Tag Archives: tissue regeneration

New wound dressings with nanofibres for tissue regeneration

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The Rotary Jet-Spinning manufacturing system was developed specifically as a therapeutic for the wounds of war. The dressings could be a good option for large wounds, such as burns, as well as smaller wounds on the face and hands, where preventing scarring is important. Illustration courtesy of Michael Rosnach/Harvard University

This image really gets the idea of regeneration across to the viewer while also informing you that this is medicine that comes from the military. A March 19,2018 news item on phys.org announces the work,

Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and the Wyss Institute for Biologically Inspired Engineering have developed new wound dressings that dramatically accelerate healing and improve tissue regeneration. The two different types of nanofiber dressings, described in separate papers, use naturally-occurring proteins in plants and animals to promote healing and regrow tissue.

Our fiber manufacturing system was developed specifically for the purpose of developing therapeutics for the wounds of war,” said Kit Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior author of the research. “As a soldier in Afghanistan, I witnessed horrible wounds and, at times, the healing process for those wounds was a horror unto itself. This research is a years-long effort by many people on my team to help with these problems.”

Parker is also a Core Faculty Member of the Wyss Institute.

The most recent paper, published in Biomaterials, describes a wound dressing inspired by fetal tissue.

A March 19, 2018 Harvard University John A. Paulson School of Engineering and Applied Science news release by Leah Burrows (also on EurekAlert), which originated the news item, provides some background information before launching into more detail about this latest work,

In the late 1970s, when scientists first started studying the wound-healing process early in development, they discovered something unexpected: Wounds incurred before the third trimester left no scars. This opened a range of possibilities for regenerative medicine. But for decades, researchers have struggled to replicate those unique properties of fetal skin.

Unlike adult skin, fetal skin has high levels of a protein called fibronectin, which assembles into the extracellular matrix and promotes cell binding and adhesion. Fibronectin has two structures: globular, which is found in blood, and fibrous, which is found in tissue. Even though fibrous fibronectin holds the most promise for wound healing, previous research focused on the globular structure, in part because manufacturing fibrous fibronectin was a major engineering challenge.

But Parker and his team are pioneers in the field of nanofiber engineering.

The researchers made fibrous fibronectin using a fiber-manufacturing platform called Rotary Jet-Spinning (RJS), developed by Parker’s Disease Biophysics Group. RJS works likes a cotton-candy machine — a liquid polymer solution, in this case globular fibronectin dissolved in a solvent, is loaded into a reservoir and pushed out through a tiny opening by centrifugal force as the device spins. As the solution leaves the reservoir, the solvent evaporates and the polymers solidify. The centrifugal force unfolds the globular protein into small, thin fibers. These fibers — less than one micrometer in diameter — can be collected to form a large-scale wound dressing or bandage.

“The dressing integrates into the wound and acts like an instructive scaffold, recruiting different stem cells that are relevant for regeneration and assisting in the healing process before being absorbed into the body,” said Christophe Chantre, a graduate student in the Disease Biophysics Group and first author of the paper.

In in vivo testing, the researchers found that wounds treated with the fibronectin dressing showed 84 percent tissue restoration within 20 days, compared with 55.6 percent restoration in wounds treated with a standard dressing.

The researchers also demonstrated that wounds treated with the fibronectin dressing had almost normal epidermal thickness and dermal architecture, and even regrew hair follicles — often considered one of the biggest challenges in the field of wound healing.

“This is an important step forward,” said Chantre. “Most work done on skin regeneration to date involves complex treatments combining scaffolds, cells, and even growth factors. Here we were able to demonstrate tissue repair and hair follicle regeneration using an entirely material approach. This has clear advantages for clinical translation.”

In another paper published in Advanced Healthcare Materials, the Disease Biophysics Group demonstrated a soy-based nanofiber that also enhances and promotes wound healing.

Soy protein contains both estrogen-like molecules — which have been shown to accelerate wound healing — and bioactive molecules similar to those that build and support human cells.

“Both the soy- and fibronectin-fiber technologies owe their success to keen observations in reproductive medicine,” said Parker. “During a woman’s cycle, when her estrogen levels go high, a cut will heal faster. If you do a surgery on a baby still in the womb, they have scar-less wound healing. Both of these new technologies are rooted in the most fascinating of all the topics in human biology — how we reproduce.”

