Samahe Sadjadi
email: samahesadjadi@yahoo.com

Maryam Akbari

Eric Monflier

Majid M Heravi

Bastien Leger

Pd nanoparticles immobilized on halloysite decorated with a cyclodextrin modified melamine-based polymer: a promising heterogeneous catalyst for hydrogenation of nitroarenes †

For the first time, a hybrid system composed of halloysite (Hal) and a cyclodextrin modified melaminebased polymer is developed and employed for immobilization of Pd(0) nanoparticles. The resulting catalytic hybrid system, Pd@HTMC, was then applied as a heterogeneous catalyst for hydrogenation of nitroarenes to the corresponding anilines. The results established that Pd@HTMC could promote hydrogenation under very mild reaction conditions and in a relatively short time. Moreover, investigation of a sterically demanding substrate, nitro-naphthalene, as well as a substrate with a competing functional group, 4-nitroacetophenone, confirmed that the catalyst is capable of hydrogenation of a sterically demanding substrate while selectively hydrogenating the nitro functional group over keto-functionality. The recyclability experiment proved that the catalyst was recyclable up to six reaction runs with a slight loss of the catalytic activity and Pd leaching. Moreover, a hot filtration test confirmed the heterogeneous nature of the catalyst. Finally, the contribution of the cyclodextrin modified melamine-based polymer to the catalysis was confirmed by comparison of the catalytic activity of Pd@HTMC with control catalysts.

Introduction

Hal is a natural dioctahedral 1 : 1 layered aluminosilicate (Al2Si2O5(OH)4•nH2O) with chemical and physical properties similar to kaolin. Hal possesses a tubular morphology with Al-OH octahedral sheet groups on the inner surface and Si-O-Si groups on the outer surface. [START_REF] Pasbakhsh | Natural Mineral Nanotubes: Properties and Applications[END_REF][START_REF] Christoforidis | [END_REF][3] The layers of Hal are separated with a monolayer of water molecules. The exterior surface of Hal is negatively charged, while the interior lumen is positively charged. 4 Besides the exceptional tubular morphology, Hal benefits from other advantages, including high thermal and mechanical resistance, availability, a non-toxic nature, biocompatibility, high surface area and the capability for both inner and outer surface modification. [5][6][7] These features render Hal as a promising candidate for application in various fields 8 such as packing, adsorbents, polymer fillers, drug delivery, 9 flame retardancy, energy storage and more importantly catalysis. 10 Recently, many attempts have been devoted to establishing the catalytic application of pristine and functionalized Hal. 10 In this line, both experimental and theoretical studies have confirmed that functionalities on the surface of Hal played an important role in the catalytic performance of the final catalyst. [11][12][13] Cyclodextrins, CDs, are cone-shaped cyclic oligosaccharides with a hydrophobic cavity and a hydrophilic exterior. 14 ,  and -CDs possess 6, 7 and 8 glucopyranoside units, respectively. Among the various CDs, -CD is of great interest due to its cavity size and relatively low cost. 15,16 CDs are not only non-toxic and biocompatible, but also capable of the formation of an inclusion complex with various guest molecules with the appropriate size and polarity. To date, CDs have been applied in a diverse range of applications such as the synthesis of nanomaterials and in the food industry, drug delivery and catalysis. [17][18][19][20][21][22][23] Among various applications, the use of CDs in catalysis has been intensively focused on. 19,22,24 Notably, CD can act as a molecular transfer shuttle and facilitate the conversion of the substrates at the aqueous/organic interface. 25,26 Anilines are versatile fine chemicals, useful for the production of agrochemicals and antipyretic drugs, dyes, pigments, and pesticides. 27,28 Conventionally, the amine derivatives are produced by the catalytic hydrogenation of nitro compounds, mostly in the presence of noble metal-based catalysts. Various homogeneous and heterogeneous catalysts have been reported for this process. However, due to the ever-increasing environmental standards and economic pressures, heterogeneous catalysts are mostly preferred for their easy separation, recovery and recyclability. In the case of heterogeneous catalysts, the conscious selection of support is an important issue, because the interaction between the support and the immobilized catalytically active metallic nanoparticles can affect the distribution, size, activity and stability of the nanoparticles. [29][30][31] To date, immobilization of hydrogenation catalysts on various supports such as activated carbon, silica, carbon nanotubes, clay and nanofibers has been disclosed. [32][33][34][35][36][37][38] Although the reported catalytic routes have provided significant achievements for the hydrogenation reaction, some of the methods are plagued by limitations in terms of yields, low catalyst recovery, long reaction times, excess of organic solvent, high temperatures and harsh reaction conditions. Therefore, the design of a new material is required to overcome these problems.

Following our research on the development of heterogeneous catalysts, 39,40 recently, we focused on the functionalization of Hal and studied its utility as a heterogeneous support for immobilization of various catalytic active species ranging from heteropolyacids 41 to nanoparticles. 42,43 Moreover, the results of studying the hybridization of CD and its polymers proved that the introduction of CD and its derivatives can improve the catalytic performance of hybrid systems due to the capability of forming an inclusion complex with the substrate and exerting a synergistic effect. [42][43][44] On the other hand, our recent studies revealed that incorporation of carbon-based materials such as graphitic carbon nitrides can effectively suppress leaching of the catalytically active species and enhance the catalytic activity and recyclability of the hybrid system. 43 Considering the possible synergism between Hal, CD and carbon porous materials, we designed and synthesized a triply hybrid system composed of Pd, Hal, and  CD-modified melamine based polymer. It was assumed that due to the presence of CD in the structure of this heterogeneous catalyst, it could promote reactions in aqueous media via formation of an inclusion complex with substrates. Moreover, it was believed that the melamine based polymer, which is a porous polymer with multiple nitrogen atoms, could increase Pd anchoring and decrease its leaching through electrostatic interactions. To verify these assumptions, the catalytic activity of Pd@HTMC in a model reaction, i.e. hydrogenation of nitrobenzenes to the corresponding anilines, was targeted. Moreover, to elucidate the role of CD and the melamine-based polymer, control catalysts (the catalysts without CD and melamine) were synthesized and their catalytic activities were compared with that of the catalysts. To investigate the generality of the reaction, the hydrogenation of a sterically demanding substrate, nitronaphthalene, as well as a substrate with a competing functional group, 4-nitroacetophenone, was also investigated. Finally, the recyclability of the catalyst, Pd leaching, and the heterogeneous nature of the catalysis were examined.

Experimental

Materials and instruments

All chemicals and reagents, including nitrobenzene, 1-nitronaphthalene, 4-nitroacetophenone, formic acid, sodium borohydride, halloysite clay (Hal), (3-chloropropyl)trimethoxysilane, thiosemicarbazide, melamine, terephthaldehyde (TPA), potassium persulfate, -cyclodextrin (-CD), Pd(OAc)2, toluene, and dimethyl sulfoxide (DMSO), were analytical grade reagents, purchased from Sigma-Aldrich, and were used without further purification. Catalyst characterization was carried out by applying various techniques, including TEM, XRD, BET, TGA, FTIR and ICP-AES. TEM was performed on a Tecnai microscope (200 kV). To perform the analysis, the samples were dispersed in water and the analysis was carried out after evaporation of the solvent. XRD patterns of the catalyst, pristine Hal and HTMC were obtained by using a Siemens, D5000 and Cu K radiation from a sealed tube. The BET analyses of the pristine Hal and the final catalyst were performed using a BELSORP Mini II instrument. Prior to analysis, the samples were pre-heated at 200 °C for 3 h. To perform thermogravimetric analysis (TGA), a METTLER TOLEDO thermogravimetric analysis apparatus was employed. The applied heating rate was 10 °C min -1 and the analysis was carried out under a N2 atmosphere over the range of 50 to 800 1C. FTIR spectra were recorded by employing a PERKIN-ELMER-Spectrum 65 instrument and ICP analyses were accomplished by using an ICP analyzer (Varian, Vista-pro).

Synthesis of Hal-Cl

Hal-Cl was synthesized according to a previous report. 11 Typically, Hal (4 mmol, 1.2 g) was dispersed in 60 mL of dry toluene via ultrasonic irradiation of power 100 W and subsequently (3chloropropyl)trimethoxysilane (15 mmol) was added dropwise. The mixture was left under constant stirring for 24 h at 110 °C. Upon completion of the reaction, the precipitate was separated by simple filtering. The functionalized clay was obtained by repeated washing with dried toluene and drying at 100 °C overnight.

Synthesis of Hal-T

Typically, thiosemicarbazide (6.6 mmol) was added to a suspension of Hal-Cl (1 g) in toluene (50 mL) in the presence of a catalytic amount of triethylamine (1 mL). The resulting mixture was then refluxed at 110 °C for 24 h. Upon completion of the reaction, the precipitate was filtered off and washed several times with toluene and dried at 100 °C overnight. Synthesis of melamine-based polymer on the surface of Hal-T: synthesis of (HTM)

The introduction of the melamine-based polymer onto Hal-T was achieved through a method provided in a previous report. 45 Briefly, a mixture of Hal-T (3 g), melamine (4 mmol), and terephthalaldehyde (9 mmol) in DMSO (50 mL) was prepared in a flask. The aforementioned mixture was then heated to 180 °C for 48 h under a nitrogen atmosphere. After cooling to room temperature, the solid product was isolated by simple filtration, washed with acetone and water and dried at 60 1C.

