Anjali Seth

Dr David Lafargue

Dr Cécile Poirier

Thomas Badier

Nathalie Delory

Alain Laporte

Jean-Marie Delbos

Dr Véronique Jeannin

Jean-Manuel Péan

Christine Ménager
email: christine.menager@upmc.fr

Prof. C Dr A Seth

Ménager

Jean- Marie Delbos

Optimization of Magnetic Retention in the Gastrointestinal Tract: Enhanced Bioavailability of Poorly Permeable Drug

Keywords: Oral delivery, Magnetic retention, Magnetic beads, Dual imaging, Pharmacokinetic

Oral administration of low permeable drugs remains a challenge as they do not cross biological membrane efficiently and therefore exhibit a poor bioavailability. Herein, the effect of magnetic retention on the circulation and bioavailability of magnetic beads in the gastrointestinal tract in the presence of an external magnetic field is evaluated. Retention efficiency is imaged using magnetic resonance and near infrared techniques. The effect on

Introduction

Bioavailability of oral drugs remains low because of the harsh gastrointestinal tract (GIT) environment. One of the major drawback of using the oral route to deliver drugs is that these molecules need to cross biological membranes in order to pass to the bloodstream and reach their physiological target. The large mucosal surface area of GIT presents opportunities as well as challenges, the former for retention of nanoparticles or microdevices and the latter as additional transport barriers [START_REF] Chen | Oral particulate delivery: Status and future trends[END_REF][START_REF] Gamboa | In vitro and in vivo models for the study of oral delivery of nanoparticles[END_REF][START_REF] Reed | Review of the gastrointestinal tract: from macro to micro[END_REF][START_REF] You | Application of Monodirectional Janus Patch to Oromucosal Delivery System[END_REF]. A large number of drugs with high clinical potential have not yet been employed because of their limited bloodstream access. In this context, a growing attention has been focused over the past few decades on the design and manufacturing of advanced formulations intended for the release of bioactive compounds to selected regions of the GIT. By controlling the site of drug liberation throughout the gut, it would be possible to limit the tolerability issues associated with treatments that mainly affect specific GI districts, enhance the bioavailability of drugs that show regional differences in their stability and/or

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M A N U S C R I P T 3 permeability profiles or, alternatively, improve the therapeutic outcome in the management of widespread local pathologies (e.g. phlogosis, ulcers, microbial infections, motility disorders).

Gastroretentive pills have been investigated for decades because increasing the residence time of pills in the stomach would greatly benefit the numerous narrow absorption window therapeutics that are primarily absorbed in the proximal small intestines [START_REF] Davis | Formulation strategies for absorption windows[END_REF][START_REF] Gröning | Acyclovir serum concentrations following peroral administration of magnetic depot tablets and the influence of extracorporal magnets to control gastrointestinal transit[END_REF][START_REF] Nayak | Gastroretentive drug delivery systems : a review[END_REF][START_REF] Polyak | Magnetic targeting for site-specific drug delivery : applications and clinical potential[END_REF][START_REF] Streubel | Drug delivery to the upper small intestine window using gastroretentive technologies[END_REF].

The most prevalent strategies for achieving gastric retention are density mismatching, geometry-based, and bioadhesive pills [START_REF] Andrews | Mucoadhesive polymeric platforms for controlled drug delivery[END_REF][START_REF] Bhardwaj | A Short Review on Gastro Retentive Formulations for Stomach Specific Drug Delivery : Special Emphasis on Floating In situ Gel Systems[END_REF][START_REF] Chirra | Planar microdevices for enhanced in vivo retention and oral bioavailability of poorly permeable drugs[END_REF][START_REF] Eiamtrakarn | Gastrointestinal mucoadhesive patch system (GI-MAPS) for oral administration of G-CSF, a model protein[END_REF][START_REF] Hari | Magnetic granules: A novel system for specific drug delivery to esophageal mucosa in oral administration[END_REF][START_REF] Salamat-Miller | The use of mucoadhesive polymers in buccal drug delivery[END_REF][START_REF] Whitehead | Oral delivery of macromolecules using intestinal patches: Applications for insulin delivery[END_REF][START_REF] Wittaya-Areekul | Preparation and in vitro evaluation of mucoadhesive properties of alginate/chitosan microparticles containing prednisolone[END_REF]. The use of magnetic force has also been described in order to increase the residence time of magnetic microparticulates. Previous studies have used static external magnets to improve the bioavailability of orally administered proteins including insulin for diabetics (Chen andLanger, 1998, 1997;[START_REF] Cheng | Magnetically responsive polymeric microparticles for oral delivery of protein drugs[END_REF][START_REF] Häfeli | Magnetically modulated therapeutic systems[END_REF], narrow absorption window (NAW) therapeutics such as acyclovir as an antiviral therapy [START_REF] Chirra | Planar microdevices for enhanced in vivo retention and oral bioavailability of poorly permeable drugs[END_REF][START_REF] Gamboa | In vitro and in vivo models for the study of oral delivery of nanoparticles[END_REF][START_REF] Gröning | Acyclovir serum concentrations following peroral administration of magnetic depot tablets and the influence of extracorporal magnets to control gastrointestinal transit[END_REF] and therapeutics for site-specific pathologies including bleomycin for esophageal cancer (Ito et al., 1990;[START_REF] Nagano | Preparation of magnetic granules containing bleomycin and its evaluation using model esophageal cancer[END_REF]. However, the magnetic force required for pill immobilization has rarely been taken into account. Two studies bring considerably more insight in the field of magnetic pill retention as a safe method to target specific window and improve the bioavailability of drugs. E. Mathiowitz and coworkers reported a method, which enables tracking and localization of a magnetic pill [START_REF] Laulicht | Understanding gastric forces calculated from high-resolution pill tracking[END_REF]. In a second publication the authors' study was focused on the forces experienced by an orally ingested magnetic pill, tracked by Hall array sensors. This paper presents a quantitative analysis of inertial net forces experienced by magnetic model pills during gastric residence in humans and two preclinical animal models both in fasted and fed states (Laulicht et al., 2011). They point out very

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important facts as the necessity to quantify the magnetic force involved, in order to have a feedback of the magnetic retention.

The orally active dipeptidyl peptidase-IV (DPP-4) inhibitor used in this study is currently developed for the treatment of type 2 diabetes mellitus (T2DM). In vivo, DPP4 rapidly inactivates incretins (GLP-1 and GIP) secreted by the intestinal cells, which stimulate glucose-induced insulin synthesis and secretion in response to food intake. However DPP4 inhibitors exhibit a very low oral bioavailability associated with a narrow absorption window in the upper part of the intestine as many highly hydrophilic molecules (acyclovir, amoxicillin, metformin) [START_REF] Amidon | A theoretical basis for a biopharmaceutic drug classification : the correlation of in vitro drug product dissolution and in vivo bioavailability[END_REF][START_REF] Lindenberg | Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system[END_REF]. Due to that, we propose to enhance the bioavailability of DPP4 inhibitors by using the magnetic retention technique.

We designed magnetic core-shell chitosan-alginate beads as theranostic carriers (Fig. 1a-c).

The magnetic nanoparticles used to fabricate the magnetic beads are biocompatible iron oxide nanoparticles (M. [START_REF] Levy | Long term in vivo biotransformation of iron oxide nanoparticles[END_REF]. These nanoparticles exhibit superparamagnetic behavior and are T 2 (negative) contrast agents in MRI (Magnetic Resonance Imaging) (Fig. 1d).

According to a covalent coupling between the polymer and a fluorophore, dynamics of the beads along the intestine is visualized by near infra-red (NIR) microscopy during 6 hours after beads administration (Fig. 1e). These magnetic beads were orally administrated to rats. A pharmacokinetic study was performed to quantify the amount of drug in plasma (Fig. 1f). The magnetic beads associated with an external magnet enabled investigation of the benefits of magnetic accumulation when compared to free drug and non-targeted beads. Finally, the safety of the magnetic beads was investigated using iron titration of the organ as well as histological examination of intestinal tissue.

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Materials and Methods

1. Materials

All chemical reagents were purchased from Sigma-Aldrich, France. Animals were provided from Charles River, France. Gelatin capsules (size 9: 2.65 mm x 8.6 mm) and cannulas (4 mm

x 220 mm) used to force feed the rats were respectively provided from Torpac and Ecimed,

France. The fluorescent probe, Alexa Fluor-750 Carboxylic Acid Succinimidyl Ester was purchased from Life Technologies, France.

Model drug

The drug used in this study was kindly provided by Technologie Servier (Fig. S1). This compound is a white powder soluble in water, highly hygroscopic which belongs to the chemical class of cyanopyrrolidines. This orally active dipeptidyl peptidase-IV (DPP-4)

inhibitor is currently developed for the treatment of type 2 diabetes mellitus (T2DM). In vivo, DPP4 rapidly inactivates GLP-1 and GIP, incretins secreted by the intestinal cells, which stimulate glucose-induced insulin synthesis and secretion in response to food intake. The development of this active pharmaceutical ingredient has been delayed due to low oral bioavailability caused by its very poor intestinal permeability. This drug is classified as a Class III molecule (Biopharmaceutical Classification System, 2011;[START_REF] Amidon | A theoretical basis for a biopharmaceutic drug classification : the correlation of in vitro drug product dissolution and in vivo bioavailability[END_REF][START_REF] Blume | The biopharmaceutics classification system (BCS): Class III drugsbetter candidates for BA/BE waiver?[END_REF]. This means that that the drug exhibits a very high solubility (12 mg/mL in phosphate buffer at pH 6) and a very low membrane permeability (Absorbed fraction on Caco-2 model is under 30%), (Y. [START_REF] Sambuy | The Caco-2 cell line as a model of the intestinal barrier : influence of cell and culture-related factors on Caco-2 cell functional characteristics[END_REF][START_REF] Artursson | Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells[END_REF][START_REF] Balimane | Cell culture-based models for intestinal permeability: a critique[END_REF]. The physicochemical properties of the drug are: Mw = 769 g/mol; pKa = 7.4 and 3.5; Partition coefficient: Log P = -1.11, log D = -1.4 at pH 7.4.

