-946.Applicant
Hoffman, “Hydrogels for Biomedical Applications”, Advanced Drug Delivery Reviews, vol. 43, (2002), pp. 3-12.Applicant
Holland, N. B., et al., “Biomimetic Engineering of Non-Adhesive glycocalyx-like Surfaces Using Oligosaccharide Surfactant Polymers”, Nature, 392, Abstract downloaded from the Internet at: http://www.nature.com, 1 page, (Apr. 1998), pp. 799-801.Applicant
Horan, R.L., et al., “In Vitro Degradation of Silk Fibroin”, Biomaterials, vol. 26, (2004), 3385-3393.Applicant
Hovinen, J., et al., “Synthesis of 3′-functionalized oligonucleotides on a single solid support”, Tetrahedron Letters, 34(50), Abstract downloaded from the Internet at: http://www.sciencedirect.com, 1 page, (Dec. 1993), pp. 8169-8172.Applicant
Huang, K., et al., “Synthesis and Characterization of Self-Assembling Block Copolymers Containing Bioadhesive End Groups”, Biomacromolecules, 3(2), (2002), pp. 397-406.Applicant
Hutcheson, K., et al., “Comparison of Benefits on Myocardial Performance of Cellular Cardiomyoplasty with Skeletal Myoblasts and Fibroblasts”, Cell Transplantation, 9(3), (2000), pp. 359-368.Applicant
Huynh, T. V., et al., “Constructing and Screening cDNA Libraries in λgt10 and λgt11”, Chapter 2 in DNA Cloning, vol. 1: A Practical Approach, ed. by D.M. Glover, (1985), pp. 49-78.Applicant
Indik, Z., et al., “Production of Recombinant Human Tropoelastin: Characterization and Demonstration of Immunologic and Chemotactic Activity”, Arch. Biochem. Biophys., 280(1), Abstract downloaded from the Internet at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed, 1 page, (Jul. 1990), pp. 80-86.Applicant
Iskandrian, A. S., et al., “Nuclear Cardiac Imaging: Principles and Applications”, second edition, F.A. Davis Co., Philadelphia, cover page, title page and TOC, (1996), 5 pages total.Applicant
Isner, J. M., “Vascular Endothelial Growth Factor: Gene Therapy and Therapeutic Angiogenesis”, Am. J. Cardiol., 82(10A), (Nov. 19, 1998), pp. 63S-64S.Applicant
Ito, Wulf D., et al., “Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion”, Max-Planck-Institute for Physiological and Clinical Research, Bad Nauheim, Germany, (Feb. 21, 1997), 829-837.Applicant
Johnson, et al., “The stabilization and encapsulation of human growth hormone nto biodegradable microspheres”, Pharmaceutical Research, vol. 14, No. 6, (1997), 730-735.Applicant
Jonasson, P., et al., “Denatured states of human carbonic anhydrase II: an NMR study of hydrogen/deuterium exchange at tryptophan-indole-Hn sites”, FEBS Letters, 445, (1999), pp. 361-365.Applicant
Kalltorp, Mia, et al., “Inflammatory cell recruitment, distribution, and chemiluminescence response at IgG precoated- and thiol functionalized gold surfaces”, Swedish Biomaterials Consortium, Swedish Foundation for Strategic Research, (Apr. 9, 1999), 251-259.Applicant
Kaplan, D.L., et al., “Spiderless Spider Webs”, Nature Biotechnology, vol. 20, (2002), 239-240.Applicant
Kawai, et al., “Accelerated tissue regeneration through incorporation of basic fibroblast growth factor-impregnated gelatin microspheres into artificial dermis”, Biomaterials, 21(5), (Mar. 2002), 489-499.Applicant
Kawasuji, M., et al., “Therapeutic Angiogenesis with Intramyocardial Administration of Basic Fibroblast Growth Factor”, Ann Thorac Surg, 69, Abstract downloaded from the Internet at: http://ats.ctsnetjournals.org/cgi/content/abstract/69/4/1155, 2 pages, (2000), pp. 1155-1161.Applicant
Kelley, et al., “Restraining Infarct Expansion Preserves Left Ventricular Geometry and Function After Acute Anteroapical Infarction”, Circulation, 99, (1999), pp. 135-142.Applicant
