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Eye implant developed at Stanford could lead to better glaucoma treatments

Lowering internal eye pressure is currently the only way to treat glaucoma. A tiny eye implant developed by Stephen Quake’s lab could pair with a smartphone to improve the way doctors measure and lower a patient’s eye pressure.

BY BJORN CAREY


For the 2.2 million Americans battling glaucoma, the main course of action for staving off blindness involves weekly visits to eye specialists who monitor – and control – increasing pressure within the eye.

Now, a tiny eye implant developed at Stanford could enable patients to take more frequent readings from the comfort of home. Daily or hourly measurements of eye pressure could help doctors tailor more effective treatment plans.

Internal optic pressure (IOP) is the main risk factor associated with glaucoma, which is characterized by a continuous loss of specific retina cells and degradation of the optic nerve fiber. The mechanism linking IOP and the damage is not clear, but in most patients IOP levels correlate with the rate of damage.

Reducing IOP to normal or below-normal levels is currently the only treatment available for glaucoma. This requires repeated measurements of the patient’s IOP until the levels stabilize. The trick with this, though, is that the readings do not always tell the truth.

Like blood pressure, IOP can vary day-to-day and hour-to-hour; it can be affected by other medications, body posture or even a neck-tie that is knotted too tightly. If patients are tested on a low IOP day, the test can give a false impression of the severity of the disease and affect their treatment in a way that can ultimately lead to worse vision.

The new implant was developed as part of a collaboration between Stephen Quake, a professor of bioengineering and of applied physics at Stanford, and ophthalmologist Yossi Mandel of Bar-Ilan University in Israel. It consists of a small tube – one end is open to the fluids that fill the eye; the other end is capped with a small bulb filled with gas. As the IOP increases, intraocular fluid is pushed into the tube; the gas pushes back against this flow.

As IOP fluctuates, the meniscus – the barrier between the fluid and the gas – moves back and forth in the tube. Patients could use a custom smartphone app or a wearable technology, such as Google Glass, to snap a photo of the instrument at any time, providing a critical wealth of data that could steer treatment. For instance, in one previous study, researchers found that 24-hour IOP monitoring resulted in a change in treatment in up to 80 percent of patients.

The implant is currently designed to fit inside a standard intraocular lens prosthetic, which many glaucoma patients often get when they have cataract surgery, but the scientists are investigating ways to implant it on its own.

“For me, the charm of this is the simplicity of the device,” Quake said. “Glaucoma is a substantial issue in human health. It’s critical to catch things before they go off the rails, because once you go off, you can go blind. If patients could monitor themselves frequently, you might see an improvement in treatments.”

Remarkably, the implant won’t distort vision. When subjected to the vision test used by the U.S. Air Force, the device caused nearly no optical distortion, the researchers said.

Before they can test the device in humans, however, the scientists say they need to re-engineer the device with materials that will increase the life of the device inside the human eye. Because of the implant’s simple design, they expect this will be relatively achievable.

“I believe that only a few years are needed before clinical trials can be conducted,” said Mandel, head of the Ophthalmic Science and Engineering Laboratory at Bar-Ilan University, who collaborated on developing the implant.

The work, published in the current issue of Nature Medicine, was co-authored by Ismail E. Araci, a postdoctoral scholar in Quake’s lab, and Baolong Su, a technician in Quake’s lab and currently an undergraduate student at the University of California, Los Angeles.

Source: Stanford News

Engineering new bone growth

Coated tissue scaffolds help the body grow new bone to repair injuries or congenital defects.

By Anne Trafton


 

CAMBRIDGE, MA — MIT chemical engineers have devised a new implantable tissue scaffold coated with bone growth factors that are released slowly over a few weeks. When applied to bone injuries or defects, this coated scaffold induces the body to rapidly form new bone that looks and behaves just like the original tissue.

This type of coated scaffold could offer a dramatic improvement over the current standard for treating bone injuries, which involves transplanting bone from another part of the patient’s body — a painful process that does not always supply enough bone. Patients with severe bone injuries, such as soldiers wounded in battle; people who suffer from congenital bone defects, such as craniomaxillofacial disorders; and patients in need of bone augmentation prior to insertion of dental implants could benefit from the new tissue scaffold, the researchers say.

“It’s been a truly challenging medical problem, and we have tried to provide one way to address that problem,” says Nisarg Shah, a recent PhD recipient and lead author of the paper, which appears in the Proceedings of the National Academy of Sciences this week.

Paula Hammond, the David H. Koch Professor in Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Department of Chemical Engineering, is the paper’s senior author. Other authors are postdocs M. Nasim Hyder and Mohiuddin Quadir, graduate student Noémie-Manuelle Dorval Courchesne, Howard Seeherman of Restituo, Myron Nevins of the Harvard School of Dental Medicine, and Myron Spector of Brigham and Women’s Hospital.

