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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Expert Rev Cardiovasc Ther. Author manuscript; available in PMC Jun 1, 2013.
Published in final edited form as:
PMCID: PMC3556462
NIHMSID: NIHMS415859
Biomaterial applications in cardiovascular tissue repair and regeneration
Mai T Lam1 and Joseph C Wu*2,3
1Department of Surgery, Division of Plastic and Reconstructive Surgery, Hagey Pediatric Regenerative Research Laboratory, Stanford University School of Medicine, CA, USA
2Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA
*Author for correspondence: Tel.: +1 650 723 6145, Fax: +1 650 723 8392, joewu/at/stanford.edu
Cardiovascular disease physically damages the heart, resulting in loss of cardiac function. Medications can help alleviate symptoms, but it is more beneficial to treat the root cause by repairing injured tissues, which gives patients better outcomes. Besides heart transplants, cardiac surgeons use a variety of methods for repairing different areas of the heart such as the ventricular septal wall and valves. A multitude of biomaterials are used in the repair and replacement of impaired heart tissues. These biomaterials fall into two main categories: synthetic and natural. Synthetic materials used in cardiovascular applications include polymers and metals. Natural materials are derived from biological sources such as human donor or harvested animal tissues. A new class of composite materials has emerged to take advantage of the benefits of the strengths and minimize the weaknesses of both synthetic and natural materials. This article reviews the current and prospective applications of biomaterials in cardiovascular therapies.
Keywords: biomaterials, cardiac repair, decellularized tissues, extracellular matrix, metals, polymers, regeneration, stem cells, tissue reconstruction
Cardiovascular disease remains the leading cause of death in the USA, resulting in nearly US$300 billion in healthcare costs annually [1]. The irreversible organ damage from the disease creates an urgent need for novel methods of repair for the heart. Treatments for cardiac disease include approaches ranging from medications to surgical interventions. Most surgical options involve circumventing the damaged tissues, as in bypass grafts, or replacing them, as in heart transplants. However, sources for human donor tissues are in chronic shortage. Creating alternative therapies would significantly expand patient care options. Efficient means for repairing, reconstructing or regenerating damaged tissues would greatly diminish the need for scarce donor organs. Biomaterials have shown increasing potential as a tool for such procedures. This article reviews the different types of biomaterials used in cardiovascular therapies and the cardiac conditions these materials are designed to treat. Novel cardiovascular treatments involving engineered tissue and composite materials are also discussed.
A biomaterial is broadly defined as a material that interacts with biological systems for medical purposes. Biomaterials fall into two main categories: synthetic and natural (Figure 1). Synthetic materials include the classically defined materials of metals, polymers and ceramics. Natural biomaterials are derived from native tissues from autogenic (same individual), allogenic (same-species donor) or xenogenic (animal) sources. Nonhuman tissues are harvested from animal sources such as cows or pigs. In medical applications, preference in the choice of biomaterial has traditionally been for inert materials, in order to minimize reaction with the biological tissues it is in contact with. Examples are titanium metal implants used in hip replacements that do not react chemically with the local area, or biologically inert gold dental fillings. However, newer research has revealed many advantages of interactive biomaterials for expanding treatments to include drug delivery for therapeutics or stem cell transplants for tissue repair and regeneration.
Figure 1
Figure 1
Overview of biomaterials currently used in cardiovascular applications
The term ‘biocompatibility’ is somewhat ambiguous, as the field continues to redefine the nomenclature based on the latest research findings. Biocompatibility generally refers to a biomaterial with properties favorable for implantation while eliciting minimal adverse reactions. Whether the need is for cardiovascular reconstruction purposes or tissue replacement, a biomaterial for implantation must have durability, strength and flexibility to withstand approximately 2 billion cardiac cycles expected to occur in an average lifetime. Equally important are the materials’ biologic properties, the most desirable of which being anti-thrombogenicity, noncalcification, hemostasis, nonimmunogenicity and endothelialization capability.
Synthetic biomaterials used in cardiovascular applications primarily encompass polymers, metals or a combination of both (Figure 2). Ceramics are used to a much lesser extent in cardiac-related treatments. The main benefits of synthetic materials are their strength and durability, although their biocompatibility issues can create complications. Toxicity is of utmost concern with synthetic materials, especially in the case of biodegradable materials, which can release potentially harmful byproducts of degradation into the body. Chemically inert materials have served as a practical foundation for implantable substances, allowing for stand-alone use or drug delivery through coatings. The most commonly used synthetic materials for cardiac-related applications are described in this article and are summarized in Table 1.
Figure 2
Figure 2
Examples of various biomaterials used in cardiovascular products
Table 1
Table 1
Applications of biomaterial products in treatment of cardiovascular conditions.
Expanded polytetrafluoroethylene
The use of expanded polytetrafluoroethylene (ePTFE) in cardiovascular applications has become routine owing to this material’s performance and ease of use. Commercially, this material is better known as Gore-tex®, and is manufactured by Gore Medical into cardiovascular products for general cardiac reconstruction, vascular grafts and pediatric shunts [201]. ePTFE is composed of a fluorocarbon polymer, formed into sheets by extrusion. A three-layer polymer is created, with a middle microporous, elastic layer surrounded by two layers of polymer fibrils [2]. The resultant structure provides for a high strength-to-weight ratio and resistance to dilatation. The chemical composition promotes low thrombogenicity, lower rates of restenosis and hemostasis, less calcification and biochemically inert properties [3-6]. In addition, ePTFE has been shown to have high resistance to allergic reaction and inflammation [7]. These material properties have made ePTFE an excellent option for creating shunts [8-10], reconstruction [11] and valve repair [12], and have even been used for covering implantable devices to minimize inflammation [5]. However, since ePTFE is a synthetic material, it can elicit a negative immune response and thrombosis.
Polyethylene terephthalate
Polyethylene terephthalate (PET), or Dacron®, is a thermoplastic polymer manufactured by Maquet Cardiovascular, with a chemical inertness contributing to its biocompatibility. This material can be manufactured in many forms, but is typically used in cardiovascular purposes as vascular grafts in the woven or knitted configuration. Woven PET has smaller pores compared with the knitted form, which therefore reduces blood leakage. In cardiovascular applications, PET is used for constructing vascular grafts. PET grafts are available with a protein coating, usually collagen or albumin, in order to reduce blood loss and to act as an antibiotic to prevent graft infection [13]. The surfaces of PET grafts are often crimped to stimulate tissue incorporation. Advantageously, PET grafts have been found to promote endothelialization by recruiting endothelial cells to the graft’s luminal surface, with no calcification or tissue overgrowth. Collagen and glycosaminoglycan deposits have also been found in implanted grafts, and circumferential mechanical properties show little degradation over time [14]. Similar to ePTFE, PET also has the disadvantage of being a synthetic material and can cause a foreign body reaction with increased chance of thrombus formation.