Kelly, E. B., “Advances in Mammalian and Stem Cell Cloning”, Genetic Engineering News, vol. 23, No. 7, (Apr. 1, 2003), pp. 17-18 & 68.Applicant
Khademhosseini, et al., “Microscale Technologies for Tissue Engineering and Biology”, PNAS, vol. 103, No. 8, (Feb. 21, 2006), pp. 2480-2487.Applicant
Kim, D. , et al., “Glow Discharge Plasma Deposition (GDPD) Technique for the Local Controlled Delivery of Hirudin from Biomaterials”, Pharmaceutical Research, 15(5), (1998), pp. 783-786.Applicant
Kim, Ung-Jin, et al., “Structure and Properties of Silk Hydrogels”, Biomacromolecules, vol. 5(3), (2004), 786-792.Applicant
Kinart, et al., “Electrochemical Studies of 2-hydroxy-3-(3,4-dimethyl-9-oxo-9H-thioxanthen-2-yloxy)N,N,N-trimethyl-1-propanium chloride”, J. Electroanal. Chem, 294, (1990), pp. 293-297.Applicant
Kipshidze, Nicholas, et al., “Therapeutic angiogenesis for critical limb ischemia to limit or avoid amputation”, University of Wisconsin Medical School, The Journal of Invasive Cardiology, vol. 11, No. 1, (Jan. 1999), 25-28.Applicant
Klein, S. , et al., “Fibroblast Growth Factors as Angiogenesis Factors: New Insights Into Their Mechanism of Action”, Regulation of Angiogenesis, I.D. Goldberg and E.M. Rosen (eds.), 79, (1997), pp. 159-192.Applicant
Klugherz, Bruce D., et al., “Gene delivery from a DNA controlled-release stent in porcine coronary arteries”, Nature Biotechnology, vol. 18, (Nov. 2000), 1181-1184.Applicant
Kohilas, K, et al., “Effect of prosthetic titanium wear debris on mitogen-induced monocyte and lymphoid activation”, John Hopkins University, Dept. of Orthopaedic Surgery, (Apr. 1999), 95-103.Applicant
Kwok, C., et al., “Design of Infection-Resistant Antibiotic-Releasing Polymers: I. Fabrication and Formulation”, Journal of Controlled Release, 62, (1999), pp. 289-299.Applicant
Laboratory of Liposome Research, “Liposomes: General Properties”, downloaded from the Internet on Feb. 9, 2006 at: http://www.unizh.ch/onkwww/lipos.htm, 5 pages.Applicant
Laham, R. J., “Intrapericardial Delivery of Fibroblast Growth Factor-2 Induces Neovascularization in a Porcine Model of Chronic Myocardial lschemia”, J. Pharmacol Exper Therap, 292(2), (2000), pp. 795-802.Applicant
Leibovich, S. J., et al., “Macrophage-Induced Angiogenesis is Mediated by Tumour Necrosis Factor-α”, Nature, vol. 329, (Oct. 15, 1987), pp. 630-632.Applicant
Leor, J., et al., “Bioengineered Cardiac Grafts—A New Approach to Repair the Infarcted Myocardium?”, Circulation, 102[suppl III], (2000), pp. III-56-III-61.Applicant
Leor, J., et al., “Gene Transfer and Cell Transplant: An Experimental Approach to Repair a ‘Broken Heart’”, Cardiovascular Research, 35, (1997), pp. 431-441.Applicant
Leroux, J. C., et al., “An Investigation on the Role of Plasma and Serum Opsonins on the Internalization of Biodegradable poly(D,L-lactic acid) Nanoparticles by Human Monocytes”, Life Sci., 57(7), Abstract downloaded from the Internet at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed, 1 page, (1995), pp. 695-703.Applicant
Lewin, B., “Repressor is Controlled by a Small Molecule Inducer”, Genes VII, Oxford University Press, 7th ed., (2000), pp. 277-280.Applicant
Li, et al., “Cell Therapy to Repair Broken Hearts” Can. J. Cardiol., vol. 14, No. 5, (May 1998), pp. 735-744.Applicant
Li, W. W., et al., “Lessons to be Learned from Clinical Trials of Angiogenesis Modulators in Ischemic Diseases”, Angiogenesis in Health & Disease: Basic Mechanisms and Clinical Applications, Rubanyi, G. (ed), Marcel Dekker, Inc. New York, (2000), Chapter 33.Applicant