Stimulating bone growth

Two of the most important bone growth factors are platelet-derived growth factor (PDGF) and bone morphogenetic protein 2 (BMP-2). As part of the natural wound-healing cascade, PDGF is one of the first factors released immediately following a bone injury, such as a fracture. After PDGF appears, other factors, including BMP-2, help to create the right environment for bone regeneration by recruiting cells that can produce bone and forming a supportive structure, including blood vessels.

Efforts to treat bone injury with these growth factors have been hindered by the inability to effectively deliver them in a controlled manner. When very large quantities of growth factors are delivered too quickly, they are rapidly cleared from the treatment site — so they have reduced impact on tissue repair, and can also induce unwanted side effects.

“You want the growth factor to be released very slowly and with nanogram or microgram quantities, not milligram quantities,” Hammond says. “You want to recruit these native adult stem cells we have in our bone marrow to go to the site of injury and then generate bone around the scaffold, and you want to generate a vascular system to go with it.”

This process takes time, so ideally the growth factors would be released slowly over several days or weeks. To achieve this, the MIT team created a very thin, porous scaffold sheet coated with layers of PDGF and BMP. Using a technique called layer-by-layer assembly, they first coated the sheet with about 40 layers of BMP-2; on top of that are another 40 layers of PDGF. This allowed PDGF to be released more quickly, along with a more sustained BMP-2 release, mimicking aspects of natural healing.

The scaffold sheet is about 0.1 millimeter thick; once the growth-factor coatings are applied, scaffolds can be cut from the sheet on demand, and in the appropriate size for implantation into a bone injury or defect.

Effective repair

The researchers tested the scaffold in rats with a skull defect large enough — 8 millimeters in diameter — that it could not heal on its own. After the scaffold was implanted, growth factors were released at different rates. PDGF, released during the first few days after implantation, helped initiate the wound-healing cascade and mobilize different precursor cells to the site of the wound. These cells are responsible for forming new tissue, including blood vessels, supportive vascular structures, and bone.

BMP, released more slowly, then induced some of these immature cells to become osteoblasts, which produce bone. When both growth factors were used together, these cells generated a layer of bone, as soon as two weeks after surgery, that was indistinguishable from natural bone in its appearance and mechanical properties, the researchers say.

“Using this combination allows us to not only have accelerated proliferation first, but also facilitates laying down some vascular tissue, which provides a route for both the stem cells and the precursor osteoblasts and other players to get in and do their jobs. You end up with a very uniform healed system,” Hammond says.

Another advantage of this approach is that the scaffold is biodegradable and breaks down inside the body within a few weeks. The scaffold material, a polymer called PLGA, is widely used in medical treatment and can be tuned to disintegrate at a specific rate so the researchers can design it to last only as long as needed.

Hammond’s team has filed a patent based on this work and now aims to begin testing the system in larger animals in hopes of eventually moving it into clinical trials.

This study was funded by the National Institutes of Health.

Source: MIT News Office

Bioengineers create functional 3-D brain-like tissue

Tissue model could change the way scientists study the brain in vitro-NIH study

Bioengineers have created three-dimensional brain-like tissue that functions like and has structural features similar to tissue in the rat brain and that can be kept alive in the lab for more than two months.

As a first demonstration of its potential, researchers used the brain-like tissue to study chemical and electrical changes that occur immediately following traumatic brain injury and, in a separate experiment, changes that occur in response to a drug. The tissue could provide a superior model for studying normal brain function as well as injury and disease, and could assist in the development of new treatments for brain dysfunction.

Confocal microscope image of neurons (greenish yellow) attached to silk-based scaffold (blue). The neurons formed functional networks throughout the scaffold pores (dark areas). Image courtesy of Tufts University.
Confocal microscope image of neurons (greenish yellow) attached to silk-based scaffold (blue). The neurons formed functional networks throughout the scaffold pores (dark areas). Image courtesy of Tufts University.

The brain-like tissue was developed at the Tissue Engineering Resource Center at Tufts University, Boston, which is funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) to establish innovative biomaterials and tissue engineering models.  David Kaplan, Ph.D., Stern Family Professor of Engineering at Tufts University is director of the center and led the research efforts to develop the tissue.

Diagram of scaffold donut showing grey-white matter compartmentalization. Rat neurons attached to the scaffold (donut ring) and also sent axons (labeled with green fluorescence) through the collagen gel-filled center.
Diagram of scaffold donut showing grey-white matter compartmentalization. Rat neurons attached to the scaffold (donut ring) and also sent axons (labeled with green fluorescence) through the collagen gel-filled center.

Currently, scientists grow neurons in petri dishes to study their behavior in a controllable environment. Yet neurons grown in two dimensions are unable to replicate the complex structural organization of brain tissue, which consists of segregated regions of grey and white matter. In the brain, grey matter is comprised primarily of neuron cell bodies, while white matter is made up of bundles of axons, which are the projections neurons send out to connect with one another. Because brain injuries and diseases often affect these areas differently, models are needed that exhibit grey and white matter compartmentalization.

