Medicine  

A newly developed bioreactor-on-a-chip could help meet growing need for blood transfusions worldwide.

Scientists at Brigham and Women's Hospital (BWH) have developed a scalable, next-generation platelet bioreactor to generate fully functional human platelets in vitro. The work is a major biomedical advancement that will help address blood transfusion needs worldwide.

The study was published recently in the journal Blood.

"The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us meet the growing need for blood transfusions," said Jonathan Thon, PhD, Division of Hematology, BWH Department of Medicine, lead study author.

"The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift."

According to the researchers, more than 2.17 million platelet units from donors are transfused yearly in the United States to treat patients undergoing chemotherapy, organ transplantation and surgery, as well as for those needing blood transfusions following a major trauma. However, increasing demand; a limited five-day shelf-life; and risk of contamination, rejection and infection have made blood platelet shortages common.

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"Bioreactor-derived platelets theoretically have several advantages over conventional, donor-derived platelets in terms of safety and resource utilization," said William Savage, MD, PhD, medical director, Kraft Family Blood Donor Center at Dana Farber Cancer Institute/Brigham and Women's Hospital, who did not contribute to the study. "A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research. This study addresses that gap, while contributing to our understanding of platelet biology at the same time."

Blood cells, such as platelets, are made in bone marrow. The bioreactor—a device that mimics a biological environment to carry out a reaction on an industrial scale—uses biologically inspired engineering to fully integrate the major components of bone marrow, modeling both its composition and blood flow characteristics. The microfluidic platelet bioreactor recapitulates features such as bone marrow stiffness, extracellular matrix composition, micro-channel size, and blood flow stability under high-resolution live-cell microscopy to make human platelets.

Thon and Joseph Italiano, Jr., PhD are both founders of Platelet BioGenesis, a company that aims to produce donor-independent human platelets from human-induced pluripotent stem cells at scal

Application of shear forces of blood flow in the bioreactor triggered a dramatic increase in platelet initiation from 10 percent to 90 percent, leading to functional human platelets.

"By being able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation to support drug development and scale platelet production," said senior study author Joseph Italiano, Jr., PhD, Division of Hematology, BWH Department of Medicine, and the Vascular Biology Program at Boston Children's Hospital.

In terms of next steps, the researchers would like to commence phase 0/I in human clinical trials in 2017.

"The regulatory bar is appropriately set high for blood products, and it is important to us that we show platelet quality, function and safety over these next three years since we'll likely be recipients of these platelets ourselves at some point," said Thon.


SOURCE  Brigham and Women's Hospital via EurekAlert

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 Regenerative Medicine  

It has long been thought once adult brain cells die, they are gone forever. Now, scientists are challenging that convention in experiments that could generate new treatments for brain injuries.

Researchers are hoping to unlock the potential of stem cells as a way of repairing neural damage to the brain.

Rachel Okolicsanyi, from the Genomics Research Centre at Queensland University of Technology's Institute of Health and Biomedical Innovation, said unlike other cells in the body which were able to divide and replicate, once most types of brain cells died, the damage was deemed irreversible.

Okolicsanyi is manipulating adult stem cells from bone marrow to produce a population of cells that can be used to treat brain damage.

"My research is a step in proving that stem cells taken from the bone marrow can be manipulated into neural cells, or precursor cells that have the potential to replace, repair or treat brain damage," she said.

The research has been published in the journal Developmental Biology, and outlines the potential stem cells have for brain damage repair.

"By manipulating this particular family of proteins we can encourage the stem cells to show a higher percentage of neural markers indicating that they could mature into neural cells rather than what they would normally do, which is form into bone, cartilage and fat."

"What I am looking at is whether or not stem cells from the bone marrow have the potential to differentiate or mature into neural cells," she said.

"Neural cells are those cells from the brain that make everything from the structure of the brain itself, to all the connections that make movement, voice, hearing and sight possible."

Okolicsanyi's research is looking at heparin sulfate proteoglycans - a family of proteins found on the surface of all cells.

"What we are hoping is that by manipulating this particular family of proteins we can encourage the stem cells to show a higher percentage of neural markers indicating that they could mature into neural cells rather than what they would normally do, which is form into bone, cartilage and fat," she said.

"We will manipulate these cells by modifying the surrounding environment. For example we will add chemicals such as complex salts and other commonly found biological chemicals to feed these cells and this will either inhibit or encourage cellular processes."

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Okolicsanyi said by doing this, it would be possible to see the different reactions stem cells had to particular chemicals and find out whether these chemicals could increase or decrease the neural markers in the cells.

"The proteins that we are interested in are almost like a tree," she said. "They have a core protein that is attached to the cell surface and they have these heparin sulfate chains that branch off.

"So when the chemicals we add influence the stem cell in different ways, it will help us understand the interactions between proteins and the resulting changes in the cell.

"In the short-term it is proof that simple manipulations can influence the stem cell and in the long-term it is about the possibility of increasing the neural potential of these stem cells."

Okolicsanyi said the big picture plan was to be able to introduce stem cells into the brain that would be able to be manipulated to repair damaged brain cells.

