���ճԹ�’s Dr. Peter Corridon has advanced tissue engineering with the development of bioengineered scaffolds made from ‘decellularized’ mouse, rat, pig, camel and sheep tissue segments, such as blood vessels, trachea, esophagi, and whole organs like the kidney and eye that may be used as replacement tissues and organs . His research is among the first to evaluate the integrity of bioartificial blood vessels and whole organs under human physiological conditions, examining how they function over time and how they can be extended to make any decellularized architecture less susceptible to degradation and more viable for long-term transplants.

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Taking organs from animals and stripping the cells from the blood vessels could be the new solution to treating medical problems, including retinopathy, amputations, and kidney failure.

After this cleaning process, all that remains is a web of collagen and protein called the extracellular matrix, which gives the blood vessel its structure. This is tissue engineering, and it forms the basis of research from Khalifa University focused on designing scaffolds for tissue and organ regrowth in patients with diseases that lead to organ failure.

Dr. Peter Corridon, Assistant Professor of Physiology and Immunology at Khalifa University, investigated the integrity of vascular networks in decellularized tissues to support the development of blood vessels for kidneys. The results of this study, published in Scientific Reports, wil aid in implementing lifesaving treatments for conditions including diabetes-induced kidney failure. Indeed, to receive a bioengineered blood vessel implant was a patient with late-stage kidney disease in 2013. Earlier this month, a US man became the first person in the world to get a heart transplant from a genetically-modified pig.

Diabetes is the leading cause of kidney disease, with about one-third of diabetic adults suffering. The kidneys function to filter wastes and water out of the blood, helping to control blood pressure and maintain a healthy balance of water, salts and minerals in the blood. Blood flows into the kidney through the renal artery, is filtered in the functional units of the kidney, called nephrons, by clusters of tiny blood vessels called glomeruli, and then flows out of the kidney through the renal vein. This occurs throughout the day, with kidneys filtering around 150 quarts of blood every day.

Over time, poorly controlled diabetes can cause damage to the blood vessels in the kidneys, eyes, legs, and feet leading to uncontrolled damage and high blood pressure. High blood pressure can cause further organ damage by increasing the pressure in the delicate capillary systems. Severe damage to these blood vessel clusters can lead to diabetic nephropathy, retinopathy and amputations.

“By the end of this year, it is expected that 30 percent of the adult population in the United Arab Emirates will be diabetic,” Dr. Corridon said. “Almost half of those with diabetes develop significant vascular complications, which can lead to chronic conditions and even end-stage organ failure. These are substantial public health problems, highlighting the need for safe, effective, and innovative ways to treat the underlying conditions of vascular dysfunction.”

For the kidney specifically, traditional methods of treating renal problems include dialysis and transplantation; while dialysis can replace lost filtration capacities, a kidney transplant is the only way to restore all kidney function. However, there is a severe global shortage of transplantable kidneys and other organs. This, coupled with the issue of organ rejection, accentuate the demand for alternative solutions.

“Recent findings suggest that one possible way of addressing this growing issue is to develop replacement blood vessels, which could be used to treat those needing surgical intervention within the UAE,” Dr. Corridon said.

Bioengineered scaffolds can be used to develop bioartificial blood vessels known as human acellular vessels. They are a scaffold for the body to incorporate and provide a platform for cell growth, tunable to each recipient. They also act immediately as blood vessels, allowing the flow of blood through the kidneys while the body’s own cells grow into the matrix.

However, there are circumstances that limit scaffold viability. Dr. Corridon investigated a simplified model to analyze conditions needed to prepare more durable scaffolds for long-term transplantation.

He is developing his scaffolds using decellularized large and small animals to achieve an accurate biomimetic vascular architecture and functionality.

Decellularization is the process of taking an existing natural organ, either from a human or a nonhuman animal donor, and sterilizing it to the extent that only the collage network base remains, forming a natural scaffold. The decellularized scaffold can then be repopulated with a patient’s own cells to produce a personalized tissue.

These porcine scaffolds were subjected to a continuous blood flow at normal human physiological rates through the arteries to examine any dynamic changes in flow through the vessels and to determine their structure.

“Few studies have evaluated the integrity and function of the decellularized vasculature in whole porcine kidneys under physiological conditions,” Dr. Corridon explained. “The majority of these studies have primarily focused on demonstrating the preservation of structure and patency after decellularization and implantation.”

Under normal conditions, the kidneys autoregulate blood flow to maintain blood pressure through the delicate smaller vessels in the glomeruli. Decellularized kidneys, and kidneys in vitro, however, are incapable of autoregulation – meaning, they would be damaged under higher flow rates.

In this study, rates of 500ml/minute and 650ml/minute were used to represent the amount of blood each kidney would receive during resting conditions. The decellularized kidneys suffered damage at these levels, presumably due to their inability to autoregulate, which suggests that the elastin and collagen fibers in the scaffold would be damaged. In comparison, native kidneys possessed ‘sufficient structural barriers’ that prevented comparable damage, even though they were affected by the continuous flow of unfiltered and unreplenished blood.