In a similar way to fibronectin fibers, the research team used RJS to spin ultrathin soy fibers into wound dressings. In experiments, the soy- and cellulose-based dressing demonstrated a 72 percent increase in healing over wounds with no dressing and a 21 percent increase in healing over wounds dressed without soy protein.

“These findings show the great promise of soy-based nanofibers for wound healing,” said Seungkuk Ahn, a graduate student in the Disease Biophysics Group and first author of the paper. “These one-step, cost-effective scaffolds could be the next generation of regenerative dressings and push the envelope of nanofiber technology and the wound-care market.”

Both kinds of dressing, according to researchers, have advantages in the wound-healing space. The soy-based nanofibers — consisting of cellulose acetate and soy protein hydrolysate — are inexpensive, making them a good option for large-scale use, such as on burns. The fibronectin dressings, on the other hand, could be used for smaller wounds on the face and hands, where preventing scarring is important.

Here’s are links and citations for both papers mentioned in the news release,

Soy Protein/Cellulose Nanofiber Scaffolds Mimicking Skin Extracellular Matrix for Enhanced Wound Healing by Seungkuk Ahn, Christophe O. Chantre, Alanna R. Gannon, Johan U. Lind, Patrick H. Campbell, Thomas Grevesse, Blakely B. O’Connor, Kevin Kit Parker. Advanced Healthcare Materials https://doi.org/10.1002/adhm.201701175 First published: 23 January 2018

Production-scale fibronectin nanofibers promote wound closure and tissue repair in a dermal mouse model by Christophe O. Chantre, Patrick H. Campbell, Holly M. Golecki, Adrian T. Buganza, Andrew K. Capulli, Leila F. Deravi, Stephanie Dauth, Sean P. Sheehy, Jeffrey A.Paten. KarlGledhill, Yanne S. Doucet, Hasan E.Abaci, Seungkuk Ahn, Benjamin D.Pope, Jeffrey W.Ruberti, Simon P.Hoerstrup, Angela M.Christiano, Kevin Kit Parker. Biomaterials Volume 166, June 2018, Pages 96-108 https://doi.org/10.1016/j.biomaterials.2018.03.006 Available online 5 March 2018

Both papers are behind paywalls although you may want to check with ResearchGate where many researchers make their papers available for free.

One last comment, I noticed this at the end of Burrows’ news release,

The Harvard Office of Technology Development has protected the intellectual property relating to these projects and is exploring commercialization opportunities.

It reminded me of the patent battle between the Broad Institute (a Harvard University and Massachusetts Institute of Technology joint venture) and the University of California at Berkeley over CRISPR (clustered regularly interspaced short palindromic repeats) technology. (My March 15, 2017 posting describes the battle’s outcome.)

Lest we forget, there could be major financial rewards from this work.

Robotics where and how you don’t expect them: a wearable robot and a robot implant for regeneration

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Generally I  expect robots to be machines that are external to my body but recently there were two news bits about some different approaches. First, the wearable robot.

A robot that supports your hip

A January 10, 2018 news item on ScienceDaily describes research into muscles that can be worn,

Scientists are one step closer to artificial muscles. Orthotics have come a long way since their initial wood and strap designs, yet innovation lapsed when it came to compensating for muscle power — until now.

A collaborative research team has designed a wearable robot to support a person’s hip joint while walking. The team, led by Minoru Hashimoto, a professor of textile science and technology at Shinshu University in Japan, published the details of their prototype in Smart Materials and Structures, a journal published by the Institute of Physics.

A January 9, 2018 Shinshu University press release on EurekAlert, which originated the news item, provides more detail,

“With a rapidly aging society, an increasing number of elderly people require care after suffering from stroke, and other-age related disabilities. Various technologies, devices, and robots are emerging to aid caretakers,” wrote Hashimoto, noting that several technologies meant to assist a person with walking are often cumbersome to the user. “[In our] current study, [we] sought to develop a lightweight, soft, wearable assist wear for supporting activities of daily life for older people with weakened muscles and those with mobility issues.”

