cOnception of bioresorbable self-rolled Patchs for the local trEatment of inflammatioN induced in the coloN after irradiation – OPENN

This new medical device will be designed with self-rolling bilayer polymer films loaded with anti-inflammatory drugs or MSC. In situ, the self-rolled bilayer tube will unfold, selectively attach to the damaged area and release anti-inflammatory drugs or bioactive molecules produced by MSCs by directed diffusion toward the inflamed mucosa. The therapeutic benefit of this new patch will be tested in vivo in rat model developing colonic damages similar to those induced in patients suffering from severe side effects after radiotherapy.
OPENN project will be organized in Workpackages to develop self-rolled tubes with polymers (WP2), load the self-rolled tubes with anti-inflammatory molecules and analyse their release (WP3), develop the cellularized self-rolled tubes and control the cell viability (WP4), and test in rats model relevant to the human pathology induced after RT treatment, the therapeutic benefit of the devices on the structure and the function of the colon (WP5).

The elastomers and hydrogels have been characterized in terms of: crosslinking rate, swelling rate, mechanical properties (traction, cyclic tests, relaxation) in the dry and hydrated state, degradation (for some still in progress). These characterizations made it possible to select the best candidates which were associated in the form of a co-photocrosslinked bilayer. The winding and unwinding capacity of these bilayers has been validated.

The next step was the synthesis and characterization of the polymer films to form the patches, in particular the active hydrogel layer which will contain the anti-inflammatories. Linear polyethylene glycols of different molecular weights were used for the development of the protocols. Characterization studies of the mesh of PEG-based hydrogels have shown that the storage and release of AIs is due to the diffusion of the molecules within the swollen matrix. PEG-PLA hydrogels released less anti-inflammatory than simple PEG. This will require optimizing the initial amounts of AI within the matrix.

The first experiments of culturing MSCs from GFP rats were carried out as well as the measurement of cell viability in the hydrogel. We opted for cross-linking of the films containing the cells under green light (˜515 nm) in order to guarantee the viability of the cells after encapsulation in the hydrogel.

The selected copolymers could be synthesized on a larger scale. This will involve loading and measuring the exact quantity of anti-inflammatory molecules encapsulated within the hydrogel matrices. Also, we will improve and standardize the thickness of the bilayers of the formed patches. In parallel, the viability and secretory capacity of the cells in the hydrogel will be analyzed.
And finally, when the different versions of the patch will be available, we will endeavor to study the therapeutic benefit in a model of inflammation of the colon induced by ionizing radiation.

1. S. Ouedraogo, M. Grosjean, L. Pieuchot, N. Mathieu, B. Nottelet, K. Anselme, A. Ponche, Preparation and characterization of polyethylene glycol-based hydrogel for anti-inflammatory drug release (oral virtuel) SBPMat 2021, Iguaçu, Brésil, 1-3 septembre 2021

2. S. Ouedraogo, A. Ponche, L. Pieuchot, N. Mathieu, B. Nottelet, M. Grosjean, K.Anselme, Polyethylene glycol based-hydrogel synthesis and characterization for anti-inflammatory drug delivery (poster virtuel) ESB 2021, Porto, Portugal, 5-9 septembre 2021

3. Mathilde GROSJEAN, Sidzigui OUEDRAOGO, Xavier GARRIC, Valeriy LUCHNIKOV, Arnaud PONCHE, Noëlle MATHIEU, Karine ANSELME, Benjamin NOTTELET. Bioresorbable bilayered elastomers/hydrogels self-rolling patch for anti-inflammatory delivery (Euromat 2021), Graz, Austria, September 13-17, 2021)

4. Mathilde GROSJEAN, Sidzigui OUEDRAOGO, Xavier GARRIC, Valeriy LUCHNIKOV, Arnaud PONCHE, Noëlle MATHIEU, Karine ANSELME and Benjamin NOTTELET. Design of degradable elastomers and hydrogels for the conception of bioresorbable anti-inflammatory patchs. (Balard Chemistry Conferences, 15-18th June 2021, Montpellier, France)