“What’s important is that the perfusion process, which is the process of bathing an organ or tissue with a fluid, damaged the internal structures of both native and decellularized organs,” Dr. Corridon said. “While a significant difference was observed between perfused and non-perfused native kidneys, no significant difference was detected between perfused native and decellularized organs when perfused at the same rate.”

These findings reveal that the decellularized organs Dr. Corridon developed behave similarly to the native organs in disease conditions.

Dr. Corridon’s study provides a means to investigate how these blood vessels function over time and can be extended to other platforms to identify ways to make any decellularized architecture less susceptible to degradation and more viable for long-term transplantation.

Decellularization technologies hold great promise for the bioartificial tissue and organ industry, and understanding the limitations of these scaffolds will provide insight into the biomechanical improvements needed to increase their quality and support their clinical utility.��

Jade Sterling
Science Writer
21 January 2022

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Two patients with unique genetic mutations in a single gene sparked the investigation of 40 researchers into the effects of gene expression on diabetes 

The discovery and mapping of the complete human genome in 2003 introduced the possibility of individualized medicine to a person’s physical and genetic makeup. Increasing evidence is now demonstrating that a patient’s unique genetic profile can be used to detect a disease’s onset, prevent its progression, and optimize its treatment.

This has led to enhanced global efforts to implement precision (personalized) medicine and pharmacogenomics in clinical practice. One such area of clinical practice is the treatment of diabetes.

In contrast, the most common types of diabetes are caused by multiple genes or lifestyle factors. Most cases of monogenic diabetes are inherited.

Dr. Pierre Zalloua, Professor and Chair of the Department of Molecular Biology and Genetics, collaborated with researchers from France, Germany, Austria, the United States, and Singapore to determine the gene responsible for two cases of monogenic diabetes. Their results were published in.

“Diabetes affects over 350 million people worldwide, and the discovery and study of genes responsible provide important insights for understanding disease mechanisms,” Dr. Zalloua explained. “With better understanding, we can improve quality of life and develop cost-effective care for diabetes patients.”

Diabetes mellitus is a group of metabolic diseases, all of which are characterized by high blood glucose levels. If left untreated, diabetes can lead to severe complications including blindness, kidney and heart disease, stroke, loss of limbs, and reduced life expectancy. It is a major public health problem, affecting hundreds of millions of people worldwide and representing a substantial economic burden on society.��

There are two types of diabetes: Type 1 and Type 2 diabetes. Type 1 usually begins in childhood with individuals suffering from their body’s inability to produce enough insulin, while Type 2 is commonly associated with obesity and usually occurs during middle age. Both types tend to run in families and genetic factors contribute to the disease, with interactions between genetic and environmental factors being critical.��

Dr. Zalloua said. “Remarkably, many of these genes encode key proteins for pancreas development.”

To determine which genes play a part in the development of diabetes, the research team examined two different patients with diabetes: one, a young French boy with neonatal diabetes, and a second Turkish child with diabetes diagnosed at 14 months. They showed that the patients inherited mutated alleles of one particular gene, ONECUT1. Two mutated alleles led to a severe form of neonatal diabetes where the child developed a small pancreas and a missing gall bladder, while one mutated allele saw an increased risk of diabetes in the second patient. The researchers were able to determine that ONECUT1 and its expression is a major player in diabetes.

Dr. Zalloua was the person who originally identified additional cases from the region linked to this gene, including a case from a patient in Lebanon. Analysis of these patients revealed various different ONECUT1 mutations, all linked to a risk of diabetes.

ONECUT1 affects a variety of processes including glucose metabolism, an important factor in the disease mechanism of diabetes. Its expression also influences the development of the pancreas and the gallbladder. Previous studies of ONECUT1 have focused on the gene’s role in retinal development, but it is now clear that ONECUT1 acts to determine what type of cell a stem cell becomes. Some human stem cells are pluripotent, meaning they can become any kind of cell in the body, and genes including ONECUT1 are the deciders. Mutations in this gene can therefore disrupt a very complex process at various stages.

The pancreas plays an essential role in converting food to fuel in the body: it helps in digestion and in regulating blood sugar. Two of the main pancreatic hormones are insulin, which acts to lower blood sugar, and glucagon, which acts to raise blood sugar. A functioning healthy pancreas automatically produces the right amount of insulin; in people with diabetes, the pancreas either produces little or no insulin, or the cells do not respond to the insulin that is produced.

To further validate their findings, the researchers examined a cohort of over 2000 German people with presumed type 2 diabetes, and identified 13 incidences of ONECUT1 mutations. In another, larger and multi-ethnic, cohort of almost 20,000 people with type 2 diabetes, the researchers also found that people with variants of the ONECUT1 gene were more likely to develop type 2 diabetes. However, they noted that the risk varied with the specific variant.

