Effect of biomaterial stiffness on cardiac mechanics in a biventricular infarcted rat heart model with microstructural representation of in situ intramyocardial injectate.

Intramyocardial delivery of biomaterials is a promising concept for treating myocardial infarction. The delivered biomaterial provides mechanical support and attenuates wall thinning and elevated wall stress in the infarct region. This study aimed at developing a biventricular finite element model of an infarcted rat heart with a microstructural representation of an in situ biomaterial injectate, and a parametric investigation of the effect of the injectate stiffness on the cardiac mechanics.

Mathematical model of mechano-sensing and mechanically induced collective motility of cells on planar elastic substrates.

Cells mechanically interact with their environment to sense, for example, topography, elasticity and mechanical cues from other cells. Mechano-sensing has profound effects on cellular behaviour, including motility. The current study aims to develop a mathematical model of cellular mechano-sensing on planar elastic substrates and demonstrate the model's predictive capabilities for the motility of individual cells in a colony.

Modified fibrin hydrogel for sustained delivery of RNAi lipopolyplexes in skeletal muscle.

RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues. Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers. Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine 3.

Effect of paclitaxel treatment on cellular mechanics and morphology of human oesophageal squamous cell carcinoma in 2D and 3D environments.

During chemotherapy, structural and mechanical changes in malignant cells have been observed in several cancers, including leukaemia and pancreatic and prostate cancer. Such cellular changes may act as physical biomarkers for chemoresistance and cancer recurrence. This study aimed to determine how exposure to paclitaxel affects the intracellular stiffness of human oesophageal cancer of South African origin in vitro.

Blood derived extracellular vesicles as regenerative medicine therapeutics.

The regenerative promise of nanosized extracellular vesicles (EVs) secreted by cells is widely explored. Recently, the capacity of EVs purified from blood to elicit regenerative effect has begun to be evaluated. Blood might be a readily available source of EVs, avoiding need for extensive cell culturing, but there are specific issues that complicate use of the biofluid in this area.

In silico stress fibre content affects peak strain in cytoplasm and nucleus but not in the membrane for uniaxial substrate stretch.

Existing in silico models for single cell mechanics feature limited representations of cytoskeletal structures that contribute substantially to the mechanics of a cell. We propose a micromechanical hierarchical approach to capture the mechanical contribution of actin stress fibres. For a cell-specific fibroblast geometry with membrane, cytoplasm and nucleus, the Mori-Tanaka homogenization method was employed to describe cytoplasmic inhomogeneities and constitutive contribution of actin stress fibres.

Tendon-like tether formation for tongue-base advancement in an ovine model using a novel implant device intended for the surgical management of obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is a serious debilitating condition with significant morbidity and mortality affecting almost one billion adults globally. The current gold standard in the non-surgical management of airway collapse is continuous positive airway pressure (CPAP). However, non-compliance leads to a high abandon rate (27-46%).

Analysis of the regenerative capacity of human serum exosomes after a simple multistep separation from lipoproteins.

Due to the abundance of lipoproteins in blood, it is challenging to characterize the biological functions and components of blood-derived extracellular vesicles. The aim of this study was to develop a multiple-step purification protocol to separate serum exosomes from serum proteins and lipoproteins and assess their regenerative potential. Exosomes were isolated by concentrating them in human serum using ultracentrifugation (UC), followed sequentially by density gradient (DG) UC and size exclusion chromatography (SEC).

Progressive Reinvention or Destination Lost? Half a Century of Cardiovascular Tissue Engineering.

The concept of tissue engineering evolved long before the phrase was forged, driven by the thromboembolic complications associated with the early total artificial heart programs of the 1960s. Yet more than half a century of dedicated research has not fulfilled the promise of successful broad clinical implementation. A historical account outlines reasons for this scientific impasse.

Tissue Ingrowth Markedly Reduces Mechanical Anisotropy and Stiffness in Fibre Direction of Highly Aligned Electrospun Polyurethane Scaffolds.