Prelining PET vascular grafts with endothelial cells has been explored as a means for improving patency rates. In animals, this approach has resulted in improved graft performance [15]; however, human clinical trials showed low patency rates compared with autologous grafts [16]. Currently, PET grafts are used more often than ePTFE ones, although new evidence shows that ePTFE offers some advantages such as lower thrombogenicity [17]. Application of either biomaterial is dependent on the parameters required for the specific cardiovascular tissue to be repaired or replaced.
Polyurethane
Polyurethanes (PUs) belong to a class of compounds called reaction polymers, and are formed by the reaction of an isocyanate group with a hydroxyl group to form a foam. Alternatively, PU can be manufactured into a harder thermoplastic form used in medical applications. Thermoplastic PU has high shear strength, elasticity and transparency. The microbial resistance is ideal for preventing infection, and the material’s pliability contributes to improved handling characteristics. The probability for thrombosis of PU is similar to other materials such as PTFE [18]. This material was used frequently in the past in valve replacements [19], until metal and bioprosthetic replacement valves emerged. Currently, PU is mostly used in cardiac pacing leads as an insulator [20]. Although PU is durable, it lacks flexibility. To solve this problem, pacing leads are manufactured with the option of a PU–silicone copolymer to take advantage of silicone’s flexibility [202]. Pacing leads coated with silicone alone are also available in the market. Silicone-coated leads have been shown to maintain electrical properties important to pacing better than PU-insulated leads [21]. Each material (PU or silicone) has its own advantages, and leads insulated in either material or a copolymer of both are selected based on the specific requirements of the patient.
On the research side, PU is being investigated as a substrate in cardiac stem cell therapy, with in vitro studies being carried out on the influence of patterned PU substrates on stem-cell-derived cardiomyocyte phenotype [22,23]. One disadvantage to PU cardiovascular implants is the material’s tendency to oxidize and degrade in vivo, creating problems after implantation. Modifications to the material have been effective, as it has been shown that chemically coating the surface with an antioxidant aids in reducing oxidation [24].
Metals
Chemically nonreactive metals have been used for many medical purposes for several decades because of their strength and biocompatibility. Commonly used biocompatible metals include titanium, stainless steel, gold and silver. In the cardiovascular arena, metals are used in stents for opening the lumen of obstructed vessels. Titanium and stainless steel have been classically used in stent design, with newer stents utilizing cobalt–chromium or platinum–chromium alloys for their greater strength [25,26]. Nitinol stents made from a nickel and titanium alloy dominated the market in the past because of their shape memory properties, but nickel allergies have since eliminated their use [27]. Metals are also extensively used in the replacement of heart valves. Mechanical replacement heart valves are constructed from metals such as stainless steel or titanium [28]. Mechanical valves can last the lifetime of a patient, although anticoagulant medications are required for the remainder of their lives because of the higher chance for blood clot formation [29]. Patients who cannot take anticoagulants must choose other valve options, such as natural tissue valves discussed in more detail below.
Whereas synthetic materials have performed better in repair and replacement of damaged cardiovascular tissues, they pale in comparison with the functional capabilities of natural tissues. Each of the tissues in the body is uniquely optimized to its specific organ system, and offers an innate biocompatibility. Autologous tissue, or tissue harvested from and used for the same patient, is the current gold standard for its superior functionality and nonimmunogenicity. Supply of tissues needed and health status of the patient are major hindrances to obtain autologous tissue. The next best choice is allogenic tissues or donor tissues from organisms of the same species; in humans, these tissues are called homografts. Unfortunately, human donor tissues needed for treating cardiovascular disease are in very limited supply, and heart transplant lists remain long. Xenogenic tissues from animals have helped to fill this need, particularly with tissue repairs or valve replacements [30].
Immune response is of particular concern with allogenic and xenogenic tissues. With allogenic human donor tissues, immunosuppressive drugs must be taken by the patient, and even then the tissue or organ may still be rejected [31]. To eliminate immune rejection with xenogenic tissues, they are decellularized before use in patients [32]. Mostly, extracellular matrix (ECM) materials such as collagens and proteins remain after decellularization, leaving a scaffold for damaged tissue to repair in and around the area. In cardiovascular applications, bovine (cow), porcine (pig) and equine (horse) tissue sources have become quite popular for their compatibility to human-sized organs. In this article, common examples of natural materials that are most often used in cardiovascular treatments are described and are summarized in Table 1.
Small intestine submucosa
A material gaining recent popularity in cardiovascular applications is derived from the submucosa of the small intestine. This material is retrieved from porcine sources. Though the small intestine submucosa (SIS) can be processed in many ways, it is generally prepared by first opening the harvested small intestine longitudinally and then mechanically removing the submucosa layer while keeping the basement membrane intact. Cells are removed with an acid, and the resultant ECM sheets are sterilized for patient use [33]. The SIS-ECM is comprised of collagens I, III, IV, V and VII, fibronectin, elastin, glycosaminoglycans, glycoproteins and growth factors such as VEGF, FGF-2 and TGF-β [34].
Used successfully for decades as a wound dressing, other clinical applications have been explored for SIS. In cardiac treatments, so far SIS has been used for pericardial reconstruction and carotid repair [35,36]. Advantages to this material include its biodegradability, hemostatic capability, nonencapsulation and noncalcification [33]. Disadvantages include a relative shortage in supply and potential immunogenicity issues from the decellularized xenogenic tissue. Interestingly, in an orthopedic application, SIS was shown to promote cell migration into itself once implanted and to encourage subsequent local tissue remodeling and regeneration [37]. These results are promising for regenerating cardiac tissue.
Several animal studies have been conducted to investigate other possible cardiac-related applications of SIS. An emulsion form of SIS has been tested for effectiveness in treating myocardial infarction (MI). Infarcted animal hearts were injected with the SIS emulsion. Angiogenesis was significantly increased compared with control infarcted hearts injected with saline. Echocardiography showed improved fractional shortening, ejection fraction and stroke volume [38]. The potential of SIS to serve as a scaffold for cardiac tissue engineering has also been examined. In one study, neonatal rat cardiac cells were mixed with a gel form of SIS and deposited onto polymer substrates. The resulting tissue constructs showed significantly higher contraction rates and greater troponin T expression compared with Matrigel™ (BD Biosciences) controls [39]. A combined SIS and stem cell therapy for treating chronic MI was also investigated. Bone marrow mesenchymal stem cells (MSCs) were seeded onto patches of SIS and grafts were implanted onto the epicardial surface of infarcted myocardium in rabbits. Patches of SIS alone were also implanted for comparison. Left ventricular contractile function and dimension, capillary density of the infarcted area and myocardial pathological changes were significantly improved in both SIS groups with and without cells.