Li, J., et al., “PR39, A Peptide Regulator of Angiogenesis”, Nature Medicine, 6(1), (Jan. 2000), pp. 49-55.Applicant
Li., Y. Y., et al., “Differential Expression of Tissue Inhibitors of Metalloproteinases in the Failing Human Heart”, Circulation, 98(17), (1998), pp. 1728-1734.Applicant
Lindsey, M., et al., “Selective Matrix Metalloproteinase Inhibition Reduces Left Ventricular Remodeling but does not Inhibit Angiogenesis after Myocardial Infarction”, Circulation, 105(6), (2002), pp. 753-758.Applicant
Long, D. M., et al., “Self-Cleaving Catalytic RNA”, FASEB Journal, 7, (1993), pp. 25-30.Applicant
Lopez, J. J., et al., “Angiogenic potential of perivascular delivered aFGF in a porcine model of chronic myocardial ischemia” The American Physiological Society, 0363-6135/98, (1998), H930-H936.Applicant
Lopez, J. J., et al., “VEGF Administration in Chronic Myocardial Ischemia in Pigs”, Cardiovasc. Res., 40(2), Abstract downloaded from the Internet at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed, 1 page, (1998), pp. 272-281.Applicant
Lu, L., et al., “Biodegradable Polymer Scaffolds for Cartilage Tissue Engineering”, Clinical Orthopaedics and Related Research, Carl T. Brighton (ed.). No. 391S, (2001), pp. S251-270.Applicant
Luo, Y., et al., “Cross-linked Hyaluronic Acid Hydrogel Films: New Biomaterials for Drug Delivery”, Journal of Controlled Release, 69, (2000), pp. 169-184.Applicant
Lutolf, M, et al., “Synthesis and Physicochemical Characterization of End-Linked Poly(ethylene glycol)-co-peptide Hydrogels Formed by Michael-Type Addition”, Biomacromolecules, vol. 4, (2003), 713-722.Applicant
Lyman, M. D., et al., “Characterization of the Formation of Interfacially Photopolymerized Thin Hydrogels in Contact with Arterial Tissue”, Biomaterials, 17(3), (1996), pp. 359-364.Applicant
Mansour, S., et al., “Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes”, Nature, 336, (1988), pp. 348-352.Applicant
Martin, S. L., et al., “Total Synthesis and Expression in Escherichia coli of a Gene Encoding Human Tropoelastin”, Gene, (1995), Abstract, 1 page.Applicant
McDevitt, T., et al., “In vitro Generation of Differentiated Cardiac Myofibers on Micropatterned Laminin Surfaces”, J. Biomed Mater Res., 60, (2002), pp. 472-479.Applicant
Meinel, L., et al., “The Inflammatory Responses to Silk Films In Vitro and In Vivo”, Biomaterials, vol. 26, (2005), 147-155.Applicant
Narmoneva, D. A., et al., “Self-assembling short oligopeptides and the promotion of angiogenesis”, Biomaterials, 26, (2005), pp. 4837-4846.Applicant
Nazarov, R., et al., “Porous 3-D Scaffolds from Regenerated Silk Fibroin”, Biomacromolecules, vol. 5(3), (2004), 718-726.Applicant
Nguyen, K. T., et al., “Photopolymerizable Hydrogels for Tissue Engineering Applications”, Biomaterials, 23, (2002), pp. 4307-4314.Applicant
Nikolic, S. D., et al., “New Angiogenic Implant Therapy Improves Function of the Ischemic Left Venticle”, Supplement to Circulation; Abstracts From Scientific Sessions 2000, 102(18), (Oct. 2000), pp. II-689, Abstract 3331.Applicant
Nitinol Technical Information, “NiTi Smart Sheets”, downloaded from the Internet on Dec. 10, 2002 at: http://www.sma-inc.com/information.html, 1 page.Applicant
Nose, et al., “A novel cadherin cell adhesion molecule: its expression patterns associated with implantation and organogenesis of mouse embryos”, Journal of Cell Biology, vol. 103 (No. 6, Pt. 2), The Rockefeller University Press, (Dec. 1986), 2649-2658.Applicant