Modification of HTM with CD: synthesis of HTMC

The modification of the melamine-based polymer with b-CD was performed via a facile solvothermal method, reported previously. 46 Briefly, an aqueous suspension of HTM (2 g in 12 mL of distilled water) was mixed with a solution of bcyclodextrin (0.7 mmol of CD in 8 mL of distilled water) at room temperature. Following this, 0.2 mL of NaOH solution (1 M) and 0.037 mmol of potassium persulfate (K2S2O8) as an initiator were added. The mixture was then stirred until the suspension became clear. Subsequently, it was transferred into an autoclave, sealed and heated to 180 1C and maintained for 12 h at this temperature. Upon completion of the reaction, the resulting precipitate was washed with distilled water and ethanol several times, and dried in a vacuum at 60 1C.

Synthesis of Pd@HTMC

The catalyst, Pd@HTMC, was prepared by incorporation of Pd nanoparticles via the wet impregnation method. Briefly, HTMC (1.2 g) was dispersed into 30 mL of dry toluene containing 0.09 mmol of Pd(OAc)2 in 12 mL of toluene. The mixture was stirred at room temperature for 8 h. Subsequently, a solution of NaBH4 in MeOH (10 mL, 0.2 N) was added into the suspension dropwise and the resulting mixture was stirred for 2 h. Finally, the solid material was filtered off, washed with MeOH and dried in an oven at 60 °C for 12 h. The schematic procedure of the synthesis of the catalyst is illustrated in Fig. 1.

Pd loading of Pd@HTMC was measured via ICP-AES analysis. First, a mixture (1 : 5) of concentrated nitric and hydrochloric acid (6 M) was prepared and a known amount of Pd@HTMC (0.002 g) was digested in the aforementioned acidic solution through constant stirring for 8 h. Subsequently, the resulting extract was analyzed by ICP-AES. The Pd content of the catalyst was measured to be about 0.45 wt%.

General procedure for the hydrogenation of nitro compounds

In a typical reaction, a mixture of nitroarene compounds (1 mmol) and the Pd@HTMC catalyst (1 wt%) in deionized water (2 mL) was placed into a reactor and heated up to 50 °C. Then, hydrogen (1 bar) was purged into the flask continuously and the mixture was stirred vigorously (800 rpm). Upon completion of the reaction (monitored by TLC), the resulting mixture was filtered to separate the catalyst, and the product was isolated by evaporation of solvent and identified by comparing its boiling/melting point and FTIR spectrum with that of the authentic sample. To recycle the catalyst, the recovered Pd@HTMC was washed with water and dried at 100 1C overnight.

Result and discussion

Catalyst characterization

As described in the Experimental section, the catalyst, Pd@HTMC, was prepared through functionalization of Hal with thiosemicarbazide and the formation of the melamine-based polymer and its modification with CD, followed by immobilization of the Pd(0) nanoparticle. The TEM images of Pd@HTMC are depicted in Fig. 2. As shown, the tubular morphology of Hal can be detected in these images, indicating that the morphology of Hal did not collapse as a result of incorporation of the CD-modified melaminebased polymer. However, comparison of the morphology of pristine Hal with that of the catalyst (Fig. S1, ESI †) implied that the diameters of the pristine Hal tubes are smaller than that of Pd@HTMC. This observation can be attributed to the coverage of the Hal surface with the CD-modified melamine-based polymer. In the TEM images of the catalyst, fine sheets of CD-modified melamine-based polymer can be observed. Moreover, Pd nanoparticles are depicted as dark spots. As shown in Fig. 2, in some parts, the Pd nanoparticles are aggregated. Using TEM images, the average size of Pd nanoparticles was estimated to be 7 0.1 nm. The structural features of Pd@HTMC were studied by recording the FTIR spectrum of the catalyst and comparing it with that of Hal, Hal-Cl, Hal-T, HTM and HTMC (Fig. 3). The characteristic bands of Hal include the bands at 3695 cm -1 and 3627 cm -1 (representing the internal hydroxyl group of Hal) and the bands at 534 (indicative of Al-O-Si vibration) and 1033 cm -1 (Si-O stretching). 47 The FTIR spectrum of Hal-Cl is very similar to that of pristine Hal and it exhibits all the characteristic bands of Hal, indicating that the structure of Hal is not destroyed after functionalization with organosilane. The spectrum of Hal-T also contained the representative bands of Hal. Furthermore, the FTIR spectrum of Hal-T showed some additional bands, i.e., a band at 1302 cm -1 that can be attributed to the C=S group in thiosemicarbazide and the bands at 3260 and 3384 cm -1 , which are the representative of the stretching and bending vibration of N-H and NH2. In the FTIR spectrum of HTM, the amine bands of thiosemicarbazide functionality disappeared, implying that this functionality participated in the polymerization reaction. Noteworthily, the characteristic band of C=N (1650 cm -1 ) that is representative of the melamine-based polymer overlapped with those of Hal. As depicted, the modification of HTM with CD did not alter the FTIR spectrum dramatically. This observation is not beyond expectation, as the characteristic bands of CD mostly overlapped with that of HTM. The FTIR spectrum of the catalyst, Pd@HTMC, is also similar to that of HTMC.

To investigate the structural features of the catalyst, the XRD pattern of Pd@HTMC was recorded (Fig. 4). Additionally, to elucidate how hybridization of Hal with the CD-modified melamine-based polymer as well as Pd immobilization can affect the structure of Hal, the XRD patterns of the pristine Hal and HTMC were obtained and compared with that of the catalyst (Fig. 4). The XRD pattern of pristine Hal is in good agreement with the literature and exhibited characteristic bands at 2y = 11.8°, 19.9°, 24.8°, 26.5°, 36°, 38.5°, 55.3° and 62.5° ( JCPDS No. 29-1487). 48,49 The XRD pattern of HTMC possessed the bands of Hal, indicating that incorporation of the CD-modified melamine-based polymer did not result in the collapse of the Hal structure. However, the intensity of the bands was reduced. Comparing the XRD pattern of pristine Hal with those of HTMC and Pd@HTMC, it can be concluded that no significant shift happened and the interlayer distance remained intact, implying that the functionalities as well as Pd nanoparticles are located on the surface, but not within the lumen of Hal. This issue was also verified in the TEM images (Fig. 2).

As depicted in the XRD pattern of Pd@HTMC, no additional bands were detected for Pd species. According to the literature, this observation can be attributed to the low loading of Pd, as also confirmed by ICP, and its high dispersion. 50 Pd@HTMC was also characterized by using BET analysis. Considering the standard nitrogen adsorption-desorption types of isotherms, the isotherm of Pd@HTMC (Fig. S2,ESI †) can be assigned as a type II isotherm with an H3 hysteresis loop. 49 Moreover, the comparison of the isotherm of the catalyst with that of pristine Hal (Fig. S3, ESI †) established the similarity of the two isotherms.

The specific surface area of Pd@HTMC was also calculated and compared with that of HTM, HTMC and Hal (Table 1). As tabulated, the specific area of Hal is 51 m 2 g -1 . Upon functionalization of Hal with the melamine-based polymer, the specific surface area of Hal decreased to 21.48 m 2 g -1 . This observation confirms that melamine-based polymer was located on the surface of Hal. Moreover, the decrease in the surface area can be attributed to the large pores of the melamine-based polymer. 45 As can be seen, upon modification of the melamine-based polymer with CD, the specific surface area increased to 58.57 m 2 g -1 . The reason for this observation is that CDs could locate within the large cavities of the melamine-based polymer. In the case of Pd@HTMC, the specific surface area slightly decreased (52.63 m 2 g -1 ). This can be attributed to the embedment of Pd nanoparticles on the surface of HTMC.

Comparing the total pore volumes of Hal, HTM, HTMC and Pd@HTMC, it was revealed that upon incorporation of the melamine-based polymer, this value slightly increased (from 0.2 to 0.28 m 3 g -1 ). This observation can be attributed to the cavities in the structure of the melamine-based polymer. 45 Upon modification of melamine-based polymer with CD, this value increased to 0.38 m 3 g -1 . This issue can be attributed to the presence of the cavities of CD. As expected, immobilization of Pd nanoparticles led to the decrease of the total pore volume. The pore diameters of Hal, HTM, HTMC and Pd@HTMC have also been compared. The results showed that upon incorporation of the melamine based polymer, this value increased from 5.42 nm (pristine Hal) to 28.65. As mentioned before, this observation can be attributed to the presence of large pores in the melamine-based polymer. 45 Notably, modification of melamine-based polymer with CD resulted in a decrease of this value to 5.42 nm. As indicated, this observation can be justified by considering the fact that CDs could locate within the large pores of the melamine-based polymer. As expected, incorporation of Pd resulted in a decrease of this value, implying the embedment of Pd nanoparticles within the pores of the catalyst structure. a SBET (BET surface areas). b Vt (total pore volume was estimated at a relative pressure of P/P0 = 0.990). c dBJH-KJS ads/des (pore diameters derived from the adsorption/desorption branch by the BJH-KJS method).

To further characterize the catalyst, the thermogram of Pd@HTMC was recorded (Fig. 5). Additionally, to estimate the content of thiosemicarbazide, the CD-modified melamine-based polymer, the thermograms of Hal, Hal-T and Hal-Cl were also obtained (Fig. 5). As illustrated in Fig. 5, the thermogram of Hal exhibits two weight losses, at about 150 °C and 550 °C, that are due to the loss of water and dehydroxylation of the Hal matrix, respectively. 51,52 Comparing the two thermograms of Hal-Cl and Hal, the amount of (3-chloropropyl)trimethoxysilane can be estimated to be ∼3.3 wt%. To measure the content of thiosemicarbazide, the thermogram of Hal-T was compared with that of Hal-Cl. The result showed that the content of T was about 4 wt%. Considering the thermogram of Pd@HTMC, the amount of CD-modified melamine-based polymer was estimated to be about 5.7 wt%.

