UCLA researchers develop new material to accelerate healing

Injectable gel fills wounds and promotes tissue regeneration

Researchers from the UCLA Henry Samueli School of Engineering and Applied Science have developed an injectable hydrogel that helps skin wounds heal more quickly. The material creates an instant scaffold that allows new tissue to latch on and grow within the cavities formed between linked spheres of gel.

The research was published online today in the journal Nature Materials. The study was led by co-principal investigators Dino Di Carlo, professor of bioengineering, and Tatiana Segura, associate professor of chemical and biomolecular engineering; and co-lead authors Donald Griffin and Westbrook Weaver, both postdoctoral scholars.

Doctors treating skin wounds try to keep the area moist because dry wounds heal much more slowly than wet ones. To accomplish this, they often use topically applied hydrogel dressings or films, to seal over or cap the wound and provide moisture. In other cases, ointments are used to fill in the wound, much like filling a pothole with new asphalt. However, none of these materials provide an optimal scaffold to allow new tissue to grow as they degrade. As a result, the new tissue growth is relatively slow and fragile.

“Achieving a biomaterial that promotes rapid regeneration while maintaining structural support has been a holy grail in the field of tissue engineering,” Di Carlo said. “Our team has achieved this in an injectable form by combining tailored material chemistry and microfluidic fabrication of uniform spherical building blocks, each about the width of a human hair.”

“Our technology is beautifully simple, as it utilizes any available chemistry to generate tiny gels that can be assembled into a large unit, leaving behind a path for cellular infiltration,” Segura said.

The result is a packed cluster of microscopic synthetic polymer spheres attached at their surfaces, something like a jar of gumballs that are stuck together. The cluster creates a scaffold of microporous annealed particles, or a MAP gel, that fills in the wound. New tissue quickly grows into the voids between the microspheres, and as the spheres degrade into the body, a matrix of newly grown tissue is left where the wound once was. New tissue continues growing until the wound is completely healed.

“The beauty of the MAP gel is that there are no other added growth factors that other technologies require to attract cells into the material,” Weaver said. “The geometry of the MAP gel networks entices cells to migrate into the gel without the need for anything other than a cell adhesive peptide, so that the cells can grab onto the gels.”

The researchers demonstrated the MAP gel can promote the growth of new cells and formation of networks of connected cells at previously unseen rates. During in vivo tests, the researchers observed significant tissue regeneration in the first 48 hours, with much more healing over five days compared to materials in use today. “We envision this material being useful for a wide range of wound applications, from acute damage, like lacerations and surgical wound closures, to more chronic applications like diabetic ulcers and large-area burn wounds,” Griffin said. He noted the hydrogel scaffolds could be useful in trauma situations, such as battlefields or emergency rooms.

Dr. Philip Scumpia, a clinical instructor of dermatology and dermatopathology at the David Geffen School of Medicine at UCLA, was also a co-author on the paper.

The research was supported by the National Institutes of Health. Griffin and Weaver received their doctoral degrees from UCLA Engineering in 2011 and 2013, respectively. The two of them, along with the faculty advisers, are looking to commercialize the technology. 

Source: http://newsroom.ucla.edu/releases/ucla-researchers-develop-new-material-to-accelerate-healing

A hydrogel that knows when to go

Brendan Watson, a graduate student at Rice University, led a project to create a hydrogel bioscaffold that is liquid at room temperature and instantly solidifies as it approaches body temperature. A second process allows the hydrogel to break down slowly as it is replaced by healthy tissue. Photo by Jeff Fitlow

Rice University bioscaffold material degrades as bone grows to replace it

Rice University bioengineers have created a hydrogel that instantly turns from liquid to semisolid at close to body temperature – and then degrades at precisely the right pace.

The gel shows potential as a bioscaffold to support the regrowth of bone and other three-dimensional tissues in a patient’s body using the patient’s own cells to seed the process.

