A miracle gel to repair your brain after a stroke?

Christophe Pellegrino and Jérôme Laurin are researchers at Aix-Marseille University and co-published in October 2018 a scientific article in the journal Biomacromolecules. They explore the properties of an injectable and degradable gel that could change our relationship to neuro-pharmacological treatments. What are the implications of this work? Are we on the trail of a new miracle treatment or is it jumping to conclusions too quickly?

Christophe Pellegrino is a PhD in neuroscience and a lecturer at Aix-Marseille University. At the Mediterranean Institute of Neurobiology (INMed), his work focuses on understanding the mechanisms put in place by the central nervous system and more particularly the brain, in order to adapt and respond to brain injuries.

Jérôme Laurin is a PhD in human movement sciences and a lecturer at Aix-Marseille University. At the Étienne-Jules MAREY Institute of Movement Sciences (ISM), his work focuses on the influence of physical exercise on brain and muscle plasticity and on the recovery of vascular accidents.

How did your collaboration begin?

“Involving several teams with different interests in the study allows us to complete our approach, to better understand the issue and to look at the problem from several points of view. Beyond the need for transversality, we had a common interest in developing this gel.

The collaboration was initiated by Jérôme, with whom I [Christophe Pellegrino] was already working on stroke. Regarding post-stroke recovery, I have a more pharmacological approach while Jérôme is closely interested in the role of physical exercise. The Institute of Radical Chemistry (ICR), notably Didier Gigmes and Thomas Trimaille, has been collaborating with the ISM for several years on the manufacture and use of gels in spinal cord traumas.”

How did you get to work on this gel?

“We learn about stroke every day, research is progressing slowly but surely. For example, we have recently learned that the earlier the return to physical activity, the more effective the recovery is, whereas a few years ago we thought we should let the patient recover in bed as much as possible. Today we know that we must act as soon as possible after the stroke.

Immediately after a stroke, there is significant inflammation and secondary neuronal death, meaning that the neurons around the area initially affected will also die. It’s these neurons that therapies try to protect! For this purpose, physical exercise is useful because it promotes brain plasticity, but not enough. Deficits persist, which motivates our approach to combine exercise and pharmacological treatment. Overall, monotherapy is not very effective and it seems necessary to combine treatments.

There is also a high demand among the population. Following the release of an overly enthusiastic article in La Provence [local newspaper], we received several calls from patients who absolutely wanted to participate in an experiment with our gel. Unfortunately, we’re not there yet.”

What are the particularities of this gel?

“The principle itself is not new! The originality of our research lies above all in the composition of the hydrogel, its evolution over time but also its ability to gradually degrade and release the pharmacological molecules – the treatment – it contains. This allows us to control exactly the speed and quantity of molecules diffused according to a well calibrated kinetics.

Our product is liquid at room temperature and becomes a gel at physiological temperature, in other words at the temperature prevailing in the brain, 37°C. The liquid state makes it possible to deliver the treatment in the desired region, via a much lighter surgery than what can usually be done in preclinical studies. A single localized injection with a minimal hole in the skull and not a significant craniotomy is all it takes. Once in the brain, the product takes the form of a gel, which greatly reduces its diffusion and allows a very localized pharmacological release. The mechanical properties of hydrogels are very similar to those of nerve tissue.

The more localized this release, the less regions that do not require pharmacological action are affected. The liquid to gel transformation allows us to be very precise and therefore to gain in efficiency. This could reduce the side effects associated with pharmacological treatments.”

Does the gel affect nerve cells?

“From our current results, the gel alone does not appear to have a deleterious effect on nerve cell function, probably because it is synthetic – and not natural like other hydrogels – and therefore does not appear to interact directly with them. Similarly, its degradation products do not appear to cause inflammation, unlike most bio-hydrogels.

As for the injection method, it does not cause an increase in intracranial pressure. In addition, performing an intracerebral injection avoids many of the problems found in other modes of administration! For example, during repeated blood injections, very large doses are sent so that a small part of the blood-brain barrier can be passed through, causing the entire body to be subjected to high doses of the pharmacological product.”

Would it be suitable for all types of drugs?

“In its current state, the gel can only contain and diffuse some of the molecules used in pharmacology, the so-called “hydrophobic” ones, mainly because of their chemical compatibility.”

What are the limits of your work?

“For the moment, we are in a fundamental phase of identifying the gel. We are in a preclinical validation phase and there is still a lot to do before any clinical trial. It can’t be done right now. First, it must be ensured that the gel releases the compounds you want, at the desired doses and for a sufficient period of time, with little to no side effects. That’s what the technique will be judged on! This is why we want to inject an appropriate dose in a more localized way. It is therefore necessary that, in the end, the distributed pharmacological product produces its beneficial effects in an optimal way, while having fewer side effects than when it is injected by other means, for example through the intravenous system.”

 What’s next?

“The gel degradation kinetics under in vivo conditions must continue to be studied and the benefit/risk balance of the technique evaluated to determine whether it is worth moving to human experiments in the medium to long term.

The rest of the study has already begun and we are currently evaluating the gains allowed by the technique on the animal in a very short period of time, up to 1 week after an injury. This time window corresponds approximately to the first three months post-injury in humans. We focus on this period of time because it seems to be the period when treatments have the most effect on recovery. »

 Could we consider a move to clinical trials?

“There are studies that use hydrogels on primates and that work rather well, with a very local distribution of treatments, without product dispersion. But clinical experimentation in humans is much more complicated, particularly because of the high inter-individual variability of patients. Between age, gender, weight, importance and conditions of stroke, the importance of recovery and many other factors, it can be said that each patient is unique. Talking about human testing is premature, we’re not there yet. »

Are there other research teams working on the same subject?

“To my knowledge, there are no other teams working on the same hydrogel in stroke. But, the use of hydrogel on clinical themes is an emerging pathway that is in full swing. »

Complete reference: Vincent Pertici, Caroline Pin-Barre, Claudio Rivera, Christophe Pellegrino, Jérôme Laurin, Didier Gigmes and Thomas Trimaille. Degradable and injectable hydrogel for drug delivery in soft tissues. Biomacromolecules, American Chemical Society, In press, 〈10.1021/acs.biomac.8b01242〉〈hal-01961903〉