The wearable system consists of plasticized polyvinyl chloride (PVC) gel, mesh electrodes, and applied voltage. The mesh electrodes sandwich the gel, and when voltage is applied, the gel flexes and contracts, like a muscle. It’s a wearable actuator, the mechanism that causes movement.

“We thought that the electrical mechanical properties of the PVC gel could be used for robotic artificial muscles, so we started researching the PVC gel,” said Hashimoto. “The ability to add voltage to PVC gel is especially attractive for high speed movement, and the gel moves with high speed with just a few hundred volts.”

In a preliminary evaluation, a stroke patient with some paralysis on one side of his body walked with and without the wearable system.

“We found that the assist wear enabled natural movement, increasing step length and decreasing muscular activity during straight line walking,” wrote Hashimoto. The researchers also found that adjusting the charge could change the level of assistance the actuator provides.

The robotic system earned first place in demonstrations with their multilayer PVC gel artificial muscle at the, “24th International Symposium on Smart Structures and Materials & Nondestructive Evaluation and Health Monitoring” for SPIE the international society for optics and photonics.

Next, the researchers plan to create a string actuator using the PVC gel, which could potentially lead to the development of fabric capable of providing more manageable external muscular support with ease.

Here’s a link to and a citation for the paper,

PVC gel soft actuator-based wearable assist wear for hip joint support during walking by Yi Li and Minoru Hashimoto. Smart Materials and Structures, Volume 26, Number 12 DOI: 10.1088/1361-665X/aa9315 Published 30 October 2017

© 2017 IOP Publishing Ltd

This paper is behind a paywall and I see it was published in the Fall of 2017. Either they postponed the publicity or this is the second wave. In any event, it was timely as it allowed me to post this along with the robotic research on regeneration.

Robotic implants and tissue regeneration

Boston Children’s Hospital in a January 10, 2018 news release on EurekAlert describes a new (to me) method for tissue regeneration,

An implanted, programmable medical robot can gradually lengthen tubular organs by applying traction forces — stimulating tissue growth in stunted organs without interfering with organ function or causing apparent discomfort, report researchers at Boston Children’s Hospital.

The robotic system, described today in Science Robotics, induced cell proliferation and lengthened part of the esophagus in a large animal by about 75 percent, while the animal remained awake and mobile. The researchers say the system could treat long-gap esophageal atresia, a rare birth defect in which part of the esophagus is missing, and could also be used to lengthen the small intestine in short bowel syndrome.

The most effective current operation for long-gap esophageal atresia, called the Foker process, uses sutures anchored on the patient’s back to gradually pull on the esophagus. To prevent the esophagus from tearing, patients must be paralyzed in a medically induced coma and placed on mechanical ventilation in the intensive care unit for one to four weeks. The long period of immobilization can also cause medical complications such as bone fractures and blood clots.

“This project demonstrates proof-of-concept that miniature robots can induce organ growth inside a living being for repair or replacement, while avoiding the sedation and paralysis currently required for the most difficult cases of esophageal atresia,” says Russell Jennings, MD, surgical director of the Esophageal and Airway Treatment Center at Boston Children’s Hospital, and a co-investigator on the study. “The potential uses of such robots are yet to be fully explored, but they will certainly be applied to many organs in the near future.”

The motorized robotic device is attached only to the esophagus, so would allow a patient to move freely. Covered by a smooth, biocompatible, waterproof “skin,” it includes two attachment rings, placed around the esophagus and sewn into place with sutures. A programmable control unit outside the body applies adjustable traction forces to the rings, slowly and steadily pulling the tissue in the desired direction.

The device was tested in the esophagi of pigs (five received the implant and three served as controls). The distance between the two rings (pulling the esophagus in opposite directions) was increased by small, 2.5-millimeter increments each day for 8 to 9 days. The animals were able to eat normally even with the device applying traction to its esophagus, and showed no sign of discomfort.

On day 10, the segment of esophagus had increased in length by 77 percent on average. Examination of the tissue showed a proliferation of the cells that make up the esophagus. The organ also maintained its normal diameter.

“This shows we didn’t simply stretch the esophagus — it lengthened through cell growth,” says Pierre Dupont, PhD, the study’s senior investigator and Chief of Pediatric Cardiac Bioengineering at Boston Children’s.

