Recent findings by a team of engineering and medical scientists at Stanford University shed new light on how cell components move around and self-renew. Part of the study’s focus was on the link between microtubules and self-organization.

Microtubules, hollow tubes about 25 nm in diameter, are critical for maintaining cell shape and movements. The study analyzed what role microtubules have in maintenance, and found that microtubules are continuously losing and gaining molecules. Understanding the mechanics of how microtubules move around and contribute to regeneration helps to light affordable paths to wound healing in humans and animals.

Cells are known to self-organize at the direction of particular protein structures, via recognized regulators of the organization. However, the Stanford team observed that some cells self-organized in the absence of their known regulators. An interaction between microtubules and other molecules on the membrane surface was the reason.

This observation raised questions about what role microtubules play in the regeneration when other elements of the system are paralyzed. The researchers described how microtubules seemed to be involved in some minimal requirements for cellular self-organization. Identifying this process opens the door to greater understanding of cell renewal.

Clarifying the precise functions of microfluidics has paved the way to viable organoids, on which assessments can be done without having to conduct tests on an entire organism. For example, the University of British Columbia researchers recently were able to architect human vascular organoids that were nurtured to duplicate diabetic blood vessels, and can be used as test models.

The UBC scientists were able to grow human blood vessels as organoids in a lab, for the first time. This spawns investigation of treatments for vascular diseases by highlighting how changes to blood vessels occur. Such changes are a major cause of death among diabetics.

An illustration of vascular organoids, lab-made human blood vessels, based on original data. Credit: IMBA

“Being able to build human blood vessels as organoids from stem cells is a game changer,” said the study’s senior author Josef Penninger. “Every single organ in our body is linked with the circulatory system. This could potentially allow researchers to unravel the causes and treatments for a variety of vascular diseases, from Alzheimer’s disease, cardiovascular diseases, wound healing problems, stroke, cancer and, of course, diabetes.”

Many diabetic symptoms are the result of changes in blood vessels that result in impaired oxygen supply of tissues, and impaired circulation. Not a lot has been known about vascular changes arising from diabetes. This creation of human blood-vessel organoids is a significant step toward tipping the scales from unknowns to knowns.

Determining how to cultivate three-dimensional human blood-vessel organoids in a lab dish is indeed a huge step toward unveiling blood-vessel change mechanisms.

These “vascular organoids” when transplanted into mice, developed into functional human blood vessels, including capillaries and arteries. So not only was it possible to engineer blood-vessel organoids from human stem cells in a dish, but they also grew a functional human vascular system in another species.

The organoids resemble human capillaries to a great extent, even on a molecular level, and can be used to study blood vessel diseases directly on human tissue. The researchers described how organoids can be used to study the lack of oxygen and nutrient delivery to blood vessels that occurs in diabetic patients, causing complications including kidney failure, heart attacks, strokes, blindness, and the peripheral artery disease that leads to amputations.

They were surprised to find the vascular organoids showed expansion of the basement membrane, which is exactly what causes the oxygen-and-nutrient depletion in humans. The damage to the vascular organoids precisely mirrored what is seen in diabetic patients.

Using the vascular organoids for testing, they found that no currently-prescribed anti-diabetic medications had positive effects on these blood vessel defects. But they did find an enzyme inhibitor that prevented thickening of the basement membrane.

The researchers noted that the findings could allow them to identify underlying causes of vascular disease, and to potentially develop and test new treatments for the world’s estimated 420 million people with diabetes.

That many patients should theoretically translate into significant Research and Development endeavors.

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Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

The post Being Able to Build Human Blood Vessels as Organoids from Stem Cells is a Game Changer appeared first on The MicroFluidic Circle.

