• No se han encontrado resultados

In this study, a novel minimally invasive method to detect glucose in the interstitial fluid based on an optofluidic ring resonator (OFRR) has been proposed. The proposed OFRR also integrates extraction and delivery of interstitial fluid, and subsequent glucose sensing with a simple PMMA capillary which is biocompatible and can be mass produced.

Primary investigation supports the novelty of proposed sensor in terms of design, functionality, sensitivity and selectivity. Mathematical simulations have confirmed the increase in evanescent field fraction, interaction volume and direct field interaction in MSF, ITF and OFRR. PMMA has been used as fibre material for better biocompatibility. Boronic acid derivatives have been identified as reagents due to their high affinity for glucose and their capability to form reversible complexes at physiological pH of 7.4. Boronic acid is also effective when immobilized in PMMA matrix for better sensor stability and reusability. The usability of this configuration has been analysed in Chapter 2 section 2.3 and been found promising. However, the same needs to be checked in-vitro for varying levels of glucose concentration. The new approach should be tested against all possibilities of biocompatibility issues, interference from other blood constituents. In future polymer optical fibres (POFs) are favoured for the low cost and simplicity of the manufacturing process.

PMMA based OFRR definitely suffer from loss due to surfacesidewall scattering loss, bending radiation loss etc. This considerably worsens the performance by widening the filter bandwidth, reduction in finesse. To compensate such losses a PMMA - OFRR with gain media can be used [44]causing a significant rise in

70

gain and hence the Q-factor and sensitivity. The same has been fabricated in this study.

Figure 4-1: Representation of proposed sensor

Figure 4-1 shows a representation of proposed sensor configuration in which the need for complex optical spectrum analysers can be avoided by using a laser diode or LED with a photo detector which can probe the shift in resonance vs glucose concentration.

71

References

[1] Alberti, Kurt George Matthew Mayer and P. Zimmet, "Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation," Diabetic Med., vol. 15, (7), pp. 539-553, 1998.

[2] J. E. Shaw, R. A. Sicree and P. Z. Zimmet, "Global estimates of the prevalence of diabetes for 2010 and 2030," Diabetes Res. Clin. Pract., vol. 87,

(1), pp. 4-14, 1, 2010.

[3] I. Diabetes Atlas, "IDF DIABETES ATLAS Sixth edition," vol. 2014, (10/08), 2013.

[4] S. K. Vashist et al, "Technology behind commercial devices for blood glucose monitoring in diabetes management: a review," Anal. Chim. Acta, vol. 703, (2), pp. 124-136, 2011.

[5] D. Daneman, "Type 1 diabetes," The Lancet, vol. 367, (9513), pp. 847- 858, 3/11–17, 2006.

[6] M. Stumvoll, B. J. Goldstein and T. W. van Haeften, "Type 2 diabetes: principles of pathogenesis and therapy," The Lancet, vol. 365, (9467), pp. 1333-1346, 4/9–15, 2005.

[7] B. E. Metzger, "Summary and recommendations of the third international workshop-conference on gestational diabetes mellitus," Diabetes, vol. 40,

(Supplement 2), pp. 197-201, 1991.

[8] D. M. Nathan, "Long-term complications of diabetes mellitus," N. Engl. J.

Med., vol. 328, (23), pp. 1676-1685, 1993.

[9] D. S. Fong et al, "Retinopathy in diabetes," Diabetes Care, vol. 27, (suppl

1), pp. s84-s87, 2004.

[10] B. Isomaa et al, "Cardiovascular morbidity and mortality associated with the metabolic syndrome," Diabetes Care, vol. 24, (4), pp. 683-689, 2001. [11] J. J. Duby et al, "Diabetic neuropathy: an intensive review," American

Journal of Health-System Pharmacy, vol. 61, (2), pp. 160-173, 2004.

[12] S. P. O'Brien, M. Schwedler and M. D. Kerstein, "Peripheral neuropathies in diabetes," Surg. Clin. North Am., vol. 78, (3), pp. 393-408, 1998.

[13] M. E. Molitch et al, "Nephropathy in diabetes," Diabetes Care, vol. 27 Suppl 1, pp. S79-83, Jan, 2004.

