In a preclinical study conducted at MGH and published in Science Advances, the researchers tested the biomaterial — which includes a novel protein called SA-FasL that promotes immune tolerance and is tethered to the surface of microgel beads — in a nonhuman primate model of type 1 diabetes. The material was mixed with islets and then transplanted to a bioengineered pouch formed by the omentum — a fold of fatty tissue that hangs from the stomach and covers the intestines. After transplantation, animals received a single anti-rejection drug (rapamycin) for three months.

“Our strategy to create a local immune-privileged environment allowed islets to survive without long-term immunosuppression and achieved robust blood glucose control in all diabetic nonhuman primates during a six-month study period,” says lead author Ji Lei, MD, MBA, an associate immunologist at MGH and an assistant professor of Surgery at Harvard Medical School. “We believe that our approach allows the transplants to survive and control diabetes for much longer than six months without anti-rejection drugs because surgical removal of the transplanted tissue at the end of the study resulted in all animals promptly returning to a diabetic state.”

Lei, who is also director of the Human Islet/Cell Processing Special Service cGMP Facility at MGH, notes that transplanting islets to the omentum has several advantages over the current clinical approach of transplanting to the liver. “Unlike the liver, the omentum is a non-vital organ allowing its removal should undesired complications be encountered,” he explains. “Thus, the omentum is a safer location for transplants to treat diabetes and may be particularly well suited for stem-cell-derived beta cells and bio-engineered cells.”

Co-corresponding author James F. Markmann, MD, PhD, chief of the Division of Transplant Surgery and director of Clinical Operations at the Transplant Center at MGH stresses that the non-human primate study is a highly relevant pre-clinical animal model. “This localized immunomodulatory strategy succeeded without long-term immunosuppression and shows great potential for application to type 1 diabetes patients,” he says.

A clinical trial is being planned based on the researchers’ results.

Additional study authors include María M. Coronel, Esma S. Yolcu, Hongping Deng, Orlando Grimany-Nuno, Michael D. Hunckler, Vahap Ulker, Zhihong Yang, Kang M. Lee, Alexander Zhang, Hao Luo, Cole W. Peters, Zhongliang Zou, Tao Chen, Zhenjuan Wang, Colleen S. McCoy, Ivy A. Rosales, Haval Shirwan and Andrés J. García.

This work was supported by the Juvenile Diabetes Research Foundation, the National Institutes of Health, and the National Science Foundation.

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In people living with Type 1 diabetes, their immune system can malfunction, causing it to attack itself, said Haval Shirwan, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, and one of the study’s lead authors.

“The immune system is a tightly controlled defense mechanism that ensures the well-being of individuals in an environment full of infections,” Shirwan said. “Type 1 diabetes develops when the immune system misidentifies the insulin-producing cells in the pancreas as infections and destroys them. Normally, once a perceived danger or threat is eliminated, the immune system’s command-and-control mechanism kicks in to eliminate any rogue cells. However, if this mechanism fails, diseases such as Type 1 diabetes can manifest.”

Diabetes affects the body’s ability to produce or use insulin, a hormone which helps regulate how blood sugar is used in the body. People living with Type 1 diabetes do not make insulin, and therefore are unable to control their blood sugar levels. That loss of control can lead to life-threatening complications such as heart disease, kidney damage and eye damage.

Over the last two decades, Shirwan and Esma Yolcu, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, have targeted a mechanism, called apoptosis, that destroys “rogue” immune cells from causing diabetes or rejection of transplanted pancreatic islets by attaching a molecule called FasL to the surface of the islets.

“A type of apoptosis occurs when a molecule called FasL interacts with another molecule called Fas on rogue immune cells, and it causes them to die,” said Yolcu, one of the study’s first authors. “Therefore, our team pioneered a technology that enabled the production of a novel form of FasL and its presentation on transplanted pancreatic islet cells or microgels to prevent being rejected by rogue cells. Following insulin-producing pancreatic islet cell transplantation, rogue cells mobilize to the graft for destruction but are eliminated by FasL engaging Fas on their surface.”

One advantage of this new method is the opportunity to potentially forgo a lifetime of taking immunosuppressive drugs, which counteract the immune system’s ability to seek and destroy a foreign object when introduced into the body, such as an organ, or in this case, cell, transplant.

“The major problem with immunosuppressive drugs is that they are not specific, so they can have a lot of adverse effects, such as high instances of developing cancer,” Shirwan said. “So, using our technology, we found a way that we can modulate or train the immune system to accept, and not reject, these transplanted cells.”