The hydrogel created in the lab of Rice bioengineer Antonios Mikos is a liquid at room temperature but, when injected into a patient, becomes a gel that would fill and stabilize a space while natural tissue grows to replace it.

The new material detailed in the American Chemical Society journal Biomacromolecules takes the state of the art a few steps further, Rice scientists said.

“This study describes the development of a novel thermogelling hydrogel for stem cell delivery that can be injected into skeletal defects to induce bone regeneration and that can be degraded and eliminated from the body as new bone tissue forms and matures,” said Mikos, Rice’s Louis Calder Professor of Bioengineering and Chemical and Biomolecular Engineering.

The hydrogel turns from liquid to semisolid as it moves from room temperature to near body temperature in an experiment. The material inside the tube quickly turns white as it gellates. Chemical links in the gel take longer to form, but help it hold its size and shape as a scaffold for growing new tissue. Photo by Jeff Fitlow

A problem with thermogelling polymers is that once they harden, they begin to collapse and then force out water, said Rice graduate student and the paper’s lead author, Brendan Watson. That process, known as syneresis, defeats the purpose of defining the space doctors hope to fill with new tissue.

“If the transition gellation temperature is one or two degrees below body temperature, these polymers slowly start to expel water and shrink down until they’re one-half or one-third the size. Then the defect-filling goal is no longer accomplished,” he said.

Watson and his colleagues at Rice’s BioScience Research Collaborative solved the problem by adding chemical cross-linkers to the gel’s molecules. “It’s a secondary mechanism that, after the initial thermogellation, begins to stabilize the gel,” he said. The links begin to form at the same time as the gel, but crosslinking takes up to a half-hour to complete.

The hydrogel is designed for stability over its long-term use as a scaffold for cells to take root and proliferate. But it’s also designed for its own timely destruction.

“I came up with the idea a few years ago, but it’s finally all come together,” said Watson, who is pursuing both a Rice doctorate and a medical degree in a joint program with nearby Baylor College of Medicine. “These chemical crosslinks are attached by phosphate ester bonds, which can be degraded by catalysts – in particular, alkaline phosphatase – that are naturally produced by bone tissue.

What started as a clear liquid at room temperature quickly turns into a white gel at body temperature. Photo by Jeff Fitlow

“The catalysts are naturally present in your body at all times, in low levels. But in areas of newly formed bone, they actually get to much higher levels,” he said. “So what we get is a semismart material for bone-tissue engineering. As new bone is formed, the gel should degrade more quickly in that area to allow even more space for bone to form.”

The fine balancing act took a lot of expertise from his colleagues and co-authors, including Paul Engel, chair of Rice’s Department of Chemistry, and F. Kurtis Kasper, a senior faculty fellow in bioengineering. “It looks like we may have just decided to try something and found that, hey, it worked! But that wasn’t the case,” said Watson, describing the months and years it took to refine the hydrogel. Engel’s help with the sophisticated chemistry was especially valuable, he said.

Watson expects that the material degradation can be tuned to match various bone growth rates.

“Optimizing the degradation kinetics is nontrivial and may be better suited for a biotech company,” he said. “We focus more on the performance of the hydrogels and the underlying molecular mechanisms”

The National Institutes of Health, the Keck Center Nanobiology Training Program of the Gulf Coast Consortia and the Baylor College of Medicine Medical Scientist Training Program supported the research.

http://news.rice.edu/2014/05/07/a-hydrogel-that-knows-when-to-go-2/#sthash.qW7y7eWn.dpuf

Hydrogel implant enables light-based communication with cells inside the body

As researchers develop novel therapies based on inducing specific cells to do specific things, getting the right message to the right group of cells at the right time remains a major challenge. Now researchers at the Wellman Center for Photomedicine at MGH have developed a way to deliver a light signal to specific tissues deep within the body.