The research team is now starting to test the robotic system in a large animal model of short bowel syndrome. While long-gap esophageal atresia is quite rare, the prevalence of short bowel syndrome is much higher. Short bowel can be caused by necrotizing enterocolitis in the newborn, Crohn’s disease in adults, or a serious infection or cancer requiring a large segment of intestine to be removed.

“Short bowel syndrome is a devastating illness requiring patients to be fed intravenously,” says gastroenterologist Peter Ngo, MD, a coauthor on the study. “This, in turn, can lead to liver failure, sometimes requiring a liver or multivisceral (liver-intestine) transplant, outcomes that are both devastating and costly.”

The team hopes to get support to continue its tests of the device in large animal models, and eventually conduct clinical trials. They will also test other features.

“No one knows the best amount of force to apply to an organ to induce growth,” explains Dupont. “Today, in fact, we don’t even know what forces we are applying clinically. It’s all based on surgeon experience. A robotic device can figure out the best forces to apply and then apply those forces precisely.”

Here’s a link to and a citation for the paper,

In vivo tissue regeneration with robotic implants by Dana D. Damian, Karl Price, Slava Arabagi, Ignacio Berra, Zurab Machaidze, Sunil Manjila, Shogo Shimada, Assunta Fabozzo, Gustavo Arnal, David Van Story, Jeffrey D. Goldsmith, Agoston T. Agoston, Chunwoo Kim, Russell W. Jennings, Peter D. Ngo, Michael Manfredi, and Pierre E. Dupont. Science Robotics 10 Jan 2018: Vol. 3, Issue 14, eaaq0018 DOI: 10.1126/scirobotics.aaq0018

This paper is behind a paywall.

Sugar in your bones might be better for you than you think

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These days sugar is often  viewed as leading to health problems but there is an instance where it may be useful—bone regeneration. From a June 19, 2017 news item on Nanowerk (Note: A link has been removed),

There hasn’t been a gold standard for how orthopaedic spine surgeons promote new bone growth in patients, but now Northwestern University scientists have designed a bioactive nanomaterial that is so good at stimulating bone regeneration it could become the method surgeons prefer.

While studied in an animal model of spinal fusion, the method for promoting new bone growth could translate readily to humans, the researchers say, where an aging but active population in the U.S. is increasingly receiving this surgery to treat pain due to disc degeneration, trauma and other back problems. Many other procedures could benefit from the nanomaterial, ranging from repair of bone trauma to treatment of bone cancer to bone growth for dental implants.

“Regenerative medicine can improve quality of life by offering less invasive and more successful approaches to promoting bone growth,” said Samuel I. Stupp, who developed the new nanomaterial. “Our method is very flexible and could be adapted for the regeneration of other tissues, including muscle, tendons and cartilage.”

Stupp is director of Northwestern’s Simpson Querrey Institute for BioNanotechnology and the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering.

For the interdisciplinary study, Stupp collaborated with Dr. Wellington K. Hsu, associate professor of orthopaedic surgery, and Erin L. K. Hsu, research assistant professor of orthopaedic surgery, both at Northwestern University Feinberg School of Medicine. The husband-and-wife team is working to improve clinically employed methods of bone regeneration.

Sugar molecules on the surface of the nanomaterial provide its regenerative power. The researchers studied in vivo the effect of the “sugar-coated” nanomaterial on the activity of a clinically used growth factor, called bone morphogenetic protein 2 (BMP-2). They found the amount of protein needed for a successful spinal fusion was reduced to an unprecedented level: 100 times less of BMP-2 was needed. This is very good news, because the growth factor is known to cause dangerous side effects when used in the amounts required to regenerate high-quality bone, and it is expensive as well.

A June 19, 2017 Northwestern University news release by Megan Fellman, which originated the news item, tells the rest of the story,

Stupp’s biodegradable nanomaterial functions as an artificial extracellular matrix, which mimics what cells in the body usually interact with in their surroundings. BMP-2 activates certain types of stem cells and signals them to become bone cells. The Northwestern matrix, which consists of tiny nanoscale filaments, binds the protein by molecular design in the way that natural sugars bind it in our bodies and then slowly releases it when needed, instead of in one early burst, which can contribute to side effects.