3. Magnetic nanoparticles synthesis

The superparamagnetic particles were synthesized according to Massart's procedure [START_REF] Massart | Preparation of aqueous magnetic liquids in alkaline and acidic media[END_REF][START_REF] Canfarotta | Engineered magnetic nanoparticles for biomedical applications[END_REF]. Magnetite (Fe 3 O 4 ) nanocrystals were prepared by alkaline coprecipitation of FeCl 3 (1.5 mol) and FeCl 2 .4H 2 O (0.9 mol) salts in g/L and volume fraction Φ = 2%). The colloidal suspension was ready to use and is stable at room temperature for years.

4. Fluorescent and magnetic chitosan-alginate core-shell beads preparation

Fluorescent and magnetic chitosan alginate core-shell beads containing the drug were prepared as previously described using a standard extrusion crosslinking method [START_REF] Seth | Performance of magnetic chitosan-alginate core-shell beads for increasing the bioavailability of a low permeable drug[END_REF]. Briefly, chitosan solution was prepared by dissolving chitosan 5% w/v in deionized water containing 5% v/v acetic acid. The fluorescent probe, Alexa Fluor-750, was grafted onto the chitosan polymer via a covalent coupling. Succinimidyl ester moieties on the fluorophore reacted with primary amino groups of the chitosan backbone. Alexa Fluor-750, previously dissolved in DMSO (1mg/100µL), was added to the mixture, 2% v/v, and was allowed to react for 1 hour at room temperature under magnetic stirring. Thereafter, 50% v/v of magnetic nanoparticles (MNPs) in water was added to the dye-polymer mixture under stirring for 10 minutes. Finally, 10% w/v of the drug was then added and the mixture was allowed to further stir for another 30 minutes. The resulting solution was added drop wise in a gently stirred water bath (10 mL) containing TPP (2% w/v) and Alginate (1% w/v) by extrusion through a syringe needle (inner diameter of 0.45 mm). Size of the beads was

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controlled by the diameter of the syringe needle (0.45 G) and the flow rate (10 mL/min) of the syringe pump. An optimal height of 30 cm was used to obtain spherical beads. The beads were then allowed to crosslink for 30 minutes under gentle magnetic stirring and subsequently collected by magnetic decantation and rinsed in deionized water. Beads were let to dry at room temperature for 24 hours prior to be used. The reticulation bath and washing water were kept for further analysis.

5. In vitro release study

Drug release from the beads was tested using a Sotax ® dissolution bath apparatus. Beads were introduced in a 500 mL bath at pH=6.8 to mimic intestinal environment and agitated at 50 rpm at a fixed temperature of 37°C. Dissolution media was prepared by mixing 136.1 g of potassium dihydrophosphate and 17.9 g of sodium hydroxide in 20 L of distilled water. Every fifteen minutes, a fixed volume was automatically withdrawn and the amount of drug was measured by UV spectrometry. Detection occurs at λ = 248 nm.

6. Iron titration by AAS

The total iron content of the ferrofluid, magnetic beads or organs was determined by atomic absorption spectroscopy (AAS) equipped with a Perkin-Elmer Analyst 100 apparatus after degrading the samples in boiling HCl (37%).

7. Scanning electron microscope (SEM) characterization

The magnetic core-shell beads were observed by SEM just after preparation (wet) or after overnight drying. The wet samples were dehydrated through concentration gradient of ethanol (30-50-70-96-100%) before critical point drying (CPD 7501, Quorum Technologies).

Samples were directly mounted on stubs, or manually freeze-fractured after a fast plunging in liquid nitrogen and then gold-sputtered (Scancoat Six, Edwards). Observation was carried out with a conventional SEM operating at 15 kV (Cambridge Stereoscan S260).

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M A N U S C R I P T 8 2.

Magnetometry measurements

Magnetic moment and magnetization measurements were performed on a Quantum Design Ltd. MPMS superconducting quantum interference device (SQUID) magnetometer. Samples were prepared as follows: one magnetic and fluorescent chitosan alginate core-shell bead was introduced in a poly-methyl methacrylate (PMMA) cell sealed with a PMMA cap and nonmagnetic glue. From the magnetic measurement realized on one magnetic bead we can deduce the magnetic moment of the bead (emu = 1.10 -3 A.m 2 ) vs the magnetic field intensity (Gauss = 1.10 3 A.m -1 ).

9. Calibration of the magnetic field gradient for in vivo experiments

A cylindrical neodymium iron boron magnet (diameter 20 mm, length 10 mm, Supermagnete ® ) was used for in vivo experiments. Magnetic field intensity was measured using a Hall-effect sensor from the center of the magnet at a distance ranging from 0 to 5 cm.

Magnetic field intensity is 2560 Gauss when in contact with the magnet.

Animal care. Male Wistar rats, 10 to 12 weeks old and about 300 g weight, were housed under barrier environment in Servier's Experimental Animal Center. All rats were maintained in an air-conditioned room and subjected to 12-h dark/light cycles. Animals were handled in accordance with the guidelines of Servier's Animal Care Council. All rats were fasted 12 hours before the experiments but were allow free access to water.

10. Ultrasound imaging for placement of the magnet on the rat abdomen

A portable ultrasound apparatus (SonoSite EDGE, Fujifilm) was used to visualize the position of the stomach of each rat under anesthesia. Once the position of the stomach and the beginning of the duodenum localized a steel pinch was used to create an artefact in order to mark the desired position of the magnet. Position of the pylorus was label with a marker on the rat's abdomen. Magnet is then placed on the rat abdomen using the marked position to ensure that the magnet is placed on the stomach-duodenum's junction and fixed using

11. In vivo bioavailability study

Male Wistar rats weighted 300g and aged 10 weeks old were fasted prior to magnetic beads administration. 16 fluorescent and magnetic beads were conditioned in 2 gelatin capsules and administered by force feeding through a cannula going to the stomach of the rat in order to administer a drug dose of 20 mg/kg. 1 mL of drinking water was then given to the rat to aid dissolution of the capsule and liberation of the beads in the stomach. At 0.5, 1, 2, 3, 4 and 6 hours after gavage, 300 µL of blood were withdrawn from the rats at the jugular vein. Blood samples were then centrifuged and 150 µL of plasma were recovered and mixed with 9 µL of hydrochlorydric acid 2% before storage at -80°C prior analysis by mass spectrometry. Drug content in rat's plasma was then measured using MS/MS mass spectrometry (API 4000 ™ , ABSciex) coupled to UPLC chain (Acquity, Waters).

Statistical analysis was performed using a Student's t-test. P-values less than 0.05 were considered statistically significant.

1Magnetic Resonance Imaging (MRI)

A 4.7 Tesla MRI apparatus (Biospec 47/40 USR, Brüker) was used to acquired sagittal plans images of the rats under isoflurane anesthesia at several selected times 1, 2, 4 and 6 hours after force feeding the rats with the beads. A "turbo RARE" spin echo sequence was used (90°+180° impulsions) with parameters: TR = 1000 ms, TE = 20 ms, -RARE factor‖ = 4.

Geometry parameters were: FOV (field of view) = 8*8cm, matrix = 256*256 and resolution = 312*312 µm.

13. Near infrared fluorescence imaging

An infrared camera (ORCA II -BT-512 C4742-98-26, Hamamatsu Photonics) was used to acquire the fluorescence images. At several selected times 1, 2, 4 and 6 hours after force feeding the rats with the beads, animals were sacrificed by exsanguination after isoflurane were then processed using an acquisition and processing software (HiPic 6.4.1 and Wasabi, Hamamatsu Photonics).

14. Iron titration in the organs

The iron content of the liver, spleen and faeces of the rats were determined by AAS and compared for two groups of three rats. The first group was the control group and the second group was rats 24 hours after administration of the magnetic beads using magnetic retention for 6 hours. The faeces were collected twice, from the beginning up to 6 hours after beads administration and from 6 to 24 hours after the beginning of the experiment. At t + 24 hours, the rats were sacrificed by exsanguination and the spleen and liver were collected. Then all the samples were degraded in HCl 37% and the iron content was determined by AAS.

15. Histology study

After the last blood sampling at t + 6 hours after administration of the beads, the animals were sacrificed by exsanguination. Several tissues (liver, spleen, fore stomach and glandular stomach, duodenum, jejunum, ileum and caecum) of the rats were harvested and stained with Prussian blue and/or hematoxylin and eosin staining for inclusion in paraffin block and histological microscopic analyses (Olympus BX 41) (R. [START_REF] Bahnemann | RITA--registry of industrial toxicology animal-data--guides for organ sampling and trimming procedures in rats[END_REF].