5. S. Ouedraogo, A. Ponche, L. Pieuchot, N. Mathieu, B. Nottelet, M. Grosjean, K.Anselme, Polyethylene glycol based-hydrogel synthesis and characterization for anti-inflammatory drug delivery (poster) BIOMAT 2021, Bourg Saint-Maurice, 18-22 octobre 2021

6. Mathilde Grosjean, Sidzigui Ouedraogo, Valeriy Luchinikov, Arnaud Ponche, Noëlle Mathieu, Karine Anselme, Benjamin Nottelet. Design of degradable star-shaped copolymers for the conception of bioresorbable anti-inflammatory patchs (Congrès Biomat 2021, 19-22 October 2021, Bourg Saint Maurice, France)

7. Communication orale
Mathilde Grosjean, Sidzigui Ouedraogo, Valeriy Luchinikov, Arnaud Ponche, Noëlle Mathieu, Karine Anselme, Benjamin Nottelet. Design of degradable star-shaped copolymers for the conception of bioresorbable anti-inflammatory patchs. (48ème journée d’étude des polymères, JEPO2021, 3-8 october 2021, Ile de Porquerolles, France)

Pelvic cancers are among the most frequently diagnosed cancers worldwide. Radiotherapy (RT) plays a growing place in the management of malignant pelvic diseases. Even though great advances have been made in RT delivery techniques, radiation exposure of significant volumes of normal bowel persists, impacting on the patient’s quality of life post-treatment. Cancer incidence increases and mortality have been reduced during the past several decades, and the number of cancer survivors has almost tripled during the same period. With an increasing cohort of cancer survivors, efforts to manage the adverse effects of RT have to be intensified. Current therapies are merely palliative. Several drugs have been investigated to prevent the pelvic radiation disease (PRD), amifostine, derivative of 5-aminosalicylic acid (5-ASA), analog of prostaglandin, sucralfate and glucocorticoids but no curative treatment exists. Moreover, these pharmacologic molecules could induce adverse effects especially when they are delivered systemically with a prolonged use. We also demonstrated that cell therapy using mesenchymal stromal cells (MSC) gave encouraging results in animal models (rats and pigs), and could be a new perspective to induce regeneration of the colon.
Today, no medical device exists for the treatment of the colon despite the number of various colonic pathologies as inflammatory diseases. Few studies demonstrated poor results with hydrogel delivered by enema. The objective of OPENN is to develop an innovative medical device dedicated to the colon that could be easily implanted by surgeons using colonoscopy. This new medical device will be designed with self-rolling bilayer polymer films loaded with anti-inflammatory drugs or MSC. In situ, the self-rolled bilayer tube will unfold, selectively attach to the damaged area and release anti-inflammatory drugs or bioactive molecules produced by MSCs by directed diffusion toward the inflamed mucosa. The therapeutic benefit of this new patch will be tested in vivo in rat model developing colonic damages similar to those induced in patients suffering from severe side effects after radiotherapy.
OPENN project will be organized in Workpackages to develop self-rolled tubes with polymers (WP2), load the self-rolled tubes with anti-inflammatory molecules and analyse their release (WP3), develop the cellularized self-rolled tubes and control the cell viability (WP4), and test in rats model relevant to the human pathology induced after RT treatment, the therapeutic benefit of the devices on the structure and the function of the colon (WP5).
The OPENN project will have an impact in development and transfer of knowledge in the field of biomaterials and innovative implantable medical devices to reinforce the French position in this field. The potential of this project for commercialization is significant since systemic anti-inflammatory treatments used for chronic diseases induce numerous adverse effects. Moreover, the use of self-rolled patch loaded with MSCs is very innovative and will provide a new concept in regenerative medicine. The consortium of the OPENN project rallied skills of physicists, chemists and biologists towards a translational research problem dedicated to public health issue.