Catalytic activity of the catalyst

Next, the catalytic activity of Pd@HTMC was assessed for the hydrogenation of nitro compounds. In an initial endeavour, the synthesis of aniline by hydrogenation of nitrobenzene in the presence of hydrogen (1 bar) at 35 °C was examined. As employing green solvents for promoting organic reactions can modernize classical procedures to make them more clean, safe and easy to perform, water was selected as a solvent. Gratifyingly, the reaction proceeded successfully to furnish aniline in a high yield (Table 2). Encouraged by this result, finding the optimum reaction conditions was targeted. In this line, the effects of several reaction variables such as the catalyst loading, temperature and hydrogen source on the yield of the model product were examined (Table 2). It is worth mentioning that the use of a lower hydrogen flow was not successful. On the other hand, an increase of temperature from 35 to 50 °C could improve the yield of the reaction. Noteworthily, a further increase of the temperature had a converse effect on the reaction yield, as at a higher temperature, the solubility of hydrogen would decrease in the solvent. Studying the effect of catalyst loading (0.5-10 wt%), it was found that 1 wt% was the optimum catalyst amount.

Next, the effect of the hydrogen source was investigated by applying H2 gas, formic acid and sodium borohydride as the hydrogen source (Table 2, entries 9 and 10). Comparing the yields of the model product under the optimized reaction conditions, it was established that hydrogen gas was the best hydrogen source and it led to the highest yield under mild reaction conditions. Thus, the 1 wt% Pd@HTMC catalyst and hydrogen gas as a hydrogen source at 50 °C in water were selected as the optimum reaction conditions for further investigations.

In the next step, the contribution of each component of the catalyst to the catalysis was studied. In this line, several control samples, including Hal-T, Pd@Hal-T, HTM, Pd@HTM, HTMC and Pd@HTM + CD, were synthesized and their catalytic activity for hydrogenation of nitrobenzene to aniline under optimized reaction conditions was studied and compared with that of Pd@HTMC, as shown in Table 3.

As expected, the Pd-free catalysts did not exhibit catalytic activity and the reaction did not proceed in the presence of these catalysts. As tabulated, the catalytic activity of Pd@Hal-T after 1 h was insignificant and only a trace amount of the desired product was obtained. In the case of Pd@HTM, the observed catalytic activity within 1 h ( yield = 25%) was higher Table 2 Effects of H2 source, temperature, and loading of catalyst on the yield of the nitrobenzene hydrogenation reaction a 4 a Reaction conditions: nitrobenzene (1 mmol), H2O (2 mL), hydrogen flow of 50 mL min -1 , agitation (800 rpm) in 1 h. b Pd loading of the catalyst is 0.45 wt%. c Isolated yields. d HCOOH (5 mmol, 0.2 mL). e NaBH4 (5 mmol, 0.185 g). Pd@HTMC 1 100 7

Pd@HTM + CD 1 50

a Reaction conditions: substrate (1 mmol), catalyst (1 wt%), H2O (2 mL), hydrogen flow of 50 mL min -1 , agitation (800 rpm) at 50 1C in 1 h. b Isolated yields.

than that of Pd@Hal-T, indicating the role of the melaminebased polymer in the catalysis. It was assumed that the observed difference in the catalytic activity could stem from different Pd loadings and the Pd particle size of the two control catalysts. To verify this assumption, the Pd particle sizes and loadings of Pd@Hal-T and Pd@HTM were measured by recording the TEM images of the two catalysts (Fig. S4, ESI †) and performing ICP analysis, respectively. The results of ICP analysis showed that the Pd loading of the latter was almost two times higher than that of the former, indicating the role of HTM in anchoring Pd nanoparticles. [53][54][55][56] Moreover, the comparison of the two TEM images confirmed that Pd@Hal-T showed a more aggregated morphology (Fig. S3, ESI †), in which the Pd nanoparticles were mostly aggregated (average particle size of 18 nm). The Pd nanoparticles in Pd@HTM, however, were more dispersed and their average particle size was 10 nm. Hence, the higher catalytic activity of Pd@HTM compared to Pd@Hal-T can be attributed to the higher dispersion and smaller size of Pd nanoparticles in Pd@HTM and its higher Pd content. According to the previous literature, 43 a higher Pd content in Pd@HTM can be justified on the basis of the electrostatic interactions of nitrogen atoms on the polymeric sheet and Pd species.

Comparison of the catalytic activity of Pd@HTM and Pd@HTMC demonstrated that the catalytic activity of the latter was significantly superior to that of Pd@HTM, implying the contribution of CD to the catalysis. Considering the previous reports, 57,58 the contribution of CD can be discussed from two points of view. The first is the capability of CD to form an inclusion complex with the hydrophobic substrate and transfer it to the aqueous reaction media. To further confirm this phenomenon, the hydrogenation reaction of a more hydrophobic substrate, 1-nitronaphthalene, was performed in the presence of the CD-free catalyst, Pd@HTM. As expected, the reaction of 1-nitronaphthalene that is insignificantly soluble in aqueous media did not proceed even after 3 h. Secondly, CD can serve as a capping agent and stabilize Pd nanoparticles. This issue is very well established in the literature. 22,[59][60][61] More precisely, in the course of the reduction of Pd(II) to Pd(0), the CDs present on the structure of the catalyst could act as a stabilizing agent and prevent Pd(0) nanoparticles from aggregating and consequently lead to the formation of Pd(0) particles with smaller sizes. To confirm this issue, the average Pd particle sizes of Pd@HTM and Pd@HTMC were compared. The results showed that the average particle size of Pd@HTMC (7 nm) was smaller than that of Pd@HTM (10 nm). Finally, to elucidate whether modification of the melaminebased polymer with CD in a hybrid system can lead to superior catalytic activity compared to the use of CD and Pd@HTM as individual components, both Pd@HTM and CD were applied as catalysts for promoting the model reaction (Table 3 entry 7). Interestingly, the use of Pd@HTM and CD led to a lower yield of the desired product compared to the hybrid Pd@HTMC. This observation confirmed that hybridization of the two components resulted in a catalytic system with superior efficiency compared to that of the separated components.

To explore the scope and limitations of this catalytic system, some other substrates with different steric and electronic properties were subjected to the hydrogenation reaction under the optimized reaction conditions (Table 4). Surprisingly, the use of the sterically demanding 1-nitronaphthalene as the substrate resulted in the hydrogenated product, with 100% conversion, in 2 h. Although the reaction time was relatively short, it was longer than for nitrobenzene. The observed longer reaction time can be attributed to the larger molecular size of 1-nitronaphthalene compared to nitrobenzene 62 that can retard formation of an inclusion complex with CD. This observation can confirm the fact that the catalyst shows size selectivity to some extent and that a substrate that can be encapsulated within the cavity of CD more easily undergoes the hydrogenation reaction.

Studying hydrogenation of 4-nitroacetophenone, a more challenging substrate containing two active functional groups, i.e. -NO2 and -C=O, it was found that the catalyst could selectively hydrogenate the nitro functional group, while the ketone functionality remained intact.

Catalyst recyclability

Next, the recyclability of the catalyst was studied in the hydrogenation of nitrobenzene under the optimized reaction conditions. For this purpose, the efficiency of the fresh Pd@HTMC catalyst was compared with the recycled ones. To recycle the catalyst, Pd@HTMC was separated via simple filtration and after washing with water and drying in an oven at 100 °C overnight, it was subjected to the next run of the reaction under the same reaction conditions. The results of recycling Pd@HTMC up to seven reaction runs are illustrated in Fig. 6. As depicted, the catalyst exhibited high recyclability up to six consecutive reaction runs. More precisely, no loss of the catalytic activity was observed upon the second use, while a slight loss of the catalytic activity was detected upon further recycling. Notably, the efficiency of Pd@HTMC upon recycling for the 7th reaction run dramatically decreased (only 45% yield of the desired product was achieved). To investigate the origin of this decrease in the yield of the product, the recycled catalyst was characterized via ICP analysis and FTIR spectroscopy. As shown in Fig. 7, the FTIR spectrum of the recycled Pd@HTMC after the 7th reaction run is very similar to that of the fresh Pd@HTMC, indicating that recycling of the catalyst did not result in the collapse of the structural features of Pd@HTMC. The investigation of Pd leaching via ICP analysis, however, showed that the Pd leaching can be affected by recycling. More precisely, no leaching was observed for the catalyst recycled for the second reaction run, while insignificant Pd leaching was observed for the catalysts recycled for the third and fourth reaction runs. Leaching of Pd nanoparticles constantly increased upon further recycling and reached the maximum amount at the seventh recycling (2.3 wt% Pd content of the catalyst). Notably, to rule out the possibility of deposition of Pd nanoparticles on the hydrogenation product, aniline, the ICP analysis was also performed for the product. The result showed that no Pd was deposited on the product. Considering these results, the loss of Fig. 6 Recyclability of Pd@HTMC in the hydrogenation of nitrobenzene. Reaction conditions: nitrobenzene (1 mmol), catalyst (1 wt%), H2O (2 mL), hydrogen flow of (50 mL min -1 ) at 50 1C. Fig. 7 The FTIR spectra of fresh and recycled Pd@HTMC in the hydrogenation of nitrobenzene. Reaction conditions: nitrobenzene (1 mmol), catalyst (1 wt%), H2O (2 mL), hydrogen flow of (50 mL min -1 ) at 50 1C.

the catalytic activity upon recycling can be attributed to the Pd leaching.