[14] H. Shamoon, H. Duffy, N. Fleischer, S. Engel, "The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term

72

Complications in Insulin-Dependent Diabetes Mellitus," N. Engl. J. Med., vol. 329, (14), pp. 977-986, 09/30; 2014/02, 1993.

[15] Anonymous "Diabetes Mellitus: Report of a WHO Study Group," World

Health Organisation, vol. Technical; Report Series, (727), 1985.

[16] B. Leese, "Prevention of diabetes mellitus. Report of a WHO Study Group. WHO technical report series 844, Geneva, 1994. No. of pages: 100. ISBN 92 4 120844 9," Health Econ., vol. 4, (4), pp. 331-332, 1995.

[17] B. H. Esteridge, A. P. Reynolds and N. J. Walters, "Basic medical laboratory techniques," in Anonymous Cengage Learning, 2000, pp. 430-431. [18] J. Wang, "Electrochemical glucose biosensors," Chem. Rev., vol. 108, (2), pp. 814-825, 2008.

[19] M. A. Arnold and G. W. Small, "Noninvasive glucose sensing," Anal.

Chem., vol. 77, (17), pp. 5429-5439, 2005.

[20] O. S. Khalil, "Non-invasive glucose measurement technologies: an update from 1999 to the dawn of the new millennium," Diabetes Technology &

Therapeutics, vol. 6, (5), pp. 660-697, 2004.

[21] N. Oliver et al, "Glucose sensors: a review of current and emerging technology," Diabetic Med., vol. 26, (3), pp. 197-210, 2009.

[22] J. Shao et al, "In Vivo Blood Glucose Quantification Using Raman Spectroscopy," PloS One, vol. 7, (10), pp. e48127, 2012.

[23] L. G. Anderson, Raman Spectroscopy,2000

[24] D. I. Ellis and R. Goodacre, "Metabolic fingerprinting in disease diagnosis: biomedical applications of infrared and Raman spectroscopy," Analyst, vol. 131, (8), pp. 875-885, 2006.

[25] V. V. Sapozhnikova et al, "Effect on blood glucose monitoring of skin pressure exerted by an optical coherence tomography probe," J. Biomed. Opt., vol. 13, (2), pp. 021112-021112-4, 2008.

[26] Y. Fujimoto, "CLEO: 2011 Baltimore ④ Plenary Session," .

[27] R. T. Kurnik et al, "Application of the mixtures of experts algorithm for signal processing in a noninvasive glucose monitoring system," Sensors

Actuators B: Chem., vol. 60, (1), pp. 19-26, 1999.

[28] V. L. Alexeev et al, "Photonic crystal glucose-sensing material for noninvasive monitoring of glucose in tear fluid," Clin. Chem., vol. 50, (12), pp. 2353-2360, 2004.

73

[29] R. Badugu, J. R. Lakowicz and C. D. Geddes, "A glucose sensing contact lens: a non-invasive technique for continuous physiological glucose monitoring," J. Fluoresc., vol. 13, (5), pp. 371-374, 2003.

[30] M. Yamaguchi, M. Mitsumori and Y. Kano, "Noninvasively measuring blood glucose using saliva," Engineering in Medicine and Biology Magazine, IEEE, vol. 17, (3), pp. 59-63, 1998.

[31] J. Hönes, P. Müller and N. Surridge, "The technology behind glucose meters: test strips," Diabetes Technology & Therapeutics, vol. 10, (S1), pp. S- 10-S-26, 2008.

[32] E. Wilkins and P. Atanasov, "Glucose monitoring: state of the art and future possibilities," Med. Eng. Phys., vol. 18, (4), pp. 273-288, 1996.

[33] J. Hönes, P. Müller and N. Surridge, "The technology behind glucose meters: test strips," Diabetes Technology & Therapeutics, vol. 10, (S1), pp. S- 10-S-26, 2008.

[34] S. Churchouse et al, "Needle enzyme electrodes for biological studies,"

Biosensors, vol. 2, (6), pp. 325-342, 1986.

[35] E. Kulcu et al, "Physiological differences between interstitial glucose and blood glucose measured in human subjects," Diabetes Care, vol. 26, (8), pp. 2405-2409, Aug, 2003.

[36] Y. Wickramasinghe, Y. Yang and S. Spencer, "Current problems and potential techniques in in vivo glucose monitoring," J. Fluoresc., vol. 14, (5), pp. 513-520, 2004.

