Novel biomaterial prevents rejection of transplants for type 1 diabetes

In type 1 diabetes, an autoimmune response attacks the pancreas's insulin-producing beta cells, leading to marked fluctuations in blood sugar levels. Lifelong daily insulin treatments are standard for patients, but replacing lost beta cells through transplants of islets, a group of cells in the pancreas, represents an attractive option. This strategy requires that patients take lifelong immunosuppressive drugs to prevent rejection, however. To address this shortcoming, a team at Massachusetts General Hospital (MGH) and Harvard Medical School collaborated with researchers at the Georgia Institute of Technology and the University of Missouri to develop a novel biomaterial that, when mixed with islets, allows islets to survive after transplant without the need for long-term immunosuppression.

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.

Read more at Science Daily

'Walking' molecule superstructures could help create neurons for regenerative medicine

 Imagine if surgeons could transplant healthy neurons into patients living with neurodegenerative diseases or brain and spinal cord injuries. And imagine if they could "grow" these neurons in the laboratory from a patient's own cells using a synthetic, highly bioactive material that is suitable for 3D printing.

By discovering a new printable biomaterial that can mimic properties of brain tissue, Northwestern University researchers are now closer to developing a platform capable of treating these conditions using regenerative medicine.

A key ingredient to the discovery is the ability to control the self-assembly processes of molecules within the material, enabling the researchers to modify the structure and functions of the systems from the nanoscale to the scale of visible features. The laboratory of Samuel I. Stupp published a 2018 paper in the journal Science which showed that materials can be designed with highly dynamic molecules programmed to migrate over long distances and self-organize to form larger, "superstructured" bundles of nanofibers.

Now, a research group led by Stupp has demonstrated that these superstructures can enhance neuron growth, an important finding that could have implications for cell transplantation strategies for neurodegenerative diseases such as Parkinson's and Alzheimer's disease, as well as spinal cord injury.

"This is the first example where we've been able to take the phenomenon of molecular reshuffling we reported in 2018 and harness it for an application in regenerative medicine," said Stupp, the lead author on the study and the director of Northwestern's Simpson Querrey Institute. "We can also use constructs of the new biomaterial to help discover therapies and understand pathologies."

A pioneer of supramolecular self-assembly, Stupp is also the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering and holds appointments in the Weinberg College of Arts and Sciences, the McCormick School of Engineering and the Feinberg School of Medicine.

The paper was published today (Feb. 22) in the journal Advanced Science.

Walking molecules and 3D printing

The new material is created by mixing two liquids that quickly become rigid as a result of interactions known in chemistry as host-guest complexes that mimic key-lock interactions among proteins, and also as the result of the concentration of these interactions in micron-scale regions through a long scale migration of "walking molecules."

The agile molecules cover a distance thousands of times larger than themselves in order to band together into large superstructures. At the microscopic scale, this migration causes a transformation in structure from what looks like an uncooked chunk of ramen noodles into ropelike bundles.

"Typical biomaterials used in medicine like polymer hydrogels don't have the capabilities to allow molecules to self-assemble and move around within these assemblies," said Tristan Clemons, a research associate in the Stupp lab and co-first author of the paper with Alexandra Edelbrock, a former graduate student in the group. "This phenomenon is unique to the systems we have developed here."

Furthermore, as the dynamic molecules move to form superstructures, large pores open that allow cells to penetrate and interact with bioactive signals that can be integrated into the biomaterials.

Interestingly, the mechanical forces of 3D printing disrupt the host-guest interactions in the superstructures and cause the material to flow, but it can rapidly solidify into any macroscopic shape because the interactions are restored spontaneously by self-assembly. This also enables the 3D printing of structures with distinct layers that harbor different types of neural cells in order to study their interactions.

Signaling neuronal growth

The superstructure and bioactive properties of the material could have vast implications for tissue regeneration. Neurons are stimulated by a protein in the central nervous system known as brain-derived neurotrophic factor (BDNF), which helps neurons survive by promoting synaptic connections and allowing neurons to be more plastic. BDNF could be a valuable therapy for patients with neurodegenerative diseases and injuries in the spinal cord but these proteins degrade quickly in the body and are expensive to produce.

One of the molecules in the new material integrates a mimic of this protein that activates its receptor known as Trkb, and the team found that neurons actively penetrate the large pores and populate the new biomaterial when the mimetic signal is present. This could also create an environment in which neurons differentiated from patient-derived stem cells mature before transplantation.

Now that the team has applied a proof of concept to neurons, Stupp believes he could now break into other areas of regenerative medicine by applying different chemical sequences to the material. Simple chemical changes in the biomaterials would allow them to provide signals for a wide range of tissues.

"Cartilage and heart tissue are very difficult to regenerate after injury or heart attacks, and the platform could be used to prepare these tissues in vitro from patient-derived cells," Stupp said. "These tissues could then be transplanted to help restore lost functions. Beyond these interventions, the materials could be used to build organoids to discover therapies or even directly implanted into tissues for regeneration since they are biodegradable."