Results with cells were slightly better [40]. These animal studies show that SIS has potential to be used for treating MI and also for cell delivery with the purpose of regenerating the damaged areas of the heart. Finally, in a clinical study on patients undergoing primary isolated coronary artery bypass grafting, a statistically significant decrease in the rate of postoperative atrial fibrillation was seen in patients who also underwent pericardial reconstruction using SIS compared with those without any reconstruction [35].
Pericardium
The pericardium is a fibroserous sac surrounding the mammalian heart. It has long been used in cardiac repair for reconstruction, valve repair and pericardial closure [41,42]. Xenogenic pericardium is commonly derived from bovine, porcine and, less frequently, equine sources. Tissues from these sources are available in large patches, allowing custom configuration to a variety of cardiovascular applications. It is largely comprised of collagen fibers and has elastic properties allowing conformity to complex anatomy. Pericardial tissue has exceptional handling characteristics and uniform suture retention. In addition, it is nonthrombogenic and naturally resists infection [43].
To reduce the probability of an adverse immune response, the pericardium is decellularized using one of many possible processing procedures, resulting in predominantly ECM components. Tissue morphology and collagen structures are dependent on the decellularization process chosen [44]. Following removal of cellular content, the tissue is typically crosslinked using glutaraldehyde for preservation and to increase strength of the biomaterial. However, calcification of pericardial grafts postimplantation is attributed to glutaraldehyde processing [45,46]. Hence, several studies have investigated new methods for processing the pericardium to maintain ECM content and structure, and to strengthen the biological tissue without causing calcification in vivo. Approaches have included treating the glutaraldehyde-processed pericardium with glutamic acid [45], modifying the decellularization procedure [44], and nanocoating pericardial grafts with titanium to prevent immune reactions and thus calcification [47]. Some anticalcification technologies are being used in commercially available pericardial grafts [203], although most techniques still require more testing in order to become routine practices.
There are slight differences between pericardium from the different sources. Pericardium from bovine sources has higher collagen content than that derived from porcine origins [48,49]. Valves fabricated from bovine pericardium have shown less obstruction than valves made from porcine pericardial tissue, although both valves show similar hemodynamic results [50]. Bovine and porcine tissues did not exhibit a significant difference in the degree of calcification under varying glutaraldehyde treatments [46].
Bioprosthetic valves
Severely damaged heart valves require replacement. Generally, metal mechanical valves or bioprosthetic (i.e., biological) valves obtained from human donor or animal sources are used. Blood has a tendency to adhere to the metal in mechanical valves, resulting in blood clots. Therefore, patients with mechanical valves must take anticoagulant medications for the rest of their lives [51]. Natural tissue valves do not require the use of anticoagulants, which is an advantage over mechanical valves. The most common animal sources for biological valves are bovine or porcine tissues [52]. On average, bovine valves typically last 15–20 years whereas porcine valves last 8–15 years [202]. Differences between commercial valves are mostly due to the variation in manufacturers’ specifications, including variable parameters such as hemodynamics, implantation method, suturability and valve dimensions [203]. When bioprosthetic valves fail, it is usually due to calcification and tearing [53].
Although mechanical valves made of titanium or carbon are stronger and last longer than biological valves (typically up to 25 years), patients implanted with mechanical valves must continually take an anticoagulant medication (e.g., Coumadin®; Bristol-Myers Squibb). Age is a major factor in longevity of a replacement valve. Children and younger patients use up replacement valves faster than older patients because of activity and metabolism [54]. Patients younger than 65–70 years of age typically receive mechanical valves, while patients older than that receive bioprosthetic valves. Middle-aged patients may select either type of valve, although there is evidence that bioprosthetic valves are a better choice for this age group because these valves are likely to last the remainder of the patients’ lives without the use of anticoagulant medications [55].
Injectable biomaterials
In recent years, injectable biomaterials have seen significant increase in application towards treating MI [56-58]. Injectable materials mostly encompass: hydrogels composed of alginate, fibrin, chitosan, collagen or matrigel; and self-assembling peptides generally in the form of nanofibers. Injectables originally generated interest owing to their biocompatibility, ability to provide beneficial chemical environments and, above all, for their potential to be delivered noninvasively. Efficacy of these materials has been explored extensively in animal infarct models and has shown success in improving cardiac function, reducing infarct size, increasing wall thickness in the infarcted area and increasing neovascularization. Alginate hydrogel is a polysaccharide derived from seaweed. It is used as a temporary ECM substitute and has affinity-binding moieties, enabling binding of proteins and their controlled release for drug delivery and transfer of growth factors [59]. Alginate gel has been shown to reverse left ventricular remodeling following MI [60]. Fibrin is formed from the interaction of the blood proteins fibrinogen and thrombin during the process of clotting in a wound following injury. Fibrin glue is used surgically as a sealant, to control bleeding, speed wound healing, to fill holes after surgery, and in drug and cell delivery [61,62]. Chitosan is a polysaccharide extracted from the exoskeleton of crustaceans and is primarily used to promote rapid blood clotting. In addition, chitosan hydrogel has been used as a delivery vehicle for proteins [63,64] and cells, which in the latter case resulted in enhanced stem cell engraftment, survival and homing in an ischemic heart [64]. As a major ECM component, collagen plays an important role in the remodeling process that occurs in infarcted tissue. Collagen gel has been a popular material to test for its ability to repair infarcted heart wall because its ECM origins have potential to recruit endogenous cells for regeneration. For this reason, collagen gel was one of the first materials to be used for cell encapsulation and delivery into the heart [56,65]. Many studies have used collagen gels to deliver MSCs to infarcted regions and have shown improvement in cardiac function by increased vascular density [66]. Matrigel is a protein mixture derived from mouse sarcoma cells, and contains many important ECM proteins such as laminin and collagen, and growth factors that promote proliferation and differentiation [56,67]. Matrigel is widely used as an attachment substrate for embryonic and induced pluripotent stem cells in culture, with logical follow-up application to support stem cell survival in in vivo animal studies. Matrigel is able to retain stem cells after injection into infarcted tissue and subsequently improve cardiac function. However, as this gel is derived from mouse tumors, it is not applicable to human use. Self-assembling peptides are nanostructures formed from spontaneous aggregation of peptides, usually into nanofibers. These peptide chains are able to provide 3D microenvironments capable of recruiting cells, promoting vascularization and delivering growth factors. When injected into an infarcted heart, infarct size was reduced, vascular density was increased and cardiac function was recovered [68]. Self-assembling peptides have also been coinjected with MSCs, resulting in sustained growth, survival and differentiation of the stem cells, and reduced infarct size and significant improvement in cardiac functional measures (e.g., systolic function indices, left ventricle ejection fraction and left ventricle fractional shortening) [69].
