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Nöral Doku Mühendisliği Uygulamalarına Yönelik Mikro-oluklu İpek Fibroin/Polietilen Oksit Film İskelelerin Geliştirilmesi

Year 2022, Issue: 41, 343 - 348, 30.11.2022
https://doi.org/10.31590/ejosat.1123769

Abstract

Nöral doku mühendisliği alanında, nanoteknolojinin ve biyomalzeme biliminin sunmuş olduğu yeni tekniklerle birlikte, alternatif sinir kılavuz kanalları geliştirmek için yoğun bir şekilde çalışılmaktadır. Fakat doğal ekstraselüler matriksi taklit edebilecek özellikte, intralüminal kanallı yapıda, uygun mikro/nano desenlemelere sahip, nöral hücreleri destekleyecek ve onlara kılavuzluk sağlayabilecek ideal bir nöral iskele henüz tam olarak geliştirilememiştir. Bu çalışmanın amacı; nöral doku mühendisliği uygulamalarına yönelik çeşitli kanal genişliklerine (1 µm, 5 µm ve 10 µm) sahip mikro-oluklu ipek fibroin/polietilen oksit (SF/PEO) film iskelelerin elde edilebilmesi için elektron demeti litografisi tekniğinin kullanımına ilaveten, dizayn edilen biyomalzemenin mekanik özelliğinin ve stabilitesinin geliştirilmesidir. Planlanan oluk genişliklerine başarıyla ulaşılmış olup, özellikle gluteraldehit buharına maruz bırakılan filmlerde stabilitenin optimal olarak sağlandığı gözlenmiştir. Yine yapıya PEO ilavesinin, filmlerin esnekliğini artırdığı görülmüştür. Geliştirilen biyomalzemenin, potansiyel nöral doku mühendisliği çalışmaları kapsamında; hücresel nöritlerin ve aksonların lineer hatlar boyunca ilerlemesine kılavuzluk etmesine yardımcı olabileceği ve bir sinir hasarı bölgesine implantasyonu sonrasında rejenerasyonu destekleyebileceği değerlendirilmiştir.

Supporting Institution

The Scientific and Technological Research Council of Turkey (TÜBİTAK)

Project Number

BİDEB-2211-C

Thanks

Bu çalışma TÜBİTAK (BİDEB-2211-C) öncelikli alanlara yönelik doktora teşvik bursu ile desteklenmiştir. Bu çalışmanın yapılmasına katkı sağladığı için TÜBİTAK’a teşekkür ederim.

