Gold nanoparticles embedded in a porous hydrogel can be implanted under the skin and used as medical sensors. The sensor is like an invisible tattoo revealing concentration changes of substances in the blood by colour change.
— © Nanobiotechnology Group, JGU Department of Chemistry

Scientists at Johannes Gutenberg University Mainz (JGU) have developed a novel type of implantable sensor which can be operated in the body for several months to detect concentrations of substances or drugs in the body. Until now implantable sensors have not been suitable to remain in the body permanently but had to be replaced after a few days or weeks.

On the one hand, there is the problem of implant rejection. On the other hand, the sensor’s colour which indicates concentration changes has been unstable and faded over time.

The newly developed sensor is based on colour-stable gold nanoparticles that are modified with receptors for specific molecules. Embedded into an artificial polymeric tissue, the nanogold is implanted under the skin where it reports changes in drug concentrations by changing its colour.

Invisible tattoo

Professor Carsten Sönnichsen’s research group at JGU has been using gold nanoparticles as sensors to detect tiny amounts of proteins in microscopic flow cells for many years. Gold nanoparticles act as small antennas for light: They strongly absorb and scatter it and, therefore, appear colourful. They react to alterations in their surrounding by changing colour. Prof. Sönnichsen’s team has exploited this concept for implanted medical sensing.

To prevent the tiny particles from swimming away or being degraded by immune cells, they are embedded in a porous hydrogel with a tissue-like consistency. Once implanted under the skin, small blood vessels and cells grow into the pores. The sensor is integrated in the tissue and is not rejected as a foreign body.

“Our sensor is like an invisible tattoo, not much bigger than a penny and thinner than one millimetre,” said Prof Sönnichsen, head of the Nanobiotechnology Group at JGU. Since the gold nanoparticles are infrared, they are not visible to the eye. However, a special measurement device can detect their colour noninvasively through the skin.

In their study published in Nano Letters, the JGU researchers implanted their gold nanoparticle sensors under the skin of hairless rats. Colour changes in these sensors were monitored following the administration of various doses of an antibiotic. The drug molecules are transported to the sensor via the bloodstream. By binding to specific receptors on the surface of the gold nanoparticles, they induce colour change that is dependent on drug concentration. Thanks to the colour-stable gold nanoparticles and the tissue-integrating hydrogel, the sensor was found to remain mechanically and optically stable over several months.

Ideal platform for implantable sensors

“We are used to coloured objects bleaching over time. Gold nanoparticles, however, do not bleach but keep their colour permanently. As they can be easily coated with various different receptors, they are an ideal platform for implantable sensors,” explained Dr Katharina Kaefer, first author of the study.

The novel concept is generalizable and has the potential to extend the lifetime of implantable sensors. In future, gold nanoparticle-based implantable sensors could be used to observe concentrations of different biomarkers or drugs in the body simultaneously. Such sensors could find application in drug development, medical research, or personalized medicine, such as the management of chronic diseases.

Reference:
Implantable Sensors Based on Gold Nanoparticles for Continuous Long-Term Concentration Monitoring in the Body, Nano Letters, 30 March 2021. DOI: 10.1021/acs.nanolett.1c00887
https://pubs.acs.org/doi/10.1021/acs.nanolett.1c00887

Guillaume Blivet, co-founder and president of REGEnLIFE

REGEnLIFE, a company specialized in the research and development of innovative photo-medical technologies for the prevention and treatment of neurodegenerative diseases, has seen promising results of the pilot clinical trial evaluating its technology in Alzheimer’s disease (AD). The results were presented by Professor Jacques Touchon, scientific advisor on the trial, at the 15th International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2021), held online from March 9 to 14, 2021.

REGEnLIFE’s innovative non-invasive technology is based on photobiomodulation, targeting both the brain and gut via a helmet and abdominal device. This cutting-edge medical device, RGn530, stimulates cells in the brain and gut and regulates inflammation – to improve cognitive functions and behaviour. It targets inflammation of the gut-brain axis, which is believed to be linked to the development of AD and other neurodegenerative diseases.

“There are increasing scientific data to endorse the hypothesis that the gut-brain axis is involved in the development of AD and other neurodegenerative disorders. We also believe that some forms of electromagnetic emissions could prevent and treat this disease. Our initial clinical data, coupled with all our preclinical proof of concept studies, led us to pursue a pivotal clinical study in AD and to consider working on other neurological diseases,” said Guillaume Blivet, co-founder and president of REGEnLIFE. “To accelerate this new phase in our development and to shortly gain early market access, we are preparing a new funding round before the end of 2021.”