Engineered tissues
Many attempts have been made to engineer various cardiac tissues, particularly of the heart valve. Although mechanical and bioprosthetic valves have been valuable for restoring heart function and quality of life for patients, each valve has its drawbacks, mostly owing to dependency on anticoagulants and limited durability due to tissue deterioration. More importantly, neither valve type is able to grow and expand with the patient as they grow older. For these reasons, tissue-engineered heart valves have been explored extensively. Desirable parameters for tissue-engineered valves include nonthrombogenicity, biocompatibility, capability for growth and remodeling, easily implantable, hemodynamically compatible and life-long durability [70]. Tissue-engineered valves would be particularly applicable to pediatric cases. The current challenge is to produce a tissue-engineered valve with the mechanical strength to withstand the blood pressure and contractility forces of the heart that is capable of seamlessly integrating with the native cells and tissues [71]. The classic approach for engineering valves is to use decellularized allo- or xeno-grafts on which different types of cells are seeded. Some examples of various combinations are homografts seeded with cardiac-derived mesenchymal stromal cells [72], porcine valve and pericardium seeded with bovine fibroblasts [73] and a fibrin gel combined with human dermal fibroblasts [74].
Despite the success in creating different types of tissue-engineered heart valves, clinical use has yet to be achieved due to lack of in vivo verification of feasibility. There have been a few clinical studies with conflicting results. One study involved 93 patients undergoing right ventricular outflow tract reconstruction using the Matrix P/Matrix Plus® (AutoTissue GmbH) xenogenic decellularized tissue-engineered pulmonary valve conduit. Conduit failure occurred in 33 patients (35.5%) and conduit dysfunction occurred in 27 patients (29%). Reasons for failure were conduit stenosis, pseudoaneurysm, conduit dilatation, stenosis of distal anastomosis involving pulmonary bifurcation and allograft dissection. Histological analysis showed inflammatory cells and poor endogenous cell seeding in all explanted specimens [75]. Conversely, in another study of 11 patients undergoing right ventricular outflow tract reconstruction, valves were replaced with pulmonary allografts seeded with autologous endothelial cells. At 10 years, multislice computed tomography showed no evidence of calcification, and echocardiography showed a mean pressure gradient of 5.4 ± 2.0 mmHg. Biopsies showed a confluent monolayer of endothelial cells covering the allograft’s inner surface [76]. In addition, another study involving the Matrix P conduit showed mixed negative and positive results of valve failure and no calcification [77]. These conflicting results demonstrate the need for further testing.
Other myocardial tissues have been created in vitro, based on the general approach of seeding cells onto a scaffolding material. Commonly used cell types have been skeletal myoblasts, murine neonatal cardiomyocytes, MSCs mainly from bone marrow or adipose tissue, cardiac progenitor cells, cardiosphere-derived stem cells, endothelial progenitor cells, embryonic stem cells and induced pluripotent stem cells [78-80]. Scaffolding material has included hydrogels, polymeric fibers (randomly configured and aligned), decellularized ECM and peptides [80-83]. Monolayers of cells have also been stacked to form scaffold-free tissues [84]. These materials are favored for their chemical, structural, biocompatible, degradability and formable characteristics. Engineered tissues transplanted into various animal models help to restore or improve tissue function, and clinical trials have shown some success [84-86]. However, as in the case of tissue-engineered valves, engineered myocardium and vascular tissue still need further developments to make them more relevant to the clinic.
Both natural and synthetic biomaterials have their limitations and can produce unwanted effects, such as limited durability and a higher chance for thrombosis. Natural biomaterials are superior in functionality and biocompatibility, but lack robustness. Synthetic biomaterials have advantages of strength and durability, but are deficient in functional capabilities. Combining materials into composites has created better options that benefit from the strengths of different materials and minimizes the weaknesses. Composite materials are achieved through the methods of blending (physically combined without forming chemical bonds), coating (by submersion or spraying), copolymerizing (polymer structure modified to form multiple block monomers then polymerized) and multilayering (sandwiching of materials followed by mechanical fixation) [87,88]. Injectable hydrogels are commonly combined with each other and other elements, and have the benefit of tunable properties that can be controlled by modifying crosslinking [89-91]. Bioprosthetic valves have been reinforced with polymeric material to abate the natural tissue’s innate lack of strength [92], providing an example of a composite taking advantage of the assets of each biomaterial.
Biomaterials can be combined with cells to provide support structure to enhance cellular growth and survival. Tissue regeneration using cellular material has been investigated as a healing mechanism for damaged and diseased heart tissue. Their proliferative capability and potential to differentiate into cardiovascular lineages make stem cells an ideal option [56]. Many different adult stem cells have been investigated in preclinical and clinical studies [56-64]. The major issue delaying stem cell therapy from widespread use is the fact that once injected in vivo, engraftment is low due to cell migration out of the wound site, and/or the cells simply die [69]. Delivering stem cells with biomaterials has become an increasingly popular method, and has developed into a field of its own. Numerous studies are testing biomaterials such as injectable hydrogels or patch material from natural and synthetic sources, or growth factors as solutions for maintaining stem cells to the wound site to improve engraftment and to aid in their survival and proliferation post-transplantation [40,56,93-95]. Most of these studies are at the preclinical stage. In one study, human MSCs incorporated into a collagen patch-assisted engraftment decreased left ventricle systolic interior diameter, increased anterior wall thickness and increased fractional shortening by 30% [94]. In another study, human bone marrow CD133+-derived cells transplanted on a collagen patch onto an injured heart resulted in formation of new microvessels, thought to be induced by the patch [95]. A mixture of growth factors was able to prolong survival of transplanted cardiomyocytes derived from human embryonic stem cells, improving cell engraftment after infarct [93]. In a clinical trial, a collagen matrix seeded with bone marrow cells was applied to the heart in patients with left ventricular postischemic myocardial scars. At 10 months after treatment, left ventricular end-diastolic volume beneficially decreased and left ventricular filling deceleration time significantly improved with the collagen matrix. Scar area thickness was increased in the matrix group through the addition of viable tissue. Ejection fraction results were independent of treatment group, as left ventricular ejection factor improved with or without the collagen matrix [85]. Overall, the research findings show that there is much potential for stem cells to effectively treat cardiovascular ailments, as long as methods for administering such treatments are developed to optimize therapeutic outcomes. In the future, successful application of stem cells will most probably involve delivery with biomaterials.
Biomaterials can be modified to extend their usefulness for drug delivery and gene therapy. Polymers are engrafted, and gels easily mixed with growth factors, cytokines and pharmaceuticals to allow drug-releasing systems capable of controlled release [96,97]. Different drugs and growth factors can be delivered, such as anticoagulants and peptides that promote endogenous cell proliferation and angiogenesis [96,98]. Tissue-engineered grafts have incorporated various drugs and growth factors into their scaffolding structure to enhance differentiation of the cells seeded onto it. Growth factors such as EGF, TGF, VEGF and BMPs have been used to stimulate differentiation of seeded cells towards cardiovascular lineages [96,99,100].
