Advancements in Engineering Techniques for Myocardial Tissue Regeneration

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Advancements in Engineering Techniques for Myocardial Tissue Regeneration

The number of people affected by cardiac problems every year is rising globally and one of the many actions taken to address this broad concern is employing tissue engineering techniques for cardiac tissue repair and regeneration. Although, there are limitations in the ability of human cardiomyocytes to regenerate completely, yet several tissue engineering strategies using hydrogels, have been deployed over the years, to overcome this limitation.

One such step is the development of a blend of collagen-fibrin based hydrogel, seeded with cardiomyocytes derived from human pluripotent stem cells, which revealed that hydrogel protein content and the population of cell seeding plays a critical role in myocardial tissue regeneration [172]. Advancements in Engineering Techniques for Myocardial Tissue Regeneration. Medical literature shows the development of 3D bio-printed gelatin-based hydrogels, which are micro channeled to help promote heart cell growth by maintaining native cardiomyocytes and at the same time utilizing mesenchymal stem cells to affect cardiac regeneration [173]. Nonetheless, more extensive research must be conducted to overcome contemporary drawbacks in cardiac tissue growth. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.

The notion of immuno- isolation was developed to protect the foreign graft material form the host immune response and to avoid complications befalling due to immune suppression. Immuno- isolation devices were designed to establish a physical barrier with the newly grafted tissues to limit their contact with host immune cells. For a graft material to be viable and functional, the device should be fabricated as such, to allow sufficient diffusion of nutrients, endocrine factors, and oxygen to the implanted tissues to sustain extended interaction with the environment [176].

The excellent biocompatibility and structural properties of smart hydrogels to mimic extracellular matrix( ECM) biology have been utilized by researchers to create injectable hydrogel matrices for delivering islets cells in the site of transplantation in the treatment of type 1 diabetes[ 177]. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.

Encapsulating these islet cells in hydrogel microspheres (microgels) before transplantation into diabetic recipients can establish an adequate immuno-isolation barrier to depreciate allogeneic rejection. Synthetic hydrogel macromers like PEG-4MAL (4-arm polyethylene glycol terminated with maleimides)can serve as an ideal candidate for immuno-isolation applications since it can be easily altered with thiolated bioactive molecules, allowing precise control of islet microenvironment [178].

Although the advancements in cell therapy, nanotechnology, biotechnology, genetic engineering, and immunology have recognized potential means of using hydrogels in accomplishing long-term viability and functionality of transplanted islet cells, many hurdles are yet to be crossed, such as islet cell apoptosis, the need of immunosuppressive drugs, and managing immune reactions for successful therapeutic results [177].

Heart disease remains one of the leading causes of death in industrialized nations with myocardial infarction (MI) contributing to at least one fifth of the reported deaths. The hypoxic environment eventually leads to cellular death and scar tissue formation. The scar tissue that forms is not mechanically functional and often leads to myocardial remodeling and eventual heart failure. Tissue engineering and regenerative medicine principles provide an alternative approach to restoring myocardial function by designing constructs that will restore the mechanical function of the heart.Advancements in Engineering Techniques for Myocardial Tissue Regeneration. In this review, we will describe the cellular events that take place after an MI and describe current treatments. We will also describe how biomaterials, alone or in combination with a cellular component, have been used to engineer suitable myocardium replacement constructs and how new advanced culture systems will be required to achieve clinical success.

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Keywords: : cardiac tissue engineering, cardiac patch, acellular scaffolds, extracellular matrix scaffolds, myocardial infarction, heart repair
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Introduction
Heart disease remains one of the leading causes of death in industrialized nations with myocardial infarction (MI) contributing to at least ∼20% of the reported deaths.1 An acute MI occurs when a coronary artery that feeds oxygenated blood to the right and left ventricles gets occluded, thus resulting in areas of hypoxia. The hypoxic environment, if maintained for sufficient amount of time, eventually leads to cellular death due to lack of oxygen and nutrients triggering an inflammatory response. The inflammatory environment is responsible for the clearing of dead cells and stimulating neighboring cells to increase matrix production ultimately leading to scar tissue formation.

The scar tissue that forms after an MI is unable to contract and, due to the high stresses present during the normal pumping action of the heart, the infarct area deforms over time leading to myocardial remodeling and reduced cardiac output. Although reperfusion and pharmacological treatments have shown some improvements in patients after an MI, the scar tissue is not completely removed and cardiac output is not restored to pre-MI levels.2 If significant damage is sustained, a heart transplant is a potential treatment option. However, heart transplantation remains limited by low availability and the need for life immunosuppression of the transplant recipient.

Tissue engineering and regenerative medicine principles provide an alternative approach to restoring myocardial function after an MI. By combining the expertise of multiple fields, such as engineering, biology, medicine, biochemistry, and pharmacology, tissue engineers try to create suitable tissue replacements capable of restoring function and improving quality of life. This review will first describe the cellular events that take place after an MI with emphasis on the host tissue response dominated by inflammatory cells such as macrophages.Advancements in Engineering Techniques for Myocardial Tissue Regeneration. The review then will describe how biomaterials, alone or in combination with a cellular component, have been used to engineer suitable myocardium replacement constructs. Given the complexity of the myocardial tissue, we will also discuss ideas for new advanced culture systems that can help assemble and test the new generation of engineered cardiac devices.