To create the nanostructures, the research team led by Stupp synthesized a specific type of sugar that closely resembles those used by nature to activate BMP-2 when cell signaling is necessary for bone growth. Rapidly moving flexible sugar molecules displayed on the surface of the nanostructures “grab” the protein in a specific spot that is precisely the same one used in biological systems when it is time to deploy the signal. This potentiates the bone-growing signals to a surprising level that surpasses even the naturally occurring sugar polymers in our bodies.

In nature, the sugar polymers are known as sulfated polysaccharides, which have super-complex structures impossible to synthesize at the present time with chemical techniques. Hundreds of proteins in biological systems are known to have specific domains to bind these sugar polymers in order to activate signals. Such proteins include those involved in the growth of blood vessels, cell recruitment and cell proliferation, all very important biologically in tissue regeneration. Therefore, the approach of the Stupp team could be extended to other regenerative targets.

Spinal fusion is a common surgical procedure that joins adjacent vertebra together using a bone graft and growth factors to promote new bone growth, which stabilizes the spine. The bone used in the graft can come from the patient’s pelvis — an invasive procedure — or from a bone bank.

“There is a real need for a clinically efficacious, safe and cost-effective way to form bone,” said Wellington Hsu, a spine surgeon. “The success of this nanomaterial makes me excited that every spine surgeon may one day subscribe to this method for bone graft. Right now, if you poll an audience of spine surgeons, you will get 15 to 20 different answers on what they use for bone graft. We need to standardize choice and improve patient outcomes.”

In the in vivo portion of the study, the nanomaterial was delivered to the spine using a collagen sponge. This is the way surgeons currently deliver BMP-2 clinically to promote bone growth.

The Northwestern research team plans to seek approval from the Food and Drug Administration to launch a clinical trial studying the nanomaterial for bone regeneration in humans.

“We surgeons are looking for optimal carriers for growth factors and cells,” Wellington Hsu said. “With its numerous binding sites, the long filaments of this new nanomaterial is more successful than existing carriers in releasing the growth factor when the body is ready. Timing is critical for success in bone regeneration.”

In the new nanomaterial, the sugars are displayed in a scaffold built from self-assembling molecules known as peptide amphiphiles, first developed by Stupp 15 years ago. These synthetic molecules have been essential in his work on regenerative medicine.

“We focused on bone regeneration to demonstrate the power of the sugar nanostructure to provide a big signaling boost,” Stupp said. “With small design changes, the method could be used with other growth factors for the regeneration of all kinds of tissues. One day we may be able to fully do away with the use of growth factors made by recombinant biotechnology and instead empower the natural ones in our bodies.”

Here’s a link to and a citation for the paper,

Sulfated glycopeptide nanostructures for multipotent protein activation by Sungsoo S. Lee, Timmy Fyrner, Feng Chen, Zaida Álvarez, Eduard Sleep, Danielle S. Chun, Joseph A. Weiner, Ralph W. Cook, Ryan D. Freshman, Michael S. Schallmo, Karina M. Katchko, Andrew D. Schneider, Justin T. Smith, Chawon Yun, Gurmit Singh, Sohaib Z. Hashmi, Mark T. McClendon, Zhilin Yu, Stuart R. Stock, Wellington K. Hsu, Erin L. Hsu, & Samuel I. Stupp. Nature Nanotechnology 12, 821–829 (2017) doi:10.1038/nnano.2017.109 Published online 19 June 2017

This paper is behind a paywall.

Antibiotic synthetic spider silk

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I have a couple of questions, what is ‘click’ chemistry and how does a chance meeting lead to a five-year, interdisciplinary research project on synthetic spider silk? From a Jan. 4, 2017 news item on ScienceDaily,

A chance meeting between a spider expert and a chemist has led to the development of antibiotic synthetic spider silk.

After five years’ work an interdisciplinary team of scientists at The University of Nottingham has developed a technique to produce chemically functionalised spider silk that can be tailored to applications used in drug delivery, regenerative medicine and wound healing.