Results

Magnetic retention: Fabrication of the magnetic carriers

Release properties of the chitosan alginate core-shell beads

Millimeter sized fluorescent magnetic chitosan-alginate core-shell beads were designed using a cross-linking process. First, chitosan polymer was marked by a flurophore (Alexa Fluor-

A C C E P T E D M A N U S C R I P T 11 750)
. Succinimidyl ester moieties of the fluorophore were covalently linked on the primary amino groups of the polymer. Fluorescent chitosan (5% w/v) was mixed with magnetic nanoparticles (50% v/v) and drug (10% w/v) (Fig. S1). This mixture was then injected through a syringe needle in a crosslinking aqueous solution containing tripolyphosphate (TPP) 2% w/v and alginate 1% w/v. TPP ions allow reticulation of the chitosan core whereas alginate precipitates at the shell due to its low solubility in acid pH. Alginate shell (30 nm thick) was clearly observed by SEM (Fig. 2b). The entrapment efficiency (EE%) of the drug was calculated using an indirect titration method. Amount of free drug that has not been able to be encapsulated into the beads was measured in the recovered crosslinking supernatant by HPLC using the standard HPLC titration method for the drug. Entrapment efficiency could then be calculated with the following equation (Eq.1):

-Entrapment efficiency in the beads was very high, EE% = 75%, compared to other formulations with this type of biopolymer [START_REF] Hari | Magnetic granules: A novel system for specific drug delivery to esophageal mucosa in oral administration[END_REF][START_REF] Seth | Performance of magnetic chitosan-alginate core-shell beads for increasing the bioavailability of a low permeable drug[END_REF][START_REF] Sezer | Release characteristics of chitosan treated alginate beads: I. Sustained release of a macromolecular drug from chitosan treated alginate beads[END_REF][START_REF] Zhang | A magnetic chitosan hydrogel for sustained and prolonged delivery of Bacillus Calmette-Guérin in the treatment of bladder cancer[END_REF]. The mean composition for each bead was water (83.76%), biopolymer (5.0 %), drug (6.64 %) and MNPs (4.6 %) in weight before drying. After drying overnight, one bead contained 368 µg of iron (approximately 10 15 MNPs) and 0.5 mg of drug.

The mean composition for dry bead was chitosan (30.7 %), drug (40.8 %) and MNPs (28.3 %) in weight. This composition will be suitable for in vivo experiments. The alginate shell is expected to prevent beads degradation when passing through the stomach region as this biopolymer is strongly insoluble in acidic pH (B. A. [START_REF] Teply | The use of charge-coupled polymeric microparticles and micromagnets for modulating the bioavailability of orally delivered macromolecules[END_REF]J. K. Vasir et al., 2003;[START_REF] Wang | pH-sensitive magnetic alginate-chitosan beads for albendazole delivery[END_REF][START_REF] Suknuntha | Characterization of muco-and bioadhesive properties of chitosan, PVP, and chitosan/PVP blends and release of amoxicillin from alginate beads coated with chitosan/PVP[END_REF]. Moreover, alginate coating of chitosan magnetic beads allowed drug release to follow a linear kinetic profile within 2 h for wet beads (Fig. 2a and2d) and is extended to 6 hours for dry beads (Fig. 2c and2d). No release of magnetic nanoparticles or fluorophore occurred throughout experiment time and

Magnetic properties of chitosan-alginate core-shell beads

The magnetic and fluorescent beads exhibit a superparamagnetic behavior like the MNPs themselves (Fig. S2A). The encapsulation did not induce any changes in their magnetic properties. The magnetic moment of one bead was measured using vibrating sample magnetometry (VSM) as a function of the applied magnetic field (Fig. S2A). The distance between the external magnet and the pylorus was experimentally determined to be 5 mm.

According to the calibration of the magnet (Fig. S2B), the value of the magnetic field is B = 611 Gauss (z = 5 mm). The magnetic force applied on the bead was calculated using the following equation (Eq. 2): .

Where µ z is the magnetic moment of the bead, µ z = 0.019 10 -3 A.m -2 (z = 5 mm and B = 611 Gauss) and the magnetic field gradient = 12 T.m -1 (z = 5 mm). The value of the magnetic force is F m,5mm = 0.23 mN.

Magnetic retention: imaging study

Magnetic Resonance Imaging

Due to their superparamagnetic properties, the beads can be easily visualized in MRI. Each bead containing a high amount of MNP (10 15 MNPs/bead) induces a negative contrast on T 2 weighted MR images (Fig. 1d). MRI study allows the localization of beads along the GI tract of rats. Imaging was performed on two groups of rats (n=3 per group). In the first group, a magnet was placed on the abdomen of animals before the start of the experiment using ultrasound imaging to locate the stomach-duodenum junction. The second group was the

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13 control group, animals without magnet on the abdomen. MR images (sagittal plans) have been acquired at 1, 2, 4 and 6 hours after administration of the beads to the rats by force-feeding in the stomach. Position of the beads along the GI tract can be visualized on the images as darker spots thanks to the negative contrast of magnetic beads (Fig. 3). For easier interpretation, position of the stomach and initial magnet placement were marked on the images respectively by red and yellow circles. One hour after administration, the beads were localized in the stomach for both groups (Fig. 3a and 3e, red circle). At t + 2 hours, some of the beads were still localized in the stomach and others began to circulate within the intestine for both groups (Fig. 3b and3d, red and yellow circles). The lack of differences between the two groups for shortest times can be explained by gastric emptying time. Beads are staying in the stomach before being pushed along the intestine. For latest times (t + 4 and t + 6 hours), localization of the beads along the GI tract becomes clearly different between the two groups. At t + 4 and t + 6 hours, it can be clearly observed that the dark zone corresponding to the magnetic beads was localized under the magnet position (Fig. 3c and3d, yellow circle. For the control groups, beads were not grouped in a special area (Fig. 3g and 3h, yellow circle). When the magnet was used in order to induce magnetic retention of the beads in the GI tract, the negative contrast due to the accumulation of the beads containing MNPs was observed localized under the initial position of the magnet. On the contrary, for the control rats without magnet, the beads could not be localized at a specific position. However, as the whole intestine was highly folded, all the loops could not be discriminated using MRI only. Therefore, NIR fluorescence was used as an additional imaging technique for further investigation of the magnetic retention of the beads in the intestines.

Near Infra-Red Fluorescence

The same protocol was used to image the beads using NIR fluorescence. Two groups of rats (n=3 per group) were studied. One group with magnet placed on the abdomen of animals before the start of the experiment to study magnetic retention and one group as a control

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14 without magnetic retention. For the times t + 1, 2, 4 and 6 hours after beads administration, fluorescence images were acquired first in the whole animal, under the initial position of the magnet (Fig. 4A). For the control group, at t + 1 and 2 hours, the fluorescence was localized under the magnet position (Fig. 4A e and f). At t + 4 and 6 hours, fluorescent intensity could no longer be observed under the initial magnet position (Fig. 4A g andh). For rats with the magnet, fluorescence intensity was strong and localized under the magnet position for every times (t + 1, 2, 4 and 6 hours) (Fig. 4A a-d), indicating that the beads were accumulated under the magnet position throughout the time of the experiment. After the first imaging setting, intestines were extracted from rats and imaged unfolded (Fig. 4B). For both groups, fluorescence was observed in the stomach, at t + 1 hour, (Fig. 4B a and e). For the rats with the magnet, fluorescence was very intense and localized in the upper part of the intestine (Fig. 4B a-d). For the control rats, fluorescence was dispersed and located lower in the intestine (Fig. 4B f-g). When magnetic retention was used, fluorescence images showed a stronger and localized intensity. This high and localized fluorescence intensity was due to beads accumulation and slower circulation time along the GI tract.

Magnetic retention: pharmacokinetics study

Pharmacokinetics study was performed to investigate the effect of magnetic retention on the bioavailability of the drug. Indeed, magnetic retention efficiency to retain the magnetic beads in vivo in the upper part of the intestine has been demonstrated by imaging. For this study the rats were fasted for 12 hours before beads administration. Three groups of three rats were used for this study. In the first group (n=3), the rats were fed magnetic beads containing the drug and a magnet was placed on their abdomen. The second (n=3) and third groups (n=3)

were the controls. In the second group, the rats were fed drug loaded magnetic beads, without the magnet. In the third group, the rats were fed with an aqueous solution of the drug. The first and second groups were to study the impact of magnetic retention of the beads on the

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bioavailability of the drug. The second and third groups were used to study the impact of the formulation of the drug inside the magnetic beads on the bioavailability of the drug. For all the rats, the dose was 20 mg/kg (16 beads per animal, 0.5 mg of drug/bead). Blood samples were taken at t + 0,5, 1, 2, 3, 4 and 6 hours after administration, then the drug concentration in plasma was measured by mass spectrometry. The drug concentrations (ng.mL -1 ) titrated in the plasma after oral administration of magnetic beads and retention with a magnet were compared to control rats without magnet and to rats fed with an aqueous solution of drug (Fig. S3), and are summarized in Fig. 5a. The peak plasma concentration (C max , Fig. 5b and5c) of the drug was reached 2 hours after administration with a value of 43.7 ng.mL -1 when magnetic retention was used compared to 15.7 ng.mL -1 without magnet and 10.2 ng.mL -1 for free drug administered in water. The increase in concentration found when magnetic retention was used was statistically relevant (p < 0.05, Student's t-test) when compared to both control groups (** p = 0.0016 and ***p = 0.0002). As a consequence the area under the curve (AUC t,, Fig. 5b and 5c) which corresponds to the integral of the concentration-time curve (after a single dose)

and represents the relative bioavailability of the drug, is 2.5 times higher for the group with magnet than that without magnet and even in the case of free drug administration (128 vs 53.2 and 40 h.ng.mL -1 ). This 2.5-fold increase in relative bioavailability when magnetic retention was used was found to be statistically relevant for both control groups (* p = 0.0109 and **p = 0.0074). The last blood sample was retrieved at t + 6 hours after beginning of the experiment and the concentration of drug was 15.3, 7.65 and 1.53 ng.mL -1 , respectively for the three groups (Fig. 5a and5b).