Future efforts should focus on perfecting composite materials to take full advantage of the optimal combination of both synthetic and natural biomaterials to improve the overall performance of implantable materials. This approach will exploit the combined advantages of both material types. Composite biomaterials have the potential to solve the current dilemma of having to choose between either synthetics or natural tissues and foregoing the benefits of one or the other material. Given the diversity of cardiovascular conditions and resulting variable treatments needed, the wider use of composite biomaterials may the best approach for improving disease management.
In addition, efforts for supporting stem cell retainment and survival using biomaterials should become more aggressive. There is much potential for translation of stem cell therapy to be realized using this approach. This could lead to regular application of tissue regeneration techniques, creating the ideal solution for cardiovascular tissue repair.
As the field develops, stem cells will increasingly enter the arena of cardiovascular therapy. Solutions to the challenges of stem cell survivability and proliferation post-transplantation are under intense exploration in the laboratory, and will probably involve the use of biomaterials. With the countless efforts towards this end, development on the material side will conceivably come to a conclusion and produce a narrowed down list of efficacious materials coupled with the appropriate stem cell. While tissue repair and replacement have been acceptable means of treatment, tissue regeneration would be far more ideal for restoring full function of the diseased heart, and is the next frontier to aim for.
Key issues
  • Biomaterials used in cardiovascular therapies fall into two major categories: synthetic and natural materials.
  • Synthetic materials used for cardiac repair mostly encompass polymeric materials, with a few applications of metals, and offer advantages of strength and durability.
  • Natural materials are derived from autologous, allogenic or xenogenic sources, and have superior functional properties but lack robustness.
  • Stem cells have potential to develop into a viable cardiovascular therapy by facilitating tissue regeneration, although problems involving cell survivability need to be overcome first and solutions thus far are heavily dependent on biomaterials.
Acknowledgments
The authors would like to thank the NIH for providing funding through grants T32 EB009035-02 to MT Lam and R33HL089027, R01EB009689 and R01HL093172 to JC Wu, and to the Burroughs Wellcome Foundation for providing support to JC Wu.
Footnotes
Financial & competing interests disclosure
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Papers of special note have been highlighted as:
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    of interest
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    of considerable interest
1. Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2–e220. [PubMed]
2. Aumsuwan N, Ye SH, Wagner WR, Urban MW. Covalent attachment of multilayers on poly(tetrafluoroethylene) surfaces. Langmuir. 2011;27(17):11106–11110. [PubMed]
3. Saha SP, Muluk S, Schenk W, 3rd, et al. Use of fibrin sealant as a hemostatic agent in expanded polytetrafluoroethylene graft placement surgery. Ann Vasc Surg. 2011;25(6):813–822. [PubMed]
4. Wang S, Gupta AS, Sagnella S, Barendt PM, Kottke-Marchant K, Marchant RE. Biomimetic fluorocarbon surfactant polymers reduce platelet adhesion on PTFE/ePTFE surfaces. J Biomater Sci Polym Ed. 2009;20(5–6):619–635. [PMC free article] [PubMed]
5. Yashiro B, Shoda M, Tomizawa Y, Manaka T, Hagiwara N. Long-term results of a cardiovascular implantable electronic device wrapped with an expanded polytetrafluoroethylene sheet. J Artif Organs. 2012 doi: 10.1007/s10047-012-0634-8. Epub ahead of print. [PubMed] [Cross Ref]
6. Barozzi L, Brizard CP, Galati JC, Konstantinov IE, Bohuta L, d’Udekem Y. Side-to-side aorto-GoreTex central shunt warrants central shunt patency and pulmonary arteries growth. Ann Thorac Surg. 2011;92(4):1476–1482. [PubMed]
7. Verbelen TO, Famaey N, Gewillig M, Rega FR, Meyns B. Off-label use of stretchable polytetrafluoroethylene: overexpansion of synthetic shunts. Int J Artif Organs. 2010;33(5):263–270. [PubMed]
8. Doble M, Makadia N, Pavithran S, Kumar RS. Analysis of explanted ePTFE cardiovascular grafts (modified BT shunt) Biomed Mater. 2008;3(3):034118. [PubMed]
9. Oda T, Hoashi T, Kagisaki K, Shiraishi I, Yagihara T, Ichikawa H. Alternative to pulmonary allograft for reconstruction of right ventricular outflow tract in small patients undergoing the Ross procedure. Eur J Cardiothorac Surg. 2012;42(2):226–232. [PubMed]
10. Miyazaki T, Yamagishi M, Nakashima A, et al. Expanded polytetrafluoroethylene valved conduit and patch with bulging sinuses in right ventricular outflow tract reconstruction. J Thorac Cardiovasc Surg. 2007;134(2):327–332. [PubMed]
11. Miyazaki T, Yamagishi M, Maeda Y, et al. Expanded polytetrafluoroethylene conduits and patches with bulging sinuses and fan-shaped valves in right ventricular outflow tract reconstruction: multicenter study in Japan. J Thorac Cardiovasc Surg. 2011;142(5):1122–1129. [PubMed]
12. Ando M, Takahashi Y. Ten-year experience with handmade trileaflet polytetrafluoroethylene valved conduit used for pulmonary reconstruction. J Thorac Cardiovasc Surg. 2009;137(1):124–131. [PubMed]
13. Kudo FA, Nishibe T, Miyazaki K, Flores J, Yasuda K. Albumin-coated knitted Dacron aortic prosthses. Study of postoperative inflammatory reactions. Int Angiol. 2002;21(3):214–217. [PubMed]
14. Nagano N, Cartier R, Zigras T, Mongrain R, Leask RL. Mechanical properties and microscopic findings of a Dacron graft explanted 27 years after coarctation repair. J Thorac Cardiovasc Surg. 2007;134(6):1577–1578. [PubMed]