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Myocardial Infarction
A heart attack or MI is caused by the stenosis and/or occlusion of a coronary artery leading to improper delivery of oxygenated blood to regions of the heart. This condition is classified based on the extent of occlusion into ST-Elevation myocardial infarction (STEMI) when occlusion is completely blocked, or non-ST-Elevation myocardial infarction (NSTEMI) when occlusion is not complete. The physiological and clinical description of MI is described in details elsewhere2; in brief, the occlusion can affect the major coronary arteries such as the left anterior descending, left circumflex, and the right coronary artery. Once the artery is sufficiently occluded, oxygenation and nutrient deficit downstream of the occlusion result in the gradual death of the myocardial tissue (Fig. 1). The infarct site refers to the portion of the necrotic myocardium that is damaged or in the process of being damaged by the hypoxic conditions. Most infarcts involve the death of the full thickness of the ventricular wall (transmural infarction), although in some cases perfusion from neighboring vessels can help delay and/or minimize injury. At the early stages of the infarct there is a decrease in aerobic glycolysis, an increase in anaerobic glycolysis (accumulation of lactic acid), production of high-energy phosphates, and reduced contractility.2

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FIG. 1.
Diagrammatic representation of an MI. (A) When symptoms of a heart attack are felt, it represents the occlusion of one or multiple coronary arteries supplying oxygen and nutrients to the heart. (B) Once the artery is occluded, there is hypoxia due to the limited diffusion of oxygen, resulting in the death of myocardial tissue. Artwork provided by Servier Medical Arts. MI, myocardial infarction. Color images available online at www.liebertpub.com/teb

Necrosis and apoptosis begin to occur, leading to the activation of the inflammatory response through the recruitment of neutrophils and subsequently monocytes from peripheral blood. Advancements in Engineering Techniques for Myocardial Tissue Regeneration. Recent studies have shown the active recruitment of circulating peripheral blood monocytes and a monocyte population resident in the spleen following an MI.3 In addition, studies have shown waves of pro- and anti-inflammatory monocytes circulating at different times after the infarct with classically activated monocytes found soon after the ischemic injury and then followed by alternatively activated monocytes.4 Once recruited to the infarct, monocytes differentiate toward macrophages and begin the labor of removing cellular debris.5,6

During the initial phase of the inflammatory response after the recruitment of the monocytes, there is a strong presence of classically activated macrophages or M1 macrophages within the myocardial tissue. These are macrophages associated with the removal of pathogens and cellular debris and express proinflammatory cytokines such as IL-1β, TNF-α, and IL-6. These macrophages are present at high numbers during the first week after an infarct in mice with a gradual decrease over time.4,5,7,8 Following this initial proinflammatory phase, there is a gradual shift in the type of macrophage toward more alternatively activated macrophages (M2), which are characterized by the secretion of CCL-17, TIMP-1, and IL-10. These macrophages are typically associated with wound healing responses and are thought to activate fibroblasts, smooth muscle, and endothelial cells.5,6,9–11

Myocardial regeneration is the process by which the injured myocardium is restored to its original structure and function. As described above, the normal healing process for postinfarction cardiac tissue involves the generation of a fibrous scar, which provides mechanical support but is devoid of functional cardiomyocytes. Most treatment strategies focus on improving the performance of an already damaged tissue and not in regenerating the myocardium to restore or establish normal function. More recently, new therapeutic approaches based on progenitor cells have been developed with the goal of regenerating tissue to its normal structure and function. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.

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Current Cardiac Treatments
Advancements in medical interventions have improved the prognosis post-MI considerably, but the incidence of heart failure is still increasing, likely as a result of the increasing number of patients who now survive the initial attack. Currently, the only approved treatments for end-stage heart failure post-MI are left ventricular assist devices and heart transplantation. The first is plagued by the complications of a chronic external assist device, which include bleeding (30%), right ventricular failure (20–30%), thromboembolism (3–35%), primary device failure (6% −6 months, 64% −2 years), and infection (18–59%).12 The second is a limited resource in which proper matching of the donor organ to the patient is a great challenge, limiting even further its use. A number of surgical approaches have been developed as preventative measures to improve patient survival and their quality of life, and which can be an option for patients excluded from cardiac transplantation lists. The most common include angioplasty, left ventricular reconstruction, and cellular cardiomyoplasty.

Ischemic tissue revascularization
There is agreement that initial treatment for STEMI is restoring blood flow to the ischemic tissue via tissue reperfusion. The main alternatives for reperfusion can be classified into pharmacologic, surgical, or mechanical. The pharmacological breakdown of blood clots (thrombus) in stenotic coronary arteries is known as thrombolysis. The mechanical alternative to reperfusion is known as primary percutaneous surgical alternative coronary intervention or primary coronary angioplasty, where the occlusion is mechanically expanded to allow blood flow to resume. The surgical alternative is known as coronary artery bypass graft (CABG) surgery, which when compared with angioplasty is highly invasive (requiring open heart surgery) and requires extra surgery to obtain the vein graft. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.