Magnetic retention: toxicity study

A preliminary toxicity study has been conducted after single administration of magnetic beads (16 beads per animal, 20 mg.kg -1 of drug), in order to determine the circulation path of the MNP after administration and retention in the intestine. MNP are well known to be easily

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16 accumulated in the spleen and liver. In this study, the iron content in spleen, liver and the faeces was measured by AAS after acid degradation. Histological examination of several organs was conducted in order to check that the accumulation of magnetic beads along the intestine did not induce any immune response from the endothelial barrier as well as the potential accumulation of iron nanoparticles in the liver and spleen.

MNPs accumulation in the organs

In this study iron content of liver, spleen, faeces were compared for two groups of rats. For the first group (n=3), magnetic retention is used to maintain magnetic beads in the GIT up to 6 hours and for the control group (n=3), animals did not receive any magnetic beads. The faeces were collected twice, from the beginning up to 6 hours after beads administration and from 6 to 24 hours after the beginning of the experiment. At t + 24 hours, rats were sacrificed by exsanguination and their spleen and liver were collected. Iron content in every samples was determined using AAS (Fig. 6a). Iron amount obtained 24 hours after administration for the first group was similar to the control group in the spleen (1.78 vs 2.36.10 -6 mol) and liver (10.8 vs 10.7.10 -6 mol), showing that no iron has been accumulated and that only endogenous iron was detected in the organs. The amount of iron in the faeces until 6 hours after administration for the first group was similar to the one of the control group (17.3.10 -6 mol vs 11.8.10 -6 mol). However iron content increased significantly (73.8.10 -6 mol) between 6 and 24 hours after administration compared to the value found for the controls (20.3.10 -6 mol). The amount of iron recovered in the faeces from t + 6 to t + 24 hours for the first group was very similar to the total amount of iron introduced in the organism by the administration of the magnetic beads (69.6.10 -6 mol). The total amount of iron introduced in the organism by the magnetic beads containing MNPs was eliminated and recovered in the faeces after the removal of the magnet from the abdomen of the rats at t + 6 hours.

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Histology study

After a single oral administration of magnetic and fluorescent chitosan-alginate core-shell beads to two groups of rats (with (n=3) or without magnet (n=3)), several tissues (liver, spleen, fore stomach and glandular stomach, duodenum, jejunum, ileum and caecum) were harvested and stained for histological microscopic analysis. In the stomach and intestinal portions, no changes considered to be of toxicological relevance were noted among rats (with or without magnet) (Fig. 6b-d). In the liver, the absence of Perls positive cells (e.g., hepatocytes, Kupffer cells) was supportive of an absence of iron uptake (Fig. 6e). The minimal to slight presence of Perls positive macrophages seen in the spleen of rats was considered to be within the spontaneous background, in line with the physiological degradation of red blood cells (Fig. 6f). No relevant microscopic changes were observed in the different portions of stomach, small intestines and caecum.

Discussion

Iron oxide nanoparticles and the drug DPP4 inhibitor (Fig. S1), were co-encapsulated in a chitosan-alginate core-shell bead through an extrusion method. This method enables the encapsulation of a large amount of magnetic nanoparticles in the matrix of the biopolymer (28.3 % in weight after drying, approximately 10 15 nanoparticles per bead) which is a key point regarding their magnetic properties. The magnetic moment of one bead has been measured by VSM (µ s = 0.347.10 -4 A.m²) and the core-shell structure was evidenced by SEM.

These core-shell beads are suitable for oral delivery because they are resistant in acidic media (stomach pH), mucoadhesive, exhibit a superparamagnetic behavior and a very high entrapment efficiency of the drug (75%). Another major advantage of our magnetic beads is that they cannot cross the GI membrane due to their millimeter-size. Therefore, the only material that is available for uptake by intestinal membrane to join the bloodstream is the (Biopharmaceutical Classification System and Formulation Development, 2011;[START_REF] Blume | The biopharmaceutics classification system (BCS): Class III drugsbetter candidates for BA/BE waiver?[END_REF][START_REF] Lindenberg | Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system[END_REF]. One of the challenges regarding the formulation is to find a drug-release profile suitable for in vivo administration. In our case the maximum drug release profile of the dry beads of 6 hours is well adapted.

The proof of concept of the magnetic retention has been made in a previous ex vivo study where the amount of drug permeated through the membrane exhibited a threefold increase when magnetic carriers were maintained near the jejunum in Ussing chambers (A. [START_REF] Seth | Performance of magnetic chitosan-alginate core-shell beads for increasing the bioavailability of a low permeable drug[END_REF]. In order to translate this concept in vivo, the magnetic charge of the beads as well as the magnetic field gradient were optimized. We evaluate the magnetic force applied by the external magnet on one magnetic bead to be 2.3 10 -4 N if we consider a uniaxial force. That is one order of magnitude lower than the magnetic force involved in the case of the magnetic retention of a magnetic pill containing a permanent magnet and an external magnetic field similar to the one used in a previous study by B. Laulicht and co-workers (2-4 mN) (Laulicht et al., 2011). The gastric emptying forces P gastric calculated in fasted rats are of the order 50.10 -5 N.cm -2 [START_REF] Laulicht | Understanding gastric forces calculated from high-resolution pill tracking[END_REF]. The gastric force can be thus calculated to be F gastric = P gastric .S = 3.9 10 -6 N for a 1 mm diameter bead. From our study we can conclude that the magnetic retention was efficient when the F mag was two orders of magnitude higher than F gastric . This is a very simple model because in this case, the interaction between the magnet and the bead is considered to be uniaxial. However this is very helpful to predict the magnetic retention because the magnetic moment of one bead can be measured and the magnetic force can be calibrated in order to know the magnetic field strength at a given distance.

According to this physical consideration we prove the efficacy of the magnetic retention of the beads when we compared two situations, with and without magnet. The retention of the magnetic beads was confirmed in vivo using both fluorescent and magnetic beads. Magnetic show an accumulation of the magnetic beads under the magnet position up to 6 hours after the administration of the beads whereas for the controls the beads cannot be localized at a specific position in the intestine. According to the high-speed acquisition of the NIR imaging we are able to give more information about the dynamics of the bead along the intestine. In the case where the intestine is folded, NIR images confirm MRI observations. Accumulation of the fluorescence signal, representative of the beads can be found under the initial position of the magnet up to 6 hours after gavage when magnetic retention is used. However when the intestine is unfolded it is possible to visualize the localization of the fluorescent beads in the intestinal loops. Magnetic beads are always located upper in the intestine when the magnet is used compared to the controls but the beads are not retained at a fixed position during the gastric emptying. The effect of the magnetic retention seems to be more related to a slowdown of the circulation time of the beads. Moreover we observe a more intense signal in the situation with magnet most likely due to the magnetic accumulation of the beads. In fact magnetic dipole-dipole interaction may contribute to the formation of aggregates, leading to an over-concentration of the magnetic carriers.

The correlation with the pharmacokinetics study is very interesting because after a single dose administration (20 mg.kg -1 ) in fasted rats we find a relative bioavailability of the drug 2.5 times higher when the magnet is used. The plasma concentrations of the drug were significantly higher after 2, 4 and 6 hours (p < 0.05, Student's t-test). The peak plasma concentration is reached 2 hours after administration that corresponds to the situation where the beads are still localized under the magnet near the absorption window of the drug (upper part of the intestine). After this time the circulation is slowed down and as a consequence the residence time in the region of interest is longer that can explain the increase of the drug plasma concentration.

In this study we prove that the magnetic retention is efficient in the case of a poorly available Biocompatibility of the magnetic chitosan-alginate beads was investigated in the GI tract tissue as well as in the organs where the MNPs are well known to be accumulated. This study demonstrated that the total amount of iron contained in the magnetic beads is recovered in the faeces after the removal of the magnet from the abdomen of the rats at t + 6 hours and digestion of these beads. The MNP are eliminated through the natural digestion route in the faeces. In addition, microscopic analysis of histological tissue section of different organs did not exhibit any sign of inflammation or increase of iron accumulation, indicating a good tolerance of these formulations in vivo.

Conclusion

The core-shell formulation of magnetic beads developed in this study is well adapted to the encapsulation of highly soluble drugs and to their oral delivery. The magnetic retention technique was used to investigate the therapeutic benefit of prolonged local delivery of therapeutics at their site of greatest absorption. The beads may be easily detected in the GIT by NIR or MR imaging and the efficiency of the magnetic retention may be evidenced before starting the pharmacokinetics study. The design of the magnetic field and of the magnetic beads must be done so that the magnetic is two times higher than the gastric force depending on the model used. Unlike delivery by intra-venous injection, no magnetic nanoparticles were found in the organs. This is a key point because for long-term treatment we can envisage the use of formulation containing magnetic nanoparticles. Magnetic localization prolongs intimate contact between the drug and the absorptive GI epithelium promoting uptake and bioavailability without damaging intestinal tissue while providing visual confirmation of localization and quantitative force-sensing feedback in real time.