Read more at Science Daily

3-D-printed biomaterials that degrade on demand

Brown researchers have found a way to 3-D print intricate temporary microstructures that can be degraded on demand using a biocompatible chemical trigger. The technique could be useful could be useful in fabricating microfluidic devices, creating biomaterials that respond dynamically to stimuli and in patterning artificial tissue.

Brown University engineers have demonstrated a technique for making 3-D-printed biomaterials that can degrade on demand, which can be useful in making intricately patterned microfluidic devices or in making cell cultures than can change dynamically during experiments.

"It's a bit like Legos," said Ian Wong, an assistant professor in Brown's School of Engineering and co-author of the research. "We can attach polymers together to build 3-D structures, and then gently detach them again under biocompatible conditions."

The research is published in the journal Lab on a Chip.

The Brown team made their new degradable structures using a type of 3-D printing called stereolithography. The technique uses an ultraviolet laser controlled by a computer-aided design system to trace patterns across the surface of a photoactive polymer solution. The light causes the polymers to link together, forming solid 3-D structures from the solution. The tracing process is repeated until an entire object is built from the bottom up.

Stereolithographic printing usually uses photoactive polymers that link together with covalent bonds, which are strong but irreversible. For this new study, Wong and his colleagues wanted to try creating structures with potentially reversible ionic bonds, which had never been done before using light-based 3-D printing. To do it, the researchers made precursor solutions with sodium alginate, a compound derived from seaweed that is known to be capable of ionic crosslinking.

"The idea is that the attachments between polymers should come apart when the ions are removed, which we can do by adding a chelating agent that grabs all the ions," Wong said. "This way we can pattern transient structures that dissolve away when we want them to."

The researchers showed that alginate could indeed be used in stereolithography. And by using different combinations of ionic salts -- magnesium, barium and calcium -- they could create structures with varying stiffness, which could then be dissolved away at varying rates.

The research also showed several ways in such temporary alginate structures could be useful.

"It's a helpful tool for fabrication," said Thomas M. Valentin, a Ph.D. student in Wong's lab at Brown and the study's lead author. The researchers showed that they could use alginate as a template for making lab-on-a-chip devices with complex microfluidic channels.

"We can print the shape of the channel using alginate, then print a permanent structure around it using a second biomaterial," Valentin said. "Then we simply dissolve away the alginate and we have a hollow channel. We don't have to do any cutting or complex assembly."

The researchers also showed that degradable alginate structures are useful for making dynamic environments for experiments with live cells. They performed a series of experiments with alginate barriers surrounded by human mammary cells, observing how the cells migrate when the barrier is dissolved away. These kinds of experiments can be useful in investigating wound-healing processes or the migration of cells in cancer.

The experiments showed that neither the alginate barrier nor the chelating agent used to dissolve it away had any appreciable toxicity to the cells. That suggests that degradable alginate barriers are a promising option for such experiments.

The biocompatibility of the alginate is promising for additional future applications, including in making scaffolds for artificial tissue and organs, the researchers say.

Read more at Science Daily

3D-Printed 'HyperElastic Bone' Could Quickly Mend Breaks

A cheap and easy to make synthetic bone material has been shown to stimulate new bone growth when implanted in the spines of rats and a monkey's skull, researchers said.

Human trials using the biomaterial, called Hyper-Elastic Bone (HB), could begin in the next five years, according to the research team from Northwestern University.

"We knew this material had great mechanical properties and it was very easy and rapid to 3-D print," said study author Adam Jakus, a researcher at Northwestern University, during a conference call with reporters.

"Its biological effects in the outcomes we observed directly were quite astounding."

The material is "made mostly of a ceramic, which contains mineral found in teeth and bones, and polymer, both of which are used in the clinic," said the study in Science Translational Medicine.

Unlike bone grafts, which are more costly, more brittle and risk being rejected in the patient's body, the biomaterial could be printed into many shapes and cut, folded, and sutured to fit on demand, according to the report.

"When implanted into experimental animals, HB quickly integrated with the surrounding tissue, regenerating bone to promote spinal fusion in rats," said the study.

A larger piece was printed to fill a hole in a rhesus macaque's skull. It healed after four weeks, with no signs of infection or other side effects, and researchers were able to see evidence of new bone growth.

"This work represents what could be the next breakthrough in orthopedic, cranial facial and pediatric surgery when it comes to repairing and regenerating bone in bone to soft tissue defects," said study author Ramille Shah, assistant professor at Northwestern University.

Researchers hope the material will one day offer personalized implants for a range of bone injuries, including spine, dental, reconstructive, and bone cancer surgeries.

"There's a lot of pediatric patients who are born, especially in Third World countries, with orthopedic or maxillofacial defects," said Shah.

"And we hope that because the Hyper-Elastic Bone is scalable and at a lower cost, that it would be accessible to those types of patients."

From Discovery News