The use of primary angioplasty for the treatment of STEMI was first described as a rescue treatment in the case of failed intracoronary thrombolysis and was studied extensively as an adjunctive therapy. In general terms, the procedure consists of feeding a deflated balloon or other device (e.g., stent) on a catheter from the inguinal femoral artery or radial artery up through blood vessels until they reach the site of blockage in the heart. At the blockage, the balloon is inflated to open the artery, allowing blood to flow. Primary angioplasty has been shown to be more effective to thrombolysis for treatment of patients with acute STEMI in randomized trials.13–16 The use of angioplasty requires the procedure to be performed preferably within 90 min of the patient presenting to the emergency room, which most hospitals cannot provide.

There is strong evidence that with increasing duration and severity of ischemia, more cardiac tissue damage can develop, allowing a variety of reperfusion-associated pathologies, known as reperfusion injury. This condition results in cardiac tissue damage through myocardial stunning, microvascular and endothelial injury, and irreversible cell damage, necrosis, apoptosis, autophagy, or necroptosis.17,18 Reperfusion injury has been observed in each of the cardiac tissue revascularization strategies mentioned above and under certain conditions can be lethal. There are various pharmacological and nonpharmacological interventions used to reduce reperfusion injury. In the case of pharmacological interventions, the use of drugs such as cyclosporine-A, metoprolol, and glucose modulators has shown some promising results, but a long list of failed examples makes them a weak alternative. In contrast, nonpharmacological interventions have focused on limiting the infarct size as means to reduce reperfusion injury.

Left ventricular reconstruction
After MI, the formation of scar tissue leads to changes in left ventricular (LV) size, shape, structure, and physiology through a process known as myocardial remodeling.19 During this process, there is thinning of the LV walls, with the elliptical LV becoming more spherical and dilated.20 A number of different surgical techniques and modifications have been developed to restore LV shape and reduce its volume to improve LV function and are collectively known as LV reconstruction.21–24 This is a specific surgical procedure developed for the management of heart failure with LV remodeling caused by coronary artery disease.25 Despite its success, these procedures have not found general acceptance in the medical community. Advancements in Engineering Techniques for Myocardial Tissue Regeneration. Possible reasons include a lack of robust prospective randomized data showing the mortality benefit of this technique in patients with ischemic cardiomyopathy and dilated ventricles that were referred for CABG. To address these concerns, the Surgical Treatment for Ischemic Heart Failure (STICH) trial was developed to evaluate the role of cardiac surgery in the treatment of patients with coronary artery disease and LV systolic dysfunction.26 A major question addressed by this study was if left ventricular reconstruction improved patient outcome when combined with CABG. The results of this clinical trial showed no significant difference between performing CABG alone or when combined with LV reconstruction.26 These surgical techniques, and the use of nonbioactive materials as tissue replacements, helped spark the interest in exploring innovative use of biomaterials and tissue engineering constructs.

Cellular cardiomyoplasty
Cell transplantation is an area of growing interest in clinical cardiology, as a potential means of treating patients after acute MI. Cellular cardiomyoplasty is a therapeutic strategy in which progenitor cells are used to repair regions of damaged or necrotic myocardium.Advancements in Engineering Techniques for Myocardial Tissue Regeneration. The ability of transplanted progenitor cells to improve function within the failing heart has been shown in experimental animal models and in some human clinical trials.27 The progenitor cells involved in these new therapeutic approaches include bone marrow or adipose tissue-derived mesenchymal stem cells (MSCs), hematopoietic precursor cells, endothelial progenitor cells, endogenous cardiac stem cells, and skeletal muscle-derived cells.28,29

Three mechanisms have been proposed to describe how cardiomyoplasty improves myocardial function: (1) transdifferentiation of the administered stem cells into cardiomyocytes, endothelial cells, and smooth muscle cells,30,31 (2) fusion between the stem cell and endogenous cardiac myocytes,32 and (3) release of paracrine factors that stimulate endogenous cardiac repair mechanisms.33,34 Conflicting results showing a lack of transdifferentiation have put into question its role in cardiomyoplasty and motivated the search of alternative hypotheses like fusion and paracrine signaling.30,35 Further studies suggested that the lack of transdifferentiation shown was related to differences in experimental procedures, but the exact mechanism remains unknown.36 In addition, it has been consistently reported that the level of fusion between stem cells and cardiomyocytes remains low,32,37 suggesting that additional mechanisms may be involved. Current results support paracrine signaling as the principal mechanism for the improvement of myocardial function. In it, stem cells release cytokines and chemokines to stimulate other cells into the regenerative process. In fact, MSCs have been shown to stimulate host myocardial precursor cells to amplify and differentiate into cardiomyocytes in vivo.38