15. Shayani V, Newman KD, Dichek DA. Optimization of recombinant t-PA secretion from seeded vascular grafts. J Surg Res. 1994;57(4):495–504. [PubMed]
16. Jensen N, Lindblad B, Bergqvist D. Endothelial cell seeded dacron aortobifurcated grafts: platelet deposition and long-term follow-up. J Cardiovasc Surg (Torino) 1994;35(5):425–429. [PubMed]
17. Roll S, Müller-Nordhorn J, Keil T, et al. Dacron vs. PTFE as bypass materials in peripheral vascular surgery – systematic review and meta-analysis. BMC Surg. 2008;8:22. [PMC free article] [PubMed]
18. Maya ID, Weatherspoon J, Young CJ, Barker J, Allon M. Increased risk of infection associated with polyurethane dialysis grafts. Semin Dial. 2007;20(6):616–620. [PubMed]
19. Kütting M, Roggenkamp J, Urban U, Schmitz-Rode T, Steinseifer U. Polyurethane heart valves: past, present and future. Expert Rev Med Devices. 2011;8(2):227–233. [PubMed]
20. Silvetti MS, Drago F, Ravà L. Long-term outcome of transvenous bipolar atrial leads implanted in children and young adults with congenital heart disease. Europace. 2012;14(7):1002–1007. [PubMed]
21. Johnson WB, Braly A, Cobian K, et al. Effect of insulation material in aging pacing leads: comparison of impedance and other electricals: time-dependent pacemaker insulation changes. Pacing Clin Electrophysiol. 2012;35(1):51–57. [PubMed]
22. Parrag IC, Zandstra PW, Woodhouse KA. Fiber alignment and coculture with fibroblasts improves the differentiated phenotype of murine embryonic stem cell-derived cardiomyocytes for cardiac tissue engineering. Biotechnol Bioeng. 2012;109(3):813–822. [PubMed]
23. Wang PY, Yu J, Lin JH, Tsai WB. Modulation of alignment, elongation and contraction of cardiomyocytes through a combination of nanotopography and rigidity of substrates. Acta Biomater. 2011;7(9):3285–3293. [PubMed]
24. Stachelek SJ, Alferiev I, Fulmer J, Ischiropoulos H, Levy RJ. Biological stability of polyurethane modified with covalent attachment of di-tert-butyl-phenol. J Biomed Mater Res A. 2007;82(4):1004–1011. [PubMed]
25. Koh AS, Choi LM, Sim LL, et al. Comparing the use of cobalt chromium stents to stainless steel stents in primary percutaneous coronary intervention for acute myocardial infarction: a prospective registry. Acute Card Care. 2011;13(4):219–222. [PubMed]
26. O’Brien BJ, Stinson JS, Larsen SR, Eppihimer MJ, Carroll WM. A platinum–chromium steel for cardiovascular stents. Biomaterials. 2010;31(14):3755–3761. [PubMed]
27. Rigatelli G, Cardaioli P, Giordan M, et al. Nickel allergy in interatrial shunt device-based closure patients. Congenit Heart Dis. 2007;2(6):416–420. [PubMed]
28. van Putte BP, Ozturk S, Siddiqi S, Schepens MA, Heijmen RH, Morshuis WJ. Early and late outcome after aortic root replacement with a mechanical valve prosthesis in a series of 528 patients. Ann Thorac Surg. 2012;93(2):503–509. [PubMed]
29. Akhtar RP, Abid AR, Zafar H, Khan JS. Anticoagulation in patients following prosthetic heart valve replacement. Ann Thorac Cardiovasc Surg. 2009;15(1):10–17. [PubMed]
30. Dalmau MJ, González-Santos JM, Blázquez JA, et al. Hemodynamic performance of the Medtronic Mosaic and Perimount Magna aortic bioprostheses: five-year results of a prospectively randomized study. Eur J Cardiothorac Surg. 2011;39(6):844–852. discussion 852. [PubMed]
31. Hodges AM, Lyster H, McDermott A, et al. Late antibody-mediated rejection after heart transplantation following the development of de novo donor-specific human leukocyte antigen antibody. Transplantation. 2012;93(6):650–656. [PubMed]
32. Byrne GW, McGregor CG. Cardiac xenotransplantation: progress and challenges. Curr Opin Organ Transplant. 2012;17(2):148–154. [PMC free article] [PubMed]
33. Badylak S, Obermiller J, Geddes L, Matheny R. Extracellular matrix for myocardial repair. Heart Surg Forum. 2003;6(2):e20–e26. [PubMed]
34•. Badylak SF. The extracellular matrix as a biologic scaffold material. Biomaterials. 2007;28(25):3587–3593. Provides an in-depth description of the small intestine submucosa material that is emerging with high potential and few disadvantages for cardiovascular application. [PubMed]
35. Boyd WD, Johnson WE, 3rd, Sultan PK, Deering TF, Matheny RG. Pericardial reconstruction using an extracellular matrix implant correlates with reduced risk of postoperative atrial fibrillation in coronary artery bypass surgery patients. Heart Surg Forum. 2010;13(5):e311–e316. [PubMed]
36. Fallon A, Goodchild T, Wang R, Matheny RG. Remodeling of extracellular matrix patch used for carotid artery repair. J Surg Res. 2012;175(1):e25–e34. [PubMed]
37. Zantop T, Gilbert TW, Yoder MC, Badylak SF. Extracellular matrix scaffolds are repopulated by bone marrow-derived cells in a mouse model of achilles tendon reconstruction. J Orthop Res. 2006;24(6):1299–1309. [PubMed]
38. Zhao ZQ, Puskas JD, Xu D, et al. Improvement in cardiac function with small intestine extracellular matrix is associated with recruitment of c-Kit cells, myofibroblasts, and macrophages after myocardial infarction. J Am Coll Cardiol. 2010;55(12):1250–1261. [PubMed]
39. Crapo PM, Wang Y. Small intestinal submucosa gel as a potential scaffolding material for cardiac tissue engineering. Acta Biomater. 2010;6(6):2091–2096. [PMC free article] [PubMed]
40. Tan MY, Zhi W, Wei RQ, et al. Repair of infarcted myocardium using mesenchymal stem cell seeded small intestinal submucosa in rabbits. Biomaterials. 2009;30(19):3234–3240. [PubMed]
41. Inoue H, Iguro Y, Matsumoto H, Ueno M, Higashi A, Sakata R. Right hemi-reconstruction of the left atrium using two equine pericardial patches for recurrent malignant fibrous histiocytoma: report of a case. Surg Today. 2009;39(8):710–712. [PubMed]
42. Shinn SH, Sung K, Park PW, et al. Results of annular reconstruction with a pericardial patch in active infective endoarditis. J Heart Valve Dis. 2009;18(3):315–320. [PubMed]
43. ASM International. Materials and Coatings for Medical Devices: Cardiovascular. ASM International; OH, USA: 2009. pp. 12–18.