Recently, tissue engineers have attempted to grow neurons in 3D gel environments, where they can freely establish connections in all directions. Yet these gel-based tissue models don’t live long and fail to yield robust, tissue-level function. This is because the extracellular environment is a complex matrix in which local signals establish different neighborhoods that encourage distinct cell growth and/or development and function.  Simply providing the space for neurons to grow in three dimensions is not sufficient.

Now, in the Aug. 11th early online edition of the journal Proceedings of the National Academy of Sciences, a group of bioengineers report that they have successfully created functional 3D brain-like tissue that exhibits grey-white matter compartmentalization and can survive in the lab for more than two months.

“This work is an exceptional feat,” said Rosemarie Hunziker, Ph.D.

Image of silk-based scaffold taken with a scanning electron microscope reveals its porous, sponge-like composition. Image courtesy of Tufts University.
Image of silk-based scaffold taken with a scanning electron microscope reveals its porous, sponge-like composition. Image courtesy of Tufts University.

, program director of Tissue Engineering at NIBIB. “It combines a deep understand of brain physiology with a large and growing suite of bioengineering tools to create an environment that is both necessary and sufficient to mimic brain function.”

The key to generating the brain-like tissue was the creation of a novel composite structure that consisted of two biomaterials with different physical properties: a spongy scaffold made out of silk protein and a softer, collagen-based gel. The scaffold served as a structure onto which neurons could anchor themselves, and the gel encouraged axons to grow through it.

To achieve grey-white matter compartmentalization, the researchers cut the spongy scaffold into a donut shape and populated it with rat neurons. They then filled the middle of the donut with the collagen-based gel, which subsequently permeated the scaffold. In just a few days, the neurons formed functional networks around the pores of the scaffold, and sent longer axon projections through the center gel to connect with neurons on the opposite side of the donut. The result was a distinct white matter region (containing mostly cellular projections, the axons) formed in the center of the donut that was separate from the surrounding grey matter (where the cell bodies were concentrated).

Over a period of several weeks, the researchers conducted experiments to determine the health and function of the neurons growing in their 3D brain-like tissue and to compare them with neurons grown in a collagen gel-only environment or in a 2D dish.

The researchers found that the neurons in the 3D brain-like tissues had higher expression of genes involved in neuron growth and function. In addition, the neurons grown in the 3D brain-like tissue maintained stable metabolic activity for up to five weeks, while the health of neurons grown in the gel-only environment began to deteriorate within 24 hours. In regard to function, neurons in the 3D brain-like tissue exhibited electrical activity and responsiveness that mimic signals seen in the intact brain, including a typical electrophysiological response pattern to a neurotoxin.

Because the 3D brain-like tissue displays physical properties similar to rodent brain tissue, the researchers sought to determine whether they could use it to study traumatic brain injury. To simulate a traumatic brain injury, a weight was dropped onto the brain-like tissue from varying heights. The researchers then recorded changes in the neurons’ electrical and chemical activity, which proved similar to what is ordinarily observed in animal studies of traumatic brain injury.

Kaplan says the ability to study traumatic injury in a tissue model offers advantages over animal studies, in which measurements are delayed while the brain is being dissected and prepared for experiments.

“With the system we have, you can essentially track the tissue response to traumatic brain injury in real time,” said Kaplan. “Most importantly, you can also start to track repair and what happens over longer periods of time.”

Kaplan emphasized the importance of the brain-like tissue’s longevity for studying other brain disorders. “The fact that we can maintain this tissue for months in the lab means we can start to look at neurological diseases in ways that you can’t otherwise because you need long timeframes to study some of the key brain diseases,” he said.

Hunziker added, “Good models enable solid hypotheses that can be thoroughly tested. The hope is that use of this model could lead to an acceleration of therapies for brain dysfunction as well as offer a better way to study normal brain physiology.”

Kaplan and his team are looking into how they can make their tissue model more brain-like.  In this recent report, the researchers demonstrated that they can modify their donut scaffold so that it consists of six concentric rings, each able to be populated with different types of neurons. Such an arrangement would mimic the six layers of the human brain cortex, in which different types of neurons exist.

As part of the funding agreement for the Tissue Engineering Resource Center, NIBIB requires that new technologies generated at the center be shared with the greater biomedical research community.

“We look forward to building collaborations with other labs that want to build on this tissue model,” said Kaplan.

This work was supported by NIH’s National Institute of Biomedical Imaging and Bioengineering under award #EB002520

NIBIB’s mission is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating the physical and engineering sciences with the life sciences to advance basic research and medical care. NIBIB supports emerging technology research and development within its internal laboratories and through grants, collaborations, and training. More information is available at the NIBIB website:http://www.nibib.nih.gov.

Source :NIH