Purpose: The lack of long-term patency of synthetic vascular grafts currently available on the market has directed research towards improving the performance of small diameter grafts. Improved radial compliance matching and tissue ingrowth into the graft scaffold are amongst the main goals for an ideal vascular graft.

Methods: Biostable polyurethane scaffolds were manufactured by electrospinning and implanted in subcutaneous and circulatory positions in the rat for 7, 14 and 28 days.

Determinants of mortality in patients with cirrhosis and uncontrolled variceal bleeding.

Background & Aims: Failure to control oesophago-gastric variceal bleeding (OGVB) and acute-on-chronic liver failure (ACLF) are both important prognostic factors in cirrhosis. The aims of this study were to determine whether ACLF and its severity define the risk of death in OGVB and whether insertion of rescue transjugular intrahepatic shunt (TIPS) improves survival in patients with failure to control OGVB and ACLF.

Methods: Data on 174 consecutive eligible patients, with failure to control OGVB between 2005 and 2015, were collected from a prospectively maintained intensive care unit registry.

Intra-myocardial alginate hydrogel injection acts as a left ventricular mid-wall constraint in swine.

Despite positive initial outcomes emerging from preclinical and early clinical investigation of alginate hydrogel injection therapy as a treatment for heart failure, the lack of knowledge about the mechanism of action remains a major shortcoming that limits the efficacy of treatment design. To identify the mechanism of action, we examined previously unobtainable measurements of cardiac function from in vivo, ex vivo, and in silico states of clinically relevant heart failure (HF) in large animals. High-resolution ex vivo magnetic resonance imaging and histological data were used along with state-of-the-art subject-specific computational model simulations.

Tuning Tissue Ingrowth into Proangiogenic Hydrogels via Dual Modality Degradation.

The potential to control the rate of replacement of a biodegradable implant by a tissue would be advantageous. Here, we demonstrate that tissue invasion can be tuned through the novel approach of overlaying an enzymatically degradable hydrogel with an increasingly hydrolytically degradable environment. Poly(ethylene glycol) (PEG) hydrogels were formed from varying proportions of PEG-vinyl sulfone and PEG-acrylate (PEG-AC) monomers via a Michael-type addition reaction with a dithiol-containing matrix-metalloproteinase-susceptible peptide cross-linker.

A Preliminary Computational Investigation Into the Flow of PEG in Rat Myocardial Tissue for Regenerative Therapy.

Myocardial infarction (MI), a type of cardiovascular disease, affects a significant proportion of people around the world. Traditionally, non-communicable chronic diseases were largely associated with aging populations in higher income countries. It is now evident that low- to middle-income countries are also affected and in these settings, younger individuals are at high risk.

Anticoagulation after Iliofemoral Vein Stenting - Old Versus New.

In recent years, there has been an increasing interest in endovascular iliofemoral vein stenting to prevent/ alleviate symptoms related to proximal venous outflow obstruction. Maintaining long-term stent patency is one of the main challenges, and risk factors for the development of re-thrombosis are not well understood. Published data on the safety and efficacy of the procedure predominantly come from cohort studies mainly focusing on mechanical aspects relating to stent placement and flow.

Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy.

Background: Mesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel containing heparin (H-HG), could ameliorate MSC engraftment and binding/release of SF, thus improving MSC therapy efficacy.

Transmural capillary ingrowth is essential for confluent vascular graft healing.

Unlabelled: Spontaneous endothelialization of synthetic vascular grafts may occur via three independent or concurrent modalities: transanastomotic (TA) outgrowth, transmural (TM) ingrowth or fallout (FO) from the blood. The limited TA and FO endothelialization, which occurs in humans, results in poor long-term patency in the small diameter position, where TM ingrowth may offer a clinically relevant alternative. To achieve sequential analysis of each mode of healing, loop grafts comprising anastomotically isolated angiopermissive polyurethane control grafts were abluminally sealed using either ePTFE wraps or solid polyurethane skins and implanted in the rat infrarenal aortic loop model for twelve weeks.