44. Goissis G, Giglioti Ade F, Braile DM. Preparation and characterization of an acellular bovine pericardium intended for manufacture of valve bioprostheses. Artif Organs. 2011;35(5):484–489. [PubMed]
45. Braile MC, Carnevalli NC, Goissis G, Ramirez VA, Braile DM. In vitro properties and performance of glutaraldehyde-crosslinked bovine pericardial bioprostheses treated with glutamic acid. Artif Organs. 2011;35(5):497–501. [PubMed]
46. Sinha P, Zurakowski D, Kumar TK, He D, Rossi C, Jonas RA. Effects of glutaraldehyde concentration, pretreatment time, and type of tissue (porcine versus bovine) on postimplantation calcification. J Thorac Cardiovasc Surg. 2012;143(1):224–227. [PubMed]
47. Guldner NW, Bastian F, Weigel G, et al. Nanocoating with titanium reduces iC3b- and granulocyte-activating immune response against glutaraldehyde-fixed bovine pericardium: a new technique to improve biologic heart valve prosthesis durability? J Thorac Cardiovasc Surg. 2012;143(5):1152–1159. [PubMed]
48. Braga-Vilela AS, Pimentel ER, Marangoni S, Toyama MH, de Campos Vidal B. Extracellular matrix of porcine pericardium: biochemistry and collagen architecture. J Membr Biol. 2008;221(1):15–25. [PubMed]
49. Liao K, Seifter E, Hoffman D, Yellin EL, Frater RW. Bovine pericardium versus porcine aortic valve: comparison of tissue biological properties as prosthetic valves. Artif Organs. 1992;16(4):361–365. [PubMed]
50. Chambers JB, Rajani R, Parkin D, et al. Bovine pericardial versus porcine stented replacement aortic valves: early results of a randomized comparison of the Perimount and the Mosaic valves. J Thorac Cardiovasc Surg. 2008;136(5):1142–1148. [PubMed]
51. Eikelboom JW, Hart RG. Antithrombotic therapy for stroke prevention in atrial fibrillation and mechanical heart valves. Am J Hematol. 2012;87(Suppl. 1):S100–S107. [PubMed]
52. McGregor CG, Carpentier A, Lila N, Logan JS, Byrne GW. Cardiac xenotransplantation technology provides materials for improved bioprosthetic heart valves. J Thorac Cardiovasc Surg. 2011;141(1):269–275. [PubMed]
53. Law KB, Phillips KR, Butany J. Pulmonary valve-in-valve implants: how long do they prolong reintervention and what causes them to fail? Cardiovasc Pathol. 2012 doi: 10.1016/j.carpath.2012.02.010. Epub ahead of print. [PubMed] [Cross Ref]
54. Weber A, Noureddine H, Englberger L, et al. Ten-year comparison of pericardial tissue valves versus mechanical prostheses for aortic valve replacement in patients younger than 60 years of age. J Thorac Cardiovasc Surg. 2012 doi: 10.1016/j.jtcvs.2012.01.024. Epub ahead of print. [PubMed] [Cross Ref]
55. Chikwe J, Filsoufi F, Carpentier AF. Prosthetic valve selection for middle-aged patients with aortic stenosis. Nat Rev Cardiol. 2010;7(12):711–719. [PubMed]
56••. Segers VF, Lee RT. Biomaterials to enhance stem cell function in the heart. Circ Res. 2011;109(8):910–922. Provides a good review of recent advances in using biomaterials to support stem cells in heart applications. [PubMed]
57••. Rane AA, Christman KL. Biomaterials for the treatment of myocardial infarction: a 5-year update. J Am Coll Cardiol. 2011;58(25):2615–2629. Provides a good review of recent advances in using biomaterials to treat myocardial infarction. [PubMed]
58. Venugopal JR, Prabhakaran MP, Mukherjee S, Ravichandran R, Dan K, Ramakrishna S. Biomaterial strategies for alleviation of myocardial infarction. J R Soc Interface. 2012;9(66):1–19. [PMC free article] [PubMed]
59. Ruvinov E, Harel-Adar T, Cohen S. Bioengineering the infarcted heart by applying bio-inspired materials. J Cardiovasc Transl Res. 2011;4(5):559–574. [PubMed]
60. Leor J, Tuvia S, Guetta V, et al. Intracoronary injection of in situ forming alginate hydrogel reverses left ventricular remodeling after myocardial infarction in Swine. J Am Coll Cardiol. 2009;54(11):1014–1023. [PubMed]
61. Kin H, Nakajima T, Okabayashi H. Experimental study on effective application of fibrin glue. Gen Thorac Cardiovasc Surg. 2012;60(3):140–144. [PubMed]
62. Wu X, Ren J, Li J. Fibrin glue as the cell-delivery vehicle for mesenchymal stromal cells in regenerative medicine. Cytotherapy. 2012;14(5):555–562. [PubMed]
63. Liu Y, Cheng XJ, Dang QF, et al. Preparation and evaluation of oleoyl–carboxymethy–chitosan (OCMCS) nanoparticles as oral protein carriers. J Mater Sci Mater Med. 2012;23(2):375–384. [PubMed]
64. Liu Z, Wang H, Wang Y, et al. The influence of chitosan hydrogel on stem cell engraftment, survival and homing in the ischemic myocardial microenvironment. Biomaterials. 2012;33(11):3093–3106. [PubMed]
65. Gupta V, Werdenberg JA, Blevins TL, Grande-Allen KJ. Synthesis of glycosaminoglycans in differently loaded regions of collagen gels seeded with valvular interstitial cells. Tissue Eng. 2007;13(1):41–49. [PubMed]
66. Frederick JR, Fitzpatrick JR, 3rd, McCormick RC, et al. Stromal cell-derived factor-1α activation of tissue-engineered endothelial progenitor cell matrix enhances ventricular function after myocardial infarction by inducing neovasculogenesis. Circulation. 2010;122(Suppl. 11):S107–S117. [PubMed]
67. Hughes CS, Postovit LM, Lajoie GA. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics. 2010;10(9):1886–1890. [PubMed]
68. Kim JH, Jung Y, Kim SH, et al. The enhancement of mature vessel formation and cardiac function in infarcted hearts using dual growth factor delivery with self-assembling peptides. Biomaterials. 2011;32(26):6080–6088. [PubMed]
69. Nguyen PK, Lan F, Wang Y, Wu JC. Imaging: guiding the clinical translation of cardiac stem cell therapy. Circ Res. 2011;109(8):962–979. [PMC free article] [PubMed]
70. Apte SS, Paul A, Prakash S, Shum-Tim D. Current developments in the tissue engineering of autologous heart valves: moving towards clinical use. Future Cardiol. 2011;7(1):77–97. [PubMed]
71. Sacks MS, Schoen FJ, Mayer JE. Bioengineering challenges for heart valve tissue engineering. Annu Rev Biomed Eng. 2009;11:289–313. [PubMed]
72. Dainese L, Guarino A, Burba I, et al. Heart valve engineering: decellularized aortic homograft seeded with human cardiac stromal cells. J Heart Valve Dis. 2012;21(1):125–134. [PubMed]
