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

Supramolecular biomaterials. A modular approach towards tissue engineering

Supramolecular chemistry is an exciting area of science that plays a central role in bringing different disciplines together, ranging from molecular medicine to nanotechnology. Materials science based on supramolecular interactions is an emerging field, which has made important steps forward in the past ten years. The self-assembly of small synthetic molecules into long-chain architectures gives rise to the careful design of supramolecular polymers or fibers based on highly directional, reversible, non-covalent interactions. Much afford is put into the development of supramolecular (polymeric) materials with true materials properties, both in solution and in the solid state. These supramolecular materials are beginning to reach the market in all kind of applications. The field of regenerative medicine in general and that of tissue engineering in particular is one of the most challenging areas in which supramolecular materials might have a high potential. In tissue engineering, the biological environment and the interactions of cells with the artificial biomaterial is of utmost importance for the functioning of the implant, i.e. the engineered tissue. Ideal biomaterials do not only have to fulfil the biomaterials trinity of tuneable mechanical properties, regulation of the degradability and the ease for bioactivity incorporation, but also have to mimic the natural environment where the materials are brought into. Therefore, a modular, self-assembly approach using several supramolecular building blocks is an exquisite way to produce such "responsive" biomaterials. It is proposed that the artificial materials described in this account have the same type of dynamic ability to adapt its biofunctionality as is so well known for the living cells in the host tissue. This account will highlight two systems, i.e. self-assembling oligopeptide fibers as pioneered by Stupp et al. and Zhang et al., and our hydrogen-bonded supramolecular polymers, to show the potential of a modular approach to dynamic biomaterials for tissue engineering