Finally, to investigate the nature of the catalysis, the hotfiltration test was performed via the standard method. 63 Briefly, the catalyst was filtrated from the reaction mixture and the progress of the reaction mixture in the absence of the catalyst was monitored. The result demonstrated that the reaction did not proceed, ruling out the possibility of the leaching of Pd nanoparticles from the support and re-deposition on it in the course of the reaction.

Conclusion

A novel catalyst, Pd@HTMC, is prepared through the growth of a melamine-based polymer on the functionalized Hal followed by its modification with CD and Pd(0) nanoparticle immobilization. Pd@HTMC could successfully hydrogenate nitrobenzene and sterically demanding nitro-naphthalene in aqueous media. In the case of 4-nitroacetophenone that contained both nitro and ketone functionality, the catalyst selectively hydrogenated the nitro group. The comparison of the catalytic activity of the catalyst with that of Pd@Hal-T and Pd@HTM confirmed the contribution of the CD-modified melamine-based polymer to the catalysis. The results established that incorporation of melamine-based polymer could improve anchoring of Pd species through electrostatic interactions, while suppressing the Pd leaching. The presence of CD on the structure of the catalyst, on the other hand, could promote the formation of an inclusion complex with a hydrophobic substrate and transfer it into the aqueous media. Moreover, CD could act as a capping agent and stabilize Pd nanoparticles. The recyclability tests revealed the high recyclability of the catalyst, up to six reaction runs, with a slight loss of the catalytic activity and leaching of Pd. Moreover, the hot filtration test confirmed the heterogeneous nature of the catalysis.

Fig. 1

 1 Fig.1The schematic procedure of the synthesis of the catalyst.

Fig. 2

 2 Fig.2TEM images of Pd@HTMC.

Fig. 3 FTIR

 3 Fig. 3 FTIR spectra of pristine Hal, Hal-Cl, Hal-T, HTM, HTMC and Pd@HTMC.

Fig. 4

 4 Fig. 4 XRD patterns of pristine Hal, HTMC and Pd@HTMC.

Fig. 5

 5 Fig.5The TGA analyses of pristine Hal, Hal-Cl, Hal-T and Pd@HTMC.

Table 1 Textural

 1

	Hal	51	0.2	5.42
	HTM	21.48	0.28	28.64
	HTMC	58.57	0.38	42
	Pd@HTMC	52.63	0.26	3.28

properties of Hal, HTM, HTMC and Pd@HTMC Sample S a (m 2 g -1 )

V b (m 3 g -1 ) d c (nm)

Table 3

 3 Comparison of catalyst systems in hydrogenation of nitrobenzene a

	Entry	Catalyst	Reaction time (h)	Yield b (%)
	1	Hal-T	1	-
	2	Pd@Hal-T	1	5
	3	HTM	1	-
	4	Pd@HTM	1	25
	5	HTMC	1	-
	6

Table 4

 4 Hydrogenation of nitro compounds by Pd@HTMC a Reaction conditions: substrate (1 mmol), catalyst (1 wt%), H2O (2 mL), hydrogen flow of 50 mL min -1 , agitation (800 rpm) at 50 1C. b Isolated yields.

	Entry Substrate	Time (h) Conversion (%) Yield b (%)
	1	Nitrobenzene	1	100	100
	2	1-Nitronaphthalene	2	100	100
	3	4-Nitroacetophenone 1.5	100	100

a

Acknowledgements

This work was supported by the Center for International Scientific Studies & Collaborations (CISSC) and the French Embassy in Iran and the Hubert Curien French-Iranian partnership ''PHC GUNDISHAPUR 2018'' no. 40870ZG. MMH and Akbari are also thankful to the Iran National Science Foundation for the individually given grant, no. 96010807.

Conflicts of interest

There are no conflicts to declare.


Gilles Tagne
email: gilles.tagne@junia.com

Mathias Blandeau
email: mathias.blandeau@uphf.fr

Othman Lakhal
email: othman.lakhal@univ-lille.fr

Eugenie Avril
email: eugenie.avril@uphf.fr

Laura Wallard
email: laura.wallard@uphf.fr

Steeve Mbakop
email: steeve.kamga-mbakop@junia.com

System of systems approach and user-centered design to improve the autonomy of people with reduced mobility

Keywords: System of systems, user-centered design, acceptability, reduced mobility, disability, modeling

HAL is

I. INTRODUCTION

The technological advances of the last few years have largely favored the development of technologies to improve the autonomy of people. However, studies show that only a small part of the technologies developed are actually used by end users. This is partly due to the fact that the real need of the end user has not been at the center of the design of the proposed solutions.

According to the World Health Organization, approximately 15 % of the world's inhabitants live with some form of disability and the worldwide estimate of the prevalence of disability is on the rise, in particular due to population aging [START_REF] Organization | World report on disability 2011[END_REF]. Taking into account, the increasing cost of medical intervention, it is now the healthcare professionals challenge to ensure a correct timing for the solution proposed to the subjects in regards to their conditions. Several parameters should be considered, possibility of evolution, risk of chronicity, missing information [START_REF] Nieminen | An early biopsychosocial intervention design for the prevention of low back pain chronicity: A multidisciplinary empirical approach[END_REF]. . . Quantitative and exhaustive functional assessment, according to the International Classification of Functioning, Disability and Health (ICF), therefore proves to be necessary as recommended by the World Health Organization.

During the design of new solutions, assessing the acceptability and acceptance of technologies is definitely a key issue in the design and deployment of technologies. It is necessary for designers to identify the factors and conditions that influence the perception of users. This one may lead to the reject or acceptance of those [START_REF] Alexandre | Acceptance and acceptability criteria: a literature review[END_REF]. To support this perception, it is important to adopt a user-centered design and more specifically a participatory approach involving the users throughout the solution's development.

In practice, the different equipments or applications developed are very often isolated cyber physical systems but which must be brought to realize a common mission; that of improving the autonomy of the Person with Reduced Mobility (PRM). The challenge is to design new modules with such a vision and to choose in an appropriate way a unified approach allowing to study and analyze its different components in interaction with each other and with the person with reduced mobility. The System of Systems (SoS) approach could be relevant in such a case.

Many SoS definitions [START_REF] Kotov | Systems of systems as communicating structures[END_REF], [START_REF] Jamshidi | System of systems engineering-new challenges for the 21st century[END_REF] has been formulated but none have been recognized as the only one. The SoS engineering (SoSE) remains an area to be developed. We can define a system of systems as a set of many autonomous systems or elements of systems that interact to provide a unique capability that none of the constituent systems can accomplish alone. To meet the demands of an SoS, Maier [START_REF] Maier | Architecting principles for systems-of-systems[END_REF] proposes five specific characteristics :

• Operational independence of the constituent systems (CS): if the system of systems is disassembled, the CS must be able to operate autonomously, • Managerial independence of the CS: the constituent systems must maintain a continuous operational existence independent of the system of systems, • Geographical distribution of its constituent systems, • Presence of emergent and cooperative behaviors to achieve a common goal, • Evolutionary development process: a system can be added or removed without changing any of the characteristics of the SoS. Even though SoS share the same characteristics, some attributes change from system to another, that's why, based on objectives of the SoS, governance, and the inter-relationship between components, SoS can be classifed into four types (categories) [START_REF] Assaad | A view on systems of systems (sos)[END_REF] [8]:

• Directed SoS: The system is built for a specific purpose, and centrally managed. • Collaborative SoS: In collaborative SoS, the central management does not have the coersitive power to run the system. • Acknowledged SoS: Which shares attributes from both directed and collaborative SoS. These systems have a central management and resources for the SoS, but the components retain their full independence. • Virtual SoS: It emerges from the interaction between components, whereas the objectives are unknown, and there is no central authority. The system is maintained through invisible mechanisms. Originally identified in the defense field, the application of SoS engineering is now much more present and still expanding in many domains [START_REF] Bar-Yam | The characteristics and emerging behaviors of system of systems[END_REF]. The SoS concept has been applied in many fields, including military [START_REF] Dahmann | Systems of systems characterization and types[END_REF]. Better known, the ISTAR system (Intelligence, Surveillance, Target Acquisition and Reconnaissance), an SoS in military aeronautics is developed. Its objective is to collect and share information to create the best possible representation of the mission scenario and improve the decision-making process. There are some SoS applications on robotics [START_REF] Lakhal | Autonomous navigation through a system of systems cooperation[END_REF], transportation [START_REF] Nielsen | Systems of systems engineering: basic concepts, model-based techniques, and research directions[END_REF] [13], crisis management [START_REF] Kadri | Proposition of a formal model for crisis management in the context of high-speed train networks in border areas[END_REF], Smart City [START_REF] Aljohani | Analysis of the smart grid as a system of systems[END_REF], Health care [START_REF] Wickramasinghe | Healthcare system of systems[END_REF] and Industry 4.0 [START_REF] Axelsson | Architecting systems-ofsystems and their constituents: A case study applying industry 4.0 in the construction domain[END_REF]. In a recent work [START_REF] Lakhal | Autonomous navigation through a system of systems cooperation[END_REF], an SoS in the transportation domain for the optimal management of intelligent autonomous vehicle (IAV) guidance in dead zones, i.e. where navigation signals are absent is developed. In this context, a cooperation between an IAV and an UAV is observed.

Recent works for new frameworks have been though of with focus on the transportation problematic from a point to another and [START_REF] Blanchard | Towards a framework for detecting temporary obstacles and their impact on mobility for diversely disabled users[END_REF], [START_REF] Whittington | Smartdisability: A smart system of systems approach to disability[END_REF], to meet these challenges, i.e., to offer technological modules that meet the needs of end-users while being modular and able to work in cooperation, in order to improve the autonomy of people with reduced mobility, we propose an integrated design solution for modules and applications combining the system of systems approach and user-centered design. We will present the methodology in section II, its application in sections III and IV. We will finish with some conclusions and future work.

