Stability issues in membrane-free coacervates have been addressed with coating strategies, but these approaches often compromise the permeability of the coacervate. Researchers from UC San Diego have invented a facile approach to maintain both stability and permeability using tannic acid and then demonstrate the value of this approach in enzyme-triggered drug release. First, the researchers developed size-tunable coacervates via self-assembly of heparin glycosaminoglycan with tyrosine and arginine-based peptides. A thrombin-recognition site within the peptide building block results in heparin release upon thrombin proteolysis. Notably, polyphenols are integrated within the nano-coacervates to improve stability in biofluids. Phenolic crosslinking at the liquid-liquid interface enables nano-coacervates to maintain exceptional structural integrity across various environments. The UCSD scientists discovered a pivotal polyphenol threshold for preserving enzymatic activity alongside enhanced stability. The disassembly rate of the nano-coacervates increases as a function of thrombin activity, thus preventing a coagulation cascade. This polyphenol-based approach not only improves stability but also opens the way for applications in biomedicine, protease sensing, and bio-responsive drug delivery. 

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a predominantly genetic-based heart disease characterized by right but also recently left ventricular dysfunction, fibrofatty replacement of the myocardium leading to fatal/severe ventricular arrhythmias leading to sudden cardiac death in young people and athletes. ARVC is responsible for 10% of sudden cardiac deaths in people ≥65 years of age and 24% in people ≤30 years of age. ARVC is thought to be a rare disease as it occurs in 1 in 1000-5000 people, although the prevalence may be higher as some patients are undiagnosed or misdiagnosed due to poor diagnostic markers. Growing evidence also reveals earlier onset since pediatric populations ranging from infants to children in their teens are also particularly vulnerable to ARVC, highlighting the critical need to identify and treat patients at an earlier stage of the disease. At present there are no effective treatments for ARVC nor has there been any randomized clinical trials conducted to examine treatment modalities, screening regimens, or medications specific for ARVC. As a result, treatment strategies for ARVC patients are directed at symptomatic relief of electrophysiological defects, based on clinical expertise, results of retrospective registry-based studies, and the results of studies on model systems. The current standard of care is the use of anti-arrhythmic drugs (sotalol, amniodarone and beta-blockers) that transition into more invasive actions, which include implantable cardioverter defibrillators and cardiac catheter ablation, if the patient becomes unresponsive or intolerant to anti-arrhythmic therapies. However, current therapeutic modalities have limited effectiveness in managing the disease, 40% of ARVC patients (a young heart disease) die within 10-11 years after initial diagnosis, highlighting the need for development of more effective therapies for patients with ARVC.

Cardiac ablations are common medical treatments for people with atrial fibrillation (Afib). During the ablation procedure, a cardiac electrophysiologist will thermally ablate, or burn off, defective heart tissue with radiofrequency or cryoablation technology. The esophagus is often in close proximity to the left atrium. Since the left atrial tissue is approximately 2mm thin, the heat can transfer through it to the esophagus in contact and cause thermal damage / lesions on the esophagus.  In worst-case rare scenarios, an atrio-esophageal fistula, or hole between the esophagus and the heart, can occur which has a ~75% mortality rate.  It would be ideal to move the esophagus away from the heart before or during the ablation procedure preventing thermal damage.

Although a wide variety of hydrogels have been developed for a multitude of uses, various functional characteristics have been hard to capture in a controllable manner. A significant feature is the ability to ‘tune’ the gel so its gelling time can be controlled in a manner suitable to its application. In this disclosure, because the gel is both tunable and its composition allows it to bond to tissue, the inventors believe it can be used to address an unmet medical need – the formation of adhesions after cardiac surgery. Current methods used are either drug therapy or various physical barriers but their success is limited.

