Tag Archives: Tristan Clemons

Transplanting healthy neurons could be possible with walking molecules and 3D printing

A February 23, 2021 news item on ScienceDaily announces work which may lead to healing brain injuries and diseases,

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 February 22, 2021 Northwestern University news release (also received by email and available on EurekAlert) by Lila Reynolds, which originated the news item, delves further into self-assembling ‘walking’ molecules and the nanofibers resulting in a new material designed to promote the growth of healthy neurons,

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.

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.”

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

Superstructured Biomaterials Formed by Exchange Dynamics and Host–Guest Interactions in Supramolecular Polymers by Alexandra N. Edelbrock, Tristan D. Clemons, Stacey M. Chin, Joshua J. W. Roan, Eric P. Bruckner, Zaida Álvarez, Jack F. Edelbrock, Kristen S. Wek, Samuel I. Stupp. Advanced Science DOI: https://doi.org/10.1002/advs.202004042 First published: 22 February 2021

This paper is open access.

Australia’s nanopatch: a way to eliminate needle vaccinations

Tristan Clemons has written a Nov. 9, 2016 essay for The Conversation on one of my favourite stories, the nanopatch,

Who likes getting a needle? I know I definitely don’t.

Someone else who doesn’t is Mark Kendall from the University of Queensland, winner of the Young Florey Medal 2016.

Mark’s work in developing the nanopatch has provided a clear pathway for vaccine delivery science to move beyond 160 year-old needle and syringe technology.

… There are approximately 20,000 projections per square centimeter on each patch, each around 60 to 100 micrometres in length. One micrometre is one million times smaller than a metre, so the height of these tiny spikes is approximately the width of a human hair.

The nanopatch is produced using a technique known as “deep reactive ion etching”, which essentially makes use of ions (charged atoms) in an electric field to selectively etch the surface of a material away. Controlling the electric field and the ions allows a high degree of control, so the microprojections are regularly spaced and of similar dimensions.

An added advantage of this approach is it has been used in the electronic circuit and solar energy industries for many years, and has the potential for increasing the scale of production.

The tiny projections on each nanopatch are invisible to the naked eye, but are long enough to breach the outermost skin layer, the stratum corneum. The stratum corneum is a layer of dead skin cells which acts as the first barrier in protecting us from infection and skin water loss.

The nanopatch projections penetrate through the stratum corneum to reach the living skin layers directly below, the epidermis and the dermis. In the epidermis are several types of immune cells that are vital for the vaccine to work.

Hence the nanopatch is well suited to the delivery of vaccines where targeting immune cells is vital for vaccination success. Examples include influenza, polio and cholera.

Mark Kendall and his colleagues have shown they are able to coat nanopatch microprojections with a vaccine, apply the nanopatch to the skin and achieve vaccination with one tenth to one thirtieth of the dose required using traditional needle and syringe approaches.

… it’s more than just a good idea. Mark Kendall and his colleagues are now running human clinical trials of nanopatches in Brisbane, and the WHO is planning a polio vaccine trial in Cuba in 2017.

The latest information I have about this research is from a Feb. 26, 2016 University of Queensland press release,

Needle-free Nanopatch technology developed at The University of Queensland has been used to successfully deliver an inactivated poliovirus vaccine.

Delivery of a polio vaccine with the Nanopatch was demonstrated by UQ’s Professor Mark Kendall and his research team at UQ’s Australian Institute for Bioengineering and Nanotechnology, in collaboration with the World Health Organisation, the US Centres for Disease Control and Prevention, and vaccine technology company Vaxxas.

Professor Kendall said the Nanopatch had been used to administer an inactivated Type 2 poliovirus vaccine in a rat model.

“We compared the Nanopatch to the traditional needle and syringe, and found that there is about a 40-fold improvement in delivered dose-sparing,” Professor Kendall said.

“This means about 40 times less polio vaccine was needed in Nanopatch delivery to generate a functional immune response as the needle and syringe.

“To our knowledge, this is the highest level of dose-sparing observed for an inactivated polio vaccine in rats achieved by any type of delivery technology, so this is a key breakthrough.”

The next step will be clinical testing.

Dr David Muller, first author of the research published in Scientific Reports, said the work demonstrated a key advantage of the Nanopatch.

“The Nanopatch targets the abundant immune cell populations in the skin’s outer layers; rather than muscle, resulting in a more efficient vaccine delivery system,” he said.

Clinical success and widespread use of the Nanopatch against polio could help in the current campaign to eradicate polio. It could be produced and distributed at a cheaper cost, and its ease of use would make it suitable for house-to-house vaccination efforts in endemic areas with only minimal training required.

World Health Organisation Global Polio Eradication Initiative Director Mr Michel Zaffran said only Afghanistan and Pakistan remained polio-endemic, but all countries were at risk until the disease was eradicated everywhere.

“Needle-free microneedle patches such as the Nanopatch offer great promise for reaching more children with polio vaccine as well as other antigens such as measles vaccine, particularly in hard-to-reach areas or areas with inadequate healthcare infrastructure,” Mr Zaffran said.

Nanopatch technology is being commercialised by Vaxxas Pty Ltd, which has scaled the Nanopatch from use in small models to prototypes for human use.

Vaxxas CEO Mr David Hoey said the first human vaccination studies are scheduled for this year [2016].

“Key attributes of the Nanopatch, including its ease of use and potential to not require refrigeration, could improve the reach and efficiency of vaccination campaigns in difficult-to-reach locations, including those where polio remains endemic,” Mr Hoey said.

The work was funded by the World Health Organisation, Vaxxas, Rotary District 9630 and the Rotary Foundation.

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

Inactivated poliovirus type 2 vaccine delivered to rat skin via high density microprojection array elicits potent neutralising antibody responses by David A. Muller, Frances E. Pearson, Germain J.P. Fernando, Christiana Agyei-Yeboah, Nick S. Owens, Simon R. Corrie, Michael L. Crichton, Jonathan C.J. Wei, William C. Weldon, M. Steven Oberste, Paul R. Young, & Mark A. F. Kendall. Scientific Reports 6, Article number: 22094 (2016) doi:10.1038/srep22094 Published online: 25 February 2016

This paper is open access.

As befitting a ‘favourite story’, I’ve been following it for a number of years starting with this April 23, 2009 posting (scroll down about 25% of the way) although you might prefer to read this more substantive July 26, 2010 posting. The last time (Aug. 3, 2011 posting) I featured the story, it was to announce an investment of AUD $15M in Vaxxas (Kendall is not listed as member of the company) in order to bring the nanopatch to market.