II. METHOD A. Definition of disability and ICF framework

Disability has long been considered solely through the medical characteristics of a person, the so-called "medical model" [START_REF] Nagi | A study in the evaluation of disability and rehabilitation potential: concepts, methods, and procedures[END_REF], requiring a medical treatment to improve the condition. Contrary to this vision, the "social model" [START_REF] Engel | The need for a new medical model: a challenge for biomedicine[END_REF] was proposed by considering the external barriers and constraints of the environment inducing a disability situation. According to this model, improving the conditions of people with disabilities must go through political and economic actions. The current approach to the situation of disability, called the "biopsychosocial model", integrates the two previous models and considers disability as resulting from biological, personal and social constraints and has opened the debate internationally on accessibility issues (c.f. Fig. 1).

Fig. 1: General framework of the ICF

The World Health Organization advocates the use of multidisciplinary analysis based on biopsychosocial approach as the use of International Classification of Functioning, Disability and Health model (ICF) [START_REF] Organization | Ifc: International classification of functioning, disability and health[END_REF] allowing a standard evaluation recommended by International Consortium for Health Outcomes Measurement. This conceptual model provides a framework for clinicians in assessing and monitoring the level of functioning of patients during the course of their care and throughout their lives. In this way, a common language is also achieved for all disciplines involved in the care of this population. The ICF model is composed of "body structures and functions", "activities", "participation" and "personal factors" domains. These domains yield a categorical profile which represents the functional state of an individual [START_REF] Cieza | The international classification of functioning disability and health: its development process and content validity[END_REF]. This may then be used as a guide in rehabilitation goal-setting, intervention planning, and follow-up. With this perspective, this quantitative and exhaustive functional assessment of these people therefore proves to be necessary providing a multiperspective approach for the classification of disability and aiming to the overall analysis of the patient compared to his disease. The study adds to the body of knowledge on the practicality, clinical utility, and applicability of the ICF in real world settings.

B. Description of the approach

When applying the SOSE approach withing the ICF framework, one must first start defining the levels of systems as represented in Fig. 2 (the basket ball game is just an example of a complex multi-agent situation). On level 0, the ICF framework can be used to provide the technical solution in order to solve the physical/functional problem while preserving the subject from future complications (pain, accident...) [START_REF] Nieminen | An early biopsychosocial intervention design for the prevention of low back pain chronicity: A multidisciplinary empirical approach[END_REF]. Not using this approach at level 0 increases the risk of failure in Human robot interaction [START_REF] Honig | Understanding and resolving failures in human-robot interaction: Literature review and model development[END_REF], ableism (assigning or denying certain abilities for a person living with a disability) [START_REF] Blanchard | Disabled dimensionalities: Normative expectations' impacts on disabled perceptions and spatialities[END_REF] or providing only a partial technological solution to a holistic problem [START_REF] Blanchard | Cripping assistive tech design: How the current disability framework limits our ability to create emancipatory technology[END_REF], [START_REF] Spartacus | On-board lived experience of manual wheelchair users: Aircraft seat satisfaction level and potential solutions to improve comfort and accessibility[END_REF].

Fig. 2: Various Levels of System of Systems

Starting from the user-centered design of modules meeting a functional need of a person with reduced mobility (level 0), advanced interaction applications are proposed depending on the acceptability of the developed modules by the person. Such low-level interaction between the person and the system can be formalized as purely biomechanical dynamic equations which are often found in the form of a descriptor system [START_REF] Blandeau | Unknown input observer for understanding sitting control of persons with spine cord injury[END_REF], [START_REF] Nguyen | Designing fuzzy descriptor observer with unmeasured premise variables for head-two-arms-trunk system[END_REF] as shown in equation 1.

E(x(t)) ẋ(t) = A(x(t))x + Bu(t) y(t) = Cx(t) (1)
This structure is very interesting because it keeps the "natural" form of the problem and avoids the distribution of the nonlinear terms withing the constant matrices hence lowering the conservativeness [START_REF] Guerra | Observer design for takagi-sugeno descriptor models: An lmi approach[END_REF].

At level 1 (see Fig. 2), due to the resolution of the functional/physical need of the person with reduced mobility, simple applications allowing the person to perform activities in a given environment are considered. Examples of applications of this level are: autonomous navigation applications, driving assistance applications, gate opening, elevators, etc.

At level 2 and above, complex applications, involving a dynamic environment, human-human, human-robot (collaboration) and robot-robot (cooperation) interactions. The integral solution is conceptualized by a systems approach. Many examples of application are proposed to illustrate the relevance of the proposed design approach.

III. APPLICATION EXAMPLES IN THE FRAMEWORK OF THE CPER RITMEA PROJECT

A. Application example 1: Development of a connected orthosis to improve the autonomy of people with reduced mobility

When designing an orthosis to a person with reduced mobility, the first step in the ICF framework is to go through the categories of the classification. Filling in information can be done through free or semi-structured interviews. Starting with a listing of impairments of body functions (physiological functions of body systems including psychological functions) and body structures (anatomical parts of the body such as organs, limbs and their components). Hence, functions like mental, sensory or neuromusculoskeletal and movement related functions and structures like brain, eye, limbs would be associated to a qualifier to represent the extent of impairments from nothing to complete impairment. This first step is more global than just focusing on a Range of Motion approach as it can be seen in previous works [START_REF] Whittington | Smartdisability: A smart system of systems approach to disability[END_REF].

The second step is to fill the Activity Limitations and Participation Restrictions part (e.g. learning, communication, mobility...). Activity is the execution of a task or action by an individual whereas Participation is involvement in a life situation. Activity Limitations are difficulties an individual may have in executing activities compared to Participation Restrictions which are problems an individual may experience in involvement in life situations. Two distinct qualifiers are then used in this step The first one describes what a person does in their actual environment. The second describes what a person does in a situation in which the effect of the context is absent or made irrelevant (such as in a standardized evaluation setting). "The gap between capacity and performance reflects the difference between the impacts of current and uniform environments, and thus provides a useful guide as to what can be done to the environment of the individual to improve performance" [START_REF] Organization | Ifc: International classification of functioning, disability and health[END_REF].

Finally the Environmental factors, making up the physical, social and attitudinal environment in which people live and conduct their lives are qualified in positive (resp. negative) qualifiers depending on their impact as facilitator (resp. barriers). Factors such as "Design, construction and building products and technology of buildings for public use", Relationships (family, friends...), Social norms and Legal services are examined.

Once all those information have been collected, the opportunity for a co-designed technical solution is at hand. Not only is the designer informed of all past and present qualifiers of the subject, but he also knows his/hers motivations and goals related to the function to regain. Several validated quiz and scales exist to improve the holistic knowledge of the subject like the Assessment of Life Habits (LIFE-H), a tool designed to document the quality of social participation of individuals with disabilities in carrying out activities of daily living and social roles by measuring the level of difficulty and the assistance required to perform a series of life habits [START_REF] Noreau | The life-h: Assessment of the quality of social participation[END_REF]. This scale could be used as a direct map to a control law setting as to whether the subject require more of less help in the required motion.

Finally, an easy and quick evaluation would be possible for a back and forth prototyping process through the well known "System Usability Scale" [START_REF] Brooke | Sus-a quick and dirty usability scale[END_REF]. This scale, despite being created for marketing purpose rather than scientific ones, has the main advantage of isolating very efficiently extreme positive or negative feedback. Previous works related to rehabilitation devices were concluding that such a structured and generalized protocol for patients would improve the overall acceptation of the device and, consequently, the whole clinical process [START_REF] Ouendi | The rehabilitation robot: factors influencing its use, advantages and limitations in clinical rehabilitation[END_REF].

B. Application example 2: Development of a fleet of wheelchair and connected objects to improve the autonomy of people with reduced mobility

In this second application example, the ICF will be considered as a representation of each subject system inside the wheelchair fleet. While the previous application was focusing on the subject and his/hers supplementary device, the current situation requires a broader definition of context and external constraints.

As presented in Fig. 3, each subjects of the wheelchair fleet can now be represented through the ICF qualifiers either for body functions, structure of activities, Participation and Environmental factors. A first network of potential interactions are possible between all members of the fleet and a final level of rules and must be considered depending on the external context. For instance, in the case of a basket-ball game, obstacle avoidance systems sensibility can be lowered in order to allow low-intensity collision for defensive purpose. Obviously such collisions are to be prohibited in the context of street mobility and the avoidance systems sensibility should be reprogrammed as such.

Fig. 3: Relation between subjects in the ICF framework and external application

One challenge in this situation is to allow the subject to use the mobility device while avoiding failures which can be separated into communicating failures (e.g. not moving the joystick in the right direction due to tremors in the hand), perception and comprehension of failures (e.g. not realizing that the wheelchair is still due to a contact with an obstacle), and solving failures (e.g. avoidance failure) [START_REF] Honig | Understanding and resolving failures in human-robot interaction: Literature review and model development[END_REF]. One method to try to reduce those failures patterns could be to inform the subject about specific percentages of reliability as a link was found between perceived reliability and trust in the system: the more the trust in automation increased, the more the perceived reliability increased [START_REF] Avril | Providing different levels of accuracy about the reliability of automation to a human operator: impact on human performance[END_REF].