References

  • Altman, G. H., Diaz, F., Jakuba, C., Calabro, T., Horan, R. L., Chen, J., Lu, H., Richmond, J., & Kaplan, D. L. (2003). Silk-based biomaterials. Biomaterials, 24(3), 401–416. https://doi.org/10.1016/s0142-9612(02)00353-8
  • Buss, A., Brook, G. A., Kakulas, B., Martin, D., Franzen, R., Schoenen, J., Noth, J., & Schmitt, A. B. (2004). Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain, 127, 34-44. https://doi.org/10.1093/brain/awh001
  • Chen, Y. F. (2015). Nanofabrication by electron beam lithography and its applications: A review. Microelectronic Engineering, 135, 57-72. https://doi.org/10.1016/j.mee.2015.02.042
  • Dalamagkas, K., Tsintou, M., & Seifalian, A. (2016). Advances in peripheral nervous system regenerative therapeutic strategies: A biomaterials approach. Materials Science & Engineering C-Materials for Biological Applications, 65, 425-432. https://doi.org/10.1016/j.msec.2016.04.048
  • Gu, X. S. (2015). Progress and perspectives of neural tissue engineering. Frontiers of Medicine, 9(4), 401-411. https://doi.org/10.1007/s11684-015-0415-x
  • Jiao, G. L., Pan, Y. Q., Wang, C. C., Li, Z. X., Li, Z. Z., & Guo, R. (2017). A bridging SF/Alg composite scaffold loaded NGF for spinal cord injury repair. Materials Science & Engineering C-Materials for Biological Applications, 76, 81-87. https://doi.org/10.1016/j.msec.2017.02.102
  • Ling, S. J., Qi, Z. M., Watts, B., Shao, Z. Z., & Chen, X. (2014). Structural determination of protein-based polymer blends with a promising tool: combination of FTIR and STXM spectroscopic imaging. Physical Chemistry Chemical Physics, 16(17), 7741-7748. https://doi.org/10.1039/c4cp00556b
  • Liu, H. F., Li, X. M., Zhou, G., Fan, H. B., & Fan, Y. B. (2011). Electrospun sulfated silk fibroin nanofibrous scaffolds for vascular tissue engineering. Biomaterials, 32(15), 3784-3793. https://doi.org/10.1016/j.biomaterials.2011.02.002
  • Madduri, S., Papaloizos, M., & Gander, B. (2010). Trophically and topographically functionalized silk fibroin nerve conduits for guided peripheral nerve regeneration. Biomaterials, 31(8), 2323-2334. https://doi.org/10.1016/j.biomaterials.2009.11.073
  • Meinel, L., Hofmann, S., Karageorgiou, V., Kirker-Head, C., McCool, J., Gronowicz, G., Zichner, L., Langer, R., Vunjak-Novakovic, G., & Kaplan, D. L. (2005). The inflammatory responses to silk films in vitro and in vivo. Biomaterials, 26(2), 147-155. https://doi.org/10.1016/j.biomaterials.2004.02.047
  • Mohammadzadehmoghadam, S., & Dong, Y. (2019). Fabrication and Characterization of Electrospun Silk Fibroin/Gelatin Scaffolds Crosslinked With Glutaraldehyde Vapor. Frontiers in Materials, 6. https://doi.org/ARTN 9110.3389/fmats.2019.00091
  • Rockwood, D. N., Preda, R. C., Yucel, T., Wang, X. Q., Lovett, M. L., & Kaplan, D. L. (2011). Materials fabrication from Bombyx mori silk fibroin. Nature Protocols, 6(10), 1612-1631. https://doi.org/10.1038/nprot.2011.379
  • Seddighi, A., Nikouei, A., Seddighi, A. S., Zali, A. R., Tabatabaei, S. M., Sheykhi, A. R., Yourdkhani, F., & Naeimian, S. (2016). Peripheral Nerve Injury: A Review Article. International Clinical Neuroscience Journal, 3(1), 1-6. https://doi.org/10.22037/icnj.v3i1.12016
  • Sofia, S., McCarthy, M. B., Gronowicz, G., & Kaplan, D. L. (2001). Functionalized silk-based biomaterials for bone formation. Journal of Biomedical Materials Research, 54(1), 139-148. https://doi.org/Doi 10.1002/1097-4636(200101)54:1<139::Aid-Jbm17>3.0.Co;2-7
  • Subramanian, A., Krishnan, U. M., & Sethuraman, S. (2009). Development of biomaterial scaffold for nerve tissue engineering: Biomaterial mediated neural regeneration. Journal of Biomedical Science, 16. https://doi.org/Artn 10810.1186/1423-0127-16-108
  • Tabesh, H., Amoabediny, G., Nik, N. S., Heydari, M., Yosefifard, M., Siadat, S. O. R., & Mottaghy, K. (2009). The role of biodegradable engineered scaffolds seeded with Schwann cells for spinal cord regeneration. Neurochemistry International, 54(2), 73-83. https://doi.org/10.1016/j.neuint.2008.11.002
