Nom du directeur de thèse : Marc BENDAHAN (PR), Tel : 04 13 94 23 03,

E-Mail : marc.bendahan@im2np.fr

Co-encadrante : Virginie LAITHIER (MCF), Tel : 04 13 94 66 33,

E-Mail : virginie.laithier@im2np.fr

Laboratoire : IM2NP-UMR CNRS 7334 – Marseille (FR)

Financement : demandé

Type de financement : contrat doctoral ED 353

Summary in English :

            The aim of this study is to develop a selective ammonia microsensor for monitoring acid load in patients with chronic renal failure to avoid an increase of the renal function failure which could involve transplantation or dialysis.

The lack of acid load regulation is characterized by default of NH4⁺ elimination. Proteins are the most important nutrient in the increasing of the acid load causing metabolic acidosis risks [1]. The control of protein intake is essential to limit these effects. The NH4⁺ concentration in urines is representative of the acid load and allows to predict the degradation of kidney efficiency [2]. These analyses are very adapted for the monitoring of the patients suffering of KCD (Kidney Chronic Disease) but they aren’t done frequently and don’t inform on the diet behavior. Develop a device that could give more data about it by non-invasive measurement would be a very important progress. The ammoniac concentration in breath measurement could be a good way but the literature demonstrates that it isn’t correlated with the blood ammonia concentration and it is influenced by the mouse microbiota [3-6]. Contrariwise, the transdermal way is a very interesting non invasive method to detect ammonia [7-9] which is a vapor among of the bioindicators emitted by the skin [10-13]. It has been demonstrated by some research works that the transdermal ammonia concentration is relied at blood ammonia concentration [9, 14] but the correlation with the acid load and the proteinic diet didn’t be studied yet [5, 9]. This work needs the development of a sensitive and reliable device able to provide real time data about the transdermal ammonia emissions. Resistive metal-oxide based gas microsensors are very adapted for this application. They have a small size, a low cost and an easy use but they present a lack of selectivity [11]. CuBr is a better candidate for microsensor realization because it reacts specifically with ammonia by complexation with high selectivity and doesn’t need heating. Last work in the MCI group showed a high sensitivity for ammonia detection in humid atmosphere. This microsensor will be integrated in a device that will have to respond to transdermal detection constraints as biocompatibility, humid atmosphere, body temperature, NH₃ reactivity…The data bases established from sensors characterization in laboratory and during clinical trials will be exploited latter to develop numerical models. These ones will be validated in laboratory and implemented in a processor.

The PHD student will have to work (as part of the Carnot Star CAMIMAC project) about the conception, the realization and the validation of the device integrating the Copper Bromide (CuBr) microsensor. The research works will be focused on the device design, the sensitive layer elaboration and the physicochemical and electronic characterizations. The microsensor performances will be optimized considering the influence of the relative humidity, the temperature and the interfering gases which will be identified in collaboration with medical partner. The prototype could be tested by medical staff to show correlation between the transdermal ammonia, the ammonia in urines and the protein intake. Several subjects will be studied in order to validate the device efficiency. The PHD student will work in Microsensors and Instrumentation group (MCI) of IM2NP, under supervision of Pr Marc BENDAHAN and Dr. Virginie MARTINI LAITHIER. The student will collaborate with other research group of the Institute and with Pr Stéphane BURTEY, nephrologist in the Conception Hospital for the clinical tests.

 The Microsensors and Instrumentation team is a part of the DETECT department of the IM2NP laboratory. This team designs and studies sensors since many years and has developed its expertise through numerous national and international projects and also several patents which currently are in industrial exploitation stage. One of the principal research work of the team has focused on gas and vapor detection for air quality and health application [5]. It collaborates with doctors since few years in order to use its skills for development of detection devices for medical monitoring. It develops both rigid and flexible support systems [6-7] and has deposition and advanced electrical characterization equipment in controlled atmosphere.

Candidate skills required

            Knowledge in the elaboration of thin-film materials, as well as experience in physicochemical and electrical characterization techniques for chemical sensors, are expected.

            Skills in electronics and data processing would be appreciated, as well as a good ability to work independently, good interpersonal skills, and a spirit of initiative.

Publications on the subject:

[1] Levitt D G and Levitt M D. A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans. Clinical and Experimental Gastroenterology. 2018;11:193-215.