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat is stored in the liver, though not caused by heavy alcohol use. NAFLD is one of the most common causes of liver disease in the United States. NAFLD it typically asymptomatic but when NAFLD advances, it can result in the development of NASH (Nonalcoholic steatohepatitis) where inflammation and fibrosis are widespread in the liver, resulting in nonalcoholic steatohepatitis and liver cirrhosis. Mechanisms of NAFLD progression are poorly understood. Experts estimate that about 20% of people with NAFLD have NASH. Between 30% and 40% of adults in the United States have NAFLD. About 3% to 12% of adults in the United States have NASH. There are no existing FDA‐approved therapies for nonalcoholic fatty liver disease (NAFLD). NAFLD it typically asymptomatic but it can progress to nonalcoholic steatohepatitis and liver cirrhosis. Mechanisms of NAFLD progression are poorly understood. There are many FDA‐approved therapies for type 2 diabetes, including metformin, insulin, sulfonylureas, Glp‐1 receptor agonists, Dpp‐4 inhibitors, and Sglt2 inhibitors. These drugs work through diverse mechanisms such as increasing insulin secretion (sulfonylureas, Glp‐1 receptor agonists, Dpp‐4 inhibitors), direct insulin replacement (insulin), reducing glucose production by the liver (metformin), and stimulating excretion of glucose into urine (Sglt2 inhibitors).

Cardiovascular disease is the leading cause of mortality and disability worldwide. It is also prevalent, affecting 9% of the population over 20 years of age. Patients with cardiovascular risk factors can reduce their risk of developing catastrophic cardiovascular events such as heart attack and stroke through lifestyle modification and medications. Unfortunately for many, the disease may go undiagnosed until the occurrence of serious events. Identifying biomarkers of subclinical ischemia can help identify patients with occult cardiovascular disease.

Cardiovascular disease (CVD) is a tremendous burden on the population in terms of morbidity and mortality, as well as on the healthcare system in terms of cost. Various forms of CVD including atherosclerosis, valve and ventricular dysfunction, aneurysms, and thrombogenesis can be identified by measuring localized abnormalities in blood flow. Accordingly, the ability to noninvasively interrogate physiological flows enables identification and diagnosis of disease, monitoring of the effects of therapy, and research on the hemodynamic nature of CVD and its associated interventions. In the clinic, blood flow measurements are primarily made using phase contrast magnetic resonance imaging (PC-MRI) and ultrasonic color Doppler imaging. Certain limitations of these techniques for patients who have contraindications or suffer from arrhythmias, as well as the desire for volumetric flow information necessitate the development of a new modality for blood flow velocimetry.

Heart failure (HF) is a disease of epidemic portions in the United States affecting over 6 million patients with heart failure in the US, with 400,000 new cases per year. It is the most common cause of non-elective admission to the hospital in subjects 65 yrs and older. The introduction of new drugs over the last 30 years that target pathways critical to progression of HF, along with implantable cardiac defibrillators and resynchronization devices have shown some successes, however, both the morbidity and mortality associated with heart failure remains at unacceptable levels, with as many as 30-40% of affected individuals dying within 5 years of diagnosis. Recently, preclinical and clinical trials have tested gene transfer to increase left ventricular (LV) function, especially in heart failure with reduced ejection fraction.

Dishevelled (Dvl) proteins are important signaling components of both the canonical β-catenin/Wnt pathway, which controls cell proliferation and patterning, migration, differentiation, stem cell renewal and the planar cell polarity (PCP) pathway. Mammals share three Dishevelled (Dvl) family members and while the roles of Dvl1 and Dvl2 have been described previously, the functions of Dvl3 have remained an area of active research. The lack of Dvl3 in mice affects the formation of the heart, neural tube, and inner ear and that the defects in these tissues are much more severe when the mice are deficient in more than one Dvl family member, indicating redundant functions for these genes. Congenital heart disease affects approximately 75 in every 1,000 live human births, and approximately 30% of these diseases are due to disruptions in the outflow tract, the region affected in mice lacking Dvl genes.

