3D Printing and Stem Cells to be Used to Regrow Skulls

Cranial reconstructions will soon be radicalised with the addition of 3D printing and stem cells into the method.  A team of scientists from Western Australia will soon attempt this new technique with the intention of seeing the reduction in risk of complications, surgical procedure duration and costs.

The first patients will be those from the Royal Perth Hospital, whose skulls have either been severely damaged or partially removed for brain surgery.

The research team, which includes a surgeon, two engineers, a neurosurgeon and chief scientist will collaborate with a Vienna-based 3D printing firm to replicate the bones from the patients' cranium. 

A printed bioceramic scaffold less than 100 microns (0.1mm) of the original bone will be infused with millions of stem cells.  This will be fitted onto the patient's skull.

This is the first time stem cells will be put to use with 3D printed scaffold to assist in bone regrowth, according to neurosurgeon Marc Coughlan.

"What we're trying to do is take it one step further and have the ceramic resorb and then be only left with the patient's bone, which would be exactly the same as having the skull back," he said.

Health minister Kim Hames says,"This project highlights some of the innovative and groundbreaking research that is under way in WA's public health system, and the commitment of the government to supporting this crucial work."

The reconstruction project is part of the nine health and medical projects in Western Australia that has been allocated  A$2 Million (US$1.5 Million) research funding grant by the state government.  The government's aim is to eventually reduce costs and improve efficiency in Australia's public health service through the help of these projects.

Previous methods by past studies had the bone part frozen and stored for later replanting. However, attempts to replant often resulted either in infection or bone resorption.  The more popular titanium plates, on the other hand, pose the problem of eventual material degradation.

http://goo.gl/TJTLcT

Scientists Created Mini Heart on Microchip With Stem Cells

Scientists belonging to the University of California of the USA conducted a research that led to the development of mini heart (Cardiac Microphysiological System) on a microchip using human stem cells. The study was led by Indian-origin scientist Anurag Mathur.

The Cardiac Microphysiological System, which is hardly the width of a human hair, is expected to replace non-human animal models that are used in drug discovery and development process.

The invention was published in the second week of March 2015 in the Scientific Reports journal in an article titled Human iPSC-based Cardiac Microphysiological System For Drug Screening Applications.

What is Microphysiological System?

Microphysiological systems are engineered organs that are developed to address the formidable pharmacological and physiological gaps between monolayer cell cultures, animal models and humans. The Cardiac Microphysiological System is the latest human organ - after a lung, a liver and a piece of intestine – were developed under laboratory environment.

How Cardiac Microphysiological System/ mini heart was developed?

It was developed using human-induced pluripotent stem cells (iPSC) that can form many different types of tissues. These cells, once tricked into forming heart tissue, were grown around a special silicon microchip with cell and media channels that mimicked the heart’s blood vessels.

Significance of Cardiac Microphysiological System

Apart from replacing the animal models used in the drug discovery process that do not mimic human responses; the organ-on-chip will help in the development of personalized medicine in future as doctors will be able to predict how certain drugs react on specific patients, thus preventing many illnesses and loss of valuable time.

Doctors will be able to calculate the approximate dose needed for patients with heart conditions by deploying this bionic heart technology as they will be able to have his or her heart modelled in a lab with all the tests done.

Researchers Create Model Of Early Human Heart Development From Stem Cells

Researchers at the University of California, Berkeley, in collaboration with scientists at the Gladstone Institutes, have developed a template for growing beating cardiac tissue from stem cells, creating a system that could serve as a model for early heart development and a drug-screening tool to make pregnancies safer.

In experiments to be published Tuesday, July 14, in the journal Nature Communications, the researchers used biochemical and biophysical cues to prompt stem cells to differentiate and self-organize into micron-scale cardiac tissue, including microchambers.

"We believe it is the first example illustrating the process of a developing human heart chamber in vitro," said Kevin Healy, a UC Berkeley professor of bioengineering, who is co-senior author of the study with Dr. Bruce Conklin, a senior investigator at the Gladstone Institute of Cardiovascular Disease and a professor of medical genetics and cellular and molecular pharmacology at UC San Francisco. "This technology could help us quickly screen for drugs likely to generate cardiac birth defects, and guide decisions about which drugs are dangerous during pregnancy."