Ohyanagi, H., et al., “Kinetic Studies of Oxygen and Carbon Dioxide Transport into or from Perfluorochemical Particles”, Proc. ISAO, vol. 1 (Artificial Organs vol. 2) (Suppl.)), (1977), pp. 90-92.Applicant
Ozbas, B., et al., “Salt-Triggered Peptide Folding and Consequent Self-Assembly into Hydrogels with Tunable Modulus”, Macromolecules, 37(19), (2004), pp. 7331-7337.Applicant
Ozbas-Turan, S., “Controlled Release of Interleukin-2 from Chitosan Microspheres”, Journal of Pharmaceutical Sciences, 91(5), (May 2002), pp. 1245-1251.Applicant
Palmiter, R., et al., “Germ-Line Transformation of Mice”, Ann. Rev. Genet., 20, (1986), pp. 465-499.Applicant
Patrick, C. R., “Mixing and Solution Properties of Organofluorine Compounds”, Preparation, Properties and Industrial Applications of Organofluorine Compounds, Chapter 10, R.E. Banks (ed.), 1st edition, Ellis-Horwood Ltd., Chichester:England, (1982), pp. 323-342.Applicant
Peattie, R. A., et al., “Stimulation of In Vivo Angiogenesis by Cytokine-Loaded Hyaluronic Acid Hydrogel Implants”, Biomaterials, 25(14), Abstract downloaded from: www.sciencedirect.com, (Jun. 2004), 2 pages.Applicant
Penta, K., et al., “Del1 Induces Integrin Signaling and Angiogenesis by Ligation of αVβ3”, J. Biolog. Chem., 274(16), (Apr. 1999), pp. 11101-11109.Applicant
Perin, E. C., et al., “Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic, Ischemic Heart Failure”, Circulation, (2003), 1 page.Applicant
Pouzet, B., et al., “Is Skeletal Myoblast Transplantation Clinically Relevant in the Era of Angiotensin-Converting Enzyme Inhibitors?”, Circulation, 104 [suppl I], (Sep. 2001), pp. I-223-I-228.Applicant
Prather, et al., “Nuclear Transplantation in Early Pig Embryos”, Biol. Reprod., 41, (1989), pp. 414-418.Applicant
Prosci Incorporated, “ILPIP (CT) Peptide”, 1 page.Applicant
Quellec, P., et al., “Protein Encapsulation Within Polyethylene Glycol-coated Nanospheres. I. Physicochemical Characterization”, J. Biomed. Mater. Res., 42(1), (1998)), Abstract, 1 page.Applicant
Ramirez-Solis, R., et al., “Gene Targeting in Embryonic Stem Cells”, Methods in Enzymology, 225, (1993), pp. 855-878.Applicant
Rowley, et al., “Alginate Hydrogels as Synthetic Extracelllular Matrix Materials”, Biomaterials, 20(1), (1999), 45-53.Applicant
Sawhney, A. S., et al., “Bioerodible Hydrogels Based on Photopolymerized Poly(ethylene glycol)-co-poly(a-hydroxy acid) Diacrylate Macromers”, Macromolecules, 26(4), (1993), pp. 581-587.Applicant
Sbaa-Ketata, E., et al., “Hyaluronan-Derived Oligosaccharides Enhance SDF-1-Dependent Chemotactic Effect on Peripheral Blood Hematopoietic CD34+ Cells”, Stem Cells, 20(6), Letter to the Editor downloaded from the Internet at: http://stemcells.alphamedpress.org/cgi/content/full/20/6/585, (2002), 585-587.Applicant
Segura, T, et al., “Crosslinked Hyaluronic Acid Hydrogels: A Strategy to Functionalize and Pattern”, Biomaterials, vol. 26(4), (Feb. 2005), 359-371.Applicant
Segura, T, et al., “DNA delivery from hyaluronic acid-collagen hydrogels via a substrate-mediated approach”, Biomaterials, vol. 26, (2005), 1575-1584.Applicant
Segura, T., et al., “Substrate-Mediated DNA Delivery: Role of the Cationic Polymer Structure and Extent of Modification”, Journal of Controlled Release, 93, (2003), pp. 69-84.Applicant
Segura, T., et al., “Surface-Tethered DNA Complexes for Enhanced Gene Delivery”, Bioconjugate Chem, 13(3), (2002), pp. 621-629.Applicant