[2] Raphael KL. Metabolic Acidosis and Subclinical Metabolic Acidosis in CKD. J Am Soc Nephrol. 2018 Feb; 29(2):376-382. doi: 10.1681/ASN.2017040422

[3] Narasimhan L R, Goodman W, and Kumar C Patel N. Correlation of breath ammonia with blood urea nitrogen and creatinine during hemodialysis. Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4617–4621.  doi: 10.1073/pnas.071057598

[4] Timmer B, Olthuis W , van den Berg A. Ammonia sensors and their applications—a review. Sensors and Actuators B. 2005;107:666–677. doi.org/10.1016/j.snb.2004.11.054.

[5] Schmidt F M, Vaittinen O , Metsälä M et al. Ammonia in breath and emitted from skin. Journal of Breath Research. 2013;7(1):017109 . DOI: 10.1088/1752-7155/7/1/017109

[6] Guntner A T, Wied M, Pineau N et al. Rapid and selective NH₃ sensing by porous CuBr. Advanced Science. 2020;7(7):1903390.

[7] Furukawa S, Sekine Y, Kimura K et al. Simultaneous and multi-point measurement of ammonia emanating from human skin surface for the estimation of whole body dermal emission rate. Journal of Chromatography B. 2017;1053:60–64. doi.org/10.1016/j.jchromb.2017.03.034

[8] Ruzsanyi V, Mochalski P, Schmid A et al. Ion mobility spectrometry for detection of skin volatiles. Journal of Chromatography B. 2012;911:84– 92. doi.org/10.1016/j.jchromb.2012.10.028

[9] Nose K, Mizuno T, Yamane N et al. Identification of ammonia in gas emanated from human skin and its correlation with that in blood. Analtical sciences. 2005 Dec;21:1471-1474.

[10] De Lacy Costello B, Amann A, Al-Kateb H et al. A review of the volatiles from the healthy human body. Journal of Breath Research. 2014;8: 1-29

[11] Jiang R, Cudjoe E, Bojko B et al. A non invasive method for in vivo skin volatile compounds sampling. Analytica Chemica Acta. 2013;804:111-119.

[12] Mochalski P, King J, Unterkofler K et al. emission rates of volatile organic compounds from skin of healthy volunteers. Journal of Chromatography B. 2014;956:62-70.

[13] Sekine Y, Toyooka S, Watts S F. Determination of acetaldehyde and acetone emanating from human skin using a passive flux sampler-HPLC system. Journal of chromatography B. 2007;859:201-207.

[14] Czarnowski D, Górski J, Jóźwiuk J, et al. Plasma ammonia is the principal source of ammonia in sweat. Eur J Appl Physiol. 1992;65:135-137

[15] Tricoli A and Neri G. Miniaturized Bio-and Chemical-Sensors for Point-of-Care Monitoring of Chronic Kidney Diseases. Sensors.2018;18:942. doi:10.3390/s18040942

[16] Lauque P, Bendahan M, Seguin JL et al. Highly sensitive and selective room temperature NH₃ gas microsensor using an ionic conductor (CuBr) film. Analytica chimica acta.2004 Jul;515(2):279 - 284. 10.1016/j.aca.2004.03.071

[17] Lauque P, Bendahan M, Seguin JL et al. Copper and Silver Halides for Resistive Gas Sensors, EOS Encyclopedia of sensors. 2006;10:1-9.

[18] Yuan Zhang, Pengcheng Xu, Jiaqiang Xu. NH₃ Sensing Mechanism Investigation of CuBr: Different Complex Interactions of the Cu⁺ Ion with NH3 and O2 Molecules. J. Phys. Chem. C .2011;115:2014–2019. dx.doi.org/10.1021/jp108732j

[19] Hua-Yao Li, Chul-Soon L, Do Hong K et al. Flexible room-temperature NH₃ sensor for ultrasensitive, selective, and humidity-independent gas detection. Applied materials and interfaces. 2018;10:27858-27867. doi.org/10.1021/acsami.8b09169

[20] Tsuboi O, Momose S, Takasu R. Mobile sensor that quickly and selectively measures ammonia gas components in breath. Fujitsu Science technology Journal. 2017 feb;53(2):38-43.

[21] Lawson B, Aguir K, Fiorido T, Martini-Laithier V, Bouchakour R, Reynard-Carette Ch, Bendahan M. Skin Alcohol perspiration Measurements Using MOX Sensors. Sensors & Actuators: B. Chemical. 2019;280:306–312. doi.org/10.1016/j.snb.2018.09.082                 

Professional integration after thesis:

Doctors who have worked on this subject will be able to apply for posts in higher education or the CNRS, but they may also find employment in industry.