The clinical application of cellular cardiomyoplasty for the treatment of the ischemic tissues after acute MI involves tissue revascularization, isolation of autologous stem cells from the patient, and implementation through repeat cardiac catheterization or intramyocardial injection.39 A major limitation for the application of cellular cardiomyoplasty as a treatment option is stem cell retention and engraftment after intramyocardial implantation.40 A significant proportion of the transplanted cells leak out through the needle track that is made by the puncturing needle or enter systemic circulation.41,42 Cell retention is normally less than 10%, regardless of the delivery route within the first 24 h.43 Although it was initially thought that cell death by apoptosis was the reason for low engraftment,44,45 it has been demonstrated that venous drainage and the contraction of the beating heart are the main reasons for cell loss.40,46 Short-term cell retention is necessary for subsequent long-term engraftment and cardiac tissue functional improvement after acute MI. Advancements in Engineering Techniques for Myocardial Tissue Regeneration. Other unresolved issues include cell delivery method and route, cell distribution, time transplantation, cell type, cell number, and viability. There are new therapeutic approaches involving engineering culture systems, the use of novel biomaterials for mechanical support of the cells and for controlled release of therapeutics, and tissue engineering (Fig. 2).

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FIG. 2.
Diagrammatic representation of the different approaches that can be used to repair infarcted myocardial tissue. An acellular patch can be used as an off-the-shelf product that can be implanted soon after myocardial infarction. Alternatively, cells can be harvested (i.e., progenitor cells) and injected back into the patient. Another approach can be the isolation of somatic cells (i.e., blood cells), reprogrammed, expanded, differentiated, and assembled into a bioengineered cardiac tissue that can then be implanted back into the patient as an autologous patch. These approaches have different timing and expenses associated with them that can have potential impact on their clinical use. Artwork provided by Servier Medical Arts. Color images available online at www.liebertpub.com/teb

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Engineered Cardiac Patch
Engineered cardiac patch is fabricated to mimic the native extracellular matrix (ECM) and offer mechanical support and cell delivery into the region of infarction. Its application helps to limit LV remodeling, prevent dilatation and thinning of the infarct zone, enhance mechanical properties of ventricle, and reduce cardiomyocyte apoptosis. In addition, it aids to retain viable transplanted stem cells, which stimulate the formation of vasculature, myofibroblasts, and cardiomyocytes. Hence, the optimal properties of a scaffold involve high porosity, microenvironment similar to ECM, good mechanical properties, biodegradability, and biocompatibility. Natural polymers (i.e., collagen, fibrin, chitosan, alginate, natural ECM, peptides) and synthetic polymers (i.e., polycaprolactone [PCL], polyglycerol sebacate [PGS], and polyurethanes) are a choice of materials to fabricate scaffolds47,48 (Fig. 3). The Tables 1 and ​and22 summarize some characteristics of natural and synthetic polymers used for cardiac patch, respectively. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.

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FIG. 3.
Diagrammatic representation of tissue engineering strategies using cellular and acellular scaffolds. The goal is to find the optimal configuration that restores myocardial function to preinfarct levels. Color images available online at www.liebertpub.com/teb

table 1.
some natural polymers for cardiac patch

Material Stem cells Porosity and/or pore size In vivo model Signaling Ref.
Collagen hMSCs — Male CDF rats α-SMA 118
Autologous stem cells 400–600 μm Male C57/BL6 mouse Anti-sarcomeric actin antibody and Anti-vWF 121
hMSCs
hESC-MC — Male athymic RNU nude rats CD105, CD73, Angiogenin, PDGF-B, VEGF, and CXCL1 105
Autologous mesenchymal stem cells — Wistar rats CD44+, CD90+, CD45−, CD34−, Desmine, and α-smooth muscle actinin 119
hESC-derived cardiovascular progenitors
Autologous r-ADSCs — Female Wistar rats Rowett nude female rats Tbx5 and Nkx 2.5 116
Natural ECM BM-MSCs 91.2% ± 1.3%; 130.5 ± 25.3 mm Male syngeneic Lewis rats α-SMA, bFGF, vWF, PDGF-B, IGF-1, HGF, MEF2D, MYH6, Type I collagen, SMMHC, CD68, and IL-6 139
hMSCs — Adult mongrel dogs Sarcomeric α-actinin, Atrial natriuretic peptide
Cardiotin, Subunit of the Cav 1.2, and cardiac troponin-T 137
Cardiac progenitor cells — — α-MHC, Troponin T, Troponin C, GATA-4, nkx 2.5, α-SMA, Smooth muscle 22α, Fibroblast-specific protein 1, vWF, tie2 135
BMMCs 19.5 ± 17.9 μm — Sarcomeric α-actinin, Myosin heavy chain
Cardiac troponin T, and vWF 134
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ADSC, adipose tissue-derived stem cell; ECM, extracellular matrix; hMSC, human mesenchymal stem cell; hESC-MC, human embryonic stem cell-derived mesenchymal cells; α-SMA, α-smooth muscle actin.