Their method utilizes technology included in a U.S. patent filed by the University of Louisville and Georgia Tech, and has since been licensed by a commercial company with plans to pursue FDA approval for human testing. To develop the commercial product, the MU researchers collaborated with Andres García and the team at Georgia Tech to attach FasL to the surface of microgels with a proof-of-efficacy in a small animal model. Then, they joined with Jim Markmann and Ji Lei from Harvard to assess the efficacy of the FasL-microgel technology in a large animal model, which is published in this study.

Incorporating the power of NextGen

This study represents a significant milestone in the process of bench-to-bedside research, or how laboratory results are directly incorporated into use by patients in order to help treat different diseases and disorders, a hallmark of MU’s most ambitious research initiative, the NextGen Precision Health initiative.

Highlighting the promise of personalized health care and the impact of large-scale interdisciplinary collaboration, the NextGen Precision Health initiative is bringing together innovators like Shirwan and Yolcu from across MU and the UM System’s three other research universities in pursuit of life-changing precision health advancements. It’s a collaborative effort to leverage the research strengths of MU toward a better future for the health of Missourians and beyond. The Roy Blunt NextGen Precision Health building at MU anchors the overall initiative and expands collaboration between researchers, clinicians and industry partners in the state-of-the-art research facility.

“I think by being at the right institution with access to a great facility like the Roy Blunt NextGen Precision Health building, will allow us to build on our existing findings and take the necessary steps to further our research, and make the necessary improvements, faster,” Yolcu said.

Shirwan and Yolcu, who joined the faculty at MU in spring 2020, are part of the first group of researchers to begin working in the NextGen Precision Health building, and after working at MU for nearly two years they are now among the first researchers from NextGen to have a research paper accepted and published in a high-impact, peer-reviewed academic journal.

“FasL microgels induce immune acceptance of islet allografts in nonhuman primates,” was published in Science Advances, a journal published by the American Association for the Advancement of Science (AAAS). Funding was provided by grants from the Juvenile Diabetes Research Foundation (2-SRA-2016-271-S-B) and the National Institutes of Health (U01 AI132817) as well as a Juvenile Diabetes Research Foundation Post-Doctoral Fellowship and a National Science Foundation Graduate Research Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Other authors on the study include Ji Lei, Hongping Deng, Zhihong Yang, Kang Lee, Alexander Zhang, Cole Peters, Zhongliang Zou, Zhenjuan Wang, Ivy Rosales and James Markmann at Harvard; Michael Hunckler, and Andrés J. García at Georgia Institute of Technology (Georgia Tech); Hao Luo at the General Hospital of Western Theater Command in Chengdu, China; Tao Chen at Xiamen University Medical School in Xiamen, China; and Colleen McCoy at Massachusetts Institute of Technology. The study’s authors would also like to acknowledge Jessica Weaver, Lisa Kojima, Haley Tector, Kevin Deng, Rudy Matheson and Nikolaos Serifis for their technical contributions.

Potential conflicts of interest are also noted. Three of the study’s authors, García, Shirwan and Yolcu, are inventors on a U.S. patent application filed by the University of Louisville and the Georgia Tech Research Corporation (16/492441, filed Feb. 13, 2020). In addition, García and Shirwan are co-founders of iTolerance, and García, Shirwan and Markmann serve on the scientific advisory board for iTolerance.

Researchers from Texas A&M University recently showcased superior tensile superelasticity by fabricating a shape memory alloy through laser powder bed fusion, nearly doubling the maximum superelasticity reported in literature for 3D printing.

Nickel-titanium shape memory alloys have various applications due to their ability to return to their original shape upon heating or upon removal of the applied stress. Therefore, they can be used in biomedical and aerospace fields for stents, implants, surgical devices and aircraft wings. However, developing and properly fabricating these materials requires extensive research to characterize functional properties and examine the microstructure.

“Shape memory alloys are smart materials that can remember their high-temperature shapes,” said Dr. Lei Xue, a former doctoral student in the Department of Materials Science and Engineering and the first author of the publication. “Although they can be utilized in many ways, fabricating shape memory alloys into complex shapes requires fine-tuning to ensure the material exhibits the desired properties.”

Laser powder bed fusion is an additive manufacturing technique that presents a way to produce nickel-titanium shape memory alloys effectively and efficiently, offering a pathway to quick manufacturing or prototyping. This technique, similar to polymer 3D printing, uses a laser to fuse metal or alloy powders layer by layer. The layer-by-layer process is beneficial because it can create parts with complex geometries that would be impossible in traditional manufacturing.

“Using a 3D printer, we spread the alloy powder over a substrate and then use the laser to melt the powder, forming one full layer,” said Xue. “We repeat this layering, scanning the same or different patterns until the desired structure is formed.”

Unfortunately, most nickel-titanium materials cannot withstand the current laser powder bed fusion process, often resulting in printing defects such as porosity, warping or delamination caused by large thermal gradient and brittleness from oxidation. In addition, the laser can change the composition of the material due to evaporation during printing.