To test the potential of the system as a drug-screening tool, the researchers exposed the differentiating cells to thalidomide, a drug known to cause severe birth defects. They found that at normal therapeutic doses, the drug led to abnormal development of microchambers, including decreased size, problems with muscle contraction and lower beat rates compared with heart tissue that had not been exposed to thalidomide.

"We chose drug cardiac developmental toxicity screening to demonstrate a clinically relevant application of the cardiac microchambers," said Conklin. "Each year, as many as 280,000 pregnant women are exposed to drugs with evidence of potential fetal risk. The most commonly reported birth defects involve the heart, and the potential for generating cardiac defects is of utmost concern in determining drug safety during pregnancy."

The new milestone comes nearly four months after Healy and other UC Berkeley researchers publicly debuted a system of beating human heart cells on a chip that could be used to screen for drug toxicity. However, that heart-on-a-chip device used pre-differentiated cardiac cells to mimic adult-like tissue structure.

In this new study, the scientists mimicked human tissue formation by starting with stem cells genetically reprogrammed from adult skin tissue to form small chambers with beating human heart cells. Conklin's lab at Gladstone, an independent, nonprofit life science research organization affiliated with UC San Francisco, supplied these human induced pluripotent stem cells for this study.

The undifferentiated stem cells were then placed onto a circular-patterned surface that served to physically regulate cell differentiation and growth.

By the end of two weeks, the cells that began on a two-dimensional surface environment started taking on a 3D structure as a pulsating microchamber. Moreover, the cells had self-organized based upon whether they were positioned along the perimeter or in the middle of the colony.

Compared with cells in the center, cells along the edge experienced greater mechanical stress and tension, and appeared more like fibroblasts, which form the collagen of connective tissue. The center cells, in contrast, developed into cardiac muscle cells. Such spatial organization was observed as soon as the differentiation started. Center cells lost the expression of octamer-binding transcription factor 4 (OCT4) and epithelial cadherin (E-cadherin) faster than perimeter cells, which are critical to the development of heart tissue.

"This spatial differentiation happens in biology naturally, but we demonstrated this process in vitro," said study lead author Zhen Ma, a UC Berkeley postdoctoral researcher in bioengineering. "The confined geometric pattern provided biochemical and biophysical cues that directed cardiac differentiation and the formation of a beating microchamber."

Could eventually replace animal models

Modeling early heart development is difficult to achieve in a petri dish and tissue culture plates, the study authors said. This area of study has typically involved the dissection of animals at different stages of development to study the formation of organs, and how that process can go wrong.

"The fact that we used patient-derived human pluripotent stem cells in our work represents a sea change in the field," said Healy. "Previous studies of cardiac microtissues primarily used harvested rat cardiomyocytes, which is an imperfect model for human disease."

The researchers pointed out that while this study focused on heart tissue, there is great potential for use of this technology to study other organ development.

"Our focus here has been on early heart development, but the basic principles of patterning of human pluripotent stem cells, and subsequently differentiating them, can be readily expanded into a broad range of tissues for understanding embryogenesis and tissue morphogenesis," said Healy.

source : http://goo.gl/BfdN7j

Stem Cells Provide Lasting Pain Relief in Mice

Chronic pain caused by the nerve damage of type 2 diabetes, surgical amputation, chemotherapy and other conditions is especially intractable because it resists painkilling medications. 

But in a study on mice, a Duke University team has shown that injections of stem cells from bone marrow might be able to relieve this type of neuropathic pain. The researchers say their findings, which appear July 13 in the Journal of Clinical Investigation, may also advance cell-based therapies in chronic pain conditions, lower back pain and spinal cord injuries. 

The team used a type of stem cell known as bone marrow stromal cells (BMSCs), which are known to produce an array of healing factors and can be coaxed into forming most other types of cells in the body. 

Stromal cells are already being tested in small-scale clinical studies of people with inflammatory bowel disease, heart damage and stroke. They have also shown promise for treating pain. However, it’s not clear how they work. 

“Based on these new results, we have the know-how and we can further engineer and improve the cells to maximize their beneficial effects,” said Ru-Rong Ji, professor of anesthesiology and neurobiology in the Duke School of Medicine.

In his team’s study, the researchers used stromal cells to treat mice with pain caused by nerve damage. They delivered the cells by a lumbar puncture, infusing them into the fluid that bathes the spinal cord. 

Mice treated with the bone marrow stromal cells were much less sensitive to painful stimuli after their nerve injury compared with the untreated mice, the researchers found. 