[37] A. M. Corstjens et al, "Accuracy and feasibility of point-of-care and continuous blood glucose analysis in critically ill ICU patients," Critical Care, vol. 10, (5), pp. R135, 2006.

[38] J. Yan et al, "The relationship among pKa, pH, and binding constants in the interactions between boronic acids and diols—it is not as simple as it appears," Tetrahedron, vol. 60, (49), pp. 11205-11209, 2004.

[39] S. Choi, D. Chung and H. Kwen, "Fabrication of Biosensors Using Vinyl Polymer-grafted Carbon Nanotubes," New Perspectives in Biosensors

Technology and Applications, pp. 245-268, 2011.

[40] S. Arimori, C. J. Ward and T. D. James, "A d-glucose selective fluorescent assay," Tetrahedron Lett., vol. 43, (2), pp. 303-305, 2002.

[41] G. Springsteen and B. Wang, "A detailed examination of boronic acid–diol complexation," Tetrahedron, vol. 58, (26), pp. 5291-5300, 2002.

74

[42] D. G. Hall, Structure, Properties, and Preparation of Boronic Acid

Derivatives. Overview of their Reactions and Applications. John Wiley & Sons:

Weinheim, Germany, 2006.

[43] S. Çubuk et al, "Development of photopolymerized fluorescence sensor for glucose analysis," Sensors Actuators B: Chem., vol. 181, pp. 187-193, 2013.

[44] H. Chen, "Theoretical analysis of active ring microresonator filter," in

Integrated Optoelectronic Devices 2007, 2007, pp. 64750K-64750K-6.

[45] V. Bhatia and A. M. Vengsarkar, "Optical fiber long-period grating sensors," Opt. Lett., vol. 21, (9), pp. 692-694, 1996.

[46] A. Iadicicco et al, "Thinned fiber Bragg gratings as high sensitivity refractive index sensor," Photonics Technology Letters, IEEE, vol. 16, (4), pp. 1149-1151, 2004.

[47] C. Dafu et al, "Optical-fibre pH sensor," Sensors Actuators B: Chem., vol. 12, (1), pp. 29-32, 1993.

[48] J. F. Alder, "Optical fibre chemical sensors," Fresenius' Zeitschrift Für

Analytische Chemie, vol. 324, (5), pp. 372-375, 1986.

[49] M. van Eijkelenborg, "Imaging with microstructured polymer fibre," Optics

Express, vol. 12, (2), pp. 342-346, 2004.

[50] K. Grattan and T. Sun, "Fiber optic sensor technology: an overview,"

Sensors and Actuators A: Physical, vol. 82, (1), pp. 40-61, 2000.

[51] R. K. Shevgaonkar, "Advanced Optical Communication," Nptel, vol. 2014,

(09/10), 2014.

[52] E. S. Bahaa and C. T. Malvin, "Fundamentals of photonics," New York/A

WILEY-INTERSCIENCE PUBLICATION, 1991.

[53] G. Keiser, Optical Fiber Communications. Wiley Online Library, 2003. [54] D. Axelrod, J. C. Long and M. W. Davidson, "Evanescent field polarization and intensity profiles," vol. 2014, (08/10), .

[55] M. Ahmad and L. L. Hench, "Effect of taper geometries and launch angle on evanescent wave penetration depth in optical fibers," Biosensors and

Bioelectronics, vol. 20, (7), pp. 1312-1319, 1/15, 2005.

[56] Y. Wu et al, "Less-mode optic fiber evanescent wave absorbing sensor: Parameter design for high sensitivity liquid detection," Sensors Actuators B:

75

[57] G. D, "Weakly guiding fibers," Appl.Opt, vol. 10, pp. 2252-2258, 1971. [58] C. R. Taitt, G. P. Anderson and F. S. Ligler, "Evanescent wave fluorescence biosensors," Biosensors and Bioelectronics, vol. 20, (12), pp. 2470-2487, 6/15, 2005.

[59] V. Ruddy, B. MacCraith and J. Murphy, "Evanescent wave absorption spectroscopy using multimode fibers," J. Appl. Phys., vol. 67, (10), pp. 6070- 6074, 1990.

