Triple-marker cardiac MRI detects sequential tissue changes of healing myocardium after a hydrogel-based therapy

Regenerative therapies based on injectable biomaterials, hold an unparalleled potential for treating myocardial ischemia. Yet, noninvasive evaluation of their efficacy has been lagging behind. Here, we report the development and longitudinal application of multiparametric cardiac magnetic resonance imaging (MRI) to evaluate a hydrogel-based cardiac regenerative therapy. A pH-switchable hydrogel was loaded with slow releasing insulin growth factor 1 and vascular endothelial growth factor, followed by intramyocardial injection in a mouse model of ischemia reperfusion injury. Longitudinal cardiac MRI assessed three hallmarks of cardiac regeneration: angiogenesis, resolution of fibrosis and (re)muscularization after infarction. The multiparametric approach contained dynamic contrast enhanced MRI that measured improved vessel features by assessing fractional blood volume and permeability*surface area product, T1-mapping that displayed reduced fibrosis, and tagging MRI that showed improved regional myocardial strain in hydrogel treated infarcts. Finally, standard volumetric MRI demonstrated improved left ventricular functioning in hydrogel treated mice followed over time. Histology confirmed MR-based vessel features and fibrotic measurements. Our novel triple-marker strategy enabled detection of ameliorated regeneration in hydrogel treated hearts highlighting the translational potential of these longitudinal MRI approaches

Уникальные ресурсы Крыма как основа для развития мистического туризма

Целью статьи является рассмотрение возможности развития мистического туризма в Крыму на основе его уникальных природных и культурно-исторических ресурсов

Influence of the Assembly State on the Functionality of a Supramolecular Jagged1-Mimicking Peptide Additive

Expanding the bioactivation toolbox of supramolecular materials is of utmost relevance for their broad applicability in regenerative medicines. This study explores the functionality of a peptide mimic of the Notch ligand Jagged1 in a supramolecular system that is based on hydrogen bonding ureido-pyrimidinone (UPy) units. The functionality of the peptide is studied when formulated as an additive in a supramolecular solid material and as a self-assembled system in solution. UPy conjugation of the DSLJAG1 peptide sequence allows for the supramolecular functionalization of UPy-modified polycaprolactone, an elastomeric material, with UPy-DSLJAG1. Surface presentation of the UPy-DSLJAG1 peptide was confirmed by atomic force microscopy and X-ray photoelectron spectroscopy analyses, but no enhancement of Notch activity was detected in cells presenting Notch1 and Notch3 receptors. Nevertheless, a significant increase in Notch-signaling activity was observed when DSLJAG1 peptides were administered in the soluble form, indicating that the activity of DSLJAG1 is preserved after UPy functionalization but not after immobilization on a supramolecular solid material. Interestingly, an enhanced activity in solution of the UPy conjugate was detected compared with the unconjugated DSLJAG1 peptide, suggesting that the self-assembly of supramolecular aggregates in solution ameliorates the functionality of the molecules in a biological context

Sustained Delivery of Insulin-Like Growth Factor-1/Hepatocyte Growth Factor Stimulates Endogenous Cardiac Repair in the Chronic Infarcted Pig Heart

Activation of endogenous cardiac stem/progenitor cells (eCSCs) can improve cardiac repair after acute myocardial infarction. We studied whether the in situ activation of eCSCs by insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) could be increased using a newly developed hydrogel in chronic myocardial infarction (MI). One-month post-MI pigs underwent NOGA-guided intramyocardial injections of IGF-1/HGF (GF: both 0.5 μg/mL, n = 5) or IGF-1/HGF incorporated in UPy hydrogel (UPy-GF; both 0.5 μg/mL, n = 5). UPy hydrogel without added growth factors was administered to four control (CTRL) pigs. Left ventricular ejection fraction was increased in the UPy-GF and GF animals compared to CTRLs. UPy-GF delivery reduced pathological hypertrophy, led to the formation of new, small cardiomyocytes, and increased capillarization. The eCSC population was increased almost fourfold in the border zone of the UPy-GF-treated hearts compared to CTRL hearts. These results show that IGF-1/HGF therapy led to an improved cardiac function in chronic MI and that effect size could be further increased by using UPy hydrogel. Electronic supplementary material The online version of this article (doi:10.1007/s12265-013-9518-4) contains supplementary material, which is available to authorized users

A Fast pH-Switchable and Self-Healing Supramolecular Hydrogel Carrier for Guided, Local Catheter Injection in the Infarcted Myocardium