Although an efficient proposition would be to let the global motion of the fleet to a purely automated algorithm, it has been shown that when having to choose for an automation level, subjects will prefer automation types offering the best humanmachine interactions quality rather that the most effective automation type [START_REF] Navarro | Influence of humanmachine interactions and task demand on automation selection and use[END_REF]. Another parameter to consider would be the amount of control allowed by the subject.

Finally, this whole application cannot seriously reach its goal without taking into consideration feedbacks and insights of people with reduced mobility in the complete design process (including when initially setting the supposed goals of the device and its specifications). Due to their small representation in industry and design schools, often leading designers forgot to involve people with disabilities altogether at this stage or will try "imagining" what the disability feels like [START_REF] Blanchard | Cripping assistive tech design: How the current disability framework limits our ability to create emancipatory technology[END_REF]. In the specific field of mobility, the dimensionality of displacement is very relevant and almost always silenced in mobility devices [START_REF] Blanchard | Disabled dimensionalities: Normative expectations' impacts on disabled perceptions and spatialities[END_REF].

IV. SOME PRELIMINARY RESULTS ON WHEELCHAIRS

In 2023, according to the WHO (World Health Organization), 15 million people will need a wheelchair on a daily basis. By 2030, one in six people in the world will be over 60 years old. Studies show that many people with mobility impairments have osteoarthritis in their hands that prevents them from maneuvering a manual or electric wheelchair. Some of them use a walker type equipment to move around, this equipment prevents them from having the mobility to open doors for example. Other PRMs have partial or total visual impairment that prevents them from properly maneuvering in a wheelchair. In addition, medical personnel are increasingly concerned about controlling the posture of people with reduced mobility in their wheelchairs. How to develop a set of technological bricks around the wheelchair allowing on the one hand to improve the living conditions of the person with reduced mobility and the working conditions of their caregivers or doctor?

The challenge is to propose integrated, modular, low-cost solutions to see them widely deployed in establishments accommodating these PRM. Based on these real needs and the methodology described in this paper, we have developed a first version of a set of connected objects around the person with reduced mobility for the improvement of autonomy by meeting several identified functional needs. We will present the integrated design of the developed solution.

A. Description of the application

We have developed a set of system components; the robotization of a wheelchair, the development of a driving aid, a fall detector, an automatic recharging system and a set of connected objects around the PMR. The figures 4, gives the SoS architecture of the developed solution.

B. System architecture and Human Machine Interface

In order to allow all the modular technological bricks of our system to exchange information with each other, it was necessary to design a simple and efficient architecture allowing the whole elementary system to interact with each other. The wireless communication should be able to send data to all the SoS components with low latency. The developed architecture is based on MQTT.

The man-machine interface is meant to be intuitive and allows the administrator to control and have an overview of the system. A web interface has been developed, allowing to supervise all the components remotely. Several tests have been done to validate the effective transmission of information. We note a maximum latency of 1 second when sending and receiving data with an average latency of 0.82 seconds for sending (object to HMI) and 0.2 seconds for receiving.

C. Automatic charging station

The goal here is to reduce non-essential travel. Putting the wheelchair in charge can be complex for a person with reduced mobility. Therefore, the aim is to design a system capable of charging different wheelchairs using lead-acid or lithium batteries. The automatic charging system consists of a docking program that will automatically bring the wheelchair close to the charging area. Once the wheelchair is close to the station, a camera attached to the back of the wheelchair allows it to be correctly aligned with the charging pods. Once the wheelchair is properly aligned, it will plug into the charging pods. An ultrasonic sensor detects the presence of the wheelchair under load (Fig. 5). The developed system has been tested. 93% of the 200 automatic charging tests were correct.

D. ADAS and Autonomous Navigation

The obstacle warning system is composed of a Lidar and 8 Ultrasounds (US). A haptic feedback on the armrests of the chair allows to communicate to the user information on the distance to the obstacle. Also, an autonomous navigation application is developed to move the wheelchair from one point to another. These systems are under development. Other connected objects are being developed to be added to the solution presented here.

V. CONCLUSION

In this paper, we have proposed a methodology for the integrated design of modular technological breakthroughs allowing to improve the autonomy of people with reduced mobility. The ICF provides a holistic way to assess needs and choose the most suitable technical solution for a specific health problem. Starting from the user-centered design, allowing to favor the acceptability by the person, modular applications answering a basic functional need are developed, advanced interaction applications modifying the environment are then proposed. The complete solution has been conceptualized through a system of systems approach. Examples of applications will illustrate the relevance of the proposed design approach. We believe this framework can be used for advocacy and empowerment of people with reduced mobility to develop a prototype of wheelchairs and orthesis connected in the framework of the CPER RITMEA project.

Fig. 4 :Fig. 5 :Fig. 6 :

 456 Fig.4: System of Systems to improve mobility of persons using wheelchairs

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Sistemas De

Eventos Discretos

En Neonatolog Ía

Edgar H Sepulveda
email: ehsepulvedao@unal.edu.co

Leonardo E Bermeo
email: lbermeoc@unal.edu.co

Luis C Mendez
email: lcmendezc@unal.edu.co

MODELO DEL PROCEDIMIENTO DE ADAPTACI ÓN DE NEONATAL INMEDIATA: UNA APLICACI ÓN DE

Keywords: Discrete event system modeling, Neonatology, Statechart, Deterministic Finite Automaton, Medical guideline or protocol. Resumen Modelamiento de sistema de eventos discretos, Neonatología, Statecharts, Autómata finito determinista, Guía o Protocolo médico

Modeling and simulation are becoming increasingly important tools for teaching and researching in medicine. Medical guidelines are systematically developed statements to assist practitioners to determine appropriate health care in specific circumstances. A medical guideline or protocol can be represented, in an abstract way, as a discrete event system model. This is indeed a promising field for applying this kind of models. In this paper, we present a finite automaton model for the Neonatal Adaptation Guideline developed by the School of Pediatrics and Neonatology of the National University of Colombia. The reported model extends the original flow chart containing the guideline, in terms of understanding, consistence and level of detail.

Introducción

El modelamiento y la consecuente simulación computacional son herramientas cada vez más relevantes en la enseñanza y la investigación en medicina.

El desarrollo de modelos en medicina con base en sistemas de eventos discretos (SED) es un área activa como lo muestran algunos trabajos representativos que mencionamos a continuación: el trabajo de [START_REF] Emerson | The effect of medical trainees on pediatric emergency department flow: A discrete event simulation modeling study[END_REF] utiliza el modelamiento de eventos discretos para el entrenamiento médico en la atención terciaria urbana, reduciendo el tiempo de espera de los pacientes; el trabajo de [START_REF] Beate | Tutorial in medical decision modeling incorporating waiting lines and queues using discrete event simulation[END_REF] evalúa las ventajas de modelos de SEDs para integrar líneas de espera y colas para tratamientos sin demoras y disponibilidad de todos los recursos necesarios en todo momento; el trabajo de Grigorov y Rudie (2011) usa control supervisorio de SEDs para el modelamiento y simulación de políticas para el control de epidemias.

Un campo prometedor de aplicación de los sistemas de eventos discretos es el modelamiento de guías y protocolos médicos [START_REF] Méry | Medical protocol diagnosis using formal methods[END_REF]. Las guías y protocolos médicos son declaraciones desarrolladas sistemática y consensuadamente para apoyar a los profesionales de la salud sobre como proceder en circunstancias específicas (ten [START_REF] Ten Teije | Improving Medical Protocols by Formal Methods[END_REF]. Existen antecedentes importantes del uso de SEDs para el modelamiento de guias médicas: en el trabajo de [START_REF] Rosalie | Discrete event modeling and control of the neonatal resuscitation program algorithm[END_REF] se usan autómatas finitos temporizados y no temporizados para representar diferentes escenarios médicos neonatales con base en información extraída del protocolo de Resucitación Neonatal Inmediata de American Heart Asociation (AHA) [START_REF] Chair | Guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care[END_REF]. Los trabajos de Guo et al. (2016) y Méry y Singh (2012) exploran, respectivamente, el uso de Statecharts y del lenguage Event B para el modelamiento y verificación formal de protocolos médicos.

Figura 1: Crecimiento exponencial del uso de simulación en medicina neonatal el número de publicaciones. El resultado presentado en la la figura 1 fue obtenido buscando artículos de que usan simulación en educación, enseñanza o aprendizaje en medicina. La búsqueda fue realizada en la base de datos PubMed bajo la siguiente ecuación de búsqueda: (simulation and (medical (teaching or education or learning)).

Dada la importancia creciente de la simulación como herramienta pedagógica y de investigación en medicina, el trabajo que estamos reportando en este artículo hace parte de un proyecto para desarrollar de una herramienta de simulación para estudiar diferentes prácticas de interés en neonatología. El diagrama funcional de esta herramienta está representado en la figura 2.

Procedimiento Médico

Paciente

Eventos

Atención clinica

Figura 2: Investigación sobre fisiopatología del paciente y la práctica clínica Desde una perspectiva general, un modelo computacional para estudiar procedimientos médicos debe considerar separadamente al paciente y al procedimiento médico. Existen avances considerables en el modelamiento de los procesos fisiológicos de un paciente usando modelos dinámicos de ecuaciones diferenciales (vea, por ejemplo, Myers y Capper (2002) y [START_REF] Albanese | An integrated mathematical model of the human cardiopulmonary system: model development[END_REF]). Para tener una representación computacional completa de la interacción del paciente y el proceso médico, es necesario desarrollar un modelo de simulación para los protocolos médicos (bloque verde de la figura 2). Puesto que los pasos de atención clínica que deben realizarse a un paciente se definen por los signos o síntomas que presenta, es natural abstraer un protocolo médico como un sistema de eventos discretos.