Shibasaki, F., et al., “Suppression of Signalling Through Transcription Factor NF-AT by Interactions Between Calcineurin and Bcl-2”, Nature, 386(6626), Abstract downloaded from the Internet at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Text&DB=pubmed, 1 page, (1997).Applicant
Shin, H., et al., “Attachment, Proliferation, and Migration of Marrow Stromal Osteoblasts Cultured on Biomimetic Hydrogels Modified with an Osteopontin-Derived Peptide”, Biomaterials, 25, (2004), pp. 895-906.Applicant
Shin, H., et al., “In vivo bone and soft tissue response to injectable, biodegradable oligo(poly(ethylene glycol) fumarate) hydrogels”, Biomaterials 24, Elseview Science Ltd., (3201-3211), 2003.Applicant
Shu, Z, et al., “Disulfide-crosslinked hyaluronan-gelatin hydrogel films: a covalent mimic of the extracellular matrix for in vitro cell growth”, Biomaterials, vol. 24(21), (Sep. 2003), 3825-3834.Applicant
Shu, Zheng, et al., “In situ crosslinkable hyaluronan hydrogels for tissue engineering”, Biomaterials, vol. 25, (2004), 1339-1348.Applicant
Simons, M., et al., “Clinical trials in coronary angiogenesis: Issues, problems, consensus, An expert panel summary”, Angiogenesis Research Center, American Heart Association, Inc.,, (Sep. 12, 2000), 1-14.Applicant
Spenlehauer, G, et al., “In vitro and in vivo degradation of poly(D,L lactide/glycolide) type microspheres made by solvent evaporation method”, Biomaterials, vol. 10, (Oct. 1989), 557-563.Applicant
Spinale, F. G., “Matrix Metalloproteinases—Regulation and Dysregulation in the Failing Heart”, Circ. Res., 90, (2002), pp. 520-530.Applicant
Springer, M., et al., “Angiogenesis Monitored by Perfusion with a Space-Filling Microbead Suspension”, Mol. Ther., 1(1), Abstract downloaded from the Internet at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed, 1 page, (2000), pp. 82-87.Applicant
Storm, G., et al., “Surface Modification of Nanoparticles to Oppose Uptake by the Mononuclear Phagocyte System”, Advanced Drug Delivery Reviews, 17(1), Abstract downloaded from the Internet at: http://www.sciencedirect.com, 1 page, (Oct. 1995), pp. 31-48.Applicant
Strauer, B., et al., “Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans”, Circulation, 106, (2002), pp. 1913-1918.Applicant
Tybulewicz, V., et al., “Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene”, Cell, 65(7), Abstract downloaded from the Internet at: http://www.sciencedirect.com, 2 pages, (Jun. 1991), pp. 1153-1163.Applicant
Unger, E. F., et al., “Effects of a Single Intracoronary Injection of Basic Fibroblast Growth Factor in Stable angina Pectoris”, Am. J. Cardiol, 85(12), Abstract downloaded from the Internet at: http://www.sciencedirect.com, 2 pages, (Jun. 2000), pp. 1414-1419.Applicant
Van Der Giessen, Willem J., et al., “Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries”, Dept. of Cardiology, Erasmus University Rotterdam, Circulation, vol. 94, No. 7, (Oct. 1, 1996), 1690-1697.Applicant
Van Luyn, M. J., et al., “Cardiac Tissue Engineering: Characteristics of In Unison Contracting Two- and Three-Dimensional Neonatal Rat Ventricle Cell (Co)-Cultures”, Biomaterials, 23, (2002), pp. 4793-4801.Applicant
Vercruysse, K. P., et al., “Synthesis and in Vitro Degradation of New Polyvalent Hydrazide Cross-Linked Hydrogels of Hyaluronic Acid”, Bioconjugate Chem, 8(5), Abstract downloaded from the Internet at: http://pubs.acs.org/cgi-bin/abstract.cgi/bcches/1997/8/i05/abs/bc9701095.html, 1 page, (1997), pp. 686-694.Applicant
Visscher, G.E., et al., “Tissue response to biodegradable injectable microcapsules”, Journal of Biomaterials Applications, vol. 2, (Jul. 1987), 118-119.Applicant