table 2.
other polymeric material for cardiac patch

Stem cell Polymer Porosity/pore size Elastic modulus (MPa) Tensile stress Tensile strain (MPa) Tensile strain at break In vivo model Signaling Ref.
Cardiomyocytes differentiated from hESC Poly(glycerol sebacate) — — Adult male Sprague Dawley rats — 144
cSca-1, BMMCs, and ADSCs Nanopeptides (cell–PuraMatrix™) — — Wild mice (C57Bl/6J) Anti-vWF), anti-SMA, anti-α-sarcomeric actinin anti-CD31,VEGF, bFGF, and PDGF-bb 152
BM-MSCs PPC, PU, and [P(3HB-co-4HB)] — — — CD34, CD45, CD90, CD73, CX43, and cTn T 153
Neonatal cardiomyocytes PGS/collagen — 2.06 MPa (TS)
57.87% (TSA)
83.65% (TSB)
4.24 (EM). — Cardiac-specific marker proteins α-actinin, Troponin, β-MHC, and cx43 146
BM-MSC PCL/Gelatin 83.6% ± 0.8%/0.83 ± 0.15 μm — Female Sprague Dawley rats CD31, cTnT, and Cx43 47
Cardiac progenitor cells PCL/CNT — 11 MPa (EM)
1.3 MPa (TS), 131% (TSB) — sca-1, CD34, GATA-4, CD44, CD29, and CD31 150
BMMSCs PGS/Fibrinogen — — Farm pigs (Sus scrofa) Yorkshire Swine α-sarcomeric actinin, troponin T, CD68, and CD31 117
hMSCs PEG/Alginate — — Male nude rats (Crl:NIH-Foxn1rnu) anti-vWF, anti-BRDU 154
Neonatal rat cardiac cell Fibrin — 86.0 ± 3.8 (EM)
75.7 ± 11.5 (UTS) Female Fisher F344 syngeneic immune-competent rats SMA +, CD31, Type I collagen and Type IV collagen 48
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PCL, poly(caprolactone); PEG, poly(ethylene glycol); PGS, polyglycerol sebacate; TS, tensile stress; TSA, tensile strain; TSB, tensile strain at break; EM, elastic modulus.

Acellular biomaterial approach to cardiac repair
Cardiac tissue has limited self-renewal capacity, which limits its ability to regenerate and repair itself after injury. Due to the challenges and limitations on the use of biomaterials with exogenous cells, acellular injectable biomaterials and patches have been evaluated as mechanical supports for MI. Acellular scaffolds have several advantages compared to cellular scaffolds such as (1) their off-the-shelf availability for immediate implantation (e.g., SynerGraft®, AlloDerm®, DermaMatrix®), (2) their limited immune reaction,49 and (3) low cost and extended shelf life.50 Cardiac tissue scaffolds should exhibit elasticity matching the myocardium, host cell integration and vascularization, mechanical stability, and nonimmunogenicity to support tissue function and regeneration. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.The following sections briefly discuss the advantages and limitations of major biomaterials used as acellular constructs for myocardial repair and regeneration with emphasis given to naturally occurring biomaterials.

Collagen
Due to its abundance in connective tissue, collagen type I scaffolds are increasingly being used in tissue repair applications. Collagen type I provides a tissue-like environment for cell attachment and growth, which facilitates host cell integration. Its main attributes include biocompatibility, biodegradability, and fibrous contractile structure.51,52 Collagen type I comprises about 80% of the collagen matrix in cardiac tissue,53 making it the choice of preference for cardiac tissue scaffolds. Gaballa et al.54 grafted a three-dimensional (3D) collagen type I scaffold onto infarcted myocardium in rats and found that the scaffold induced neovessel formation and reduced LV remodeling 3 weeks after implantation. However, solid porous collagen has a lower elastic modulus,55 which can limit its mechanical integration to the cardiac tissue. Serpooshan et al. optimized the elastic modulus of collagen type I gel to improve myocardial contractility in the injured heart.56 Collagen type I was molded using a plastic compression technique to generate dense tissue scaffolds with a high elastic modulus. Four weeks post-MI in mice, collagen type I patches showed host cell infiltration and new blood vessel formation. Echocardiography showed significant improvement in cardiac function, diminished fibrosis, and inhibition of LV dilation and wall thinning.

Collagen in combination with other biomaterials such as chitosan has shown an increase in compression modulus, which makes it more suitable for the stabilization of the ventricular wall.57 Incorporation of angiogenic factors, such as thymosin β4, in composite collagen–chitosan hydrogels has been shown to induce cell migration and improve angiogenesis in vivo.58 Other forms of collagen such as gelatin have shown good cardiac cell attachment and viability, but the tensile strength and degradation rates are inferior to collagen, making it a less attractive option for cardiac tissue implants. These results indicate that collagen scaffolds can exert beneficial effects on cardiac remodeling and function after injury. Cardiac cell integration and function should be further evaluated to determine its long-term clinical potential.