En este trabajo presentamos el modelo, como sistema de eventos discretos, del procedimiento de Adaptación Neonatal Inmediata (ANI), desarrollado durante muchos años de práctica clínica por la Escuela de Perinatología y Neonatología de la Universidad Nacional de Colombia (EPN-UNC) y publicado en el 2004 [START_REF] Currea | La adaptación neonatal inmediata. La reanimación neonatal[END_REF]. La elección correcta del momento del pinzamiento del cordón umbilical y las prácticas clínicas adecuadas de adaptación neonatal pueden beneficiar a cerca 700,000 colombianos que nacen cada año.

Con la motivación precedente, presentamos este artículo, estructurado de la siguiente forma: en la sección 2 presentamos los flujogramas de representación de protocolos médicos, su modelamiento como autómatas finitos y también introducimos las características de los Statecharts necesarias en este trabajo. En la sección 3 discutimos el flujograma del procedimiento de adaptación neonatal inmediata y presentamos su modelo como sistema de eventos discretos. En la sección 4 presentamos opiniones de realimentación recibidas de diferentes profesionales. Finalmente, en la sección 5 presentamos las conclusiones y recomendaciones para trabajos futuros.

Preliminares

Con el fin de brindar al lector los principales elementos que fundamentan este trabajo, a continuación vamos a revisar los siguientes temas: (i) Flujogramas de procedimientos médicos; (ii) Autómatas finitos y su aplicación en medicina; y, (iii) Statecharts.

Flujogramas de protocolos médicos

Una forma usual de presentar secuencialmente un protocolo médico es a través de un flujograma. Esta es una forma de representación visual que sintetiza la información del protocolo, a manera de algoritmo (vea algunos ejemplos de flujogramas, usados en diferentes contextos médicos, en [START_REF] Keltya | Dismantling the justice silos: Flowcharting the role and expertise of forensic science, forensic medicine and allied health in adult sexual assault investigations[END_REF], Caicedo-Cuenca (2017) y [START_REF] Mencarini | Pulmonary tuberculosis followed by sarcoidosis in an hiv-infected patient: A case report and a simplified diagnostic flowchart for diagnosis and treatment of sarcoidosis[END_REF]). A continuación presentamos un flujograma muy sencillo para ilustrar el proceso de modelamiento de flujogramas.

Ejemplo 1 El flujograma de la figura 3 es un protocolo para definir el riesgo por posible estado de gestación para un exámen de medicina nuclear diagnóstica [START_REF] James | Development of consensus statements for pregnancy screening in diagnostic nuclear medicine: a delphi study[END_REF].

Es importante resaltar que el flujograma de la figura 3 es el resultado del consenso, obtenido sistemáticamente, entre varios médicos. En general, la obtención de estos flujogramas es un proceso iterativo realizado por profesionales de la salud, que necesita varios ciclos de revisión y consenso, antes de convertirse en un protocolo. Figura 3: Flujograma de evaluación de riesgo de pacientes con posible gestación para un exámen de medicina nuclear diagnóstica. La abreviatura en inglés LMP significa último periodo menstrual (Last Menstrual Period ).

La selección de una herramienta formal de modelamiento de protocolos médicos debe considerar cuidadosamente los siguientes aspectos:

Versatilidad: posibilidad de ser usada para modelar diferentes guías y protocolos médicos de manera eficaz y comprensible Escalabilidad: Los modelos realizados pueden ser modificados fácilmente, aumentando progresivamente los detalles de un procedimiento médico.

Complejidad moderada: La representación visual del modelo debe ser lo suficientemente clara para ser interpretada fácilmente por personal de la salud, de ingeniería o de otras profesiones interesadas en el uso del modelo. Esto permite acelerar los procesos de desarrollo interdisciplinario.

Teniendo las características anteriores decidimos usar autómatas finitos y Statecharts como herramientas de modelamiento. A continuación expondremos la relación existente entre flujogramas y autómatas finitos y las definiciones más importantes usadas en este trabajo.

Autómatas finitos y su aplicación en medicina.

Formalmente, un autómata finito, denotado por G, es un modelo matemático representado por la séxtupla:

G = (Σ, X, f, Γ, x 0 , X m ),
en la cual Σ es el conjunto de eventos, X es el conjunto de estados, f : Σ × X → X es la función de transición de estado, Γ : X → 2 Σ es la función de eventos activos, x 0 ∈ X es el estado inicial

q 0 q 2 q 1 q 4 q 5 q 6 q b a c g h d e f i i 3
Figura 4: Automáta que describe el flujograma del de la figura 3 y X m ⊆ X es el conjunto de estados marcados. El siguiente ejemplo ilustra la relación entre un flujograma y un autómata.

Ejemplo 2 La figura 4 muestra un autómata que representa el flujograma médico presentado en la figura 3. El estado inicial de este autómata es q 0 (rotulo que significa el inicio del test de riesgo, de acuerdo con la tabla 1a). Los estados marcados Tabla 1: Estados y eventos del autómata de la figura 4

(a) Estados del automata Definición q 0 Inicio del test q 1 Ciclo menstrual establecido q 2 Ciclo menstrual incierto q 3 Gestación probable q 4 Gestación improbable q 5 Se realiza el procedimiento q 6 Se pospone el procedimiento son q 5 (rótulo que significa que se realiza el procedimiento) y q 6 (rótulo que significa que se pospone el procedimiento). El conjunto de eventos es Σ = {a, b, c, d, e, f, g, h, i} (rótulos que expresan las transiciones entre los estados, de acuerdo con la tabla 1b). Por ejemplo, el evento a significa que la mujer ha sido clasificada en un rango de edad entre los 18 y 55 años. La función de transición expresa los cambios de estado del autómata, de acuerdo con el procedimiento. Por ejemplo, en términos de autómatas decimos: f (q 1 , d) = q 4 . Traducido a términos médicos esto significa de acuerdo al rango de edad (estado q 1 ) y dadas las condiciones informadas por el paciente (evento d) se diagnostica un posible estado de gestación (estado q 4 ). Todos los significados médicos que corresponden a estos rótulos de los estados y eventos están contenidos en la tabla 1.

Un modelo de un procedimiento médico debe mantener una complejidad visual moderada para, así, facilitar su subsecuente verificación y refinamiento por parte de un equipo interdisciplinario. Esto nos lleva al uso de la representación de Statecharts, descrita brevemente a continuación.

Statecharts

El formalismo denominado Statecharts, propuesto por [START_REF] Harel | Statecharts: A visual formalism for complex systems*[END_REF], define una representación visual jerárquica de autómatas finitos. Dentro de este formalismo nos interesa usar dos elementos fundamentales: superestados y transiciones condicionadas. Estos elementos serán explicados a continuación. [START_REF] Harel | Statecharts: A visual formalism for complex systems*[END_REF].

Transición condicionada. El autómata de la figura 5(b) posee una transición condicionada, representada por B g(X)

---→ C. De acuerdo al formalismo Statecharts, esta transición implica que el autómata pasa del estado B al estado C si y solo si se produce el evento g, mientras se cumple la condición X.

En síntesis, los Statechart son un formalismo visual para presentar modelos basados en autómatas finitos, cuya finalidad es representarlos con una menor complejidad visual. Aquí hemos omitido muchos detalles técnicos de autómatas y Statecharts, teniendo en cuenta el carácter interdisciplinario de este trabajo.

Modelo del procedimiento de Adaptación Neonatal Inmediata

En esta sección presentamos el modelo, como sistema de eventos discretos, del flujograma que representa el procedimiento de Adaptación Neonatal inmediata recomendado por la Escuela de Perinatología y Neonatología de la Universidad Nacional de Colombia (EPN-UNC).

Flujograma de Adaptación Neonatal Inmediata

La figura 6 representa el flujograma de Adaptación Neonatal Inmediata [START_REF] Currea | La adaptación neonatal inmediata. La reanimación neonatal[END_REF]. La fi- Figura 6: Flujograma de la adaptación neonatal inmediata de la EPN-UNC [START_REF] Currea | La adaptación neonatal inmediata. La reanimación neonatal[END_REF]. nalidad de este flujograma es describir los pro-cedimientos clínicos de adaptación de un neonato a sus nuevas condiciones vitales. Con este fin, se recomienda el uso de una escala de medición de la vitalidad del neonato llamada escala AP-GAR [START_REF] Apgar | A proposal for a new method of evaluation.of the newborn infant[END_REF] para determinar la evolución del paciente en diferentes momentos del proceso de adaptación neonatal. Así mismo, clasifica diferentes tipos de pinzamiento del cordón umbilical. Para determinar si hay ventilación y definir si está haciéndose con esfuerzo, se utiliza la escala de SILVERMAN-ANDERSEN [START_REF] Silverman | A controlled clinical trial of effects of water mist on obstructive respiratory signs, death rate and necropsy findings among premature infants[END_REF]. Según los signos y condiciones fisiológicas del paciente, su proceso de adaptación puede ser espontáneo, conducido o inducido. Los bloques en verde de la figura 6 contienen información de la adaptación neonatal espontánea; los bloques en azul, de la adaptación conducida; y, en los bloques en rojo se consigna el proceso de adaptación inducida.

Modelo de eventos discretos del Procedimiento de Adaptación Neonatal Inmediata

El modelo de eventos discretos que presentamos a continuación contiene información detallada de los procesos de adaptación espontánea y conducida del neonato. En la parte correspondiente a la adaptación inducida se omiten detalles de modelamiento correspondientes a la cateterización, manejo de volúmenes y suministro de medicamentos, debido a que nuestro interés actual se centra en el estudio de las prácticas de pinzamiento del cordón umbilical.