  NH 4 OH, 7 mol). In order to be completely oxidized from magnetite into maghemite (γ-Fe 2 O 3 ), the solid phase was separated from the supernatant and immersed in a boiling solution of ferric nitrate (0.8 mol in 0.8 L, 30 min at 90-100 °C). After washing steps in acetone and diethyl-ether to remove the excess ions, the nanoparticles readily dispersed in water and formed a true -ionic ferrofluid‖ made of maghemite nanoparticles. The iron oxide surface bore a positive charge due to adsorption of protons in acidic media (HNO 3 , 4 mol, solution at pH between 1.2 and 1.7). On the microscopic scale, this colloidal suspension of maghemite nanoparticles exhibit a Log-Normal distribution of diameters with parameters d 0 = 7.5 nm and = 0.35, as measured by vibrating sample magnetometry (VSM). The final iron content was checked by atomic absorption spectrometry (AAS) (C Fe = 1.3 mol.L -1 , m Fe = 104

  Magnet was placed on rats' abdomen one hour before the start of the experiments.

  A C C E P T E D M A N U S C R I P T 10 anesthesia. The skin was removed under the position of the magnet. Bright field and fluorescence images were then acquired to visualize the beads under the magnet. Thereafter, the rib cage was open and the intestine was observed from the stomach to the caecum. Bright field and fluorescence images were acquired to localize the beads along the intestine. Images

  only due to passive diffusion. The iron concentration has been titrated in the released buffer at the end of each experiment to determine whether some MNPs were released from the biopolymer matrix. During the time of the experiment no iron was detected in the media.

  encapsulated drug. This drug is an antidiabetic molecule referred as class III molecule (BCS A C C E P T E D M A N U S C R I P T 18 classification), however the formulation can be generalized to other hydrophilic drugs

  infrared imaging were performed over a time-course of 6 hours. MRI

  the same physico-chemical characteristics than a lot of drugs.

Fig. 1 .

 1 Fig. 1. Scheme of the synthesis of the magnetic and fluorescent core-shell chitosan-alginate

Fig. 2 .

 2 Fig. 2. (a)-(c) SEM images of the magnetic and fluorescent chitosan-alginate core-shell beads.

Fig. 3 .

 3 Fig. 3. MRI sagittal images of the rat after magnetic beads administration at time a) and e) 1

Fig. 4 .

 4 Fig. 4. Fluorescence and bright field merged images of the beads in the rats intestine A) under

Fig. 5 .

 5 Fig. 5. a) Mean plasma concentration-time profiles following the oral administration of one

Fig. 6 .

 6 Fig. 6. (a) Iron content (10 -6 mol) in the spleen (), in the liver () and in the faeces at

Acknowledgements

The authors would like to thank Aude Michel for magnetic nanoparticles synthesis and iron spectrometry measurements; Michaël Trichet and the Service de Microscopie Electronique de l'IFR 83/FRE 3595 -CNRS-UPMC for the SEM images; all the technical support from Servier, Laure Pellé for her expertise on Ussing chambers; Catherine Caddor and Eric Jacquemin for their work with the animals. This research was supported by pharmaceutical company Servier and University Pierre et Marie Curie. Anjali Seth was financially supported by Servier.

Supporting Information

Supporting Information is available from the Wiley Online Library or from the author.

ToC


Emilie Ressouche

Sandrine Pensec

Benjamin Isare

Guylaine Ducouret

Laurent Bouteiller

Rational Design of Urea-Based Two-Component Organogelators


Bouchaib Riyami
email: b.riyami@gmail.com

Khalifa Mansouri
email: khmansouri@hotmail.com

Franck Poirier
email: franck.poirier@univ.ubs.fr

TOWARDS INTEGRATING MOOC IN THE MOROCCAN HIGHER EDUCATIONAL SYSTEM: ECONOMIC PEDAGOGICAL MODEL BASED ON ICT FOR ON-GOING EDUCATION AND TEACHER MOTIVATION

Keywords: Periodic continuous training, teachers' motivation, adaptability of training, economic model, distance training, MOOC, ICT for education

After launching LMD (Licence, Master, Doctorat) educational reform in 2013, the Moroccan higher education system encountered many problems and obstacles concerning the integration of information and communication technologies (ICT) in the traditional teaching methods, as tools to enable all training institutions to achieve higher level educational services, especially in a competitive mass education environment.

Several targets have been set in this direction:

-Improving continuing education of teachers using ICT.

-Modernizing teaching practices in training institutions by integrating ICT.

-Computerizing and sharing educational content with university learners.

-Raising awareness among university students on the importance of distance learning platforms through ICT.

Currently, with the provision of training and distance learning platforms such as MOOCs (Massive Open Online Courses), several trainings and online courses, in favor of learners and teachers can be proposed and organized by international training institutions and universities. Distance monitoring will improve the level, motivation and involvement of learners and teachers and therefore the feasibility and adaptability of such training in better and more adequate conditions and situations, especially the commitments of teachers.

This paper is an attempt to shed light on teachers' expectations in terms of periodic continuing education. It offers an educational business model of work, using ICT, which meets the requirements of LMD reform for the improvement of the teaching level and the teaching practices. It offers a set of management processes for the moral and material motivation of teachers, their involvement and their massive integration in on-going, periodic distance training using MOOCs. Finally, it suggests the inclusion of actual efficient and effective approaches in the use of ICT in teaching to facilitate teachers' daily work. This modeling has applications in the Moroccan educational context, especially in some large universities taken as examples for study.

INTRODUCTION

In recent years, the major question of the quality of higher education has become central in the Moroccan political scene and has raised much controversy. The landscape of higher education is in turmoil; the reforms have been applied continually, but the crisis in the educational sector still persists.

We must distinguish between problems of general education and the problems of higher education. The current crisis in higher education can be traced back to the problems of primary and secondary school education. To straighten the top, i.e. tertiary education, we have to solve the problems of primary and secondary education. Once this issue is settled, the level of students and raised, and the quality of training of our graduates rectified, continuity at the top will itself, with some changes in the organization and management of university structures, become smooth.

We can explain the problem of general education by: -The diversification of educational content in the different levels of education i.e. general education (primary and secondary school), higher education, and vocational training, in both the public and the private sectors, further complicates things. These systems are completely contradictory in passing from one cycle to another. There is no continuity in the program content between different levels of training.

-The failure of human resource management in terms of the teaching and administrative staff, especially after the implementation of the strategies advanced by several political key players to ameliorate higher education and human capital development, such as:

-The Reform of Moroccan Higher Education (LMD). [START_REF] Aamili | La formation des formateurs en TIC au Maroc : quelles stratégies ? », 4e ouvrage du RIFEFF[END_REF] -Integration of ICT in higher education Morocco (Morocco Numeric2013, INJAZ Program).

-The State-Universities contract (Commitment of universities and state).

In this paper, we propose an economic pedagogy model based on current market trends after the (LMD) reform to meet the needs of human resources, especially teachers. In addition, we also offer a management plan for the motivation and involvement of teachers in their pedagogical tasks. [START_REF] Karsenti | Trois stratégies pour favoriser l'engagement des participants à un MOOC[END_REF]

STATE OF THE ART OF UNIVERSITY TEACHERS ON-GOING TRAINING IN MOROCCO

In this part, we present the current situation of human resource management in terms of training teachers and administrators. The two categories are interdependent. No one category can claim superiority over the other, the failure of one automatically leads to the failure of the other. Unfortunately, today, Morocco does not have the potential categories to replace the existing ones.

Having teachers with the skills to be able to disseminate knowledge and educate future generations means that our university has infrastructural and educational resources to form this type of profile. However, this is not the case and it is not the university's fault. Freshmen coming to the universities either do not have the prerequisites to be successful or they are victims of a misguided choice from the start. The greatest danger of the Moroccan educational system can be traced to its inability to produce competent, specialized and motivated teachers, both in terms of quantity and quality.

For several years, the Moroccan state no longer recruits on the basis of skills and motivation as it did before. Those who choose to enter the public service as teachers do it out of necessity and not vocation or love of the profession. Moreover, the Ministry of Education has opted for direct recruitment for several years, by hiring teachers who joined the teaching profession without the required qualifications and without any pedagogical training. This step had quite negative repercussions on the quality of education at the university.

Teachers should be selected according to their skills, their level of education and their motivation and love of the teaching profession. [START_REF] Beers | Graduate training in the teaching of psychology: Essential skills for newinstructors[END_REF] They must be trained in specialized training centers using the most effective methodologies and new teaching approaches. These teachers must receive ongoing and periodic trainings [START_REF] Chanier | Communauté d'apprentissage et communauté de pratique en ligne : le processus réflexif dans la formation des formateurs[END_REF] [5] to be able to update and improve their course materials and their methodology, which would go hand in hand with the ultimate goal of the LMD reform.

The administrative and managerial staff are also recruited through an accumulation system of points (inspectors grades and seniority). Those lucky enough to be chosen for this mission of administration or management are usually quite old and tired as a result of their long years in the teaching or administrative jobs, lagging far behind in ICT and aspire only for rest/retirement. We propose continuous and periodic training on information systems (IS) to properly train young managers and administrative staff for schools.

GENERAL QUESTION FOR RESEARCH

The Moroccan Higher Education Reform (LMD system)

Among the solutions taken by the Moroccan state to address the major problems of higher education is the reform of the educational system, which started during the 2003-2004 academic year. It is based on a fundamental change in the program structures, educational practices and evaluation system.