REGEnLIFE’s technology safe and well-tolerated
The trial enrolled adult volunteers aged 55 to 85, with mild to moderate Alzheimer’s disease. They were equipped with a helmet and a photobiomodulation abdominal belt; the patients benefited from a total of 40 sessions; these lasted for 25 minutes and were spread over a two-month period. The volunteers were evaluated in a series of tests during the trial and up to one month after treatment ended. This double-blind, randomized, monocenter, placebo-controlled clinical trial began in 2018; it ended prematurely in 2020 due to the COVID-19 pandemic. Out of the 64 planned patients, 53 were randomized into two groups (treated and placebo) and 43 patients benefited from the full duration of the treatment.

The primary efficacy endpoint was measured by the evolution of the total ADAS-Cog score, (Alzheimer’s Disease Assessment Scale), between inclusion and the end of the two-month period of treatment. The REGEnLIFE RGn530 device was shown to be safe; no major side effects were reported. Compliance with treatment sessions was very high for the vast majority of patients (92%). This level of compliance also confirms the good tolerance of the device. While the primary efficacy endpoint was not statistically met, there was a clear improvement trend in a set of cognitive functions. The results of this pilot study showed that REGEnLIFE’s technology is safe and well-tolerated by patients. These very encouraging safety and efficacy results will now be confirmed in a pivotal or phase III clinical trial.

“The therapeutic strategy for AD should involve several targets. Drug treatments targeting the two characteristic proteins of the Alzheimer’s process (beta-amyloid and tau proteins) must be supplemented by other therapies – targeting less specific but very important mechanisms in the pathophysiological AD cascade, such as inflammation and oxidative stress,” said Professor Jacques Touchon, neurologist and psychiatrist, scientific advisor on the clinical trial. “REGEnLIFE’s photobiomodulation technology acts at the early stages of this cascade, (mitochondria, inflammation, oxidative stress), and could be the non-drug complement to the next-generation therapeutic strategy. This technology also makes it possible to act on both the brain and the gut, a significant advantage when we know the important role of the gut-brain axis and microbiota in neurodegenerative pathologies.”

Photobiomodulation technology
Photobiomodulation is based on photonic emissions in the near-infrared, it has already shown analgesic, anti-inflammatory and healing properties. One of the most reproducible effects is the overall reduction in inflammation, especially in the brain < https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.trci.2017.12.003 >. REGEnLIFE’s technology could therefore be used on brain diseases and on pathologies linked to neuroinflammation. REGEnLIFE developed this device employing this scientific approach, using medical technology never before applied to neurology.

According to Alzheimer’s Disease International, 35 million patients worldwide have AD. The annual cost of the disease worldwide is estimated at €850bn. Currently, there are no treatments to cure Alzheimer’s.

In order to address public health issues related to a disease that affects elderly and vulnerable people, REGEnLIFE chose to develop a non-invasive technology with low constraints for patients. The cost of this device is expected to be reasonable for patients and national healthcare systems.

Cells used to study the human blood-brain barrier in the lab aren’t what they seem, throwing nearly a decade’s worth of research into question, a new study from scientists at Columbia University Vagelos College of Physicians and Surgeons and Weill Cornell Medicine suggests.

The team also discovered a possible way to correct the error, raising hopes of creating a more accurate model of the human blood-brain barrier for studying certain neurological diseases and developing drugs that can cross it.

The study was published online Feb. 4 in the Proceedings of the National Academy of Sciences (PNAS).

“The blood-brain barrier is difficult to study in humans and there are many differences between the human and animal blood-brain barrier. So it’s very helpful to have a model of the human blood-brain barrier in a dish,” says co-study leader Dritan Agalliu, Ph.D., associate professor of pathology and cell biology (in neurology) at Columbia University Vagelos College of Physicians and Surgeons.

The in vitro human blood-brain barrier model, developed in 2012, is made by coaxing differentiated adult cells, such as skin cells, into stem cells that behave like embryonic stem cells. These induced pluripotent stem cells can then be transformed into mature cells of almost any type – including a type of endothelial cell that lines the blood vessels of the brain and spinal cord and forms a unique barrier that normally restricts the entry of potentially dangerous substances, antibodies, and immune cells from the bloodstream into the brain.

Agalliu previously noticed that these induced human “brain microvascular endothelial cells,” produced using the published approach in 2012, did not behave like normal endothelial cells in the human brain. “This raised my suspicion that the protocol for making the barrier’s endothelial cells may have generated cells of the wrong identity,” says Agalliu.

“At the same time the Weill Cornell Medicine team had similar suspicions, so we teamed up to reproduce the protocol and perform bulk and single-cell RNA sequencing of these cells.”

Their analysis revealed that the supposed human brain endothelial cells were missing several key proteins found in natural endothelial cells and had more in common with a completely different type of cell (epithelial) that is normally not found in the brain.

The team also identified three genes that, when activated within induced pluripotent cells, lead to the creation of cells that behave more like bona fide endothelial cells. More work is still needed, Agalliu says, to create endothelial cells that produce a reliable model of the human blood-brain barrier. His team is working to address this problem.

Reference:

https://doi.org/10.1073/pnas.2016950118