  • Tucker, B. A., & Mearow, K. M. (2008). Peripheral Sensory Axon Growth: From Receptor Binding to Cellular Signaling. Canadian Journal of Neurological Sciences, 35(5), 551-566. https://doi.org/Doi 10.1017/S0317167100009331
  • Wade, R. J., & Burdick, J. A. (2014). Advances in nanofibrous scaffolds for biomedical applications: From electrospinning to self-assembly. Nano Today, 9(6), 722-742. https://doi.org/10.1016/j.nantod.2014.10.002
  • Wang L., Wang Y., Qu J., Hu Y., You R. and Li M. (2013). The Cytocompatibility of Genipin-Crosslinked Silk Fibroin Films. Journal of Biomaterials and Nanobiotechnology, 4(3), 213-221. doi: 10.4236/jbnb.2013.43026
  • Wang, C. Y., Zhang, K. H., Fan, C. Y., Mo, X. M., Ruan, H. J., & Li, F. F. (2011). Aligned natural-synthetic polyblend nanofibers for peripheral nerve regeneration. Acta Biomaterialia, 7(2), 634-643. https://doi.org/10.1016/j.actbio.2010.09.011
  • Wang, T. G., Xu, J., Zhu, A. H., Lu, H., Miao, Z. N., Zhao, P., Hui, G. Z., & Wu, W. J. (2016). Human amniotic epithelial cells combined with silk fibroin scaffold in the repair of spinal cord injury. Neural Regeneration Research, 11(10), 1670-1677. https://doi.org/10.4103/1673-5374.193249
  • Wang, Y. X., Qin, Y. P., Kong, Z. J., Wang, Y. J., & Ma, L. (2014). Glutaraldehyde Cross-linked Silk Fibroin Films for Controlled Release. Advances in Materials and Materials Processing Iv, Pts 1 and 2, 887-888, 541-546. https://doi.org/10.4028/www.scientific.net/AMR.887-888.541
  • Wang, Y., Rudym, D. D., Walsh, A., Abrahamsen, L., Kim, H. J., Kim, H. S., Kirker-Head, C., & Kaplan, D. L. (2008). In vivo degradation of three-dimensional silk fibroin scaffolds. Biomaterials, 29(24-25), 3415-3428. https://doi.org/10.1016/j.biomaterials.2008.05.002
  • Wei, Y. J., Gong, K., Zheng, Z. H., Wang, A. J., Ao, Q., Gong, Y. D., & Zhang, X. F. (2011). Chitosan/silk fibroin-based tissue-engineered graft seeded with adipose-derived stem cells enhances nerve regeneration in a rat model. Journal of Materials Science-Materials in Medicine, 22(8), 1947-1964. https://doi.org/10.1007/s10856-011-4370-z
  • White, J. D., Wang, S. R., Weiss, A. S., & Kaplan, D. L. (2015). Silk-tropoelastin protein films for nerve guidance. Acta Biomaterialia, 14, 1-10. https://doi.org/10.1016/j.actbio.2014.11.045
  • Willerth, S. M., & Sakiyama-Elbert, S. E. (2007). Approaches to neural tissue engineering using scaffolds for drug delivery. Advanced Drug Delivery Reviews, 59(4-5), 325-338. https://doi.org/10.1016/j.addr.2007.03.014
  • Xu, Y. Q., Zhang, Z. H., Chen, X. Y., Li, R. X., Li, D., & Feng, S. Q. (2016). A Silk Fibroin/Collagen Nerve Scaffold Seeded with a Co-Culture of Schwann Cells and Adipose-Derived Stem Cells for Sciatic Nerve Regeneration. Plos One, 11(1). https://doi.org/ARTN e0147184 10.1371/journal.pone.0147184
  • Yang, Y. M., Chen, X. M., Ding, F., Zhang, P. Y., Liu, J., & Go, X. S. (2007). Biocompatibility evaluation of silk fibroin with peripheral nerve tissues and cells in vitro. Biomaterials, 28(9), 1643-1652. https://doi.org/10.1016/j.biomaterials.2006.12.004
  • Yang, Y., Chen, X., Ding, F., Zhang, P., Liu, J., & Gu, X. (2007). Biocompatibility evaluation of silk fibroin with peripheral nerve tissues and cells in vitro. Biomaterials, 28(9), 1643–1652. https://doi.org/10.1016/j.biomaterials.2006.12.004
  • Yang, Y., Ding, F., Wu, H., Hu, W., Liu, W., Liu, H., & Gu, X. (2007). Development and evaluation of silk fibroin-based nerve grafts used for peripheral nerve regeneration. Biomaterials, 28(36), 5526-5535. https://doi.org/10.1016/j.biomaterials.2007.09.001
  • Zhang, H., Li, L. L., Dai, F. Y., Zhang, H. H., Ni, B., Zhou, W., Yang, X., & Wu, Y. Z. (2012). Preparation and characterization of silk fibroin as a biomaterial with potential for drug delivery. Journal of Translational Medicine, 10. https://doi.org/Artn 117 10.1186/1479-5876-10-117
  • Zhang, Q., Zhao, Y. H., Yan, S. Q., Yang, Y. M., Zhao, H. J., Li, M. Z., Lu, S. Z., & Kaplan, D. L. (2012). Preparation of uniaxial multichannel silk fibroin scaffolds for guiding primary neurons. Acta Biomaterialia, 8(7), 2628-2638. https://doi.org/10.1016/j.actbio.2012.03.033