“Organoids are useful in retinal stem cell research,” said Dr. Dennis Clegg, a pioneer in the use of stem cells to reverse blindness resulting from age-related macular degeneration, during a live-streamed November 2018  “Ask the Stem Cell Team” webinar hosted by the California Institute for Regenerative Medicine. Clegg explained how IPS (Induced Pluripotent Stem) cells can be donated by patients with a mutation that causes the blind condition called Retinitis Pigmentosa, or RP, and then used to generate organoids.

“Ask the Stem Cell Team” webinar was hosted by the California Institute for Regenerative Medicine in November 2018.

“It is possible to make a retinal organoid,” Clegg said. “An organoid is organ-like so it’s not exactly like retinas, but it is very useful in research. You can take an IPS cell from a patient who has a retinal disease and make retinal organoids. It’s not exactly like the retina but it’s similar. It’s useful in research; you can take an IPS cell from a patient, make that cell into an organoid, and compare it to a normal, non-mutated cell.”

Clegg is founder of the University of California Santa Barbara Center for Stem Cell Biology and Engineering, a Co-Principal Investigator of The California Project to Cure Blindness, and a National Eye Institute lecturer.

Organoids are helpful because they mimic the layered structure of the eye’s retina. Organoids might yield a population of cells “that may be useful for treating disease,” according to Clegg. “If you are going to try to replace the photoreceptor cells that are perishing in a patient’s eye, you could even build a layered structure — an organoid — in the lab and then implant that to rebuild that retina.

“Patients become legally blind when they’ve lost both the rod and cones, the eye’s photoreceptors,” Clegg explained. In a clinical trial, “We started with patients who’d lost photoreceptors. The goal was safety. We wanted to show our process is safe. For patients who were lacking photoreceptors, the surprise was that some patients showed improvement in vision. We’ve shown it’s safe and we think if we catch the disease early enough, we can rescue photoreceptors.”

The use of microfluidic-sustained organoids is in many cases more applicable to humans than the use of experimental animals — and avoids ethical conflict. “For many aspects of research there are no good animal models, and retinal research is one of them,” Clegg noted. “You could even screen for drugs that might improve that retina-in-the-dish, and that would greatly speed up drug testing.”The webinar highlighted what cutting-edge advances are on the horizon, with other “Stem Cell Team” members Dr. Henry Klassen, and clinical trial volunteer Rosie Barrero. University of California Irvine’s Klassen is also a long-time researcher into the use of stem cell treatment to restore vision to people blinded by degenerative eye disease.

Some of Barrero’s vision was restored during a clinical trial. Klassen explained that volunteers like Barrero can describe what they see and what they don’t — which animal subjects cannot do. “We learn a lot more listening to Rosie than what our experimental rats could ever tell us,” he said. “It’s a wonderful surprise to hear these good reports coming from patients. I think we’ve all heard how cancer was cured in a mouse and then does not work in humans.”

Throughout her childhood, Barrero had steadily lost vision in both eyes due to RP — inherited and incurable. “I did not have night vision, I was very near-sighted, very myopic,” Barrero said. “My parents were protective and careful, they took care to not let me get into situations where I would injure myself. I did not know why.” As an adult, after giving birth to twins, she noticed a significant loss, which worsened after her next pregnancy. “After my third child was born I lost central vision.” She felt devastated to know she was going blind. She could not read, and by the time she met Klassen, “I had gotten to the point where I lost hope.” She volunteered for a 2016 trial.

“Rosie’s retinas were pretty beat up and she was blind,” Klassen said. “For her to see something coming back is a bit astonishing, really.”

“I received one million stem cells in the first injection,” Barrero said. “I have seen the most improvement from that first injection. I was blind and now I can see peripherally. The procedure was simple and lasted just a few seconds. I do not have a central vision but I can see out of the side of my eyes. It’s the simple things — I can see color. Before it was blurred, but now I can see colors through my periphery vision.

“When I received the stem cells I really noticed a huge jump in my vision,” Barrero said. “Even if it was just peripheral.” For the first time, “I’ve gone running with my daughter, and I look to my right somewhat. She tells me where there’s a branch or something to avoid. I can’t run on my own, but I can see on one side on my own, which is incredible.”