La figura 7 es el modelo de eventos discretos (con descripción matemática de autómata finito y extensión visual de Statechart) que sintetiza el resultados de este trabajo. En la tabla 3 está la descripción de los estados del modelo, compuesto en total por 19 estados (rotulados de 0 a 18) y 3 superestados (rotulados como A, B y C). Note que cada estado corresponde con un diagnóstico o con un procedimiento que debe ser realizado al paciente. Por ejemplo, el estado 7 indica que debe practicarse asistencia ventilatoria no invasiva al paciente neonato. La tabla 2 contiene la descripción de los 27 eventos del modelo. Aquí es interesante recalcar que la palabra "evento" del lenguaje de autómatas se asocia con un signo vital, un síntoma, o una característica del paciente que puede ser detectada por el médico, esto es, con un evento médico. Para ilustrar esto consideremos, por ejemplo, la transición 6 cv1 --→ 8, aquí el evento cv 1 indica que el paciente tiene un número de pulsaciones cardiacas por minuto por debajo de 59 (paro cardiovascular relativo) por tanto debe pasar del estado 6 en que se le ha diagnosticado deficiencia respiratoria al estado 8 en que requiere asistencia invasiva y/o masaje cardiovascular.

Los estados marcados sirven para definir momentos definitivos del proceso de Adaptación Neo-Tabla 2: Eventos del autómata de la figura 7 Los estados 17 y 18 indican que el proceso de adaptación neonatal ha terminado y que el neonato debe ser trasladado a la unidad de cuidado neonatal (estado 17) o con al alojamiento conjunto con la madre (estado 18). En algunos casos el neonato nace muerto o con condiciones vitales que no permiten que sobreviva, por lo cual debe ser declarado fallecido (estado 12).

Metodología

La metodología usada para la realización de este modelo fue realizada por refinamiento incremental. Iniciamos con un modelo con poco nivel de detalle que fue refinado progresivamente como resultado de la interacción entre especialistas de neonatología e ingeniería. Es importante resaltar que la elaboración de este modelo implicó adicionar un gran nivel de detalle aportado por la experiencia e interpretación clínica de los participantes. Como ha sido señalado por ten [START_REF] Ten Teije | Improving Medical Protocols by Formal Methods[END_REF], el uso de métodos formales de modelamiento para protocolos médicos conlleva inherentemente un análisis, refinamiento de detalle e interpretación que produce, necesariamente, una ampliación del protocolo.

Relevancia del uso de Statecharts

Es importante comentar que el uso de Statecharts en este modelo produce una reducción visual considerable de transiciones (producida por los superestados) y de estados (producida por las transiciones condicionadas).

Según la tabla 2, la condición N P significa que el cordón umbilical no ha sido pinzado. Así, las transiciones condicionadas

IP P (N P ) ------→ 15 y 14 CP H(N P )
-------→ 16 solo ocurrirán cuando el cordón umbilical no haya sido pinzado. Desde el punto de vista médico, el pinzamiento del cordón es un hecho irreversible, así que el neonato pasa a la condición P , en la cual el cordón umbilical ya ha sido pinzado. Sin usar estas transiciones, se hace necesario adicionar estados sin significado médico en el modelo, dificultando la comprensión.

El uso del formalismo visual de Statecharts nos permite describir correctamente y sintéticamente la estructura del procedimiento médico modelado. Sin embargo, es importante comentar que un modelo como el presentado aqui puede ser traducido fácilmente en un autómata finito determinista, posibilitando, así, el uso de métodos de verificación y diagnóstico desarrollados para SEDs modelados por autómatas finitos.

Retroalimentación recibida

El modelo presentado en la sección 3.2 fue evaluado por un panel interdisciplinario con personal de la salud, ingeniería y diseño industrial. El uso de autómatas con extensión visual Statecharts permitió establecer un lenguaje visual común, entendido por profesionales de diferentes disciplinas. A continuación consignamos algunas de opiniones de los participantes acerca del modelo de adaptación neonatal presentado en este trabajo: Profesional de la salud: Crear un modelo que represente un procedimiento rutinario de una manera sencilla de comprender, sirve de base para plasmar en un futuro distintos procedimientos interdisciplinarios que permitan plantear nuevos modelos más complejos que incluyen detalles desde diferentes áreas del conocimiento. Sin embargo, se debe reducir aún más la complejidad visual, teniendo en cuenta que a futuro contendrá aún más información.

Profesional de diseño industrial: Este modelo funciona como complemento en la formación de personal de la salud y facilita la retroalimentación y extensión de la información enseñada en el aula obteniendo un modelo más completo. Incluso, podría en un momento dado, disminuir el margen de error durante el procedimiento clínico. Adoptando este diseño visualmente resulta fácil leer y comprender la información incluso para personas ajenas a la práctica médica convirtiéndose en una posible herramienta de trabajo para investigaciones interdisciplinarias.

Profesional de ingenieria: El desarrollo de este modelo permite concebir herramientas para presentar las guías y procedimientos médicos de forma interactiva. Estos ser entendidos por personas con formación diferente a la salud, incluyendo, por supuesto, a los pacientes. Esto también permite el desarrollo de simuladores con escenarios médicos de entrenamiento.

Conclusiones

Hemos presentado un modelo de autómata finito con extensión visual para el procedimiento de adaptación neonatal inmediata. El modelo desarrollado contiene niveles de detalle, consistencia y comprensión que amplian el flujograma original que describe el procedimiento. El modelo es una herramienta de apoyo para la enseñanza en neonatología y un paso en el desarrollo de herramientas de simulación para investigación en el área.

Los modelos de autómatas finitos y los Statecharts proveen un lenguaje visual común que permiten la interacción entre especialistas de diferentes áreas para desarrollar modelos de procedimientos médicos.

Como trabajos futuros pueden usarse autómatas temporizados para reducir aún más la complejidad visual. Es también importante introducir la noción de observación parcial (signos no visibles en el paciente) para que los especialistas médicos dispongan de herramientas de apoyo en diagnóstico o pronóstico a partir a partir de los modelos de sistemas de eventos discretos desarrollados.

Agradecimentos

Los autores agradecen al Departamento de Ingeniería Eléctrica y Electrónica y al Departamento de Pediatria de la Universidad de Colombia por su apoyo en este trabajo.

  (b) Eventos del autómata a 18 <Edad <55 años b 12 <Edad <17 años c Presenta menstruación d La paciente descarta posible gestación e La paciente NO descarta posible gestación f Último periodo menstrual (LMP) <10 días g NO presenta menstruación h Histerectomía ó Edad >50 años ó último periodo menstrual >12 meses i Último periodo menstrual (LMP) >10 días

  Figura 5: Ejemplo autómata con transición condicionada y super estados de los Statecharts

  Riesgo aumentado con indicación de nacimiento vía abdominal r 2 Riesgo habitual o Riesgo aumentado sin indicación de nacimiento vía abdominal (b) Valoración de vitalidad escala APGAR e 3 Evaluación Apgar (8 -10) e 2 Evaluación Apgar (4 -7) e 1 Evaluación Apgar (0 -3) e 0 Evaluación Apgar (0) (c) Valoración en la Escala Silverman-Andersen d 0 No presenta esfuerzo ventilatorio (0 puntos) d 1 Esfuerzo ventilatorio leve (1-3 puntos) d 2 Esfuerzo ventilatorio moderado (4-6 puntos) d 3 Esfuerzo ventilatorio severo (7-10 puntos) (d) Ventilación v 0 Paro ventilatorio -Apnea v 1 Bradipnea (1 a 29 respiraciones por minuto) v 2 Taquipnea por liquido en el pulmón v 3 Taquipnea por prematuro v Presenta esfuerzo ventilatorio (e) Estado cardiovascular cv 0 Paro cardiovascular absoluto (0 latidos por minuto) cv 1 Paro cardiovascular relativo (1-59 latidos por minuto) cv 2 Bradicardia (60-99 latidos por minuto) , los estados 4, 15 y 16 indican el tipo de pinzamiento del cordón umbilical realizado al neonato.

  vitalidad -ventilación minuto 5 11 Diagnóstico vitalidad -ventilación minuto 10 12 Neonato declarado fallecido 13 Diagnóstico de vitalidad normal 14 Diagnóstico de ventilación normal 15 Pinzamiento Precoz 16 Pinzamiento Habitual o Diferido 17 Traslado a la unidad de cuidado neonatal 18 Traslado con la madre al alojamiento conjunto A Asistencia ventilatoria y cardiaco vascular B Diagnóstico temporal de vitalidad y ventilación C Tipo de pinzamiento realizado

Figura 7 :

 7 Figura 7: Autómata con superestados que representa el flujograma de Adaptación Neonatal Inmediata de la figura 6

El uso de métodos y técnicas formales de modelamiento de protocolos médicos tiene dos propósitos fundamentales: (i) Mejorar la estructura de los mismos en términos de consistencia, reducción de ambiguedad y completitud[START_REF] Ten Teije | Improving Medical Protocols by Formal Methods[END_REF]; y, (ii) Desarrollar herramientas de simulación computacional para que los practicantes puedan aprender y entrenarse con los protocolos médicos. Si bien la experiencia clínica es una metodología de aprendizaje irreemplazable en medicina, los avances tecnológicos actuales permiten utilizar herramientas de simulación para complementar el entrenamiento del personal de la salud.En relación a la importancia de la simulación como método de enseñanza en medicina, la figura 1 revela un crecimiento exponencial por año en