Development of Micro-grooved Silk Fibroin/Polyethylene Oxide Film Scaffolds for Neural Tissue Engineering Applications

Year 2022, Issue: 41, 343 - 348, 30.11.2022
https://doi.org/10.31590/ejosat.1123769

Abstract

In the field of neural tissue engineering, intensive work is being done to develop alternative nerve guide channels with the new techniques offered by nanotechnology and biomaterials science. However, an ideal neural scaffold capable of mimicking the natural extracellular matrix, having an intraluminal channel structure, have suitable micro/nano patterns, can support neural cells and guide them has not been fully developed yet. The aim of this study is the use of electron beam lithography technique to obtain micro-grooved silk fibroin/polyethylene oxide (SF/PEO) film scaffolds with various channel widths (1 µm, 5 µm and 10 µm) for neural tissue engineering applications. In addition, it is also aimed to improve the mechanical properties and stability of the designed biomaterial. The planned groove widths were successfully achieved, and it was observed that the stability was optimally achieved, especially in films exposed to glutaraldehyde vapor. It has also been observed that the addition of PEO to the structure increases the flexibility of the films. It was concluded that it can help guide the progression of cellular neurites and axons along linear lines, within the scope of future potential neural tissue engineering studies of the developed biomaterial. It has also been evaluated that the material can promote regeneration after implantation at a nerve injury site.