Live-streaming viewers were able to submit questions, and one person who submitted comment was one of Barrero’s children. She wrote: “Hi Mom. I hope you’ll still want to go shopping with me when you can fully see the price tags and don’t need me anymore!”

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Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

The post Microfluidics Drives Real-Life Applicability of Organoid Advances appeared first on The MicroFluidic Circle.

Some estimates of global market value — covering microfluidic components, applications, and key end-use sectors — hover near US$4.5 billion by 2023. Because all life involves fluids, from single-cell cytoplasm to lymph, blood and urine movements, the potential seems endless. Microfluidic models usher in precise control to more microenvironments than conventional models. With regard to areas such as drug discovery, the field is as exciting as fireworks. Yet among the challenges is authentic promotion: some of the systems are not as universally applicable as they sound, and realistic experience in identifying the right applications, according to one observer, “will be critical in fostering more widespread adoption”. The publish-or-perish demand of the academic nest is not necessarily proof of feasibility. Laboratory processes might be hidebound, and great lab throughput doesn’t always smoothly translate to industrial settings. Questions about returns on investments, cost reductions and timely incorporation into existing workflows arise. Along with fireworks, there are also mundane hurdles.

Warnings aside, there’s no denying the promise. Microfluidic systems are debuting into adult society with a splash — of ink. Using bio-ink, 3D printers can produce microfluidic tools capable of moving in all spatial dimensions, to form complex architectures and simplify networks for microfabricated designs. Yet also, confirming that bioprinted systems are reliably safe and effective can become a process that stretches out over time.

A recent study in an American Society of Clinical Oncology publication includes microfluidic tools on a list of next-generation, noninvasive, cancer molecular diagnostics platforms, particularly their cell enrichment usefulness in treating both metastatic and localized prostate cancer. Another recent study, in Urology Today, describes a microfluidic approach for harvesting intact urinary tract tumour cells either individually or in clusters, in a clean environment, which is critical for minimizing cross-contamination or misreads. The microfluidic method appeared capable of better specificity and sensitivity, when compared to other bladder-cancer-detection techniques. Other reports clarify how, due to precision manipulation of fluids at small volumes, microfluidic systems are becoming a pragmatic tool for detection of a wide variety of biomarkers.

As in so many other fields of endeavour, from rocket design to gas stations and bakeries, the microfluidics fledgling will be incorporating robotic systems. In a new University of Washington study, researchers described creating robots to process stem cells into organoids. Robots introduced stem cells into plates that contained hundreds of miniature wells, and then coaxed them to turn into kidney organoids. Each little microwell typically contained ten or more organoids, and each plate contained thousands of organoids. Robots’ speed appeared to produce many organoids in a fraction of the time non-robotic methods take.

Now that microfluidic models do fuel the creation of tissue with striking physiological relevance, could a robotic process do that job, or a portion of that job? The robots would have to be designed, created and maintained by humans, of course, but would a production scale-up point to fewer of those humans?

One Artificial-Intelligence-scented observation by the UW researchers is: “The robots were also programmed to analyze the organoids they produced.”

Getting enough scientists trained up to the needed level of expertise is a legitimate concern of microfluidics investors — but when that is achieved, will there be jobs for all of them?

All manner of challenges, some as yet undefined, loom on the horizon.

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Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

The post As Microfluidic Systems Come of Age, Both Rough Waters and Smooth Sailing Lie Ahead appeared first on The MicroFluidic Circle.

That’s the plot of the play Patience, which premiered in 2017 in Edinburgh. Inspired by actual patient experiences, Patience unravels the struggles facing decision-makers in the organ-transplant universe. Two women in need of a transplant, and the doctor who must decide which of them will get it, are the main characters. One patient is a young woman with autoimmune hepatitis, whose life is riddled with hospitalizations. The other is a recovering alcoholic.