Hyaluronic acid
Hyaluronic acid (HA), also known as hyaluronan, is a natural linear polysaccharide abundantly found in the ECM of several tissues. Its structure and ligand binding properties have been linked to angiogenesis59 and tissue repair.60 Thus, HA has become an important component in scaffolds used for tissue repair and regeneration. In cardiac tissue, HA has shown modest results for cardiac function recovery postinfarction. Yoon et al. were one of the first groups that demonstrated the regenerative potential of HA for heart tissue. Advancements in Engineering Techniques for Myocardial Tissue Regeneration. A significant decrease in both infarcted area and apoptotic index as well as an increase in local vasculature were observed in rats injected with an acrylated HA hydrogel into the epicardium of the infarcted region.61 Similar results have been observed by Abdalla et al. by evaluating the recovery of cardiac function in the infarcted heart of rats postinjection of HA gel into the peri-infarct region.62 Transthoracic echocardiography revealed a significant increase of about 18% in ejection fraction in HA-injected groups compared to the control group. Decreased collagen deposition and increased levels of VEGF were also observed supporting reduced scarring and new vasculature formation in response to HA.

The molecular weight of HA has been shown to affect its regenerative potential in the myocardium. Evaluation of different molecular weights of HA-based hydrogels (50, 130, and 170 kDa) showed that the lowest molecular weight had the most significant regeneration and function recovery of the infarcted myocardium.63 The regenerative potential of HA-based hydrogel was markedly reduced in chronic models of MI, indicating that the injection time is a major determinant for cardiac repair. The compressive modulus of HA gels is also an important variable for stabilization of the infarcted myocardium. Use of hydrogels with high compression modulus (43 kPa) significantly reduced LV remodeling and improved function when compared with lower modulus hydrogel and control groups in an ovine model.64 Due to the increase in wall stress during systole, a high compression modulus may be more suitable to reduce myocardial stress distribution. Thus, two major factors, the molecular weight of HA and injection time, are main determinants for HA-mediated repair in the infarcted myocardium. Overall, several studies support the use of HA-based hydrogels as a promising novel therapy to reduce scarring and promote vasculature formation in the infarcted myocardium.

Alginate
Alginate is an anionic polysaccharide present in brown seaweed. It is biocompatible and has been used for food and pharmaceutical applications.65 Its capacity for in situ gelation and nonthrombogenic properties makes it attractive for cardiac tissue applications. In heart tissues, intramyocardial injections of alginate hydrogels have shown significant clinical potential for the improvement of LV function and reduced remodeling potentially by providing mechanical support to the damaged ECM. Yu et al. showed that acellular alginate hydrogels could improve cardiac function, reduce remodeling, and increase neovascularization in a chronic rodent model of ischemic cardiomyopathy.66 The angiogenic effect of alginate can be further enhanced by incorporating RGD peptides into the biopolymer, but the structural changes reduce the therapeutic effects of the hydrogel.67 Landa et al. evaluated the effect of alginate hydrogel in the recovery of cardiac function of rats post-MI.68 There was an increase in scar thickness, and reduced LV systolic and diastolic dilatation was typically observed even after injection 60 days postinfarction. These results were comparable to those achieved by neonatal cardiomyocyte transplantation. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.

The use of alginate hydrogels has also been shown to improve cardiac function in large animal models. Intracoronary injection of alginate hydrogel prevented LV remodeling and increased scar thickness in a swine model of MI.69 The alginate hydrogel was replaced by myofibroblasts, which support local tissue restoration while limiting general myocardial remodeling. Implantation of alginate hydrogel in dogs with heart failure produced by intracoronary microembolizations (LV ejection fraction <30%) significantly improved ventricular wall stability and function.70 Injection of alginate hydrogel expanded the LV wall and improved the LV systolic and diastolic functions at levels comparable to those observed in dogs in long-term therapy with beta-blockers.71 These observations motivated evaluation in patients with ischemic (n = 4) and nonischemic (n = 2) dilated cardiomyopathy. Patients that received alginate implants showed improvements in LV size and function as early as 3 days. Reductions in LV volumes and an increase in ejection fractions were sustained for over 3 months. Due to their promising results, alginate hydrogels are to date the only and first injectable biomaterial in clinical trials for treating MI. However, lack of integration between alginate and cardiac cells might be the major limitation for tissue regenerative applications.

Chitosan
Chitosan is a cationic hydrophilic polysaccharide derivate from chitin commonly found in crustacean shells. It has been extensively used in biomedical applications, including wound healing,72,73 drug delivery systems,74 and surgical adhesives.75 The porosity of chitosan can be controlled as a function of freeze-drying,76 which is important for host cell migration and tissue integration. However, chitosan alone is noncell adhesive and has a high compressive modulus, which requires its chemical modification and/or mixing with other biomaterials to obtain optimal mechanical and physiological properties for cardiac tissue. Pok et al. evaluated a multilayered scaffold formed by a gelatin–chitosan hydrogel around a self-assembled PCL core for use as a cardiac patch.77 Gelatin and chitosan ratios of 50:50 and 25:75 significantly improved cell adhesion while retaining the mechanical strength of PCL. Mixtures of chitosan and collagen have also shown potential to improve cardiac function. Deng et al. combined chitosan with collagen to increase the compressive modulus of collagen as a potential implant for stabilization of the ventricular wall.57 Ahmadi et al. investigated the effects of a collagen chitosan matrix on cardiac remodeling.78 Mice received local injection of collagen–chitosan matrix 2 weeks post-MI. LV ejection fraction was improved only in collagen–chitosan-treated mice over a 3-week follow-up period. Thus, combination of porous chitosan with lower compressive moduli and cell-adherent biomaterials may have the potential to increase tissue integration and therefore increase the mechanical stability of the ventricle postinfarction. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.