To combat this issue, the researchers used an optimization framework they created in a previous study, which can determine optimal process parameters to achieve defect-free structure and specific material properties.

With this framework, as well as the change in composition and refined process parameters, the researchers fabricated nickel-titanium parts that consistently exhibited a room temperature tensile superelasticity of 6% in the as-printed condition (without post-fabrication heat treatment). This level of superelasticity is nearly double the amount previously seen in literature for 3D printing.

The ability to produce shape memory alloys through 3D printing with increased superelasticity means the materials are more capable of handling applied deformation. Using 3D printing to develop these superior materials will reduce the cost and time of the manufacturing process.

In the future, the researchers hope their discoveries will lead to increased use of printed nickel-titanium shape memory alloys in biomedical and aerospace applications.

“This study can serve as a guide on how to print nickel-titanium shape memory alloys with desired mechanical and functional characteristics,” said Xue. “If we can tailor the crystallographic texture and microstructure, there are far more applications these shape memory alloys can be used in.”

This research was funded by the U.S. Army Research Laboratory, the National Priorities Research Program grant, the Qatar National Research Fund and the U.S. National Science Foundation grant.

Other contributors to the publication include materials science and engineering department head Dr. Ibrahim Karaman; materials science and engineering professors Dr. Kadri Can Atli and Dr. Raymundo Arroyave; former materials science and engineering student Dr. Abhinav Srivastava and current student Nathan Hite; Wm Michael Barnes ’64 Department of Industrial Systems and Engineering professor Dr. Alaa Elwany; industrial systems and engineering student Chen Zhang; and U.S. Army Research Laboratory researchers Dr. Asher C. Leff, Dr. Adam A. Wilson and Dr. Darin J. Sharar.

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If bacteria or viruses attack living cells or other foreign substances appear in them, the danger sensor with the abbreviation NLRP3 is activated. “The protein deposits in the brain that are characteristic of Alzheimer’s disease, the so-called amyloid-ß plaques, can also set NLRP3 in motion,” says Prof. Dr. Matthias Geyer from the Institute for Structural Biology at the University Hospital Bonn, referring to earlier studies. As these previous studies by the researchers show, this reaction increasingly fuels itself: The inflammatory reaction triggered by NLRP3 promotes the further deposition of amyloid-ß plaques and contributes significantly to the disease process.

Once activated, several NLRP3 proteins attach to each other and in this way form the nucleus for a thread-like structure at which more and more proteins gather. “The reaction kicks in as soon as about a dozen of the NLRP3 molecules are present,” Geyer reports. In theory, an infinite number of NLRP3 molecules can join together and extend the thread-like structure — scientifically called a “filament” — further and further. Inga Hochheiser from Prof. Geyer’s team has now been able to show the direction in which this filament grows and continues to expand. “We were able to gain these insights using cryo-electron microscopy. This method makes it possible to observe protein molecules with up to 80,000-fold magnification and thus make them directly visible,” says Hochheiser.

“Still image” of the thread-like structure under the microscope

In tiny steps, the scientist drizzled NLRP3 isolated from cells onto a sample carrier and flash-froze this mixture. This provided the researchers with a kind of “still image” under the cryo-electron microscope. The emerging thread-like structure of NLRP3 molecules arranged side by side was thus visualized. “These individual images made it possible to understand how the filaments elongate, just like in a film,” says Hochheiser. As the molecules fall differently on the sample carrier when drizzled, they can be seen from different perspectives under the microscope. These different views can be combined on the computer to create a three-dimensional image. The results showed that the filaments only form in one direction. “This allowed us to visualize part of the inflammatory apparatus and literally read the direction of growth,” says Prof. Geyer, who led the study and is a member of the Cluster of Excellence ImmunoSensation2 and the Transdisciplinary Research Area “Life and Health” at the University of Bonn.

Stopping chronic inflammatory diseases

“The technical challenge was to find the transitions in the thread-like structures and make them visible in the image,” says Prof. Dr. Elmar Behrmann from the Institute for Biochemistry at the University of Cologne. “The new findings now allow us to target the growing end of the inflammatory response using antibodies or drugs,” Hochheiser explains. This brings the researchers closer to their goal of stopping the further build-up of the inflammatory apparatus and thus counteracting chronic inflammation.

Participating institutions and funding:

In addition to the Institute of Structural Biology and the Institute of Innate Immunity of the University Hospital Bonn, the Institute of Biochemistry of the University of Cologne and The Walter and Eliza Hall Institute of Medical Research in Melbourne (Australia) are involved in the study. Measurements were carried out at the research center caesar in Bonn and at the Rudolf Virchow Center at the University of Würzburg. The study was funded by the Else Kröner-Fresenius Foundation and the German Research Foundation.

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