The main causes for this change are:

-The low success rate;

-The fact that 50% of students leave university without a degree; -The training system was based on the passive transmission of knowledge oriented towards final exams and did not promote the development of analysis and synthesis.

The solutions proposed in the context of the educational reform face the challenge of improving the level of students and promoting success at the university by the implementation of:

-A new educational architecture (LMD);

-New learning and assessment practices;

-Training all students, regardless of option, in languages, ICT, techniques of expression and communication and methodology.

The integration of ICT in education is considered an important factor in promoting success and avoiding failure.

The development of ICT skills is identified as a transversal competence to be built and used by the student as part of the activities in various subjects of the curriculum. [START_REF] Ghouati | Réforme LMD au Maghreb : éléments pour un premier bilan politique et pédagogique[END_REF] Some of the objectives of the integration of ICT in teaching and learning as part of the educational reform are to:

-

Problems of on-going education for Moroccan teachers.

Other problems and barriers for higher education in Morocco in the establishment of a teacher training in the best conditions include among other variables such as, the availability, involvement and motivation of teachers, the suitability of the training, the monitoring of continuous and periodic trainings and especially the difficulty, if not the impossibility, of physical attendance during continuous trainings.

Today, and with the provision of training and distance learning platforms, based on online courses such as MOOC (Massive Open Online Courses) [START_REF] Nawrot | Building Engagement for MOOC Students -Introducing Supprot for Time Management on Online Learning Platforms[END_REF], in favor of teachers, can be proposed and organized by educational institutions (schools, universities, institutions, etc.). The Remote monitoring aspect of these courses can enhance the level, the motivation and the involvement of teachers and, therefore, the feasibility and adaptability of such trainings to various teacher situations and in better and more adequate conditions.

To support the use of MOOC by Moroccan teachers, the government has launched several projects to motivate the entire administrative staff, teachers and university students, especially INJAZ project (INJAZ Al-Maghrib), which is based on the acquisition of laptops and modems for quite low prices, and a free broadband connection for a year. We can also cite the MARWAN project (Morocco Wide Area Network) to interconnect all the Moroccan universities and educational institutions; the GENIE project (Generalization of ICTs in Education 2009-2013) [START_REF] Kabbaj | Programme GENIE au Maroc : TICE et développement professionnel[END_REF], the proposed financing of all integrations of educational platforms in all universities and Moroccan educational institutions and finally the spread of broadband internet access in all rooms, corridors and halls in all Moroccan universities.

For the purposes of on-going and periodic trainings, whereby teachers' attendance is necessary, large budgets are allocated by the government. But the major problem encountered is that in general teachers encounter many obstacles to attend these trainings. These obstacles include among others:

-Time constraints: teachers do not have enough time to travel in order to attend these trainings, -Content Problems: most of these trainings, whereby attendance is obligatory, are based on content that is not always updated, -Problem of content adaptation: at times, the training offered does not match the teachers' real needs and does not respect their levels and skills, -Traceability Problem: the lack of year-to-year follow-ups and gradation of these continuous and periodic trainings.

-The Training Evaluation Problem.

Following the requirements of the LMD reform and techno modern teaching approaches, such as the use of ICT in teacher training, we offer an information system (IS) [START_REF] Germak | Management des systèmes d'information », Manuel and applications[END_REF] [12] capable of managing and effectively monitoring and tracking continuing education offered in favor of Moroccan teachers.

PROPOSAL OF AN ECONOMIC PEDAGOGY MODEL FOR TEACHER TRAINING

In this section, we offer a pedagogical plan using MOOC for teacher training [START_REF] Cisel | Chronique des MOOC[END_REF]. MOOC platforms offer updated content, well adapted to the level, the specialty and type of course (theoretical course, tutorial or practical work). Some details about some MOOC platforms are considered in Table 1 bellow: The MOOC platforms, in Table 1, are xMOOC (transmissive) MOOC [START_REF] Pomerol | Les MOOC Conception, usages, et modèles économiques[END_REF], that is to say, they use the same educational approaches as the traditional face-to-face system, and their educational content is made of videos, documents, tutorials, quizzes and of practical workshops. Teachers are encouraged to use these platforms for self-training, in function of their specialty, level and type of course, to improve the educational content of their courses and to benefit from new experiences of other teachers on a global scale.

Our pedagogical teacher-training plan is as follows:

-For teachers of modules in relation or closer to project management, planning, project management diagrams and flowcharts, production management, we assume that the most suitable MOOC platform would be the MOOC ABC project management. This platform is animated by the best teachers in Lille center school and supervised by Professor Rémi Bachelet [START_REF] Delpeyroux | Intégrer un MOOC dans un cursus de formation initiale[END_REF]. It is a project management-oriented MOOC.

-For teachers of modules such as mathematics, statistics and operational research, we feel that the Khan Academy MOOC, specialized in preparing students for math exams, is the most appropriate for these scientific modules. -For teachers of computer modules, we offer Openclassroom, distance-learning platform that provides these learners (students and teachers) with in step-by-step web-oriented tutorials. It also contains general IT and business management modules. This MOOC platform is the European leader in the field of programming and computer web. -For teachers of other general modules we suggest the Coursera MOOC, Edx and FUN that offer digital-rich content to learners, for any type and category of course. They are of a more general nature.

All these MOOCs offer courses, follow-ups and current resources for the benefit of learners (students and teachers), which are disseminated by the best schools in the world. This is a precious opportunity for self-training and on-going education for Moroccan teachers. [START_REF] Karsenti | MOOC Révolution ou simple effet de monde[END_REF]

PROPOSAL OF A MANAGEMENT PLAN FOR THE MOTIVATION OF TEACHERS IN TRAINING.

To better benefit from the MOOC novelty and reliability, presented above, under the form of tools and resources for ongoing training, we invite teachers to:

-Attend regular periodic trainings on these learning platforms to update their teaching content, -Share, continuously and permanently, their knowledge and experience with teachers from around the world, -Improve their educational content by exploiting the digital content disseminated by the best universities in the world, -Educate students on free international learning platforms such as MOOC (Massive Open Online Course) -Interact with learners when using online courses (emails, forums and discussions via social networks) -Have supporting documentation for training from officials, such as MOOC certificates, badges and, of course, participation certificates [START_REF] Zheng | Understanding Student Motivation, Behaviors, and Perceptions in MOOCs[END_REF].

-Ensure Traceability of control and monitoring by training teachers on MOOC. To do so, we provide a good information system that will provide and manage these operations.

The MOOCs also offer ways for motivating learners, such as certificates, badges, certificates of participation and free membership in some new modules.

In conclusion, teachers are encouraged to apply, share and experience the key input obtained from the MOOC in their daily work with students, with the ultimate aim of improving the Moroccan educational system, which, in turn, must incorporate information technology and communication for education (ICTE) to good use. [START_REF] Trouche | Les recherches francophones en TICE dans le pourtour sud de la Méditerranée[END_REF]

CONCLUSION AND PERSPECTIVE

We proposed continuous and periodic training for the benefit of teachers as self-study via MOOC, in order to face the problems of lack of time and the difficulty to attend face-to-face trainings.

  Modernize the educational practices in training institutions, -Communicate, inform, search and collaborate remotely, anytime, -Keep track of one's learning, -Organize more independently one's homework, -Benefit from a stimulating digital learning environment,-Connect to a library and a media library on a global level.[START_REF] Benchenna | L'appui de la France à la Rérofme de l'Enseignement supérieur (ES) au Maroc : quelles finalités et quels enjeux ?[END_REF]

Table 1 :

 1 Some details of the MOOC

	MOOC Platform	Learners level	Type of course	Specialty	Institution
					partners
	Coursera	Intermediate and	All types of	All course	University :
		expert	courses	categories	Edimbourg, of
					Amsterdam,
					Colorado à
					Boulder
	Edx	Beginner,	All types of	All course	MIT, Harvard
		intermediate and	courses	categories	University,
		expert			Berkeley
					University of
					California
	FUN	Beginner and	All types of	All course	Le CNAM, INRIA,
		intermediate	courses	categories	University of
					Bordeaux, Institut
					des Mines-
					Télécoms

We also advanced an educational plan based on the use of MOOC by specialty, level and type. In the end, we mentioned a set of benefits and managerial processes for motivating teachers to take distance learning. [10] [16] In conclusion, we propose a reform in on-going education and distance learning for the benefit of teachers, and an integration of MOOC in the Moroccan educational system [14] by expert teachers in the field.


Bouchaîb Riyami

Khalifa Mansouri

Franck Poirier

TOWARDS A HYBRID UNIVERSITY EDUCATION, INTEGRATION OF MOOCS IN INITIAL TRAINING PROGRAMS: A CASE OF A BIG PRIVATE EDUCATION STRUCTURE IN MOROCCO

Keywords: ICT, MOOC, Moodle, face-to-face training, distance training, educational system, evaluation system, hybrid evaluation

For several decades, the main elements of the educational triangle of higher education in Morocco: the teacher, the learner and the knowledge very marginally profited from information and communication technologies (ICT). But with the explosion of the learning management systems as Moodle, platforms of electronic learning such as MOOC (Massive Open Online Courses) and the appearance of the new mobile devices as smartphones and tablets, the process of initial training in the Moroccan universities changed a lot and in-depth.

This article presents the experience of implementation of an integration process of distance learning platforms such as MOOCs in programs of initial trainings of a big private structure of higher education in Morocco for the benefit of 2000 students, distributed on eight training centers and supervised by approximately 250 teachers.