Vlodavsky, I., et al., “Extracellular Matrix-resident Basic Fibroblast Growth Factor: Implication for the Control of Angiogenesis”, J. Cell Biochem, 45(2), Abstract downloaded from the Internet at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed, 1 page, (Feb. 1991), pp. 167-176.Applicant
Wang, M., et al., “Mechanical Properties of Electrospun Silk Fibers”, Macromolecules, vol. 37(18), (2004), 6856-6864.Applicant
Wasielewski, “Ischamische Erkrankungen, Gefassneubildung anregen”, Deutsche Apotheker Zeitung, vol. 140, No. 3, Stuttgart (DE), (Jan. 20, 2000), 232-233.Applicant
Wilensky, R., et al., “Direct intraarterial wall injection of microparticles via a catheter: a potential durg delivery strategy following angioplasty”, American Heart Journal, 122, (1991), p. 1136.Applicant
Witzenbichler, B., et al., “Vascular Endothelial Growth Factor-C (VEGF-C/VEGF-2) Promotes Angiogenesis in the Setting of Tissue lschemia”, AM Pathol., 153(2), (Aug. 1998), pp. 381-394.Applicant
Yager, P., et al., “Silk Protein Project”, www.faculty.washington.edu/yagerp/silkprojecthome.html, (Aug. 23, 1997), 18 pages.Applicant
Yamamoto, N., et al., “Histologic evidence that basic fibroblast growth factor enhances the angiogenic effects of transmyocardial laser revascularization”, Basic Research in Cardiology, vol. 95, No. 1, (Feb. 1, 2000), 55-63.Applicant
Yeo, L.Y., et al., “AC Electrospray Biomaterials Synthesis”, Biomaterials, (2005), 7 pages.Applicant
Zervas, L., et al., “On Cysteine and Cystine Peptides. II. S-Acylcysteines in Peptide Synthesis”, J. Am. Chem. Soc., 85(9), (May 1963), pp. 1337-1341.Applicant
Zheng, W., et al., “Mechanisms of coronary angiogenesis in response to stretch: role of VEGF and TGF-beta”, Am J Physiol Heart Circ Physiol., 280(2), (Feb. 2001), pp. H909-H917.Applicant
Zimmermann, W., et al., “Engineered Heart Tissue for Regeneration of Diseased Hearts”, Biomaterials, 25, (2004), pp. 1639-1647.Applicant
Hanawa, T., et al., “New oral dosage form for elderly patients: preparation and characterization of silk fibroin gel”, Chemical and Pharmaceutical Bulletin, Pharmaceutical Society of Japan, Tokyo, vol. 43, No. 2, (Jan. 1995), 284-288.Applicant
Kweon, H. Y., et al., “Preparation of semi-interpenetrating polymer networks composed of silk fibroin and poly(ethyleneglycol) macromer”, Journal of Applied Polymer Science, John Wiley and Sons Inc., New York, NY, vol. 80, (Jan. 2001), 1848-1853.Applicant
Friedman, Paul M., et al., “Safety Data of Injectable Nonanimal Stabilized Hyaluronic Acid Gel for Soft Tissue Augmentation,” Dermatologic Surgery, 2002, vol. 28, pp. 491-494.Applicant
Abbott Cardiovascular Systems, Non Final Office Action dated Apr. 6, 2009 for U.S. Appl. No. 11/447,340.Applicant
Abbott Cardiovascular Systems, Non Final Office Action dated Mar. 30, 2009 for U.S. Appl. No. 10/792,960.Applicant
Abbott Cardiovascular Systems, Non Final Office Action dated Apr. 13, 2009 for U.S. Appl. No. 11/566,643.Applicant
Abbott Cardiovascular Systems, Non Final Office Action dated Apr. 29, 2009 for U.S. Appl. No. 12/013,286.Applicant
Abbott Cardiovascular Systems, Non Final Office Action dated Mar. 13, 2009 for U.S. Appl. No. 10/414,602.Applicant
Abbott Cardiovascular Systems, Non final office action dated Jul. 9, 2009 for U.S. Appl. No. 11/561,328.Applicant
Elbert, D. L., et al., “Protein delivery from materials formed by self-selective conjugate addition reactions”, Journal of Controlled Release, 76, (2001), 11-25.Applicant

Abstract