“This analgesic effect was amazing,” Ji said. “Normally, if you give an analgesic, you see pain relief for a few hours, at most a few days. But with bone marrow stem cells, after a single injection we saw pain relief over four to five weeks.”

Pictures of the animals’ spinal cords showed that the injected stem cells had set up shop alongside the nerve cells in the spinal cord.

To understand how the stem cells alleviated pain, the researchers measured levels of anti-inflammatory molecules that had been previously linked to pain, finding that one in particular, TGF-β1, was present in higher amounts in the spinal fluid of the stem cell-treated animals compared with the untreated animals. 

TGF-β1 is a protein that is typically secreted by immune cells and is common throughout the body. Research has shown that people with chronic pain have too little TGF-β1, Ji said.

In the new study, chemically neutralizing TGF-β1 reversed the pain-killing benefit of the BMSCs, suggesting that the secretion of this protein was a major reason why the cells helped with pain. Injecting TGF-β1 directly into spinal cord fluid provides relief too, but only for a few hours, Ji said.

By contrast, bone marrow stromal cells stay on site for as much as three months after the infusion, the scientists found. This is the right length of time, Ji said, because if the stem cells stayed permanently there could be risk of them becoming cancerous.  

Importantly, BMSCs also migrate to the site of injury. That’s because a molecule emitted from the injured nerve cells called CXCL12 -- which has also previously been linked to neuropathic pain -- acts as a homing signal of sorts, attracting the stem cells. 

The next step will be to find a way to make the stromal cells more efficient. “If we know TGF-β1 is important, we can find a way to produce more of it,” Ji said. In addition, the cells may produce other pain-relieving molecules; Ji’s group is working to identify those. 

source : http://goo.gl/IIBCdD

Researchers Develop Patient-Specific Heart Cells From Stem Cells

Induced pluripotent stem cells (IPSC) could be the key to the future of personalized medicine, as a new study published by Stanford Cardiovascular Medicine has successfully used the stem cells to recreate patient-specific heart cells. Their research could carve the path for other areas of medicine to use IPSC, which can be transformed into any body cell, to develop patient-specific treatments for any disease.

Published on June 18, the study advances the general quest in the medical community to develop personalized medicine using IPSC, which are easy to find and can be taken from the skin of patients. The transformed cells in the study seemed as if they came directly from the patient’s heart itself, explained lead author and postdoctoral scholar HaoDi Wu. Wu said the heart cells were even beating in the petri dish.

IPSC are preferred by scientists as they carry specific DNA of patients and can be used to treat patient-specific diseases, such as dilated cardiomyopathy (DCM), a common heart condition caused by genetic mutations. The researchers’ study focused specifically on looking at DCM mutations within a single family.

Although they did discover the specific mutation that caused DCM in one family of patients as well as a compound to treat the disease, the significance of their experiment lay in the method.  Their novel use of IPSC to model human cells allowed them to narrow the target for finding the DCM mutations in the whole human genome.

Senior author of the paper Joseph Wu, director of the Stanford Cardiovascular Institute and professor of medicine and of radiology, described how their results highlight the potential of IPSC. Today, doctors often go through trial and error to find the right drugs for their patients; IPSC would allow them to test drugs on stem cells first, not the patients themselves.

“We’re hoping that in the future, instead of you being the guinea pig, it’ll be patient-specific, IPS-cell-derived brain cells, derived heart cells, derived kidney cells, liver cells in a dish,” Joseph Wu said. “In essence, you’re doing a clinical trial in a dish.”

The study was funded by the American Heart Association (AHA) and the National Institutes of Health. Joseph Wu received the Established Investigator Award from the AHA for funding, and according to AHA project coordinator Micah Moughon, the best applications for funding are those that accomplish the mission stated on their website: “to build healthier lives free of cardiovascular diseases and stroke.”

“People have been working for a very long time, fighting for cardiomyopathy,” HaoDi Wu said. “This will be the initial step – we take advantage of the IPSC cardiomyocyte system to find the detailed mechanism of the single-gene mutation in cardiomyopathy.”

While the study narrows down the target for finding mutations that cause cardiomyopathy, it cannot guarantee that the mutation exists in all patients. The researchers explained that their team has a long way to go before they can even consider the possibility of a new drug or bringing IPSC to current medicine.