The paper will handle the general concept of the issue problem, the modelling and the implementation of the process of integration, the motivation mechanisms of the teachers and the learners to pursue them during the phase of the change, the control system and the follow-up of the feasibility by the P3M (Principal Permanent Professor MOOC), conditions of use (isolated or collaborative), as well as the proposal of a hybrid evaluation system.

The paper presents the advantages, interests and saving (time and costs) generated from this experience, as well as the moral and material values created through the integration of this process in trainings within the university group under question and in particular the increase of the success rate of the students.

INTRODUCTION

Today, the success of MOOCs (Massive Open Online Courses) is not limited only to their openness to all heterogeneous learners, but also in their integration into the curricula of initial training in higher educational institutions. In the latter case, it is a very different situation of the opening to the public because it is no more about free learners (often industrial professionals), but it is rather students groups following their mandatory courses as part of their initial degree training curriculum. In case of requirement of these parallel training as part of initial training, we will analyze the situation in a double: the rate of satisfaction of learners and teachers in the use of MOOCs and success rate in the achievement of the aimed objectives.

In this article, we present the experience of implementing an integration process of distance learning platforms MOOCs into the curricula of initial training of a large private higher education structure for the benefit of 2000 students spread over eight training centers and supervised by about 250 teachers.

In the first part, we recall the general context of the research, and then we describe the process of integrating MOOC in initial training courses in the higher education group. We then present the motivation mechanisms for learners and teachers, and try to introduce a System of assessment and traceability of learners in MOOC as well as a dual assessment system. Finally, we present the benefits, interest and savings derived through the use of this educational approach.

GENERAL RESEARCH CONTEXT

The general context of our research is about the experience of implementing a process of integration of distance learning platforms in initial training curriculum of a private higher education group in Morocco. Since its creation in 1981, the group uses a policy of excellence enabling it to rise to the top ranks of private higher Moroccan engineering and management schools distinguishing itself by the quality of the training of its graduates, its close ties with business partners, its dense network of former graduates and its influence both nationally and internationally.

Today in figures, the group consists of:

• Eight training centers nationwide, three centers in Casablanca, one in Rabat, one in Marrakech, a one in Fez, a one in Eljadida and one in Settat.

• Thirty-five years of experience in the field of Moroccan private higher education.

• Over 250 permanent teachers and individual contractors.

• More than twenty outsourced training in alternation with French partner universities (UBS southern Brittany, Lorraine, Rennes, Perpignan, Tours, Lyon 1, Upper Alsace, INSA Lyon).

• Over ten thousand winners in the job market.

• More than students from more than 20 countries.

• More than ten higher education courses accredited by the state.

• Several certificates prepared by the students of the group, such as CISCO 1 Certified IT PEARSON VUE2 .

Since the creation of the group and along several years, all initial, continuous and outsourced foreign universities are held-face-to-face. But today it has chosen to follow the following trends:

• Integration of distance learning platforms open to all the public as MOOCs.

• Use of digital content management e-learning platforms as Moodle

• Application of the set of the Higher Education Ministry which states, for new processes of accreditation, integration, in all courses, of distance learning via a MOOCs or LMS (Learning Management Systems) to diversify the style of training.

• Monitoring the experience of launching the first MOOC platform by the University Hassan II in Casablanca in January 2015 [5].

According to the above trends, our group is obliged to integrate MOOCs in the initial training course as an experience based on a precise specification to enhance its classical traditional face-to-face system and achieve other specific objectives related to the quality of training, such as:

• Heavy use of information and communication technologies in the field of education (ICTE).

• Alignment of group trends and innovation of information and communication technologies ICT in education systems.

• Opening internationally to improve its levels of learners.

• Interaction of the group's students with students from around the world via discussion forums of MOOC.

• Interaction of the group's teachers with their students and with teachers and learners around the world to enrich their experiences in teaching.

• Learners build their knowledge by themselves without the presence of his teacher.

But beyond this observation, we set the following methodological issues:

• How to motivate students to use MOOC in their learning?

• How to motivate teachers to use MOOCs to complement their teaching materials?

• What MOOC to be used for a given level in the course of initial training? And why?

• How do teachers assess learners during using MOOC?

MODELING AND IMPLEMENTATION OF THE INTEGRATION MOOC PROCESS

Presentation of the traditional curriculum of initial training of the group

The initial training curriculum of the group are conducted in face-to-face and for five years of study, both for engineering (Figure 1) and for management (Figure 2).

Modeling and implementation of the integration MOOC process

To improve the initial training curriculum in our group and align its educational system to current trends in international educational systems as in the case of micro master, experience launched by the USA [2] [START_REF] Pomerol | Les MOOC Conception, usages, et modèles économiques[END_REF]. Integrating of information and communication technologies (ICT) in its education system, we propose a hybrid teaching process [START_REF] Ja Konstan | Teaching recommender systems at large scale: Evaluation and lessons learned from a hybrid MOOC[END_REF], a part of it consists of face-to-face training and another part of it is distance learning through the world-famous e-learning platforms such as ABC MOOC Project Management [START_REF] Delpeyroux | Intégrer un MOOC dans un cursus de formation initiale[END_REF], Coursera, EdX, FUN, Udacity, khan academy and OpenClassroom.

According to the programs of initial training courses, the blended learning process (set of hybrid training) must be adapted to different levels of options and pathways, and must meet specific requirements in education for the group. For this reason, we have applied the hybrid teaching process at each level of initial training for each sector after discussions with the group managers, and from our experience as trainers of ICT for more than fifteen years. Table 1 presents our proposed process for integrating MOOC at each level of initial training curricula of both engineering and management. And for each level, we have MOOC according to their degrees of difficulties and their educational content.

Justification

From Table 1, the first two years of initial training courses are face-to-face about 100%, as learners, arrive very young, without experience and without autonomy, just after obtaining their bachelor's degrees to integrate higher studies. They have many gaps as for the use of Information and Communication Technologies (ICT). These two years are considered preparatory base years in which they need are 100% face-to-face supervising. So we will not integrate MOOC along the first year of training.

From the third year, we have proposed the integration of MOOC as Open classroom, FUN and EdX with a rate of about 25%, and the rest of the training is face-to-face. The MOOCs proposed at this intermediate level offer courses to the public of all levels beginner, intermediate and advanced. The MOOCs are xMOOC (MOOC transmissive) [START_REF] Pomerol | Les MOOC Conception, usages, et modèles économiques[END_REF], that is to say, they have the same educational approaches that the traditional face-to-face system has and their educational content are composed of videos, documents, work directed to quiz and practical workshops.

OpenClassroom is a distance-learning platform, which offers courses to students in the form of stepby-step tutorials, web oriented, general computer and business management modules. Academy with a rate of about 50%. This choice is motivated by the fact that at the fourth year, all options and fields of study have a first training module about project management. We think that the best MOOC platform suitable for this module is the MOOC ABC project management, which is animated by the best teachers of the school and the center of Lille supervised by Professor Rémi Bachelet [START_REF] Bachelet | compilation des interventions disponibles en vidéo, des diapositives de présentations[END_REF]. The second introduced module, concerning mathematics, statistics, and operations research and optimization techniques. We found that the MOOC Khan Academy specializes in preparing learners for mathematics exams, is the most suitable for this training module.

For the fifth year level of all fields of study and options, we have increasingly proposed, Coursera and Udacity MOOC, increasing the utilization rate to about 75%. As students have achieved a high level of maturity in distance learning. In addition, our group offers to its students to follow the initial training courses during the day or evening. Learners at this level don't need a direct supervision by teachers except by a rate of 25% in training. Among the benefits that one can also cite the MOOC digital content that is richer and includes advanced modules and adapted at this level such as: business intelligence, business games, advanced databases, pricing policy, product politics, CRM, etc. [START_REF] Waters | Breaking the MOOC model[END_REF].

LEARNERS AND TEACHERS MOTIVATION MECHANISMS

In our approach, we invite teachers to attend periodic and ongoing training organized by our group on MOOCs platforms [START_REF] Vachon | Préparation des nouveaux enseignants et intervenants en FAD au canada francophone[END_REF]. And through these continuous training, teachers will have the opportunity to interact with teachers from around the world to [START_REF] Karsenti | La formation de formateurs et d'enseignants à l'ère du numérique : stratégies politiques et accompagnement pédagogique, du présentiel à l'enseignement à distance. Montréal[END_REF], share their experiences with other teachers, enrich their educational content for digital content shared with teachers of the best schools and university in the world such as MIT, Harvard University, Stanford. And to use the digital content made available by MOOCs as MOOC ABC Project Management works of to hand in Rémi Bachelet [START_REF] Bachelet | Cours de Gestion de projet[END_REF] providing content as a PDF, doc, video, quizzes, and work to make.

As for teachers of our group who are aligned to this new approach to teaching, they have to respect the clauses of periodic continuous training offered by the group on the one hand. Also to explain and share the great benefits of MOOCs platforms of profiles' learners, and accompany learners throughout the period of a programmed module on the MOOC.

Note also that there are other motivational projects for teachers on information and communications technologies (ICT) for education, set up by government departments as INJAZ [3] LAWHATI [4], mainstreaming of ICT [START_REF] Kabbaj | Programme GENIE au Maroc : TICE et développement professionnel[END_REF] and MARWAN [START_REF]Moroccan Academic and Research Wide Area Network[END_REF].

The MOOCs platforms provide learners with supporting documents at the end of the online training. These documents are certificates, certificates of participation or badges, which motivate learners to take courses on MOOCs hoping to also, improve the quality and content of their CVs [START_REF] Zheng | Understanding Student Motivation, Behaviors, and Perceptions in MOOCs[END_REF].