Aortic aneurysms account for 1-2% of deaths in Western countries, and despite improvements in surgical repair, morbidity and mortality remain high, especially with thoracic aortic aneurysms and dissections (TAAD). Degeneration of the medial layer of the aorta leads to aortic dilation and/or rupture; pathological changes in the media include progressive elastin fiber fragmentation, loss of smooth muscle cells, and proteoglycan accumulation. Mutations causing hereditary TAAD affect proteins regulating transforming growth factor-β signaling (e.g., Loeys-Dietz syndrome and Marfan syndrome), or components of the smooth muscle cell contractile apparatus. Aortic pathology has been attributed to smooth muscle cell phenotypic alterations and activation of stress pathways, leading to increased production of tissue-destructive matrix metalloproteinases and increased oxidative stress. Abdominal aortic aneurysms (AAAs) may share with TAAD some of these pathogenic mechanisms. While blood pressure control with β-adrenergic or angiotensin receptor blockers modestly improve the prognosis of patients with TAAD, there is no treatment to prevent the pathologic changes in the aorta.          

Magnetic resonance imaging (MRI) has been noted for its excellent soft tissue imaging capability with zero radiation dose. It has repeatedly been touted as the imaging modality of the future, but due to its complexity, long exam times and high cost, its growth has been severely limited. This especially has been the case for cardiac MRI, which only accounts for about I percent of all MRI exams in the United States. Delayed enhancement (DE) imaging is an essential component of cardiac MRI, widely used for the evaluation of myocardial scar and viability. The selection of an optimal inversion time (TI), known as the myocardial null point (TINP), to suppress the background myocardial signal is required to optimize image contrast in myocardial delayed enhancement (MDE) acquisitions. Incorrect selection of TINP can impair diagnostic quality. In certain diffuse myocardial diseases such as amyloidosis, it may be difficult to identify a single optimal null point. Further, it is known that TINP varies after intravenous contrast administration, and is therefore time-sensitive. In practice, selection of myocardial inversion time is generally performed through visual inspection and selection of TINP from an inversion recovery scout acquisition. This is dependent on the skill of a technologist or physician to select the optimal inversion time, which may not be readily available outside of specialized centers. However, such methods still rely on visual inspection of an image series by a trained human observer to select an optimal myocardial inversion time. A way to overcome these deficiencies is to embrace Deep learning approaches, including convolutional neural networks (CNNs),     which have the potential to automate selection of inversion time, and are the current state-of-the-art technology for image classification, segmentation, localization, and Spatial Temporal Ensemble Myocardium Inversion NETwork (STEMI-NET) prediction. However, these static CNN models have some drawbacks which could be overcome via the use of dynamic temporal activities for object recognition.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. The primary prevention of CVD is dependent upon the ability to identify high-risk individuals long before the development of overt events. This highlights the need for accurate risk stratification. An increasing number of novel biomarkers have been identified to predict cardiovascular events. Biomarkers play a critical role in the definition, prognostication, and decision-making regarding the management of cardiovascular events. There are several promising biomarkers that might provide diagnostic and prognostic information. The myocardial tissue-specific biomarker cardiac troponin, high-sensitivity assays for cardiac troponin, and heart-type fatty acid binding potential help diagnose myocardial infarction (MI) in the early hours following symptoms. Inflammatory markers such as growth differentiation factor-15, high-sensitivity C-reactive protein, fibrinogen, and uric acid predict MI and death and many others. However, there is a high unmet medical need for the more specific biomarkers that reflect different aspects of the development of atherosclerosis. 

The heart consists of a multitude of diverse cardiomyocyte cell types, including atrial, ventricular and pacemaker cells, which cooperate to ensure proper cardiac function and circulation throughout the body. The rhythm of the heart beat is regulated by the sinoatrial node (SAN), functionally known as the cardiac pacemaker. Loss or dysfunction of these pacemaker cardiomyocytes leads to severe cardiac arrhythmias, syncope and/or even death. Although artificial pacemakers exist to help overcome these issues, several serious limitations and problems have emerged with this approach over the past several decades including electrode fracture or damage to insulation, infection, re-operations for battery exchange, and venous thrombosis. Moreover, size mismatch and the fact that pacemaker leads do not grow with children are a concerning problem. Thus, replacing artificial pacemakers with biological pacemakers potentially overcomes these artificial pacemaker issues including the expense and complications associated with device replacement, device or lead failure, and infection. To achieve these goals, understanding how pacemaker cardiomyocytes are generated is necessary to develop a human biological pacemaker for cardiac cellular therapies.

