We were recently invited by Dr. Fabrizio Gelain to visit the new ‘Center for Nanomedicine and Tissue Engineering’ (CNTE) located at the Niguarda Hospital in Milan, Italy.
Dr. Gelain is co-director of the center and has been working on Spinal Cord Injury (SCI) research for several years. He showed us the new labs and gave us an interview to explain what his team is working on with regards to a cure for SCI.
1) Could you tell us about this new research center and the nanotechnologies that your team is working on?
“Nanotechnology is the production and/or manipulation of materials that have a dimension between 1 and 100 nano-meters; in other words 1 nano-meter = 1 millionth of a millimeter.
At the Center for Nanomedicine and Tissue Engineering (CNTE) we design, synthesize, characterize nanostructured bio-prosthesis that can be naturally absorbed by the body. Here we utilize principles of nanomedicine, physics, materials science, cellular biology and medicine to develop prosthesis implantable in living organisms to repair damaged tissues. Often nanotechnologies are only considered for creating nanoparticles for a controlled release of drugs, for some tumor therapies or for imaging techniques. Our work is dedicated to other important sections of nanomedicine. We synthesize scaffolds that may also contain cells to repair important lesions of biological tissues. We also conduct three-dimensional cell culture experiments in vitro: a more complex paradigm than 2D but much more reliable to predict results in living organisms. That allows us to reduce animal studies which is very important from an ethical point of view and it also significantly reduces time and costs of research.”
2) How nanotechnology can be used to cure spinal cord injury (SCI)?
“In the case of severe injuries, a portion of biological tissue is lost and it becomes useful to use a scaffold rather than just a cell therapy approach as it is necessary to provide physical and biochemical guidance for endogenous tissue to make regeneration happen. At the same time a scaffold keeps in the right place transplanted cells and guides them to a proper engraftment with the host tissue. In case of SCI very often there is a formation of scar tissue and also of a cyst. In this damaged area it becomes very useful to use a scaffold. Furthermore we have the possibility to design our scaffolds at a molecular level. That allows us to control the integration of the scaffold with the biological tissue, to control the release of drugs contained in the scaffold and to transplant more accurately cells which are useful for regeneration.”
3) What is the difference between acute SCI and chronic SCI?
“In humans SCI is considered acute in the first few days (up to few weeks) after the lesion. Then it becomes “sub-acute” and finally chronic and stable. When exactly SCI can be considered chronic is still controversial, but there is a growing consensus that SCI can be considered chronic after one year. From a pathophysiological perspective acute and chronic lesions are extremely different. Acute SCI has hematoma, damaged but still present tissue, a strong immune response etc.. Usually (except in very severe lesions such as a gunshot wound) there is still the presence of tissue structure that will be lost gradually moving toward the chronic stage. In this phase interventions have the goal to prevent the secondary damage using mechanisms of neuroprotection. After the cascade of events that starts with SCI (also known as “secondary damage”) we have the chronic lesion that has a greater loss of nerve fibres, a glial scar all around the lesion and often in humans there are also internal cavities. The cysts and the gliotic scar are a physical and chemical barrier to regeneration. Moreover at this stage the lesion is much bigger in comparison to the acute lesion and that makes regeneration even more difficult.”
“Doing research on acute SCI is very different than doing chronic SCI research. Chronic has more hurdles; scientific, logistical and also in terms of resources. In case of acute SCI the goal is to find a cure for future patients, while in chronic SCI we try to find a cure for people that already suffer the consequences of SCI. Often both basic and clinical research focus on acute SCI as experimental paradigms are shorter (a few months instead of up to a year), costs are lower and usually lesions are less severe since the secondary damage has not yet occurred. This can lead to positive results but in very specific conditions of patients to come. We have done and published research on acute lesions to get a rapid screening of new solutions in case of multiple variables (= possible solutions) that we can change thanks to the nanotechnologies. Preliminary results in short term are essential, but for 12 years our main focus has been chronic SCI even given all the difficulties we have mentioned including longer timeframes for each experiment and much higher costs). Nonetheless we keep our mind on the real significance and translationality of results we have obtained and on the ones we hope to achieve.”
5) What is your approach to solve the scar problem?
“The answer to this question is very complex and above all isn’t clear yet to us and to the scientific community in general. In many studies enzymes have been used to degrade essential components of the scar. This is a good approach to make the scar matrix weaker. In our case we have the necessity to have a space to insert the components of our scaffold (currently made of micro-tubes of about 200 micron in diameter) and at the moment we do a pre- treatment to weaken the scar which then needs to be partially removed surgically. Clearly this procedure is critical: the lesion has to be first studied in details using the most modern imaging techniques and then the previously weakened scar can be partially removed but leaving a safety layer of tissue to avoid damaging intact nervous tissue. Then one more treatment to weaken the scar (still using enzymes) can be done to facilitate axons to enter the implant. To be able to undertake this intervention it is essential to first do an accurate three-dimensional study of the lesion site.”
6) In 2011 you published in ACS Nano the results of a study in which rats with chronic SCI have shown a significant recovery. What progress has been made since then?
“We have continued to improve the approach that we used in the above mentioned study, which was also just a starting point for the international scientific community. Indeed our results have been listed among the 5 more important recent discoveries in nanomedicine. (Scientific American ).
We have gone forward by improving chemical components and biological functionalities of the biomaterials and we have developed additional interventions (before and after surgery) that are essential to obtain stronger results. We have had better preliminary results, but because of the time and costs of this research we don’t have trustable results to share yet. Our general strategy consists of synergically merging the promising strategies already published by others with our discoveries (multidisciplinary approach) to develop a more complex but more promising therapy. We will keep presenting at symposia and publishing in international scientific journals our results so that they can be analyzed impartially by the scientific community and patients.”
7) Do you collaborate with other groups of research?
“We have several national and international collaborations. In Italy the most important ones are with the Casa Sollievo della Sofferenza Hospital from S. Giovanni Rotondo with which we share many important parts of our projects and the Cell Factory of Terni. Additionally, we collaborate with the University of Milan-Bicocca, the University of Trieste and others. Internationally we have important collaborations with scientific teams at the Massachusetts Institute of Technology, the Lawrence Berkeley National Lab, the University of Alberta and the University of Florida. We remain very open to new collaborations since it is when different disciplines merge that the best results occur. I also believe that regeneration of the spinal cord is a very complex target, well beyond a single approach.”
8) What are the necessary steps to bring your discoveries to clinical trials?
“Before we can start clinical trials our results needs to be replicated by independent labs. Meanwhile, as I have said at the moment we are improving our approach with the goal to improve the results and make it applicable on people. Then we will need to produce our bioprostheses to standard GMP (Good Manufacture Practice) to meet the quality criteria necessary for clinical application. Lastly we will have to apply to ethical and medical authorities and do all the necessary paper work to get the authorization to conduct clinical trials.”
9) Is there any particular obstacle?
“Unfortunately the main obstacle is the lack of funding and that is slowing down our progress. We have a tremendous potential but we proceed at a much slower speed than we could.”
10) What economic resources are necessary to get ready for clinical trials?
“That is a very critical question; I can say that in terms of infrastructures we have made good progress in the last few years. The critical aspect at the moment is to hire more people to do the necessary research work. We will then need funding to produce GMP bioprostheses and finally to do all the paper work to get the authorization to do a phase I clinical trial. All this will require a few million Euros.”
We thank Dr. Gelain for his precious work and for giving us the opportunity to visit the center and for answering our questions.
Cure Girls Loredana and Arcangela