Identifying the cause means we can pinpoint the best treatment, offering an opportunity to shift focus from broad population-based standards of care to tailored treatments targeted to an individual molecular profile.

“We found that ONECUT1 controls mechanisms regulating endocrine development, which is involved in a wide spectrum of diabetes types,” Dr. Zalloua said. “We highlighted the broad contribution of ONECUT1 to diabetes pathogenesis, marking an important step towards precision medicine for diabetes.”

Jade Sterling
Science Writer
18 January 2022

The post ���ճԹ� Researcher Contributes to the Finding of a Novel Gene Involved in Human Diabetes appeared first on ���ճԹ�.

Real-time monitoring of sugar molecules is crucial in diabetes treatment, but current methods are invasive and expensive. Researchers from Khalifa University collaborated with an international team to investigate holey graphene, a novel low-cost material, for glucose sensors.��

The World Health Organization estimates that over 382 million people worldwide have diabetes, a metabolic disorder affecting blood sugar levels. The underlying cause of diabetes varies by type, but each type can lead to excess sugar in the blood, which could cause serious health problems. For all patients, blood sugar monitoring plays a crucial role in treatment.

The sugar molecules adsorb onto a layer of holey graphene, which alters the electronic properties of the material. These changes can be measured and correspond to blood sugar monitoring data to check the blood sugar levels without invasive testing.

Dr. Muhammad Sajjad, Postdoctoral Fellow, and Dr. Nirpendra Singh, Assistant Professor, both in the Khalifa University Department of Physics, collaborated with Dr. Puspamitra Panigrahi, Hindustan Institute of Technology and Science, India, Dr. Deobrat Singh and Prof. Rajeev Ahuja, Uppsala University, Sweden, Dr. Tanveer Hussain, The University of Queensland, Australia, and Prof. J. Andreas Larsson, Lulea University of Technology, Sweden. They published their results in.

“Since the first invention of a biosensor for glucose detection, there has been tremendous demand for low-cost, portable, and reliable glucose sensors,” Dr. Singh said. “So far, most of the available devices are dependent on an expensive glucose oxidase enzyme-based recognition unit and require people to deal with the painful finger-pricking process.”

Continuous monitoring of glucose levels in people with diabetes is essential to managing the disease and avoiding the complications associated with poorly-managed treatment. There are two types of glucose monitoring sensors, enzymatic and non-enzymatic, currently available in the market.

Enzyme-based sensors use glucose dehydrogenase (GDH) or glucose oxidase (GOx), which interact with glucose molecules, resulting in an electrical response correlated to the concentration of glucose. However, these sensors are expensive to manufacture and are sensitive to environmental conditions. Non-enzymatic sensors allow glucose to be oxidized directly on the surface of the sensor, where the atoms at the surface act as the electrocatalysts, resulting in high stability with repeated use and cost-effective fabrication.

Different materials have been used to develop non-enzymatic sensors, and although each material has its own advantages and limitations, the research team focused on graphene—specifically, holey graphene.

Graphene is a unique material comprising densely packed carbon atoms arranged in a hexagonal honeycomb lattice and can be exfoliated from the graphite. It is extremely versatile and has potential applications in various fields, particularly thanks to its superior optical, electrical, thermal, and mechanical properties.

In its purest form, graphene offers myriad applications. However, in recent years, the nanoscale perforation of 2D materials has emerged as an effective strategy to enhance and widen the applications of the material beyond its pristine form.

Holey graphene is a form of graphene with nanopores in its plane. The performance of the material is affected by the pore size, density, shape, and volume. Uniform pore shape and size distribution are usually optimal as it leads to enhanced thermal, mechanical and electrical properties. These pores are perfect for adsorption, where target molecules are collected by attaching to the surface of the pores.

“Since the performance of an electrochemical biosensor depends on the surface area to improve charge transfer and catalytic activity, two-dimensional graphene-like nanomaterials and functionalized graphene are now the best possible materials for a new generation of highly sensitive glucose sensors,” Dr. Singh said. “The holey graphene is very sensitive even at very low concentrations of glucose.”

These fluids are easily accessed without the need for any finger pricking and can be examined to identify various biomarkers, such as those involved in cancer, Alzheimer’s disease, Parkinson’s disease, cystic fibrosis, systemic sclerosis and glaucoma, and blood sugar levels for diabetes management.

When saliva, tears, or sweat hit the surface, the sugars interact with a layer of nitrogenated holey graphene (C2N) that is only a single atom thick. Glucose, fructose and xylose are the sugar molecules found in the body and when they interact with the holey graphene layer, the electronic properties of the layer are altered. These changes are measured and interpreted as various levels of sugar in the bodily fluid tested.

This work was supported by the Swedish Research Council, the Abu Dhabi Department of Education and Knowledge, and Khalifa University of Science and Technology.

Jade Sterling
Science Writer
20 December 2021

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