The Nottingham research team has shown for the first time how ‘click-chemistry’ can be used to attach molecules, such as antibiotics or fluorescent dyes, to artificially produced spider silk synthesised by E.coli bacteria. The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) is published today in the online journal Advanced Materials.

A Jan. 3, 2016 University of Nottingham press release (also on EurekAlert), which originated the news item, provides a few more details about ‘click’ chemistry (not enough for me) and more information about the research,

The chosen molecules can be ‘clicked’ into place in soluble silk protein before it has been turned into fibres, or after the fibres have been formed. This means that the process can be easily controlled and more than one type of molecule can be used to ‘decorate’ individual silk strands.

Nottingham breakthrough

In a laboratory in the Centre of Biomolecular Sciences, Professor Neil Thomas from the School of Chemistry in collaboration with Dr Sara Goodacre from the School of Life Sciences, has led a team of BBSRC DTP-funded PhD students starting with David Harvey who was then joined by Victor Tudorica, Leah Ashley and Tom Coekin. They have developed and diversified this new approach to functionalising ‘recombinant’ — artificial — spider silk with a wide range of small molecules.

They have shown that when these ‘silk’ fibres are ‘decorated’ with the antibiotic levofloxacin it is slowly released from the silk, retaining its anti-bacterial activity for at least five days.

Neil Thomas, a Professor of Medicinal and Biological Chemistry, said: “Our technique allows the rapid generation of biocompatible, mono or multi-functionalised silk structures for use in a wide range of applications. These will be particularly useful in the fields of tissue engineering and biomedicine.”

Remarkable qualities of spider silk

Spider silk is strong, biocompatible and biodegradable. It is a protein-based material that does not appear to cause a strong immune, allergic or inflammatory reaction. With the recent development of recombinant spider silk, the race has been on to find ways of harnessing its remarkable qualities.

The Nottingham research team has shown that their technique can be used to create a biodegradable mesh which can do two jobs at once. It can replace the extra cellular matrix that our own cells generate, to accelerate growth of the new tissue. It can also be used for the slow release of antibiotics.

Professor Thomas said: “There is the possibility of using the silk in advanced dressings for the treatment of slow-healing wounds such as diabetic ulcers. Using our technique infection could be prevented over weeks or months by the controlled release of antibiotics. At the same time tissue regeneration is accelerated by silk fibres functioning as a temporary scaffold before being biodegraded.”

The medicinal properties of spider silk recognised for centuries.

The medicinal properties of spider silk have been recognised for centuries but not clearly understood. The Greeks and Romans treated wounded soldiers with spider webs to stop bleeding. It is said that soldiers would use a combination of honey and vinegar to clean deep wounds and then cover the whole thing with balled-up spider webs.

There is even a mention in Shakespeare’s Midsummer Night’s Dream: “I shall desire you of more acquaintance, good master cobweb,” the character ‘Bottom’ said. “If I cut my finger, I shall make bold of you.”

The press release goes on to describe the genesis of the project and how this multidisciplinary team was formed in more detail,

The idea came together at a discipline bridging university ‘sandpit’ meeting five years ago. Dr Goodacre says her chance meeting at that event with Professor Thomas proved to be one of the most productive afternoons of her career.

Dr Goodacre, who heads up the SpiderLab in the School of Life Sciences, said: “I got up at that meeting and showed the audience a picture of some spider silk. I said ‘I want to understand how this silk works, and then make some.’

“At the end of the session Neil came up to me and said ‘I think my group could make that.’ He also suggested that there might be more interesting ‘tweaks’ one could make so that the silk could be ‘decorated’ with different, useful, compounds either permanently or which could be released over time due to a change in the acidity of the environment.”

The approach required the production of the silk proteins in a bacterium where an amino acid not normally found in proteins was included. This amino acid contained an azide group which is widely used in ‘click’ reactions that only occur at that position in the protein. It was an approach that no-one had used before with spider silk — but the big question was — would it work?

Dr Goodacre said: “It was the start of a fascinating adventure that saw a postdoc undertake a very preliminary study to construct the synthetic silks. He was a former SpiderLab PhD student who had previously worked with our tarantulas. Thanks to his ground work we showed we could produce the silk proteins in bacteria. We were then joined by David Harvey, a new PhD student, who not only made the silk fibres, incorporating the unusual amino acid, but also decorated it and demonstrated its antibiotic activity. He has since extended those first ideas far beyond what we had thought might be possible.”