Minimally invasive intervention strategies after myocardial infarction use state-of-the-art catheter systems that are able to combine mapping of the infarcted area with precise, local injection of drugs. To this end, catheter delivery of drugs that are not immediately pumped out of the heart is still challenging, and requires a carrier matrix that in the solution state can be injected through a long catheter, and instantaneously gelates at the site of injection. To address this unmet need, a pH-switchable supramolecular hydrogel is developed. The supramolecular hydrogel is switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1-m long catheter while rapidly forming a hydrogel in contact with tissue. The hydrogel has self-healing properties taking care of adjustment to the injection site. Growth factors are delivered from the hydrogel thereby clearly showing a reduction of infarct scar in a pig myocardial infarction model

Sustained Delivery of Insulin-Like Growth Factor-1/Hepatocyte Growth Factor Stimulates Endogenous Cardiac Repair in the Chronic Infarcted Pig Heart

Activation of endogenous cardiac stem/progenitor cells (eCSCs) can improve cardiac repair after acute myocardial infarction. We studied whether the in situ activation of eCSCs by insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) could be increased using a newly developed hydrogel in chronic myocardial infarction (MI). One-month post-MI pigs underwent NOGA-gu ided intramyocardial injec- tions of IGF-1/HGF (GF: both 0.5 μ g/mL, n =5) or IGF-1/HGF incorporated in UPy hydrogel (UPy-GF; both 0.5 μ g/mL, n =5). UPy hydrogel without added growth factors was administered to four control (CTRL) pigs. Left ve ntricular ejection fraction was increased in the UPy-GF and GF animals compared to CTRLs. UPy-GF delivery reduced pathological hypertrophy, led to the formation of new, small cardiomyocytes, and increased capillarization. The eCSC popula tion was increased almost four- fold in the border zone of the UPy-GF-treated hearts compared to CTRL hearts. These results show that IGF-1/HGF therapy led to an improved cardia c function in chronic MI and that effect size could be further increased by using UPy hydrogel

The effect of chronic kidney disease on tissue formation of in situ tissue-engineered vascular grafts.

Vascular in situ tissue engineering encompasses a single-step approach with a wide adaptive potential and true off-the-shelf availability for vascular grafts. However, a synchronized balance between breakdown of the scaffold material and neo-tissue formation is essential. Chronic kidney disease (CKD) may influence this balance, lowering the usability of these grafts for vascular access in end-stage CKD patients on dialysis. We aimed to investigate the effects of CKD on in vivo scaffold breakdown and tissue formation in grafts made of electrospun, modular, supramolecular polycarbonate with ureido-pyrimidinone moieties (PC-UPy). We implanted PC-UPy aortic interposition grafts (n = 40) in a rat 5/6th nephrectomy model that mimics systemic conditions in human CKD patients. We studied patency, mechanical stability, extracellular matrix (ECM) components, total cellularity, vascular tissue formation, and vascular calcification in CKD and healthy rats at 2, 4, 8, and 12 weeks post-implantation. Our study shows successful in vivo application of a slow-degrading small-diameter vascular graft that supports adequate in situ vascular tissue formation. Despite systemic inflammation associated with CKD, no influence of CKD on patency (Sham: 95% vs CKD: 100%), mechanical stability, ECM formation (Sirius red +, Sham 16.5% vs CKD 25.0%-p:0.83), tissue composition, and immune cell infiltration was found. We did find a limited increase in vascular calcification at 12 weeks (Sham 0.08% vs CKD 0.80%-p:0.02) in grafts implanted in CKD animals. However, this was not associated with increased stiffness in the explants. Our findings suggest that disease-specific graft design may not be necessary for use in CKD patients on dialysis

Off-the-Shelf Synthetic Biodegradable Grafts Transform In Situ into a Living Arteriovenous Fistula in a Large Animal Model

Current vascular access options require frequent interventions. In situ tissue engineering (TE) may overcome these limitations by combining the initial success of synthetic grafts with long-term advantages of autologous vessels by using biodegradable grafts that transform into autologous vascular tissue at the site of implantation. Scaffolds (6 mm-Ø) made of supramolecular polycarbonate-bisurea (PC-BU), with a polycaprolactone (PCL) anti-kinking-coil, are implanted between the carotid artery and jugular vein in goats. A subset is bio-functionalized using bisurea-modified-Stromal cell-derived factor-1α (SDF1α) derived peptides and ePTFE grafts as controls. Grafts are explanted after 1 and 3 months, and evaluated for material degradation, tissue formation, compliance, and patency. At 3 months, the scaffold is resorbed and replaced by vascular neo-tissue, including elastin, contractile markers, and endothelial lining. No dilations, ruptures, or aneurysms are observed and grafts are successfully cannulated at termination. SDF-1α-peptide-biofunctionalization does not influence outcomes. Patency is lower in TE grafts (50%) compared to controls (100% patency), predominantly caused by intimal hyperplasia. Rapid remodeling of a synthetic, biodegradable vascular scaffold into a living, compliant arteriovenous fistula is demonstrated in a large animal model. Despite lower patency compared to ePTFE, transformation into autologous and compliant living tissue with self-healing capacity may have long-term advantages