[60] A. W. Snyder and J. Love, Optical Waveguide Theory. Springer, 1983190. [61] G. Keiser, Optical Fiber Communications. Wiley Online Library, 2003. [62] C. S. Burke et al, "Planar optical sensors and evanescent wave effects," in

Optical Chemical SensorsAnonymous Springer, 2006, pp. 193-215.

[63] R. T. Schermer and J. H. Cole, "Improved bend loss formula verified for optical fiber by simulation and experiment," Quantum Electronics, IEEE Journal

Of, vol. 43, (10), pp. 899-909, 2007.

[64] B. Eggleton et al, "Microstructured optical fiber devices," Optics Express, vol. 9, (13), pp. 698-713, 2001.

[65] S. O. Konorov et al, "Hollow-core photonic crystal fiber-optic probes for Raman spectroscopy," Opt. Lett., vol. 31, (12), pp. 1911-1913, 2006.

[66] J. Ma and W. Bock, "Modeling of photonic crystal fiber with air holes sealed at the fiber end and its application to fluorescent light collection efficiency enhancement," Optics Express, vol. 13, (7), pp. 2385-2393, 2005. [67] T. M. Monro et al, "Sensing with microstructured optical fibres,"

Measurement Science and Technology, vol. 12, (7), pp. 854, 2001.

[68] R. B. Thompson, "Fluorescence-based fiber-optic sensors," in Topics in

Fluorescence SpectroscopyAnonymous Springer, 2002, pp. 345-365.

[69] J. Knight et al, "All-silica single-mode optical fiber with photonic crystal cladding," Opt. Lett., vol. 21, (19), pp. 1547-1549, 1996.

[70] T. M. Monro and D. J. Richardson, "Holey optical fibres: Fundamental properties and device applications," Comptes Rendus Physique, vol. 4, (1), pp. 175-186, 2003.

[71] I. Thorlabs, "Hollow Core Photonic Crystal Fibers ," vol. 2014, 2014. [72] S. Li and K. Ng, "Monte Carlo study of the sphere packing problem,"

Physica A: Statistical Mechanics and its Applications, vol. 321, (1), pp. 359-

76

[73] H. Ho et al, "Optimizing microstructured optical fibers for evanescent wave gas sensing," Sensors Actuators B: Chem., vol. 122, (1), pp. 289-294, 2007.

[74] A. Cucinotta et al, "Holey fiber analysis through the finite-element method," Photonics Technology Letters, IEEE, vol. 14, (11), pp. 1530-1532, 2002.

[75] C. Schulze et al, "Mode resolved bend loss in few-mode optical fibers,"

Optics Express, vol. 21, (3), pp. 3170-3181, 2013.

[76] J. A. Howarter and J. P. Youngblood, "Optimization of silica silanization by 3-aminopropyltriethoxysilane," Langmuir, vol. 22, (26), pp. 11142-11147, 2006.

[77] J. Brzoska, I. B. Azouz and F. Rondelez, "Silanization of solid substrates: a step toward reproducibility," Langmuir, vol. 10, (11), pp. 4367-4373, 1994. [78] J. H. Cramp, R. M. Mortier, R. T. Murray and R. F. Reid, "Fibre optic sensor with bonded dye," US 4560248 A, 1985.

[79] I. Malitson, "Interspecimen comparison of the refractive index of fused silica," Josa, vol. 55, (10), pp. 1205-1208, 1965.

[80] S. N. Kasarova et al, "Analysis of the dispersion of optical plastic materials," Optical Materials, vol. 29, (11), pp. 1481-1490, 7, 2007.

[81] G. M. Hale and M. R. Querry, "Optical constants of water in the 200-nm to 200-µm wavelength region," Appl. Opt., vol. 12, (3), pp. 555-563, 1973. [82] S. G. Johnson, "Notes on perfectly matched layers (PMLs)," Lecture

Notes, Massachusetts Institute of Technology, Massachusetts, 2008.

[83] A. Taflove and S. C. Hagness, "Computationai Electrodynamics," 2000. [84] M. Heiblum and J. H. Harris, "Analysis of curved optical waveguides by conformal transformation," IEEE J. Quant. Electron., vol. 11, pp. 75-83, 1975. [85] Y. L. Hoo et al, "Design and modeling of a photonic crystal fiber gas sensor," Appl. Opt., vol. 42, (18), pp. 3509-3515, 2003.

