Acellular Injectable Biomaterials for Treating Cardiovascular Disease

In the last decade, the field of tissue engineering has emerged as a potential therapeutic strategy for the regeneration and/or repair of various tissues afflicted by cardiovascular disease, such as myocardial infarction (MI) or peripheral artery disease (PAD). Among the different tissue engineering strategies, injectable hydrogels have been extensively studied and show encouraging results in both small and large animal models. An injectable hydrogel provides a favorable microenvironment for endogenous regeneration or repair, and depending on the material's design can be used either alone or as a carrier to deliver therapeutic molecules or stem cells. The type of injectable biomaterial is key for a successful hydrogel-based treatment, and in this chapter, we will focus on acellular injectable biomaterial approaches for both MI and PAD

A bioprinted cardiac patch composed of cardiac-specific extracellular matrix and progenitor cells for heart repair

Congenital heart defects are present in 8 of 1000 newborns and palliative surgical therapy has increased survival. Despite improved outcomes, many children develop reduced cardiac function and heart failure requiring transplantation. Human cardiac progenitor cell (hCPC) therapy has potential to repair the pediatric myocardium through release of reparative factors, but therapy suffers from limited hCPC retention and functionality. Decellularized cardiac extracellular matrix hydrogel (cECM) improves heart function in animals, and human trials are ongoing. In the present study, a 3D-bioprinted patch containing cECM for delivery of pediatric hCPCs is developed. Cardiac patches are printed with bioinks composed of cECM, hCPCs, and gelatin methacrylate (GelMA). GelMA-cECM bioinks print uniformly with a homogeneous distribution of cECM and hCPCs. hCPCs maintain >75% viability and incorporation of cECM within patches results in a 30-fold increase in cardiogenic gene expression of hCPCs compared to hCPCs grown in pure GelMA patches. Conditioned media from GelMA-cECM patches show increased angiogenic potential (>2-fold) over GelMA alone, as seen by improved endothelial cell tube formation. Finally, patches are retained on rat hearts and show vascularization over 14 d in vivo. This work shows the successful bioprinting and implementation of cECM-hCPC patches for potential use in repairing damaged myocardium

Evidence for mechanisms underlying the functional benefits of a myocardial matrix hydrogel for post-MI treatment

Background There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. Objectives This study sought to elucidate the tissue-level mechanisms underlying the therapeutic benefits of myocardial matrix injection. Methods Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague-Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks after injection. Whole transcriptome microarrays were performed on RNA isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histologic quantification confirmed expression of key genes and their activation in altered pathways. Results Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected control subjects. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing after MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. Conclusions These results indicate that the myocardial matrix alters several key pathways after MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy

Tournaisian (Mississippian) brachiopods from the Mobarak Formation, North Iran

Following detailed stratigraphic work on the Mississippian marlstone and bioclastic limestone of the Mobarak Formation of the Alborz Mountains in North Iran, forty-eight of the most important brachiopod taxa are here systematically described and illustrated. The ranges of the taxa are given along the Abrendan and Simeh Kuh stratigraphic sections, located north of Damgham. The examined brachiopod species date the base of the Mobarak Formation to the Tournaisian, in absence of age-diagnostic foraminifers. Change in brachiopod settling preferences indicates a shift from high energy, shallow-water settings with high nutrient supply in the lower part of the formation to quieter, soft, but not soppy substrates, with lower nutrient supply in the middle part of the Mobarak Formation. Brachiopod occurrence is instead scanty at its top. The palaeobiogeographic affinity of the Tournaisian brachiopods from North Iran indicates a closer relationship to North America, Western Europe and the Russian Platform than to cold-water Australian faunas, confirming the affinity of the other biota of the Alborz Mountains. This can be explained by the occurrence of warm surface-current gyres widely distributing brachiopod larvae across the Palaeotethys Ocean, where North Iran as other peri-Gondwanan blocks acted as staging-posts

Bone marrow-derived cells can acquire cardiac stem cells properties in damaged heart

Experimental data suggest that cell-based therapies may be useful for cardiac regeneration following ischaemic heart disease. Bone marrow (BM) cells have been reported to contribute to tissue repair after myocardial infarction (MI) by a variety of humoural and cellular mechanisms. However, there is no direct evidence, so far, that BM cells can generate cardiac stem cells (CSCs). To investigate whether BM cells contribute to repopulate the Kit+ CSCs pool, we transplanted BM cells from transgenic mice, expressing green fluorescent protein under the control of Kit regulatory elements, into wild-type irradiated recipients. Following haematological reconstitution and MI, CSCs were cultured from cardiac explants to generate 'cardiospheres', a microtissue normally originating in vitro from CSCs. These were all green fluorescent (i.e. BM derived) and contained cells capable of initiating differentiation into cells expressing the cardiac marker Nkx2.5. These findings indicate that, at least in conditions of local acute cardiac damage, BM cells can home into the heart and give rise to cells that share properties of resident Kit+ CSCs