We have also proposed to our group, in the motivational part of learners on the use of MOOCs, and as part of quality control, communication and marketing to distribute to learners tablets or mini netbooks with a broadband connection. With this motivation, the group will have more students in the coming years and may include costs incurred in the purchase of such equipment and included in student registration fees [START_REF] Caron | Présentation d'une méthode et d'outils pourévaluer les perceptions des apprenants dans un MOOC[END_REF].

TRACKING CONTROL SYSTEM OF LEARNER TRAINING.

Our group has established a teacher-based P3M (Principal Permanent Professor MOOC) having as a role to control MOOCs responsible teacher of each level of the curriculum. That are the items checked are: the interactions between learner-learner, learner-teacher and teacher-teacher, the online courses continuity monitoring and management of locks and problems of MOOCs.

In our educational approach and in this control and traceability system for teachers and learners, we offer the mapping presented in Figure 3. In this control approach, we propose the following approach as motivation for the successful integration of MOOCs in initial training curriculum of our group.

School Director of Management

• Each P3M teacher is responsible for monitoring the works of supervising of one or more teachers per MOOC platform and level.

• Each teacher is assigned to a MOOC platform, according to his/her specialty and population (same level of several centers), and responsible for overseeing the public and is supervised by a P3M.

• Each teacher is responsible for controlling all interactions learners together, and the interactions of learners in quizzes, multiple choice and work to hand in.

• End of the semester, teachers are to prepare a report to be given to P3M to assess learners according traceability interactions carried out and according to a dual assessment system we are proposing in the next paragraph.

HYBRID EVALUATION SYSTEM

The current MOOC platforms tend to integrate online assessment activity of a large number of learners at the same time. The question that is always asked is, whether or not a learner should be assessed after training made on a MOOC. And if so, why should he/she be assessed? And what is the right way to get a better assessment and verify the validity of this distance assessment?

We should evaluate to educate learners about the importance of the use of MOOC, and to help them validate their achievements and therefore advance in their training. But the big problem is that we are in a logic of self-study and individual work which could lead to cheating or plagiarism which may distort the expected assessment.

There are several ways to assess learners online like automatic assessment, peer assessment and self-assessment [START_REF] Monter Un Mooc De A À Z | Matthieu Cisel Professeur de l'ENS de Cachan chapitre Scénarisation des activités d'évaluation[END_REF].

We can note several ongoing research on the integration of online learner's evaluation activities, such as the work launched by the designers of the EDX MOOC platform hosted by MIT and Harvard University, and fifteen other world universities. These designers have announced the creation of an automatic correction software short answer to questionnaires, tests, homework, essays and critical analyzes [START_REF] Konstan | Teaching Recommender Systems at Large Scale: Evaluation and Lessons Learned from a Hybrid MOOC[END_REF].

In our approach, we consider that the online assessment is not sufficient, that is why we offer a hybrid evaluation system hoping for the success of the experience of in integrating MOOCs in initial training courses of our group. This can be described as follows:

• Following courses on the MOOC platforms'.

• Tracking and tracing the interactions and works of learners by their teachers on MOOCs.

• Quizzes, multiple choice answers (MCA) and works to hand in by learners via automatic evaluation platform MOOC.

• Reception for validation of MOOC supporting documents such as certificates, badges or certificates of participation in the chapters of the course.

• Back in class to take face-to-face exams, monitored by a conventional evaluation by the teacher or the teaching team.

These points lead us to propose a final assessment on the following criteria:

Final mark = Average (face-to-face exam + learners traceability + supporting documents).

Learners traceability = Average (Quiz mark + MCA mark + peers mark)

Peers mark = an evaluation mark given by learners to each other [START_REF] Monter Un Mooc De A À Z | Matthieu Cisel Professeur de l'ENS de Cachan chapitre Scénarisation des activités d'évaluation[END_REF].

Supporting documents = MOOC certificate or badge or certificate of participation

EARNINGS, BENEFITS AND SAVINGS DERIVED BY THE GROUP USING THIS APPROACH

The teaching model and the hybrid evaluation process of learners that we have proposed had many benefits, interest and produced a lot of savings for our group, and had a big positive impact on all learners, teachers and the teaching staff (see table 2).

Table 2: Advantages, interest and savings from using the new hybrid-teaching model.

Advantages Interests Savings

-Openness of learners and diversification of information resources.

-Learners can benefit from the experiences of other learners in the world.

-Teachers can improve their teaching methods, their educational content and experiences.

-Relieve the teaching team through the automatic feedback, through selfassessment and peer review.

-Learners enjoy the best digital educational content.

-Learners work in groups and in better conditions according to programmed time slots on MOOCs.

-Learners construct their knowledge themselves.

-Teachers take advantage of periodic and ongoing training on MOOC organized by our group.

-More free space in the premises of the group, the fact that students learn online, at home or in groups in public spaces.

-Teaching teams relieved and simply guide learners at weekly meetings to meet specific needs of learners.

-The foreign teachers should travel less which would.

CONCLUSION AND PERSPECTIVES

Through this contribution, we were able to show the experience of a private university group in Morocco in the establishment of a new hybrid learning process that responded to very specific needs.

The integration of the approaches we have proposed in this article and which is primarily based on hybrid teaching process, the hybrid evaluation system [START_REF] Karsenti | MOOC Révolution ou simple effet de mode ? Revue internationale des technologies en pédagogie universitaire[END_REF], the motivation of learners and teachers had much impact on this group and generate many benefits, interests and tangible and intangible savings. However, this approach is limited to local initial training curriculum of the group without having the opportunity to expand it to other continuing education3 , and outsourced training in collaboration with French universities.

In order to minimize travels for teachers of French universities partners of the group, requiring, usually a very complicated logistics to find suitable time slots for both sides to schedule courses, it is desirable and beneficial for partners to apply our approach to training and assessment and allow learners to follow distance learning and online through MOOCs [START_REF] Engel | Qualité de la Science Française[END_REF].

Figure 3 :

 3 Figure 3: Mapping of control and traceability system for teachers and learners by P3M

Cycle Engineering degree 5th year Degree from the IGA engineering school Possibility of double diploma Master of French university partners Diploma engineer or master Project engineer and company internship

		Computer Science Methods Applied to Business Management	Software engineering and image processing	Network engineering and security systems	Automated systems engineering and quality control	Telecom Engineering embedded systems and networks	Engineering schools in France or French universities
		Project engineer and company internship
	4th year	Computer Science Methods Applied to Business Management	Software engineering and image processing	Network engineering and security systems	Automated systems engineering and quality control	Telecom Engineering embedded systems and networks	Engineering schools in France or French universities
	3rd

year Undergraduate degree of the IGA Possibility of double diploma of French partner universities licenses Project and internship application in business Computer systems engineering Electronic systems engineering Preparatory cycle 2nd year Project and internship application in business Computer and electronic engineering systems 1st year Project and internship application in business Computer and electronic engineering systems Cursus Scientific or technical baccalaureate

			DEC -
	CEC	6th	year
			Figure 1: Traditional initial training Curriculum: Engineering

Accounting degree DSCG -Higher Diploma in Accounting and Management Management cycle degree 5th year Degree from the IGA engineering school Possibility of double diploma Master of French university partners

					Manageme
					nt school
					diploma or
					master
		Project and business manager internship
					Business
		Information System Audit and Management Control	Information and Financial Engineering System	Information System Marketing and Trade	schools in France or French
					universities
		Project and business manager internship
					Business
	4th year	Information System Audit and Management Control	Information and Financial Engineering System	Information System Marketing and Trade	schools in France or French universities
	3rd

year Undergraduate degree of the IGA Possibility of double diploma of French partner universities licenses Project and internship application in business Information System Finance and Control Information System Marketing and Trade Preparatory cycle 2nd year Project and internship application in business Information systems and business management 1st year Project and internship application in business Information systems and business management Cursus Bachelor all options Figure

2: Traditional initial training Curriculum: Business Management

In general, and in both cases, the initial training courses in engineering courses and those of business management, the first two years are considered preparatory years in which, students follow a general and versatile training. From the third year, students choose a specialization, fourth, and fifth year, they choose again a second greater specialization.

Table 1 :

 1 The integration process of MOOC for each level of initial training of the two streams of group in question.

	Curriculum of Engineering	MOOC	Level	Curriculum of management
		Open
		Classroom, FUN,
		EdX, Coursera, Udacit, ABC Project	5th year
		Management,
		Khan academy
		OpenClassroom,
		FUN, EdX, ABC Project Management,	4th year
		Khan academy
		OpenCloassroo	3th
		m, FUN, EdX	year
		No MOOC,
		formation face-
		to-face 100%.	1st
			and
			2nd
			year

  It is the European leader in the MOOC sector.

	EdX: MOOC is an open source, which provides learners with training modules for beginners,
	intermediate and advanced, and most of the courses are in English. The course modules are in the
	form of videos, Word documents, PDF and PowerPoint. It is a US platform and its partners are the
	most prestigious universities in the world such as MIT (Massachusetts Institute of Technology),
	Harvard University and University of California Berkeley [11].

FUN: is a French MOOC platform, which offers courses with the same principle as EdX, It is technically supported by the open source, open EdX platform and supported by Google since September 2013 [6].

For the fourth year levels of training courses within our group, we have proposed the same MOOC platforms used in the third year, plus two other platforms ABC Project Management and Khan

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