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Cardiovascular disease is the leading cause of death in the world. Stem cell-based therapies have been widely investigated for cardiac regeneration in patients with heart failure or myocardial infarction (MI) and surged ahead on multiple fronts over the past two decades. To enhance cellular therapy for cardiac regeneration, numerous engineering techniques have been explored to engineer cells, develop novel scaffolds, make constructs, and deliver cells or their derivatives. This review summarizes the state-of-art stem cell-based therapeutics for cardiac regeneration and discusses the emerged bioengineering approaches toward the enhancement of therapeutic efficacy of stem cell therapies in cardiac repair. We cover the topics in stem cell source and engineering, followed by stem cell-based therapies such as cell aggregates and cell sheets, and biomaterial-mediated stem cell therapies such as stem cell delivery with injectable hydrogel, three-dimensional scaffolds, and microneedle patches. Finally, we discuss future directions and challenges of engineering stem cell therapies for clinical translation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ischemic heart disease represents the leading cause of death worldwide. Heart failure following myocardial infarction (MI) is associated with severe fibrosis formation and cardiac remodeling. Recently, injectable hydrogels have emerged as a promising approach to repair the infarcted heart and improve heart function through minimally invasive administration. Here, a novel injectable human amniotic membrane (hAM) matrix is developed to enhance cardiac regeneration following MI. Human amniotic membrane is isolated from human placenta and engineered to be a thermoresponsive, injectable gel around body temperature. Ultrasound-guided injection of hAM matrix into rat MI hearts significantly improves cardiac contractility, as measured by ejection fraction (EF), and decrease fibrosis. The results of this study demonstrate the feasibility of engineering as an injectable hAM matrix and its efficacy in attenuating degenerative changes in cardiac function following MI, which may have broad applications in tissue regeneration., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Repairing cardiac tissue after myocardial infarction (MI) is one of the most challenging goals in tissue engineering. Following ischemic injury, significant matrix remodeling and the formation of avascular scar tissue significantly impairs cell engraftment and survival in the damaged myocardium. This limits the efficacy of cell replacement therapies, demanding strategies that reduce pathological scarring to create a suitable microenvironment for healthy tissue regeneration. Here, we demonstrate the successful fabrication of discrete hyaluronic acid (HA)-based microrods to provide local biochemical and biomechanical signals to reprogram cells and attenuate cardiac fibrosis. HA microrods were produced in a range of physiological stiffness and shown to degrade in the presence of hyaluronidase. Additionally, we show that fibroblasts interact with these microrods in vitro, leading to significant changes in proliferation, collagen expression and other markers of a myofibroblast phenotype. When injected into the myocardium of an adult rat MI model, HA microrods prevented left ventricular wall thinning and improved cardiac function at 6 weeks post infarct., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Heart failure continues to be a major health care concern with relatively few options for severely advanced heart failure patients. The hallmark of heart failure is the progressive dilatation of the left ventricle, thinning of the left ventricular wall leading to increased wall stress and increased myocardial oxygen consumption. Applying Laplace's law to the failing dilated ventricle, left ventricular augmentation utilizes a tissue engineering strategy to increase wall thickness and reduce chamber diameter, resulting in a decrease in wall stress and improved left ventricular function. A review of the rationale for an in situ tissue engineering approach for this treatment of heart failure and early clinical results of the Algisyl-LVR™ program are presented.

Myocardial repair remains a major challenge for both cellular and tissue engineering approaches. Several studies have been conducted looking at utilizing extracellular matrix-based therapies to promote repair after a myocardial infarction. In this review, strategies for treating myocardial infarctions using extracellular matrix-derived peptides are discussed. Using an ischemia/reperfusion myocardial infarction rodent model, we showed that extracellular-matrix-derived peptides were able to induce angiogenesis and alter the negative remodeling seen after a myocardial infarction. This therapy opens up a potentially new non-invasive strategy for repairing damaged cardiac tissue.

The combination of scaffold material and cell transplantation therapy has been extensively investigated in cardiac tissue engineering. However, many polymers are difficult to administer or lack the structural integrity to restore LV function. Additionally, polymers need to be biological friendly, favorably influence the microenvironment and increase stem cell retention and survival. This study determined whether human mesenchymal stem cells (hMSCs) encapsulated in RGD modified alginate microspheres are capable of facilitating myocardial repair. The in vitro study of hMSCs demonstrated that the RGD modified alginate can improve cell attachment, growth and increase angiogenic growth factor expression. Alginate microbeads and hMSCs encapsulated in microbeads successfully maintained LV shape and prevented negative LV remodeling after an MI. Cell survival was significantly increased in the encapsulated hMSC group compared with PBS control or cells alone. Microspheres, hMSCs, and hMSCs in microspheres groups reduced infarct area and enhanced arteriole formation. In summary, surface modification and microencapsulation techniques can be combined with cell transplantation leading to the maintenance of LV geometry, preservation of LV function, increase of angiogenesis and improvement of cell survival., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

An overview for the use of stem cells for myocardial repair and regeneration is provided. The overview provides the rationale for use of stem cells in myocardial repair. Potential stem cell types and technological challenges are highlighted.