73. Cigliano A, Gandaglia A, Lepedda AJ, et al. Fine structure of glycosaminoglycans from fresh and decellularized porcine cardiac valves and pericardium. Biochem Res Int. 2012;2012:979351. [PMC free article] [PubMed]
74. Robinson PS, Johnson SL, Evans MC, Barocas VH, Tranquillo RT. Functional tissue-engineered valves from cell-remodeled fibrin with commissural alignment of cell-produced collagen. Tissue Eng Part A. 2008;14(1):83–95. [PubMed]
75. Perri G, Polito A, Esposito C, et al. Early and late failure of tissue-engineered pulmonary valve conduits used for right ventricular outflow tract reconstruction in patients with congenital heart disease. Eur J Cardiothorac Surg. 2012;41(6):1320–1325. [PubMed]
76. Dohmen PM, Lembcke A, Holinski S, Pruss A, Konertz W. Ten years of clinical results with a tissue-engineered pulmonary valve. Ann Thorac Surg. 2011;92(4):1308–1314. [PubMed]
77. Konertz W, Angeli E, Tarusinov G, et al. Right ventricular outflow tract reconstruction with decellularized porcine xenografts in patients with congenital heart disease. J Heart Valve Dis. 2011;20(3):341–347. [PubMed]
78. Feinberg AW, Alford PW, Jin H, et al. Controlling the contractile strength of engineered cardiac muscle by hierarchal tissue architecture. Biomaterials. 2012;33(23):5732–5741. [PubMed]
79. Cashman TJ, Gouon-Evans V, Costa KD. Mesenchymal stem cells for cardiac therapy: practical challenges and potential mechanisms. Stem Cell Rev. 2012 doi: 10.1007/s12015-012-9375-6. Epub ahead of print. [PubMed] [Cross Ref]
80••. Karam JP, Muscari C, Montero-Menei CN. Combining adult stem cells and polymeric devices for tissue engineering in infarcted myocardium. Biomaterials. 2012;33(23):5683–5695. Discusses recent advances in using polymeric materials to support stem cells for myocardial transplantation. [PubMed]
81. Wang B, Tedder ME, Perez CE, et al. Structural and biomechanical characterizations of porcine myocardial extracellular matrix. J Mater Sci Mater Med. 2012;23(8):1835–1847. [PMC free article] [PubMed]
82. Eschenhagen T, Eder A, Vollert I, Hansen A. Physiological aspects of cardiac tissue engineering. Am J Physiol Heart Circ Physiol. 2012;303(2):H133–H143. [PubMed]
83. Ravichandran R, Venugopal JR, Sundarrajan S, Mukherjee S, Sridhar R, Ramakrishna S. Expression of cardiac proteins in neonatal cardiomyocytes on PGS/fibrinogen core/shell substrate for cardiac tissue engineering. Int J Cardiol. 2012 doi: 10.1016/j.ijcard.2012.04.045. Epub ahead of print. [PubMed] [Cross Ref]
84. Haraguchi Y, Shimizu T, Sasagawa T, et al. Fabrication of functional three-dimensional tissues by stacking cell sheets in vitro. Nat Protoc. 2012;7(5):850–858. [PubMed]
85. Chachques JC, Trainini JC, Lago N, et al. Myocardial assistance by grafting a new bioartificial upgraded myocardium (MAGNUM clinical trial): one year follow-up. Cell Transplant. 2007;16(9):927–934. [PubMed]
86. Shinoka T, Breuer C. Tissue-engineered blood vessels in pediatric cardiac surgery. Yale J Biol Med. 2008;81(4):161–166. [PMC free article] [PubMed]
87. Pok S, Jacot JG. Biomaterials advances in patches for congenital heart defect repair. J Cardiovasc Transl Res. 2011;4(5):646–654. [PubMed]
88. Place ES, George JH, Williams CK, Stevens MM. Synthetic polymer scaffolds for tissue engineering. Chem Soc Rev. 2009;38(4):1139–1151. [PubMed]
89. Tous E, Weber HM, Lee MH, et al. Tunable hydrogel–microsphere composites that modulate local inflammation and collagen bulking. Acta Biomater. 2012;8(9):3218–3227. [PMC free article] [PubMed]
90. Chiu LL, Janic K, Radisic M. Engineering of oriented myocardium on three-dimensional micropatterned collagen–chitosan hydrogel. Int J Artif Organs. 2012;35(4):237–250. [PubMed]
91. Deng C, Vulesevic B, Ellis C, Korbutt GS, Suuronen EJ. Vascularization of collagen–chitosan scaffolds with circulating progenitor cells as potential site for islet transplantation. J Control Release. 2011;152(Suppl. 1):e196–e198. [PubMed]
92. Wang Q, McGoron AJ, Pinchuk L, Schoephoerster RT. A novel small animal model for biocompatibility assessment of polymeric materials for use in prosthetic heart valves. J Biomed Mater Res A. 2010;93(2):442–453. [PubMed]
93. Laflamme MA, Chen KY, Naumova AV, et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007;25(9):1015–1024. [PubMed]
94. Simpson D, Liu H, Fan TH, Nerem R, Dudley SC., Jr A tissue engineering approach to progenitor cell delivery results in significant cell engraftment and improved myocardial remodeling. Stem Cells. 2007;25(9):2350–2357. [PMC free article] [PubMed]
95. Pozzobon M, Bollini S, Iop L, et al. Human bone marrow-derived CD133(+) cells delivered to a collagen patch on cryoinjured rat heart promote angiogenesis and arteriogenesis. Cell Transplant. 2010;19(10):1247–1260. [PubMed]
96. Spadaccio C, Chello M, Trombetta M, Rainer A, Toyoda Y, Genovese JA. Drug releasing systems in cardiovascular tissue engineering. J Cell Mol Med. 2009;13(3):422–439. [PubMed]
97. Zhang G, Suggs LJ. Matrices and scaffolds for drug delivery in vascular tissue engineering. Adv Drug Deliv Rev. 2007;59(4–5):360–373. [PubMed]
98. Polizzotti BD, Arab S, Kühn B. Intrapericardial delivery of gelfoam enables the targeted delivery of periostin peptide after myocardial infarction by inducing fibrin clot formation. PLoS ONE. 2012;7(5):e36788. [PMC free article] [PubMed]
99. Chiu LL, Radisic M. Controlled release of thymosin β4 using collagen–chitosan composite hydrogels promotes epicardial cell migration and angiogenesis. J Control Release. 2011;155(3):376–385. [PubMed]
100. Zeng F, Lee H, Allen C. Epidermal growth factor-conjugated poly(ethylene glycol)-block-poly(delta-valerolactone) copolymer micelles for targeted delivery of chemotherapeutics. Bioconjug Chem. 2006;17(2):399–409. [PubMed]
Websites
201. W.L. Gore & Associates, Inc., Medical Products Division; www.goremedical.com/vgpedshunt/
202. Medtronic, Inc; www.medtronic.com.
203. Edwards Lifesciences Corp; www.edwards.com.
204. Maquet Cardiovascular, LLC; www.maquet.com.
205. St Jude Medical, Inc; www.sjmprofessional.com.
206. Cook Biotech, Inc; www.cookbiotech.com.
207. CorMatrix Cardiovascular, Inc; www.cormatrix.com.
208. CryoLife, Inc; www.cryolife.com.
210. Vascutek Terumo, Ltd; www.vascutek.com.
211. Sorin Group. www.sorin.com.