“Before you get that goal of doing clinical trial in a dish or doing personalized medicine 10, 20 years from now, you [have] got to do these experiments to show the feasibility [of IPSC],” Joseph Wu said. “There are other patients with other mutations that cause cardiomyopathy. So the question is, ‘Does this finding also hold true for other mutations?’ And does this finding also hold true for patients without mutations but also heart failure?”

The project already had years of research behind it when it started – research on the possibility of even creating IPSC, on using them in experiments. Although the lab spent about two years of work to find the mutation for only one family, as the experiment is reviewed and tested more, it will be easier to narrow down and streamline the process to apply to all kinds of patients and not just in cardiology.

“This is a novel and unprecedented approach to diagnosing disease, physiology,” said Tzung Hsiai, friend of Joseph Wu and cardiology professor at UCLA. “The ramification is not limited to cardiomyopathy disease but has relation to many other diseases. We will be able to predict pharmacological treatments – for laymen’s terms, drug treatments and patient’s responses to medication.”

Joseph Wu explained that there is a widespread interest to develop personalized medicine and incorporate it into the industry. There is still a long way to go but most areas of medicine are taking strides toward this concept and are hopeful for the future, he said.

“We just happened to focus in cardiology because I’m a cardiologist; it’s a cardiac lab, and we’ve been doing this for a while,” Joseph Wu said. “Other labs are focused on using the same set up to address Parkinson’s disease,  Alzheimer’s disease.”

“[It’s a] general movement toward using these IPS cells for disease modeling, understanding the disease, drug discovery and for personalized medicine,” he added.

Source : http://goo.gl/FRESfa

Stem Cells Show Promise as Treatment for Diabetic Neuropathy

A scientific team from the U.S. and Korea reports that laboratory rats models of diabetic neuropathy (DN) can experience both angiogenesis and nerve re-myelination following injections of mesenchymal stem cells derived from bone marrow (BM-MSCs). The study (“Bone marrow-derived mesenchymal stem cells improve diabetic neuropathy by direct modulation of both angiogenesis and myelination in peripheral nerves”), which will be published in a future issue of Cell Transplantation, is currently available online.

The researchers used mesenchymal stem cells, which can be easily isolated from a variety of sources, such as adipose tissues, tendons, peripheral blood, umbilical cord blood, and bone marrow. BM-MSCs have been among the most successfully transplanted cells, offering therapeutic benefits for a wide range of conditions, from serious burns to cardiovascular diseases, including heart attack and stroke.

In this study, the animals were randomly assigned to BM-MSC or saline injection groups 12 weeks after the induction of diabetes. The non-diabetic control group of rats was age- and sex-matched. DN was confirmed by latency in nerve conduction velocity tests.

"We investigated whether local transplantation of BM-MSCs could attenuate or reverse experimental DN by modulating angiogenesis and restoring myelin, the electrically insulating substance surrounding nerves that is reduced by DN," said study co-author Young-sup Yoon, M.D., professor at the department of medicine, division of cardiology at Emory University School of Medicine. "In this study we have provided the first evidence that intramuscular injected BM-MSCs migrate to nerves and can play a therapeutic role."

According to the researchers, their findings indicate that intramuscular injection of MSCs resulted in an increase of multiple angiogenic and neurotrophic factors associated with blood vessel growth and subsequently aided the survival of diabetic nerves, suggesting that BM-MSC transplantation restored both the myelin sheath and nerve cells in diabetic sciatic nerves.

"We identified several new mechanisms by which MSCs can improve DN," noted the researchers. "First, we demonstrated that numerous engraftments migrated to and survived in the diabetic nerves. Second, we demonstrated a robust increase in vascularity. Third, we found the first evidence that MSCs can directly modulate re-myelination and axonal regeneration."

The scientists concluded that DN, for which there is no other therapeutic option, can be an "initial target for cell therapy" and that transplantation of BM- MSCs "represents a novel therapeutic option for treating DN."

"Currently, the only treatment options available for DN are palliative  in nature, or are directed at slowing the progression of the disease by tightly controlling blood sugar levels," says John R. Sladek, Jr., Ph.D., professor of neurology, pediatrics, and neuroscience, department of neurology at the University of Colorado School of Medicine. "This study offers new insight into the benefits of cell therapy as a possible treatment option for a disease that significantly diminishes quality of life for diabetic patients. Safety and efficacy for human application must be evaluated to further determine the feasibility of BM-MSC transplantation for treatment of DN." 

Source : http://goo.gl/45IHrb