Cardiovascular disease is a major public health problem in the United States. In many survivors, extensive tissue damage from myocardial infarction leads to the development of congestive heart failure. Unfortunately, thus far, heart transplantation has remained the only viable treatment for end-stage congestive heart failure. Lack of available donor hearts has thus led to search for alternative therapies. Among these, cell therapy has raised a great enthusiasm for myocardial repair. However, it suffers limitations associated with cell retention, survival and differentiation. In addition, the results from preclinical and clinical studies based on such treatments have generated mixed results. For this reason, hybrid therapies that incorporate tissue engineering are being developed as potentially new therapeutic approaches for repair of myocardial tissue. Here, we review the current progress in cardiac tissue repair and engineering; and discuss the new emerging technologies.

The field of cardiovascular tissue engineering has experienced tremendous advances in the past several decades, but the clinical reality of engineered heart tissue and vascular conduits remains immature. Stem cells and progenitor cells are promising cell sources for engineering functional cardiovascular tissues. To realize the therapeutic potential of stem cells and progenitor cells, we need to understand how microenvironmental cues modulate and guide stem cell differentiation and organization. This review describes the current understanding of the chemical and physical regulation of embryonic and adult stem cells for potential applications in cardiovascular repair, focusing on cardiac therapies after myocardial infarction and the engineering of vascular conduits.

For nearly a decade, researchers have investigated the possibility of cell transplantation for cardiac repair. More recently, the emerging fields of tissue engineering and biomaterials have begun to provide potential treatments. Tissue engineering approaches are designed to repair lost or damaged tissue through the use of growth factors, cellular transplantation, and biomaterial scaffolds. There are currently 3 biomaterial approaches for the treatment of myocardial infarction (MI). The first involves polymeric left ventricular restraints in the prevention of heart failure. The second utilizes in vitro engineered cardiac tissue, which is subsequently implanted in vivo. The final approach entails injecting cells and/or a scaffold into the myocardium to create in situ engineered cardiac tissue. This review gives an overview of the current progress in the growing field of biomaterials for the treatment of MI.

Skeletal muscle consists of parallel bundles of myotubes formed by the fusion of myoblasts. We fabricated nanofibrous and micropatterned polymers as cell culture substrates to guide the morphogenesis of muscular tissue. The nanoscale and microscale topographic features regulate cell and cytoskeleton alignment, myotube assembly, myotube striation, and myoblast proliferation. This bottom-up approach from nanoscale to tissue level demonstrates the potential of nanofibrous polymers for engineering the assembly of cell and tissue structure.

Repairing cardiac tissue after myocardial infarction (MI) is one of the most challenging goals in tissue engineering. Following ischemic injury, significant matrix remodeling and the formation of avascular scar tissue significantly impairs cell engraftment and survival in the damaged myocardium. This limits the efficacy of cell replacement therapies, demanding strategies that reduce pathological scarring to create a suitable microenvironment for healthy tissue regeneration. Here, we demonstrate the successful fabrication of discrete hyaluronic acid (HA)-based microrods to provide local biochemical and biomechanical signals to reprogram cells and attenuate cardiac fibrosis. HA microrods were produced in a range of physiological stiffness and shown to degrade in the presence of hyaluronidase. Additionally, we show that fibroblasts interact with these microrods in vitro, leading to significant changes in proliferation, collagen expression and other markers of a myofibroblast phenotype. When injected into the myocardium of an adult rat MI model, HA microrods prevented left ventricular wall thinning and improved cardiac function at 6 weeks post infarct.

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection into the infarct zone of adult rats. Here, we show dose-dependent down-regulation of expression of genes associated with the mechanical fibrotic response in the presence of microstructures. Injection of this microstructured material into the infarct zone decreased levels of collagen and TGF-β, increased elastin deposition and vascularization in the infarcted region, and improved functional outcomes after six weeks. Our results demonstrate the efficacy of these discrete anti-fibrotic microstructures and suggest a potential therapeutic materials approach for combatting pathologic fibrosis.

Aims: AUGMENT-HF was an international, multicentre, prospective, open-label, randomized, controlled evaluation testing the hypothesis that Algisyl (injectable calcium alginate hydrogel) is superior to standard medical therapy (SMT) for improving functional capacity and clinical outcomes in patients with advanced heart failure (HF). We previously reported results following 6 months of follow-up. This report presents the results from 1 year of extended follow up for this clinical trial. Methods and Results: We enrolled 78 patients with advanced HF, randomized (1:1), to Algisyl with SMT or SMT alone as previously reported. Patient inclusion criteria were LVEF ≤35%, peak VO2 of 9.0-14.5 mL/min/kg and LV end-diastolic diameter (LVEDD) index 30-40 mm/m(2) (LVEDD/body surface area). Patients must have been on stable, evidence-based therapy for HF. A total of 58 patients, mean age 62.3 ± 9.6 years, with ischaemic (57.7%) or non-ischaemic (42.3%) HF completed 12 months of follow-up. Treatment with Algisyl was associated with improved peak VO2 at 12 months; treatment effect vs. control of +2.10 mL/kg/min (95% confidence interval 0.96-3.24, P < 0.001). Statistically significant improvements were observed for VO2 at anaerobic threshold, 6-min walk test distance, and NYHA functional class (all P < 0.001). Through 12 months of follow-up there were 4 (10.5%) deaths in the control group and 9 (22.5%) deaths in the Algisyl group. Conclusions: Algisyl in addition to SMT was more effective than SMT alone for providing sustained 1-year benefits in exercise capacity, symptoms, and clinical status for patients with advanced HF. These data support larger clinical evaluations of this novel therapy. [ABSTRACT FROM AUTHOR]