David Harvey’s work is described in this paper but Professor Thomas and Dr Goodacre say this is just the start. There are other joint SpiderLab/Thomas lab students working on uses for this technology in the hope of developing it further.

David Harvey, the lead author on this their first paper, has just been awarded his PhD and is now a postdoctoral researcher on a BBSRC follow-on grant so is still at the heart of the research. His current work is focused on driving the functionalised spider silk technology towards commercial application in wound healing and tissue regeneration.

Here’s a link to and a citation for the paper,

Antibiotic Spider Silk: Site-Specific Functionalization of Recombinant Spider Silk Using “Click” Chemistry by David Harvey, Philip Bardelang, Sara L. Goodacre, Alan Cockayne, and Neil R. Thomas. Advanced Materials DOI: 10.1002/adma.201604245 Version of Record online: 28 DEC 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

I imagine Mr. Cockayne’s name has led to much teasing over the years. People who have names with that kind of potential tend to either change them or double down and refuse to compromise.

Encapsulation of proteins in nanoparticles no longer necessary for time release?

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A team of researchers at the University of Toronto (Canada) have developed a technique for the therapeutic use of proteins that doesn’t require ‘nanoencapsulation’ although nanoparticles are still used according to a May 27, 2016 news item on ScienceDaily,

A U of T [University of Toronto] Engineering team has designed a simpler way to keep therapeutic proteins where they are needed for long periods of time. The discovery is a potential game-changer for the treatment of chronic illnesses or injuries that often require multiple injections or daily pills.

For decades, biomedical engineers have been painstakingly encapsulating proteins in nanoparticles to control their release. Now, a research team led by University Professor Molly Shoichet has shown that proteins can be released over several weeks, even months, without ever being encapsulated. In this case the team looked specifically at therapeutic proteins relevant to tissue regeneration after stroke and spinal cord injury.

“It was such a surprising and unexpected discovery,” said co-lead author Dr. Irja Elliott Donaghue, who first found that the therapeutic protein NT3, a factor that promotes the growth of nerve cells, was slowly released when just mixed into a Jello-like substance that also contained nanoparticles. “Our first thought was, ‘What could be happening to cause this?'”

A May 27, 2016 University of Toronto news release (also on EurekAlert) by Marit Mitchell, which originated the news item, provides more in depth explanation,

Proteins hold enormous promise to treat chronic conditions and irreversible injuries — for example, human growth hormone is encapsulated in these tiny polymeric particles, and used to treat children with stunted growth. In order to avoid repeated injections or daily pills, researchers use complicated strategies both to deliver proteins to their site of action, and to ensure they’re released over a long enough period of time to have a beneficial effect.

This has long been a major challenge for protein-based therapies, especially because proteins are large and often fragile molecules. Until now, investigators have been treating proteins the same way as small drug molecules and encapsulating them in polymeric nanoparticles, often made of a material called poly(lactic-co-glycolic acid) or PLGA.

As the nanoparticles break down, the drug molecules escape. The same process is true for proteins; however, the encapsulating process itself often damages or denatures some of the encapsulated proteins, rendering them useless for treatment. Skipping encapsulation altogether means fewer denatured proteins, making for more consistent protein therapeutics that are easier to make and store.

“This is really exciting from a translational perspective,” said PhD candidate Jaclyn Obermeyer. “Having a simpler, more reliable fabrication process leaves less room for complications with scale-up for clinical use.”

The three lead authors, Elliott Donoghue, Obermeyer and Dr. Malgosia Pakulska have shown that to get the desired controlled release, proteins only need to be alongside the PLGA nanoparticles, not inside them. …

“We think that this could speed up the path for protein-based drugs to get to the clinic,” said Elliott Donaghue.

The mechanism for this encapsulation-free controlled release is surprisingly elegant. Shoichet’s group mixes the proteins and nanoparticles in a Jello-like substance called a hydrogel, which keeps them localized when injected at the site of injury. The positively charged proteins and negatively charged nanoparticles naturally stick together. As the nanoparticles break down they make the solution more acidic, weakening the attraction and letting the proteins break free.