Improved vascularization of porous scaffolds through growth factor delivery from heparinized polyethylene glycol hydrogels.

Unlabelled: Surface modification with heparin has previously been shown to increase vascularization of porous scaffolds. In order to determine its efficacy with sustained release, heparin (Hep) was covalently incorporated into degradable (Type D) and non-degradable (Type N) polyethylene glycol (PEG) hydrogels. After in vitro characterization of their physicochemical properties, growth factor (GF) loaded, heparinised Type D gels were formed within the pores of porous polyurethane disks, which were then implanted and evaluated in a subcutaneous model.

Personalised computational cardiology: Patient-specific modelling in cardiac mechanics and biomaterial injection therapies for myocardial infarction.

Predictive computational modelling in biomedical research offers the potential to integrate diverse data, uncover biological mechanisms that are not easily accessible through experimental methods and expose gaps in knowledge requiring further research. Recent developments in computing and diagnostic technologies have initiated the advancement of computational models in terms of complexity and specificity. Consequently, computational modelling can increasingly be utilised as enabling and complementing modality in the clinic-with medical decisions and interventions being personalised.

Infarcted rat myocardium: Data from biaxial tensile and uniaxial compressive testing and analysis of collagen fibre orientation.

Myocardial infarction was experimentally induced in rat hearts and harvested immediately, 7, 14 and 28 days after the infarction induction. Anterior wall infarct samples underwent biaxial tensile and uniaxial compressive testing. Orientation of collagen fibres was analysed following mechanical testing.

Cast Tube Assay: A 3-D in vitro assay for visualization and quantification of horizontal chemotaxis and cellular invasion.

Directed cell motility, as controlled by soluble factors, is crucial for many biological processes, including development, cancer progression, and wound healing. The use of directed cell motility also shows promise for applications in regenerative medicine such as therapeutic angiogenesis. Unfortunately, current in vitro 3-D migration and invasion models limit our understanding and application of these processes.

Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression.

Understanding the passive mechanical properties of infarcted tissue at different healing stages is essential to explore the emerging biomaterial injection-based therapy for myocardial infarction (MI). Although rats have been widely used as animal models in such investigations, the data in literature that quantify the passive mechanical properties of rat heart infarcts is very limited. MI was induced in rats and hearts were harvested immediately (0 day), 7, 14 and 28 days after infarction onset.

Excessive volume of hydrogel injectates may compromise the efficacy for the treatment of acute myocardial infarction.

Biomaterial injectates are promising as a therapy for myocardial infarction to inhibit the adverse ventricular remodeling. The current study explored interrelated effects of injectate volume and infarct size on treatment efficacy. A finite element model of a rat heart was utilized to represent ischemic infarcts of 10%, 20%, and 38% of left ventricular wall volume and polyethylene glycol hydrogel injectates of 25%, 50%, and 75% of the infarct volume.

Coacervate Delivery of Growth Factors Combined with a Degradable Hydrogel Preserves Heart Function after Myocardial Infarction.

Regenerative therapies to improve prognosis after heart attack and mitigate the onset of heart failure are urgently needed. To this end, we developed a bioactive therapy of sustained release of the morphogen Sonic hedgehog (Shh) and the anti-inflammatory cytokine interleukin-10 (IL-10) from a coacervate delivery vehicle. This is combined with a structural therapy consisting of a biodegradable polyethylene glycol (PEG) hydrogel, harnessing the benefits of both components.

Pharmacodynamic effects of C-domain-specific ACE inhibitors on the renin-angiotensin system in myocardial infarcted rats.

Introduction: The renin-angiotensin system (RAS) is a dynamic network that plays a critical role in blood pressure regulation and fluid and electrolyte homeostasis. Modulators of the RAS, such as angiotensin-converting enzyme (ACE) inhibitors, are widely used to treat hypertension, heart failure and myocardial infarction.

Methods: The effect of ACE inhibitors (lisinopril and C-domain-selective LisW-S) on the constituent peptides of the RAS following myocardial infarction was examined in rats.