Fibrin
Fibrin-based scaffolds are biopolymer gels formed from fibrinogen, a glycoprotein that contains two Arginine–Glycine–Aspartic acid (RGD) sequences in each amino acid chain and is converted by thrombin into fibrin during blood clot formation simulating the last step of the blood coagulation cascade.79,80 Fibrin polymerizes in situ upon the combination of fibrinogen and thrombin. Fibrin glue has been tested as an injectable scaffold for cardiac tissue repair. Christman et al. examined the effects of injectable fibrin glue as a scaffold and wall support in the ischemic myocardium in rats. Fibrin glue alone or with skeletal myoblasts was injected into the LV 1–2 days after left coronary artery occlusion. Five weeks after injection, fibrin glue alone or with cells preserved infarct wall thickness, reduced infarct size, increased blood flow, and improved cardiac ejection function.81,82 Huang et al. performed a comparative study to determine the therapeutic potential of fibrin, collagen type I, and Matrigel as injectable biomaterials for MI repair. Injection of each individual biomaterial into the infarct zone significantly increased vascularization compared to the saline solution control group at 5 weeks post-treatment in rats. The angiogenic potential was similar for all three polymers probably due the shared common binding sites for avb3 integrin, which is associated to angiogenesis. The major disadvantage of fibrin gels is poor mechanical properties, not able to support the stresses generated during myocardial contraction.83 Therefore, fibrin should be combined with other high-compression moduli components such as chitosan or collagen to increase mechanical strength and reduce degradation rates.

Decellularized extracellular matrices
Decellularized matrices are derived from biological tissues in which cells have been removed, but the architecture and components of the ECM are preserved. The main advantages of decellularized matrices are preserved structure, size, and components of native ECM without the presence of cellular antigens that could induce an immune reaction.84 In cardiac tissue studies, decellularized matrices have shown to promote endothelial cell and cardiac cell infiltration. Decellularized urinary bladder ECM (UB-ECM) has been evaluated as an epicardial patch for repairing the infarcted LV.85 At 6–8 weeks postinfarction, pigs received either a UB-ECM or expanded polytetrafluoroethylene (ePTFE) patch in the LV. At 3 months, the decellularized matrix was resorbed showing a highly vascularized tissue enriched in collagen and myofibroblasts. At the same time point, ePTFE had a foreign body response and calcification. Similarly, Robinson et al.85 used a urinary bladder matrix (UBM) scaffold for repairing the infarcted LV in pigs. Results showed that after 3 months the constructs had a significant increase in cardiac marker expression (i.e., α-smooth muscle actin (SMA)+ myofibroblasts, α-sarcomeric actin, myosin-HC, tropomyosin, and connexin 43) and the number of contractile cells (i.e., expressing α-SMA).Advancements in Engineering Techniques for Myocardial Tissue Regeneration. It has been well established that UBM scaffolds are superior to synthetic Dacron in regenerating myocardial tissue. This fact is due to their potential capacity to promote cardiomyocyte differentiation and/or migration, allowing the ventricular wall to approach its normal thickness, and finally resulting in improved regional mechanical function.86,87 Moreover, natural matrices from small intestine submucosa (SIS)88 and porcine sternum89 used in rats models have showed to be a good alternative to promote angiogenesis, enhance cardiac function, and decrease apoptosis, through the recruitment of c-kit+ cells, myofibroblasts, and macrophages after MI. Tan et al. used a decellularized SIS patch with MSCs on a MI rabbit model90 and showed significant improvements in LV function, wall thickness, and vasculature. Decellularized ventricular and pericardial matrices are two additional options for MI repair.91–93 Singelyn et al. have shown that decellularized porcine ventricular tissue can be solubilized and self-assembled in situ upon injection into myocardial tissue. Smooth muscle cells and endothelial cells were able to infiltrate the decellularized matrix both in vitro and in vivo with a significant increase in blood vessel density. These studies were performed in the healthy rat myocardium, which have better recovery rates than in MI.