Aging Reveals a Role for Nigral Tyrosine Hydroxylase ser31 Phosphorylation in Locomotor Activity Generation

BACKGROUND:Tyrosine hydroxylase (TH) regulates dopamine (DA) bioavailability. Its product, L-DOPA, is an established treatment for Parkinson's disease (PD), suggesting that TH regulation influences locomotion. Site-specific phosphorylation of TH at ser31 and ser40 regulates activity. No direct evidence shows that ser40 phosphorylation is the dominating mechanism of regulating TH activity in vivo, and physiologically-relevant stimuli increase L-DOPA biosynthesis independent of ser40 phosphorylation. Significant loss of locomotor activity occurs in aging as in PD, despite less loss of striatal DA or TH in aging compared to the loss associated with symptomatic PD. However, in the substantia nigra (SN), there is equivalent loss of DA or TH in aging and at the onset of PD symptoms. Growth factors increase locomotor activity in both PD and aging models and increase DA bioavailability and ser31 TH phosphorylation in SN, suggesting that ser31 TH phosphorylation status in the SN, not striatum, regulates DA bioavailability necessary for locomotor activity. METHODOLOGY AND PRINCIPAL FINDINGS:We longitudinally characterized locomotor activity in young and older Brown-Norway Fischer 344 F(1) hybrid rats (18 months apart in age) at two time periods, eight months apart. The aged group served as an intact and pharmacologically-naïve source of deficient locomotor activity. Following locomotor testing, we analyzed DA tissue content, TH protein, and TH phosphorylation in striatum, SN, nucleus accumbens, and VTA. Levels of TH protein combined with ser31 phosphorylation alone reflected inherent differences in DA levels among the four regions. Measures strictly pertaining to locomotor activity initiation significantly correlated to DA content only in the SN. Nigral TH protein and ser31 phosphorylation together significantly correlated to test subject's maximum movement number, horizontal activity, and duration. CONCLUSIONS/SIGNIFICANCE:Together, these results show ser31 TH phosphorylation regulates DA bioavailability in intact neuropil, its status in the SN may regulate locomotor activity generation, and it may represent an accurate target for treating locomotor deficiency. They also show that neurotransmitter regulation in cell body regions can mediate behavioral outcomes and that ser31 TH phosphorylation plays a role in behaviors dependent upon catecholamines, such as dopamine

Experimental and Numerical Performance Survey of a MW-Scale Supercritical CO2 Compressor Operating in Near-Critical Conditions

Closed power cycles based on carbon dioxide in supercritical conditions (sCO2 in the following) are experiencing a growing scientific, technical and industrial interest, due to the high energy conversion efficiency and components compactness. Despite these advantages, the use of a working fluid operating in proximity to the critical point, especially for the compressor, entails multidisciplinary challenges related to the severe non-ideality of the supercritical fluid, which includes the potential onset of phase change at the impeller intake. On the technical and industrial grounds, the phase-transition might dramatically affect the aerodynamics, the performance and the rangeability of the compressor. On the scientific ground, the modelling of two-phase flows in transonic/supersonic conditions still remains an open issue that demands a thorough experimental assessment. This work illustrates the results of a wide experimental campaign focused on the evaluation of the operative map of a MW-scale high-load sCO2 compressor operating in plant-representative conditions, i.e. in proximity to the critical point (P = 79.8 bar, T = 33°C), designed in the frame of the sCO2Flex project, EU Horizon 2020 funded program (grant agreement #764690). In the design process, the machine had been object of a thorough computational investigation, performed by using a homogeneous equilibrium model equipped with a barotropic equation of state, which revealed a significant impact of the phase change on the compressor aerodynamics and on its rangeability for flow rates higher than the design one. Such phenomena are connected to the sudden drop of the speed of sound, originated when the fluid thermodynamic condition crosses the saturation line, and they weaken as the compressor loading reduces. Experiments carried out on a first of a kind 5 MW sCO2 prototype compressor manufactured and tested by Baker Hughes in 2021 remarkably well matched the predicted compressor performance and, especially, the anticipated and sudden choking of the compressor at nominal peripheral Mach number. Results demonstrates experimentally, for the first time ever, the effects of the phase-change on the operation of a realistic sCO2 compressor, also providing significant insights on the predictive capabilities of the physical models employed for the calculation of two-phase flows in this class of machines

A ruptured ectopic pregnancy in a patient with an intrauterine device: A case report.

Intrauterine devices (IUDs) are used worldwide. The 2 types that are used are the levonorgestrel IUD and a copper containing IUD. This is a case study of a 30-year-old female with a levonorgestrel IUD who was diagnosed with a ruptured ectopic pregnancy in the emergency department (ED). Point-of-care urine pregnancy test and point-of-care ultrasound (POCUS) were vital in making this diagnosis and should be utilized in patients assigned female at birth who present with abdominal pain