The G protein-coupled receptors (GPCRs) are a very important family of cell surface receptors that respond to extracellular signals which then transduce those signals into intracellular responses.  They are also the largest family of targets of currently available therapeutics. Adrenergic receptors belong to the GPCR superfamily and their natural ligands are the catecholamines, epinephrine and norepinephrine. Adrenergic receptors can be further divided into two receptor subfamilies, α and β that exhibit differences in tissue distribution, ligand specificity and cellular output. The β adrenergic receptors (βARs) are important mediators in diseases like asthma, Parkinson’s disease, hypertension and heart failure. Therefore, there is a direct need for new modulators for the βARs receptors.

In the United States and most other developed countries, atherosclerosis is the leading cause of illness and death. In 2015, cardiovascular disease, primarily coronary artery disease (atherosclerosis that affects the arteries supplying blood to the heart) and stroke, caused almost 15 million deaths worldwide, making atherosclerosis the leading cause of death worldwide. Atherosclerosis means hardening of the arteries due to the presence of plaques, which are deposits of fatty materials. Atherosclerosis can affect the medium-sized and large arteries of the brain, heart, kidneys, other vital organs, and legs. Atherosclerosis begins when an injured artery wall creates chemical signals that cause certain types of white blood cells (monocytes and T cells) to attach to the wall of the artery. These cells move into the wall of the artery. There they are transformed into foam cells, which collect cholesterol and other fatty materials and trigger growth of smooth muscle cells in the artery wall. In time, these fat-laden foam cells accumulate. They form patchy deposits (atheromas, also called plaques) covered with a fibrous cap in the lining of the artery wall. With time, calcium accumulates in the plaques. Plaques may be scattered throughout medium-sized and large arteries, but they usually start where the arteries branch. Existing treatment options for atherosclerosis and cardiovascular disease are aimed at lowering Low-density lipoprotein (LDL) cholesterol by either increasing hepatic LDLR expression by using statins and PCSK9 inhibitors, or by reducing cholesterol absorption by using ezetimibe. Further development of therapeutic strategies is warranted due to various drawbacks and limitations using the current therapeutic options.

Cardiovascular disease manifested as a myocardial infarction (MI) usually results in the irreversible death of heart muscle cells. While medical treatments can mitigate some symptoms, they often fail to prevent heart failure after a MI. The current standard of care for MI relies on surgical intervention via a coronary artery bypass. An alternative therapeutic approach has been taken in the last few years with the introduction of biomaterials designed to promote neovascularization after an MI and help prevent negative left ventricle remodeling by increasing infarct wall thickness and decreasing volume, fibrosis, and infarct size. 

Cerebral cavernous malformation (CCM) is a neurovascular disease that causes epilepsy and stroke for which there is no medical therapy. It has a prevalence of 5 per thousand in western populations and occurs in familial forms as a consequence of mutations in 3 CCM genes: CCM1/KRIT1, CCM2, CCM3/PCDC10 resulting in the formation of CCMs; mutations in the CCM1/KRIT1 gene account for 40% of the inherited cases. Once identified, CCM patients have a lifetime risk of CCM development and progression with increasing risk of stroke, epilepsy, or neurological impairment. 

Heart failure following a myocardial infarction (MI) continues to be one of the leading causes of death. Immediately after MI, there is an initial inflammatory response with cardiomyocyte death and degradation of the extracellular matrix. This results in negative left ventricular (LV) remodeling leading to wall thinning, LV dilation, and depressed cardiac function. Several experimental approaches have been examined to inhibit this negative remodeling process. One promising direction is the use of injectable biomaterials, which can be used as stand-alone scaffolds to encourage endogenous repair or for delivering therapeutics such as cells, growth factors, or small molecules. Early intervention of MI has the potential to slow or inhibit the progression of negative LV remodeling. To date, most therapeutic delivery strategies have involved intramyocardial biomaterial injections, although translation to acute MI patients is unlikely given the increased risk of ventricular rupture immediately post-MI. One promising, minimally invasive strategy is the systemic injection of nanoparticles. However, many of the investigated systems lack long-term retention within the MI. 

