Bi-layered polyurethane – Extracellular matrix cardiac patch improves ischemic ventricular wall remodeling in a rat model

D’Amore, Antonio; Yoshizumi, Tomo; Luketich, Samuel K.; Wolf, Matthew T.; Gu, Xinzhu; Cammarata, Matteo; Hoff, Richard; Badylak, Stephen F.; Wagner, William R.

doi:10.1016/j.biomaterials.2016.07.039

Cited by 118 publications

(121 citation statements)

References 55 publications

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“…31 Thus, new therapies must be developed to overcome the poor prognosis of MI. Several alternative strategies based on drug treatments, 32 injections of stem cells or proteins, 4,5 surgical interventions 33 and epicardial restraint devices 34 have been used to regenerate the infarcted heart. The effects of liraglutide have been shown to be beneficial for the treatment of MI.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction

Qi¹,

Lü

Li³

et al. 2017

IJN

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The local, intramyocardial injection of proteins into the infarcted heart is an attractive option to initiate cardiac regeneration after myocardial infarction (MI). Liraglutide, which was developed as a treatment for type 2 diabetes, has been implicated as one of the most promising protein candidates in cardiac regeneration. A significant challenge to the therapeutic use of this protein is its short half-life in vivo. In this study, we evaluated the therapeutic effects and long-term retention of liraglutide loaded in poly(lactic- co -glycolic acid)–poly(ethylene glycol) (PLGA–PEG) nanoparticles (NP-liraglutide) on experimental MI. PLGA–PEG nanoparticles (NPs) have been shown to efficiently load liraglutide and release bioactive liraglutide in a sustained manner. For in vitro test, the released liraglutide retained bioactivity, as measured by its ability to activate liraglutide signaling pathways. Next, we compared the effects of an intramyocardial injection of saline, empty NPs, free liraglutide and NP-liraglutide in a rat model of MI. NPs were detected in the myocardium for up to 4 weeks. More importantly, an intramyocardial injection of NP-liraglutide was sufficient to improve cardiac function ( P <0.05), attenuate the infarct size ( P <0.05), preserve wall thickness ( P <0.05), promote angiogenesis ( P <0.05) and prevent cardiomyocyte apoptosis ( P <0.05) at 4 weeks after injection without affecting glucose levels. The local, controlled, intramyocardial delivery of NP-liraglutide represents an effective and promising strategy for the treatment of MI.

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Section: Discussionmentioning

confidence: 99%

Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction

Qi¹,

Lü

Li³

et al. 2017

IJN

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“…Therefore, the strain range investigated (0–12%) covered both physiological and overphysiological levels of tissue deformation. All data were referenced to the postpreconditioned free‐float state (D'Amore et al ., 2014, 2016). …”

Section: Methodsmentioning

confidence: 99%

Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion

et al. 2017

Self Cite

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SummaryAge‐related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification. Quantification of ECM topology and muscle mechanical properties reveals decreased collagen tortuosity and muscle stiffening with increasing age. Age‐related ECM alterations directly disrupt MuSC responses, and MuSCs seeded ex vivo onto decellularized ECM constructs derived from aged muscle display increased expression of fibrogenic markers and decreased myogenicity, compared to MuSCs seeded onto young ECM. This fibrogenic conversion is recapitulated in vitro when MuSCs are seeded directly onto matrices elaborated by aged fibroblasts. When compared to young fibroblasts, fibroblasts isolated from aged muscle display increased nuclear levels of the mechanosensors, Yes‐associated protein (YAP)/transcriptional coactivator with PDZ‐binding motif (TAZ), consistent with exposure to a stiff microenvironment in vivo. Accordingly, preconditioning of young fibroblasts by seeding them onto a substrate engineered to mimic the stiffness of aged muscle increases YAP/TAZ nuclear translocation and promotes secretion of a matrix that favors MuSC fibrogenesis. The findings here suggest that an age‐related increase in muscle stiffness drives YAP/TAZ‐mediated pathogenic expression of matricellular proteins by fibroblasts, ultimately disrupting MuSC fate.

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“…In fact, elevated ventricular wall stresses have been proposed to drive the infarct expansion seen post-myocardial infarction (53,54), as well as increase ventricular dilation in dilated cardiomyopathy patients (55)(56)(57). Further, strategies aimed at reducing the ventricular wall stress by integrating a temporary patch over the myocardial infarct (58) or injecting materials to thicken the ventricle wall (59) have proved successful to combat the pathological remodeling observed following myocardial infarction. While there have been recent advances in engineering ventricle-like chambers using scaffolds and 3D bioprinting (22,(60)(61)(62), compared to our dyn-EHT these chambers are much more difficult to fabricate, require a relatively large number of cells to form, and must be connected to a complicated flow system with valves and pressure transducers in order to generate preload.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype

Bliley

Vermeer

Duffy

et al. 2020

Preprint

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The role mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes in the heart. However, most EHT systems are unable to model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained fractional shortening of >10%.To do this, 3D EHTs are integrated with an elastic polydimethylsiloxane (PDMS) strip that provides mechanical pre-and afterload to the tissue in addition to enabling contractile force measurements based on strip bending. Our results demonstrate in wild-type EHTs that dynamic loading is beneficial based on the magnitude of the forces, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we use hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy (ACM) due to mutations in desmoplakin. We demonstrate that manifestation of this desmosome-linked disease state requires the dyn-EHT conditioning and that it cannot be induced using 2D or standard 3D EHT approaches. Thus, dynamic loading strategy is necessary to provoke a disease phenotype (diastolic lengthening, reduction of desmosome counts, and reduced contractility), which are akin to primary endpoints of clinical disease, such as chamber thinning and reduced cardiac output.Studying the effects of mechanical loading on adaptive and maladaptive changes in heart structure and function is challenging in human patients, driving the need to develop new approaches. Animals have been used to model a wide range of human cardiovascular disease states, but there are inherent differences in physiology, gene expression and pharmacokinetics that limit the ability to replicate complex pathology (6). In vitro 2-dimensional (2D) culture of cardiomyocytes on microengineered surfaces have been used to study structure-function relationships and to create region-specific ventricular myocardium (7,8) Muscular thin films (MTFs), consisting of cells cultured on a flexible film, have enabled these 2D platforms to measure contractility (9,10), and combined with patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes can model cardiomyopathies such as Barth's syndrome (11). However, 2D cardiomyocytes are adhered to a surface (12) and thus do not have the same mechanical cell-cell coupling as found in the native heart (13). To address this, researchers have developed more physiologically-relevant 3D engineered heart tissues (EHTs) in the form papillary muscle-like linear bundles (14-18) myocardium-like sheets (19,20), and ventricle-like chambers (21,22). Incorporating human induced pluripotent stem cell (hi...

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Bi-layered polyurethane – Extracellular matrix cardiac patch improves ischemic ventricular wall remodeling in a rat model

Cited by 118 publications

References 55 publications

Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction

Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction

Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion

Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype

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