"The idea, for example, is that in stroke patients where the patient loses movement, speech or control of one side of their face because the brain's electrical current is impaired, that these stem cells will be able to be introduced and help the electrical current reconnect by bypassing the damaged cells."


SOURCE  Queensland University of Technology

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 Biotech  

Researchers have created the first method to reproduce the structure, functions and cellular make-up of bone marrow in the laboratory. The new device gives scientists a much-needed new method to test the effects on bone marrow of toxic agents and new drugs to prevent lethal radiation poisoning and dangerous side effects of cancer therapies, all without animal testing.

The latest organ-on-a-chip from Harvard's Wyss Institute for Biologically Inspired Engineering reproduces the structure, functions and cellular make-up of bone marrow, a complex tissue that until now could only be studied intact in living animals, Institute researchers report in the journal Nature Methods. The DARPA-funded reseach device, dubbed "bone marrow-on-a-chip," gives scientists a much-needed new tool to test the effects of new drugs and toxic agents on whole bone marrow.

"We figured, why not allow Mother Nature to help us build what she already knows how to build."

Specifically, the device could be used to develop safe and effective strategies to prevent or treat radiation's lethal effects on bone marrow without resorting to animal testing, a challenge that is being pursued at the Institute with funding support from the U.S. Food & Drug Administration (FDA). In an initial test, the engineered bone marrow, like human marrow, withered in response to radiation unless a drug known to prevent radiation poisoning was present.

The bone marrow-on-a-chip could also be used in the future to maintain a cancer patient's own marrow temporarily while he or she underwent marrow-damaging treatments such as radiation therapy or high-dose chemotherapy.

"Bone marrow is an incredibly complex organ that is responsible for producing all of the blood cell types of our body, and our bone marrow chips are able to recapitulate this complexity in its entirety and maintain it in a functional form in vitro ," said Don Ingber, M.D., Ph.D., Founding Director of the Wyss Institute, Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, Professor of Bioengineering at SEAS, and senior author of the paper.

Ingber leads a large effort to develop human organs-on-chips – small microfluidic devices that mimic the physiology of living organism. So far the research teams have built lung, heart, kidney, and gut chips that reproduce key aspects of organ function, and they have more organs-on-chips in the works. The technology has been recognized internationally for its potential to replace animal testing of new drugs and environmental toxins, and as a new way for scientists to model human disease.

To build organ chips, in the past Wyss teams have combined multiple types of cells from an organ on a microfluidic chip, while steadily supplying nutrients, removing waste, and applying mechanical forces the tissues would face in the body. But bone marrow is so complex that they needed a new approach to mimic organ function.

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This complexity arises because bone marrow has an integral relationship with bone. Marrow sits inside trabecular bone — a solid-looking type of bone with a porous, honeycombed interior. Throughout the honeycomb, conditions vary: Some areas are warmer, some cooler; some are oxygen-rich, others oxygen-starved — and the dozen or so cell types each have their own preferred spots. To add complexity, bone marrow cells communicate with each other by secreting and sensing a variety of biomolecules, which act locally to tell them whether to live, die, specialize or multiply.

Rather than trying to reproduce such a complex structure cell by cell, the researchers enlisted mice to do it."We figured, why not allow Mother Nature to help us build what she already knows how to build," said Catherine S. Spina, an M.D.-Ph.D. candidate at Boston University, researcher at the Wyss Institute, and co-lead author of the paper.

Specifically, Wyss Institute Postdoctoral Fellow Yu-suke Torisawa and Spina packed dried bone powder into an open, ring-shaped mold the size of a coin battery, and implanted the mold under the skin on the animal's back.

After eight weeks, they surgically removed the disk-shaped bone that had formed in the mold and examined it with a specialized CAT scanner. The scan showed a honeycomb-like structure that looked identical to natural trabecular bone.

The marrow looked like the real thing as well. When they stained the tissue and examined it under a microscope, the marrow was packed with blood cells, just like marrow from a living mouse. And when the researchers sorted the bone marrow cells by type and tallied their numbers, the mix of different types of blood and immune cells in the engineered bone marrow was identical to that in a mouse thighbone.

To sustain the engineered bone marrow outside of a living animal, the researchers surgically removed the engineered bone from mice, then placed it in a microfluidic device that steadily supplied nutrients and removed waste to mimic the circulation the tissue would experience in the body.

Marrow in the device remained healthy for up to one week — long enough, typically, to test the toxicity and effectiveness of a new drug.

The device also passed an initial test of its drug-testing capabilities. Like marrow from live mice, this engineered marrow was also susceptible to radiation — but an FDA-approved drug that protects irradiated patients also protects the marrow on the chip.

In the future, the researchers could potentially grow human bone marrow in immune-deficient mice. "This could be developed into an easy-to-use screening-based system that's personalized for individual patients," said coauthor James Collins, Ph.D., a Core Faculty member at the Wyss Institute and the William F. Warren Distinguished Professor at Boston University, where he leads the Center of Synthetic Biology.


SOURCE  Wyss Institute

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