Project Number

BİDEB-2211-C

References

  • Altman, G. H., Diaz, F., Jakuba, C., Calabro, T., Horan, R. L., Chen, J., Lu, H., Richmond, J., & Kaplan, D. L. (2003). Silk-based biomaterials. Biomaterials, 24(3), 401–416. https://doi.org/10.1016/s0142-9612(02)00353-8
  • Buss, A., Brook, G. A., Kakulas, B., Martin, D., Franzen, R., Schoenen, J., Noth, J., & Schmitt, A. B. (2004). Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain, 127, 34-44. https://doi.org/10.1093/brain/awh001
  • Chen, Y. F. (2015). Nanofabrication by electron beam lithography and its applications: A review. Microelectronic Engineering, 135, 57-72. https://doi.org/10.1016/j.mee.2015.02.042
  • Dalamagkas, K., Tsintou, M., & Seifalian, A. (2016). Advances in peripheral nervous system regenerative therapeutic strategies: A biomaterials approach. Materials Science & Engineering C-Materials for Biological Applications, 65, 425-432. https://doi.org/10.1016/j.msec.2016.04.048
  • Gu, X. S. (2015). Progress and perspectives of neural tissue engineering. Frontiers of Medicine, 9(4), 401-411. https://doi.org/10.1007/s11684-015-0415-x
  • Jiao, G. L., Pan, Y. Q., Wang, C. C., Li, Z. X., Li, Z. Z., & Guo, R. (2017). A bridging SF/Alg composite scaffold loaded NGF for spinal cord injury repair. Materials Science & Engineering C-Materials for Biological Applications, 76, 81-87. https://doi.org/10.1016/j.msec.2017.02.102
  • Ling, S. J., Qi, Z. M., Watts, B., Shao, Z. Z., & Chen, X. (2014). Structural determination of protein-based polymer blends with a promising tool: combination of FTIR and STXM spectroscopic imaging. Physical Chemistry Chemical Physics, 16(17), 7741-7748. https://doi.org/10.1039/c4cp00556b
  • Liu, H. F., Li, X. M., Zhou, G., Fan, H. B., & Fan, Y. B. (2011). Electrospun sulfated silk fibroin nanofibrous scaffolds for vascular tissue engineering. Biomaterials, 32(15), 3784-3793. https://doi.org/10.1016/j.biomaterials.2011.02.002
  • Madduri, S., Papaloizos, M., & Gander, B. (2010). Trophically and topographically functionalized silk fibroin nerve conduits for guided peripheral nerve regeneration. Biomaterials, 31(8), 2323-2334. https://doi.org/10.1016/j.biomaterials.2009.11.073
  • Meinel, L., Hofmann, S., Karageorgiou, V., Kirker-Head, C., McCool, J., Gronowicz, G., Zichner, L., Langer, R., Vunjak-Novakovic, G., & Kaplan, D. L. (2005). The inflammatory responses to silk films in vitro and in vivo. Biomaterials, 26(2), 147-155. https://doi.org/10.1016/j.biomaterials.2004.02.047
  • Mohammadzadehmoghadam, S., & Dong, Y. (2019). Fabrication and Characterization of Electrospun Silk Fibroin/Gelatin Scaffolds Crosslinked With Glutaraldehyde Vapor. Frontiers in Materials, 6. https://doi.org/ARTN 9110.3389/fmats.2019.00091
  • Rockwood, D. N., Preda, R. C., Yucel, T., Wang, X. Q., Lovett, M. L., & Kaplan, D. L. (2011). Materials fabrication from Bombyx mori silk fibroin. Nature Protocols, 6(10), 1612-1631. https://doi.org/10.1038/nprot.2011.379
  • Seddighi, A., Nikouei, A., Seddighi, A. S., Zali, A. R., Tabatabaei, S. M., Sheykhi, A. R., Yourdkhani, F., & Naeimian, S. (2016). Peripheral Nerve Injury: A Review Article. International Clinical Neuroscience Journal, 3(1), 1-6. https://doi.org/10.22037/icnj.v3i1.12016
  • Sofia, S., McCarthy, M. B., Gronowicz, G., & Kaplan, D. L. (2001). Functionalized silk-based biomaterials for bone formation. Journal of Biomedical Materials Research, 54(1), 139-148. https://doi.org/Doi 10.1002/1097-4636(200101)54:1<139::Aid-Jbm17>3.0.Co;2-7
  • Subramanian, A., Krishnan, U. M., & Sethuraman, S. (2009). Development of biomaterial scaffold for nerve tissue engineering: Biomaterial mediated neural regeneration. Journal of Biomedical Science, 16. https://doi.org/Artn 10810.1186/1423-0127-16-108
  • Tabesh, H., Amoabediny, G., Nik, N. S., Heydari, M., Yosefifard, M., Siadat, S. O. R., & Mottaghy, K. (2009). The role of biodegradable engineered scaffolds seeded with Schwann cells for spinal cord regeneration. Neurochemistry International, 54(2), 73-83. https://doi.org/10.1016/j.neuint.2008.11.002