The younger woman whose fate was the disease, and not bad choices around drunkenness, seems more deserving. But she upends expectations when she refuses to take steroids she needs to prepare for surgery— because they make her look fat. In contrast, the recovering alcoholic is desperate to do anything necessary to rehabilitate herself and her career in biochemistry. So by the time the decision is made, the audience feels sympathy for both patients.

Organoid advancement might make this theatrical plot obsolete. More thorough understanding of liver-stem-cell practicality may answer the question, who gets a new liver? And the answer might be — anyone who needs it.

Liver organoid progress may banish the concept of “deserving” to the history books. Liver failure is currently treatable only with transplants. More than one million patients worldwide die annually while waiting for donor livers, which are in short supply.

A 2017 U.S. National Institutes of Health hepatology study covers novel approaches to human liver organogenesis. The researchers identified signals that seem to regulate the differentiation of liver cells, by dissecting the mechanism of organoid formation. Innovations in their methodology point to personalized studies using patient-derived cells for disease and toxicology experiments.

Hans Cleversleads the Hubrecht Institute for Developmental Biology and Stem Cell Research, and is a professor of Molecular Genetics at The Netherlands’ University Medical Center in Utrecht. Over many years his team has innovated culturing methods for liver organoids. The Hubrechtteam has developed ways to culture a twin of a full-grown liver from a single liver stem cell. The tissue was genetically the same as healthy liver tissue and stable as well.

Printing, or more accurately “bioprinting” of 3D organoids, turns cells from human donor organs into bio-ink, to generate— or bioprint — liver organoids. Such liver organoids can be used to test drug safety. The UK’s Medical Research Council is spearheading the generation of 3D liver tissue to treat chronic liver disease, by developing 3D implantable organoids. In the U.S., in December 2017, the Food and Drug Administration granted special status to the Organovo company to treat a rare genetic deficiency, utilizing 3D-bioprinted liver tissue.

Dr. Meritxell Huch at the UK’s University of Cambridge has worked with Clevers to develop culture methods for obtaining liver organoids. Her team researches organoids that replicate original pathophysiology of liver tumours. They focus on retaining tissue function and genetic stability. This preserves aspects of the original tumor, enabling discrimination between various tumor tissues for analysis. These organoids led to the identification of a potential therapy for liver cancer. The organoids that the Huch and Clevers teams develop are furthering the understanding of liver cancer biology and developing personalized medicine approaches.

A*STAR’s Genome Institute of Singapore (GIS) and Institute of Molecular and Cellular Biology (IMCB), in collaboration with the Stanford University School of Medicine, is also investigating the generation of liver cells from stem cells to treat liver failure. Dr. Ng Huck Hui, Executive Director of GIS, explains the project: “The ability to generate large quantities of stem-cell derived liver cells holds the potential to sustain patients with liver failure while they await a full liver transplant.

“This holds great promise for helping to improve patient survival rates and alleviating the burden of liver failure on societies.”

That would be welcome by liver patients and their families.

There is no spoiler alert in this blog. The ending of the play Patience won’t be revealed. The play “deserves” to be seen — even if functional organoid research makes it irrelevant.

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Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

The post Liver Organoid Progress Brings New Perspective appeared first on The MicroFluidic Circle.

Oliver was born with good eyesight, but due to a hereditary condition, over a decade he had gradually lost much of his vision. For years his sight had been worsening until he underwent experimental stem cell surgery in a Florida-based treatment study. His vision loss was reversed by that surgery in 2015. “I went from legally blind to legal-to-drive in eight weeks,” said the Nashville, Tenn., man.

Oliver’s own retinal specialist had described his condition as “incurable” in no uncertain words. Yet days after surgery, “I came out of the surgeon’s office and saw the crisp sparkle of cars in the sun parked in the parking lot. And the leaves on the trees.” And a few months later, he saw his grandchildren’s’ faces for the first time.