Synthetic materials
Synthetic materials have been widely used in tissue engineering applications due to improved mechanical properties, material uniformity, and low risk of infection compared to natural biomaterials. Synthetic polymers can be modified with high precision to meet tissue-specific properties such as appropriate degradation rates, porosity, and mechanical strength. Several synthetic polymers have been evaluated for cardiac tissue implants, including poly(ethylene glycol)(PEG), polyvinyl alcohol, poly(caprolactone)(PCL), polypropylene, polyester, and poly(N-isopropylacrylamide) (PNIPAM).94,95 Meshes made of polyester and poly(propylene) have been successfully used as LV restraints to prevent LV remodeling and dilation in animal models and human patients.96–100 Injection of a thermosensitive hydrogel containing PCL and PNIPAM into the myocardium 4 days postinfarction in rabbits was found effective to prevent ventricular wall thinning and reduce systolic and diastolic dilatation after 30 days of treatment.95 Similarly, PEG hydrogels have prevented LV remodeling and dilation, but lack vascularization unless codelivered with cells.101 While the mechanical properties and stability of synthetic polymers are superior to natural polymers, cell integration is a major limitation. Advancements in Engineering Techniques for Myocardial Tissue Regeneration. Blends of synthetic and natural polymers with or without growth factors are often preferred to support cell migration and tissue replacement of the implant.102,103

Engineered cellular constructs for cardiac repair
Although acellular scaffolds have many advantages over cellular scaffolds, the use of cells has also been shown to improve healing and tissue regeneration. In many cases, the addition of a cellular component showed improvement over the material alone.104 The use of an engineered cellular construct is a therapeutic strategy to regenerate the myocardium lost after an MI by supporting the function of the myocardium via a mechanically suitable material and the surviving cells using an appropriate exogenous repair cell. The cardiac patch is a 3D carrier for cell delivery fabricated in vitro and implanted over the infarcted tissue47 with the goals of improving repair cell retention and engraftment, limiting LV remodeling, preventing LV dilatation and thinning, enhancing the mechanical properties of ventricle, and reducing cardiomyocyte apoptosis.48 In addition, it can also provide the means to stimulate angiogenesis, release of cytokines, and myocardial perfusion.48,105 All these properties depend on the choice of scaffold material and repair cells that will ultimately couple with the native cells.

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One of the first patches developed for delivering cells to an MI site consisted of a cardiomyocyte-enriched extract from fetal rat ventricular muscle dispersed in a commercially available gelatin scaffold (i.e., Gelfoam, Merck, Co.).106 Although this cardiac patch showed improved cell survival and retention, it was not able to demonstrate any improvement in cardiac function. In contrast, a similar type of patch based on alginate and fetal rat cardiomyocytes showed improvement on both cell survival and cardiac function in a rat MI model.107 This variability in results is common and needs to be considered. These are mainly due to differences in degree of injury to the heart due to the infarct procedure used.108 Additional studies in the development of cardiac patches have shown a limited use of cardiomyocytes. This is because these cell types are terminally differentiated, thus limiting their proliferative capacity.109

As an alternative, many researchers are studying a recently detected small population cardiac progenitor cells (CPCs) negative for blood lineage markers (Lin−) and positive for stem cell surface markers (i.e., c-kit, Sca-1, and MDR-1), which have the potential for myocardial regeneration.110 A potential treatment option could be to attract this cell population to the infarct site and provide them with the appropriate environment to stimulate myocardial regeneration.Advancements in Engineering Techniques for Myocardial Tissue Regeneration. This environment should promote not only the migration of CPCs but also of any other cell types that might promote myocardial regeneration (e.g., macrophages, MSCs).

It is important to first differentiate between the term repair, which defines the natural healing process that replaces the damaged tissue with a scar, and regeneration (our therapeutic objective), in which the damaged tissue rebuilds itself to its normal structure and function.111 The cardiac repair process involves an inflammatory response, where macrophages remove dead cardiomyocytes and secrete angiogenic and profibrotic cytokines, chemokines, and proteases.112 This is followed by fibrosis, in which macrophages and myofibroblasts work together in reinforcing the ventricular wall through the secretion of connective tissue, eventually forming the scar tissue. This structure is so dense that it prevents the migration of CPCs, essential for cardiac regeneration, making fibrosis an important hurdle in mammals’ capacity to regenerate myocardium after MI.113 In addition, it has been found that acute inflammation is necessary to activate the regenerative response in the neonatal mouse heart.114

Another type of progenitor cells that have been tested for myocardial regeneration are MSCs loaded into scaffolds made of natural and synthetic polymers.115 Collagen, fibrin, PGS, PCL, nanopeptides, polyurethane (PU), and 3-hydroxybutyrate-co-4hydroxybutyrate [P(3HB-co-4HB)] are examples of these scaffold biomaterials. The use of these patches has shown increased vascularization and improvement in cardiac function. They are also an improvement over cellular cardiomyoplasty, which is limited because in this technique cell survival involves enzymatic cell dissociation before injection and because of the poor vascularization in the infarct site.116 Cardiac patches could overcome these limitations by retaining viable transplanted stem cells in a scaffold that would facilitate cell migration and cell adhesion toward the infarcted area.48 In addition, these transplanted cells could stimulate formation of vasculature and cardiomyocytes. As with most of the cell-bearing scaffolds, optimal properties of these include high porosity, high surface area to volume ratio, microenvironment similar to natural ECM, good mechanical properties, biodegradability, and biocompatibility.47,117 These parameters can be modulated with the choice of materials used and the synthesis conditions chosen for its fabrication. Advancements in Engineering Techniques for Myocardial Tissue Regeneration.