[86] R. T. Schermer and J. H. Cole, "Improved bend loss formula verified for optical fiber by simulation and experiment," Quantum Electronics, IEEE Journal

Of, vol. 43, (10), pp. 899-909, 2007.

[87] J. Peter et al, "Microring lasing from a dye-doped polymer-coated silica fiber," Laser Physics, vol. 23, (11), pp. 115104, 2013.

77

[88] J. C. Knight, "Photonic crystal fibres," Nature, vol. 424, (6950), pp. 847- 851, 2003.

[89] P. Russell, "Photonic crystal fibers," Science, vol. 299, (5605), pp. 358- 362, Jan 17, 2003.

[90] F. Cox, A. Argyros and M. Large, "Liquid-filled hollow core microstructured polymer optical fiber," Optics Express, vol. 14, (9), pp. 4135-4140, 2006. [91] A. Dupuis et al, "Prospective for biodegradable microstructured optical fibers," Opt. Lett., vol. 32, (2), pp. 109-111, 2007.

[92] W. Lukosz, "Integrated optical chemical and direct biochemical sensors,"

Sensors Actuators B: Chem., vol. 29, (1), pp. 37-50, 1995.

[93] C. F. Bohren and D. R. Huffman, Absorption and Scattering of Light by

Small Particles. Wiley New York, 198310.

[94] J. C. Pickup et al, "Fluorescence-based glucose sensors," Biosensors and

Bioelectronics, vol. 20, (12), pp. 2555-2565, 2005.

[95] S. Çubuka et al, "UV Cured Boronic Acid Based Fluorescence Sensor for the Determination of Glucose," Chemical Engineering, vol. 32, 2013.

[96] S. Çubuk et al, "Development of photopolymerized fluorescence sensor for glucose analysis," Sensors Actuators B: Chem., vol. 181, pp. 187-193, 2013.

[97] H. Sakalak et al, "One-pot synthesis of biocompatible boronic acid- functionalized poly (methyl methacrylate) nanoparticles at sub-100 nm scale for glucose sensing," Journal of Nanoparticle Research, vol. 16, (12), pp. 2767, 2014.

[98] H. Ali, "Al-Hamdani, Rafa, H. Rajaa Nader." Study the spectral Properties of thin films of Rhodamine 6G dyes doped polymer (PMMA) dissolved in Chloroform," Iraqi Journal of Physics, vol. 12, (23), pp. 59-64, 2014.

[99] E.Marin, Optical fiber sensors-Evanescent field. SCIRN - PRN University of

Maine,2007

78

Appendix - MATLAB code for simulation of OFRR

clear all; close all; clc; % 2D- Plot m = 600 n1 = 1.320; n2 = 1.4816; n3 = 1.0; R1 = 85; R2 = 146.2 ; lam = 1.064; k0 = 2*pi/lam; J11 = besselj(m,k0*n1*R1); J21 = besselj(m,k0*n2*R1); J22 = besselj(m,k0*n2*R2); Jd22 = (besselj(m-1,k0*n2*R2) - besselj(m+1,k0*n2*R2))/2;

79 H12 = besselh(m,k0*n1*R2); H32 = besselh(m,k0*n3*R2); Hd12 = (besselh(m-1,k0*n1*R2) - besselh(m+1,k0*n1*R2))/2; Y21 = bessely(m,k0*n2*R1); Y22 = bessely(m,k0*n2*R2);

Yd22 = (bessely(m-1,k0*n2*R2) - bessely(m+1,k0*n2*R2))/2;

C = (n2*H12*Yd22 - n3*Hd12*Y22)/(n3*Hd12*J22 - n2*H12*Jd22); Am1 = (C*J21 + Y21)/J11; Am3 = (C*J22 + Y22)/H32; theta=0; R = 0:0.1:1.2*R2; for ii = 1:length(R) r= R(ii);

80

if r < R2 if r < R1

Ez(ii) = Am1*besselj(m,k0*n1*r)*exp(1i*m*theta);

else Ez(ii) = (C*besselj(m,k0*n2*r) + bessely(m,k0*n2*r))*exp(1i*m*theta);

end

else Ez(ii) = Am3*besselh(m,k0*n3*r)*exp(1i*m*theta); end end Iz=real(Ez).^2; plot(R,real(Iz)); grid axis([70,150,0,.045],"square"); graphics_toolkit("gnuplot");