According to the World Health Organization, about 36 million people worldwide are blind and 217 million have vision impairment. Fortunately for them, the list of innovative ways microfluidics technology promises to buttress stem cell treatment for blindness is impressive. Microfluidics engineering has the potential to advance the design of tiny systems and procedures to make stem-cell-generated organoids and tissues-on-chips more functional — more like a real human organ, thus advancing understanding of stem cell effectiveness.

Living organs comprise branched vascular networks, and almost all cells are close to a capillary, for sufficiency. Vascularization that delivers oxygen and nutrients to organoids is necessary; during organoids’ early development they were isolated in lab dishes and were therefore by definition diffusion-limited. Control of microfluids within tissue-chips could help to mimic natural human physiology. This is one way that microfluidic engineering might move stem cells’ capabilities forward.

Microchannels can permit fluid flow at real-life rates. Microfluidic devices in tissues-on-chips can innovatively duplicate essential functions of blood vessels for oxygen flow, while also removing waste.

Although much has been demystified by science in recent decades, much is still unknown about how stem cells work. Microfluidic devices may offer a way to study the decision-making process of stem cells. They can imitate the structural physiology of organs and provide a platform for further study. “The Organoid Revolution” seminars at the World Stem Cell Summit in Miami in January 2018 highlighted new developments.

Stem cells have been successfully used in a number of patient-consented, experimental surgeries, internationally as well as in several U.S. National Institutes of Health-sponsored clinical trials. The need for thorough, prudent painstaking research of the highest quality and maintained at rigorous academic standards — a long, slow process — can be at odds with vulnerable people seeking timely access to treatments for any number of serious conditions — especially those who see that stem cell treatment works for others. Microfluidics engineering has the potential to speed understanding of stem cells’ effectiveness and could potentially shorten approval processes, while simultaneously thwarting unethical use.

Doug Oliver, left, President of the Regenerative Outcomes Foundation, recently interviewed Dr. Francis Collins, Director of the U.S. National Institutes of Health, in connection with the World Stem Cell Summit. The interview is one of Oliver’s “Pioneers of Hope” series.
Credit: Regenerative Outcomes Foundation 2017

The vision was restored for Oliver after he was nearly blind for 11 years. His treatment could have been classified as “unproven” by the FDA, although his outcome has been clinically verified, and he is currently undergoing additional testing at the U.S. National Eye Institute. He considers himself living proof of the game-changing benefits of cell therapy. Organoid systems offer one of the most promising platforms for harnessing stem cells’ power.

Doug Oliver now spends much of his time advocating for patients seeking treatment for vision loss and other serious conditions to access clinical trials that might restore their health. In 2016, he founded The Regenerative Outcomes Foundation, to support outcomes research, inspire hope and raise awareness, and provide resources to help smooth the way for patients navigating the bureaucracy of clinical trials. “I want these treatment trials to be available sooner and to more people who have no hope of treatment in the near future,” he says.

FDA approval of drugs requires evidence they are safe and effective, something that historically has cost drug companies millions of dollars and many years of clinical trials to achieve. Some have proposed even longer approval processes to deter unsafe stem cell practitioners offering “snake oil” treatments.

Oliver believed a process could be designed that struck a balance between access for patients and the need for safe and effective treatments for serious conditions, including vision loss. In 2016, the U.S. Congress agreed and enlisted Oliver to help craft the 21^st Century Cures Act. “I wanted these treatment trials to be available sooner and to more people who have no hope of treatment in the near future for blindness,” Oliver says. He guided the Senate HELP Committee in developing FDA procedures that enforce safety while not “suffocating ingenuity the nation needs.”

Ingenuity is exactly where microfluidics research comes in.

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Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

The post Seeing Is Believing: Tissue-Chips on the Quest to End Blindness appeared first on The MicroFluidic Circle.