  • Tucker, B. A., & Mearow, K. M. (2008). Peripheral Sensory Axon Growth: From Receptor Binding to Cellular Signaling. Canadian Journal of Neurological Sciences, 35(5), 551-566. https://doi.org/Doi 10.1017/S0317167100009331
  • Wade, R. J., & Burdick, J. A. (2014). Advances in nanofibrous scaffolds for biomedical applications: From electrospinning to self-assembly. Nano Today, 9(6), 722-742. https://doi.org/10.1016/j.nantod.2014.10.002
  • Wang L., Wang Y., Qu J., Hu Y., You R. and Li M. (2013). The Cytocompatibility of Genipin-Crosslinked Silk Fibroin Films. Journal of Biomaterials and Nanobiotechnology, 4(3), 213-221. doi: 10.4236/jbnb.2013.43026
  • Wang, C. Y., Zhang, K. H., Fan, C. Y., Mo, X. M., Ruan, H. J., & Li, F. F. (2011). Aligned natural-synthetic polyblend nanofibers for peripheral nerve regeneration. Acta Biomaterialia, 7(2), 634-643. https://doi.org/10.1016/j.actbio.2010.09.011
  • Wang, T. G., Xu, J., Zhu, A. H., Lu, H., Miao, Z. N., Zhao, P., Hui, G. Z., & Wu, W. J. (2016). Human amniotic epithelial cells combined with silk fibroin scaffold in the repair of spinal cord injury. Neural Regeneration Research, 11(10), 1670-1677. https://doi.org/10.4103/1673-5374.193249
  • Wang, Y. X., Qin, Y. P., Kong, Z. J., Wang, Y. J., & Ma, L. (2014). Glutaraldehyde Cross-linked Silk Fibroin Films for Controlled Release. Advances in Materials and Materials Processing Iv, Pts 1 and 2, 887-888, 541-546. https://doi.org/10.4028/www.scientific.net/AMR.887-888.541
  • Wang, Y., Rudym, D. D., Walsh, A., Abrahamsen, L., Kim, H. J., Kim, H. S., Kirker-Head, C., & Kaplan, D. L. (2008). In vivo degradation of three-dimensional silk fibroin scaffolds. Biomaterials, 29(24-25), 3415-3428. https://doi.org/10.1016/j.biomaterials.2008.05.002
  • Wei, Y. J., Gong, K., Zheng, Z. H., Wang, A. J., Ao, Q., Gong, Y. D., & Zhang, X. F. (2011). Chitosan/silk fibroin-based tissue-engineered graft seeded with adipose-derived stem cells enhances nerve regeneration in a rat model. Journal of Materials Science-Materials in Medicine, 22(8), 1947-1964. https://doi.org/10.1007/s10856-011-4370-z
  • White, J. D., Wang, S. R., Weiss, A. S., & Kaplan, D. L. (2015). Silk-tropoelastin protein films for nerve guidance. Acta Biomaterialia, 14, 1-10. https://doi.org/10.1016/j.actbio.2014.11.045
  • Willerth, S. M., & Sakiyama-Elbert, S. E. (2007). Approaches to neural tissue engineering using scaffolds for drug delivery. Advanced Drug Delivery Reviews, 59(4-5), 325-338. https://doi.org/10.1016/j.addr.2007.03.014
  • Xu, Y. Q., Zhang, Z. H., Chen, X. Y., Li, R. X., Li, D., & Feng, S. Q. (2016). A Silk Fibroin/Collagen Nerve Scaffold Seeded with a Co-Culture of Schwann Cells and Adipose-Derived Stem Cells for Sciatic Nerve Regeneration. Plos One, 11(1). https://doi.org/ARTN e0147184 10.1371/journal.pone.0147184
  • Yang, Y. M., Chen, X. M., Ding, F., Zhang, P. Y., Liu, J., & Go, X. S. (2007). Biocompatibility evaluation of silk fibroin with peripheral nerve tissues and cells in vitro. Biomaterials, 28(9), 1643-1652. https://doi.org/10.1016/j.biomaterials.2006.12.004
  • Yang, Y., Chen, X., Ding, F., Zhang, P., Liu, J., & Gu, X. (2007). Biocompatibility evaluation of silk fibroin with peripheral nerve tissues and cells in vitro. Biomaterials, 28(9), 1643–1652. https://doi.org/10.1016/j.biomaterials.2006.12.004
  • Yang, Y., Ding, F., Wu, H., Hu, W., Liu, W., Liu, H., & Gu, X. (2007). Development and evaluation of silk fibroin-based nerve grafts used for peripheral nerve regeneration. Biomaterials, 28(36), 5526-5535. https://doi.org/10.1016/j.biomaterials.2007.09.001
  • Zhang, H., Li, L. L., Dai, F. Y., Zhang, H. H., Ni, B., Zhou, W., Yang, X., & Wu, Y. Z. (2012). Preparation and characterization of silk fibroin as a biomaterial with potential for drug delivery. Journal of Translational Medicine, 10. https://doi.org/Artn 117 10.1186/1479-5876-10-117
  • Zhang, Q., Zhao, Y. H., Yan, S. Q., