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The project stems from a fact: stem cells are a major step forward in medicine but usual cell culture methods (T-Flasks) do not provide sufficient amounts neither for clinical studies nor clinical application. Upscaling and automation of the process will be required in the near future to ensure reproductibility and quality of the cell acquisition process. So far, the most promising technique is based on the use of microbeads that provide a large adhesion surface. Those microbeads are suspended in a stirred bioreactor allowing stem cells to grow at their surface. This technique, already use for animal cell culture (vaccine production), presents special issues for stem cells that need to be harvested without being damaged.
The aim of the project Improve-Stem is to develop an integrated set of tools required for mesenchymal stem cell amplification (MSC) to promote their application in clinical cell therapy. Those tools will be based on the development of microcarriers with optimised surface design allowing the control of cell adhesion alongside to the design of an adapted bioreactor with operating conditions adjusted for stem cell culture on microcarriers. Cell behavior will be monitored to ensure quality, homogeneity and purety of the cells.
Excellence Platform in the Greater Region
Our multidisciplinary consortium involves keys competencies in materials science, bioprocess engineering and cell biology. At the level of the Greater Region, it provide a solid basis for a platform of excellence in the field of mesenchymal stem cell culture.
The project received the label « University of the Greater Region (UniGR) »
IMPROVE-STEM consists of a demanding set plan of interconnected tasks over a period of 42 months designed to provide maximum benefit and reach the end goal in the most effective and synergistic manner possible. The workplan is divided into 5 experimental research actions (Actions 3-7) and 2 supporting actions (Actions 1-2).
Actions 3 – 4
These tasks are focused on the surface modification of commercial microcarriers in view to control the adhesion / detachment of Mesenchymal Stem Cells (MSC) within bioreactors. Various analytical methodologies will be adopted to analyse in depth these new bio-reactive surfaces but also to monitor the behaviour of the cells.
The aim of Action 5 is the selection of an optimal design of stirred tank bioreactor for efficient stem cell (MSC) amplification on microcarriers. Its operating conditions will be adjusted to allow microcarrier suspension, while minimizing hydromechanical stresses related to the flow field and to collisions.
Action 6 aims at optimizing MSCs extraction and isolation from umbilical cords and scaling-up the culture process from 2D T-flasks to mechanically stirred GMP (Good Manufacturing practices) bioreactors. More specifically the focus is put on the validation of most adapted operating conditions (extraction time, mixing, aeration, adhesion and detachment protocols) and the set-up of the continuous perfused mode of culture.
Action 7 focus on the development of a harvest process of mesenchymal stem cells after expansion on microcarriers in bioreactor and on the research of biomarkers and the development of methods for the phenotypical and functional characterization of the cells.
Results and impacts
Results « Microcarriers »
With the complementary expertise and methodologies of the 4 research units involved in tasks 3 and 4, new generations of non degradable microcarriers with smart surfaces should be available. According to a close feedback loop between material scientists, biologists and clinicians, this project should give a better understanding of the parameters controlling the adhesion strength between MSC and material surface within dynamic conditions met in a typical bioreactor used for cell amplification. On the medium term, IMPROVE- STEM should provide an original solution to facilitate the large scale production of MSC in a controlled culture medium, according to pharmaceutical GMP standards.
Results « Bioreactor»
Using numerical simulations and dedicated experimental techniques, a better understanding of the impact of bioreactor design and operation (impeller, vessel, agitation rate) on the hydromechanical stresses encountered by the microcarriers and the MSCs will be reached. This will guide the choice of most adapted agitation conditions for MSCs culture in the stirred tank bioreactor (Action 5). Besides that, a screening protocol will be applied to stirred cultures of MSCs to identify the microcarrier chemistry and the biochemical conditions (pH, dissolved oxygen concentration, culture medium composition) that lead to the best cell growth performance, without quality loss. These culture conditions will be finally validated by achieving a GMP continuous-perfused culture of MSCs.
Results « Protocols »
The project should allow, by the understanding of cell/microcarrier adhesion, the development of an optimized process to detach cells from microcarriers after culture on bioreactors. A set of biomarkers and methods to determine the quality of the cells produced on bioreactors should be provided. This will improve the clinical use of the cells
Long term impact
On the basis of the project results, i.e. innovative tools for the scale-up of mesenchymal stem cells amplification (MSC) processes and for the assessment of their quality, one may expect an increased availability of MSCs, with a controlled quality, usable for clinical applications in cell therapy and in tissue engineering. For the medical research sector, it will allow speeding up and possibly widening clinical trials for emerging applications. In the longer term, it will open perspectives for the development of new treatments and applications. Competencies and knowledge acquired during the project will also be valorized in other processes or applications. For example, the characterization methods, developed by the cell biology specialists, for assessing the stem cell quality, are applicable to all amplification processes, including, the current 2D techniques used in clinical labs. In the materials science sector, the mastering of microcarrier surface properties will allow tailoring them for new applications. In the engineering field, the new prediction tools for the behavior of solid particles in suspension will meet the interest of numerous chemical processes. All these applications in various sectors (health, materials science, engineering) will reinforce the innovation potential in the Great Research (companies, research centers, universities) which is certainly valuable for its economy and for its attractiveness.
About stem cells
Stem cells are undifferentiated cells that have two interesting properties for the therapeutics, self-renewal and differentiation into specialized cells. Stem cells with different potency can be isolated and characterized at different stages of the human life. Despite the promise of embryonic stem cells, in many cases, adult or even fetal stem cells provide a more interesting approach for clinical applications. Among them, it is undeniable that mesenchymal stem/stromal cells (MSC) are of potential interest in regenerative medicine because they are easily available without ethical problems for their uses. MSCs are ubiquitously distributed and found in adult tissues like bone marrow, adipose, skeletal muscle, dermis or in fetal tissues like umbilical cord or placenta. More importantly MSCs are multipotent cells that differentiate into many different cell types and can be extensively expanded in vitro.
MSC were used in more than 500 clinical trials in different forms (infusion or transplantation in a biomaterial) for various applications such as bone, cartilage, neurological or cardiovascular diseases, but also for diabetes, hematological disorders or even graft versus host disease (non-exhaustive list). Studies so far showed that MSC administration is well tolerated and beneficial effect have been observed even if the cells seem to be quickly eliminated. By their presence, they can communicate via cell contact and paracrine action to modulate immune system, to promote wound healing and angiogenesis.
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Ce projet se fonde sur un ensemble de compétences scientifiques et technologiques transversales disséminées dans plusieurs universités de l'UniGR et associant des centres de recherche.