Market: Approximately 5 million people in the US currently suffer from congestive heart failure.  Of these, approximately 50% have left ventricular (LV) systolic dysfunction (weak heart muscle) and have a 5x increased risk for Stroke.

Regulatory T cells (Treg) are important to control immune homeostasis and control inflammation. In autoimmunity Tregs play a critical role in down-sizing autoreactive T cells and, via interleukin-10 (IL-10) secretion, they regulate not only inflammation but also the fibrotic process that often complicates systemic autoimmune diseases. IVIG therapy is successfully used in many autoimmune conditions, such as immune-mediated thrombocytopenia, autoimmune hemolytic anemia, autoimmune vasculitides and in neurological conditions including Guillain-Barré syndrome, narcolepsy, Parkinson’s, Alzheimer’s.  The expansion of Fc-specific Treg may account as the critical mechanism as the autoimmune pathogenesis in these diseases is now proven and the immunodominant Fc peptides bind HLA molecules strongly associated with these diseases. IVIG treatment is very expensive and is provided as an infusion that requires hospitalization, so alternative treatments are needed. Immune regulation appears to be the most relevant therapeutic success in down-sizing endothelial inflammation and the vasculitis in Covid-19 infected patients. Suppressive lymphokines and in particular interleukin (IL)-10, the hallmark of regulatory T cells, regulates IL-1 and IL-6 secretion in the vascular compartment. Fc immune modulatory peptides are anticipated to stimulate Treg with potential effects not only on naïve T cell differentiation toward a pro-inflammatory phenotype, but also on innate cells representing a novel therapeutic approach with potential long lasting effects in maintaining  the immune homeostasis.

Brief description not available

Brief description not available

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, in part due to contraction and increased proliferation of pulmonary artery smooth muscle cells (PASMC). PAH causes symptoms such as shortness of breath, fatigue and chest pain. As the condition worsens, its symptoms may limit physical activity and can result in enhanced morbidity and early mortality. PAH results in added stress on the heart with strain and weakness of the right ventricle. The heart may become so weak that it can no longer pump sufficient blood, resulting in heart failure, the most common cause of death associated with PAH. Since the second messenger 3’5’-cyclic adenosine monophosphate (cAMP) produces relaxation and decreases proliferation of PASMC, drugs that activate G protein-coupled receptors (GPCRs) to stimulate Gαs or to inhibit Gαi, both of which effects will increase cAMP, may provide therapeutic approaches to treat PAH and such GPCRs may be novel therapeutic targets. The GPCR targets revealed here may prove of benefit to the large number of patients with various types of pulmonary hypertension who share the same vascular pathology.

Heart failure is the most common cause of non-elective admission to the hospital in subjects 65 years and older. Despite optimal drug and device therapy, prognosis in heart failure is dismal. Many clinical trials of drugs that increase heart function (“inotropes”) have failed, possibly due to the deleterious effects of agents that increase cAMP. An alternative strategy is to alter myocardial calcium handling or myofilament response to calcium using agents that do not affect cAMP. Expression of a catalytically impaired adenylate cyclase type 6 mutant molecule (AC6mut), one that markedly reduces cAMP production, is associated with normal cardiac function in response to β-adrenergic receptor stimulation. The mechanism is through enhanced effects of AC6mut on Ca2+ handling - effects that do not require cAMP. These data are important in clinical settings for two reasons: 1) the results provide additional insight regarding the interplay between Ca2+ handling and βAR signaling vis-à-vis LV function; and 2) AC6mut may provide inotropic support free from the potentially deleterious effects of increased cAMP.

There is a general need to improve the efficacy of the resuscitation programs and the survival rate of patients undergoing cardiac arrest.