Light passing through an optical fiber (left) can either carry in a signal that stimulates the activity of cells embedded in the hydrogel implant or bring back a signal generated by cells responding to something in their environment. (Harvard Bio-Optics Lab/Wellman Center for Photomedicine, Mass. General Hospital)

As researchers develop novel therapies based on inducing specific cells to do specific things, getting the right message to the right group of cells at the right time remains a major challenge.  The use of light to communicate with cells has been restricted by its limited ability to pass through tissues.  Now researchers at the Wellman Center for Photomedicine at Massachusetts General Hospital have developed a way to deliver a light signal to specific tissues deep within the body.  They describe their accomplishment in the current issue of Nature Photonics. 

"Scientists only began investigating light-activated therapy a few years ago, but it is generating huge interest," says Wellman investigator Seok Hyun (Andy) Yun, PhD, senior author of the study.  "One of the best known example is use of optogenetics – activation or deactivation of brain cells by illumination with different colors of light – to treat brain disorders. But how to deliver light deep within the brain or other tissues has been a common problem.  The implant we have developed may help solve this problem."

Called a light-guiding hydrogel, the implant is constructed from a polymer-based scaffolding capable of supporting living cells and contains cells genetically engineered either to carry out a specific activity in response to light or to emit light in response to a particular metabolic signal.  An optical fiber connects the implant to either an external light source or a light detector.  

The investigators first determined the properties of the hydrogel scaffolding – including transparency, flexibility and stability – that would be most appropriate for delivering or detecting a light signal.  After determining how many cells could be implanted into the hydrogel without significantly reducing its ability to transmit a light signal, they developed and tested in mice two different systems, both involving implantation of a 4-centimeter hydrogel beneath the animal's skin.

The first system's implants contained cells genetically engineered to express light-emitting green fluorescent protein (GFP) upon contact with a toxin.  After confirming in vitro the hydrogels' response to nanoparticles containing the toxic metal cadmium, the researchers implanted the hydrogels beneath the skin of three groups of mice.  One group was then injected with the cadmium nanoparticles, the second received nanoparticles encased in a polymer shell that shielded cells from the toxin, and the third received a control saline injection.  The implants only produced a GFP-signal in response to the unshielded nanoparticles, indicating their ability to sense a change – in this instance the presence of a toxin – in the cellular environment.

To investigate a possible therapeutic application for the system, the investigators used a hydrogel implant containing cells that respond to blue light by producing glucagon-like peptide-1 (GLP-1), a protein playing an essential role in glucose metabolism.  After the implants were placed under the skin of mice with diabetes, the blue light signal was delivered for 12 hours.  A day and a half later – 48 hours after the implant – the animals that received the light signal had double the level of GLP-1 in their blood, along with significantly better results in a glucose tolerance test, than did implanted mice not treated with light.

"This work combines several existing technologies well known in their respective fields – such as drug delivery, genetic engineering, biomaterial science, and photonics – to build a new implant system that enables the delivery of photomedicine deep in the body," says Yun, an associate professor of Dermatology at Harvard Medical School and director of the Harvard Bio-Optics Lab. "This is the first time anyone has shown the ability to talk optically – by means of light – with cells deep within the body, both to sense the presence of a toxin and to deliver a cell-based therapy."

The researchers add that future studies should investigate how changing the shape and structure of the hydrogel can improve the implant's light-guiding properties, ways to improve the production and delivery of a therapeutic protein, how the immune system would react to long-term implantation and ways to deliver or detect the light signal that would not require passing a fiber through the skin.

Myunghwan Choi, PhD, of the Wellman Center at MGH is lead author of the Nature Photonics article. Additional co-authors are Jin Woo Choi, Sedat Nizamoglu, and Sei Kwang Hahn, PhD, Wellman Center; and Seonghoon Kim, Korea Advanced Institute of Science and Technology.  Support for the study includes National Institutes of Health grant R21 EB013761, National Science Foundation grant ECS-1101947 and Department of Defense grant FA9550-10-1-0537.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.