“We are particularly excited to show long-term, controlled protein release by simply controlling the electrostatic interactions between proteins and polymeric nanobeads,” said Shoichet. “By manipulating the pH of the solution, the size and number of nanoparticles, we can control release of bioactive proteins. This has already changed and simplified the protein release strategies that we are pursuing in pre-clinical models of disease in the brain and spinal cord.”

“We’ve learned how to control this simple phenomena,” Pakulska said. “Our next question is whether we can do the opposite—design a similar release system for positively charged nanoparticles and negatively charged proteins.”

Here’s a link to and a citation for the paper,

Encapsulation-free controlled release: Electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles by Malgosia M. Pakulska, Irja Elliott Donaghue, Jaclyn M. Obermeyer, Anup Tuladhar, Christopher K. McLaughlin, Tyler N. Shendruk, and Molly S. Shoichet. Science Advances  27 May 2016: Vol. 2, no. 5, e1600519 DOI: 10.1126/sciadv.1600519

This paper appears to be open access.

Dr. Molly Shoichet was featured here in a May 11, 2015 posting about the launch of her Canada-wide science communication project Research2.Reality.

Tissue regeneration by injection

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I’ve got two items: one from the University of Nottingham (UK) where they’re working on tissue regeneration for bones, muscles, and the heart.The second item is from Simon Fraser University (Vancouver, Canada)where the focus is on regenerating bones.

Here’s more about the work at the University of Nottingham from the [July 3, 2012] news item on Nanowerk,

The University of Nottingham has begun the search for a new class of injectable materials that will stimulate stem cells to regenerate damaged tissue in degenerative and age related disorders of the bone, muscle and heart.

The work, which is currently at the experimental stage, could lead to treatments for diseases that currently have no cure. The aim is to produce radical new treatments that will reduce the need for invasive surgery, optimise recovery and reduce the risk of undesirable scar tissue.

The research, which brings together expertise in The University of Nottingham’s Malaysia Campus (UNMC) and UK campus, is part of the Rational Bioactive Materials Design for Tissue Generation project (Biodesign). This €11m EU funded research project which involves 21 research teams from across Europe is made up of leading experts in degenerative disease and regenerative medicine.

The original July 3, 2012 news release from the University of Nottingham includes a video which offers some additional insight (sadly ,it cannot be embedded here) and more information (Note: I have removed a link),

Kevin Shakesheff, Professor of Advanced Drug Delivery and Tissue Engineering and Head of the School of Pharmacy, said: “This research heralds a step-change in approaches to tissue regeneration. Current biomaterials are poorly suited to the needs of tissue engineering and regenerative medicine. The aim of Biodesign is to develop new materials and medicines that will stimulate tissue regeneration rather than wait for the body to start the process itself. The aim is to fabricate advanced biomaterials that match the basic structure of each tissue so the cells can take over the recovery process themselves.”

The Canadian project at Simon Fraser University features a singular focus on bone regeneration, from the July 19, 2012 news release on EurekAlert,

A Simon Fraser University researcher is leading a team of scientists working to create new drugs to stimulate bone regeneration – research that will be furthered by a $2.5 million grant from the Canadian Institutes of Health Research (CIHR).

Lead researcher Robert Young heads a team of internationally recognized experts in bone disease and drug development. The researchers are focusing on developing small molecule compounds and nano-medicines that stimulate bone regeneration, and hope to identify new therapeutic approaches by improving understanding of bone renewal biology.

Their objective is to develop new therapeutic agents that promote bone repair, regeneration and renewal, and prove their efficiency in reproducing or improving bone strength.

…

The research involves studying the “natural controls” that guide the development of cells in the bones toward either bone forming or bone resorbing cells, setting the stage for the next generation of bone regenerative therapies.

The grant is one of three announced today by the federal government targeting bone health research and totalling $7 million. The others focus on wrist fractures management and identifying bone loss in gum disease.

The funding is through the CIHR’s Institute of Musculoskeletal Health and Arthritis and addresses priorities identified at a 2009 national Bone Health Consensus Conference.

I’ve decided to focus on tissues today so there will be something about tissue engineering and jellyfish (artificial) shortly.