Background A tissue engineering approach to augment the left ventricular wall has been suggested as a means to treat patients with advanced heart failure. This study evaluated the safety and feasibility of Algisyl-LVR™ as a method of left ventricular augmentation in patients with dilated cardiomyopathy undergoing open-heart surgery. Methods and results Eleven male patients (aged 44 to 74 years) with advanced heart failure (NYHA class 3 or 4), a left ventricular ejection fraction (LVEF) of < 40% and requiring conventional heart surgery received Algisyl-LVR delivered into the LV myocardial free wall. Serial echocardiography, assessment of NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ) and 24-hour Holter monitoring were obtained at baseline, days 3 and 8 (for echocardiography and Holter monitoring), and at 3, 6, 12, 18 and 24 months. A total of 9 (81.8%) patients completed 24 months of follow-up. Two patients withdrew consent after day 8 and at the 3 month visit. Operative mortality was 0% (n = 10 with 30 day follow-up). There were no adverse events attributed to Algisyl-LVR. Mean LVEF improved from 27.1 (± 7.3) % at screening to a mean LVEF of 34.8 (± 18.6) % 24 months post-discharge. Improvements of NYHA class were corroborated with improvements in KCCQ summary scores. Holter monitor data showed a significant decrease in the episodes of nonsustained ventricular tachycardia following administration of Algisyl-LVR. Conclusions Administration of Algisyl-LVR to patients with advanced HF at the time of cardiac surgery is feasible and safe; warranting continued development of Algisyl-LVR as a potential therapy in patients with advanced HF. [ABSTRACT FROM AUTHOR]

Abstract: Mesenchymal stromal cells (MSCs) are multipotent cells that have high expansion yields and fibrin is a native extracellular matrix (ECM) material widely used for cell delivery and surgery. MSCs and fibrin have tremendous potential for tissue engineering applications, but the effect of fibrin on MSCs is not well characterized. The purpose of this study was to analyze the role of fibrin in modulating MSC phenotype by gene expression analysis. The results demonstrate that fibrin up-regulated MSC gene expression of vasculogenic (FLK1, ACTA2, VECAD, SM22 and CNN1), myogenic (MYF5 and MYH13), neurogenic (TH and GFAP) and chondrogenic (COL2A1) markers after 5days incubation. These gene expression results were supported by induction of expression on the protein level for early lineage-specific markers such as ACTA2, FLK1 and MYF5. The ability of fibrin to modulate MSC gene expression was not affected by matrix pore size (80–110μm diameter) or Young’s modulus (5–25kPa) and the differential expression of some phenotypic markers could be partially mimicked by other ECM proteins, such as fibronectin and collagen I. In some cases the inductive effect of fibrin on gene expression could be further augmented by the treatment with growth factors such as nerve growth factor. However, the effect of fibrin appeared to be limited, as MSCs did not differentiate into fully mature cells based on immunofluorescence staining after 12days. This body of work provides a rational approach for studying the interactions of MSC with fibrin, which has important therapeutic implications for the delivery of stem cells. [ABSTRACT FROM AUTHOR]

Abstract: The conductive polymer polypyrrole was blended with alginate to investigate its potential in tissue engineering applications. This study showed that increasing the polypyrrole content altered the macroscopic structural morphology of the polymer blend scaffold, but did not alter the overall conductivity of the polymer blend, which was 10−2 S/cm2. Culturing of human umbilical vein endothelial cells on the polymer blend scaffolds showed that addition of polypyrrole mediated cell attachment to the polymer scaffold. However, cell proliferation was dependent on the polypyrrole content with 0.025% v/v polypyrrole giving the best results. Using an ischemia–reperfusion rat myocardial infarction model, local injection of 0.025% polypyrrole in alginate polymer blend into the infarct zone yielded significantly higher levels of arteriogenesis at 5 weeks post-treatment when compared with the saline control group and the alginate only treatment group. In addition, this alginate–polypyrrole polymer blend significantly enhanced infiltration of myofibroblasts into the infarct area when compared with the control group. The results of this study highlight the potential clinical benefit of using this alginate–polypyrrole polymer blend as an injectable scaffold to repair ischemic myocardium after myocardial infarction. [Copyright &y& Elsevier]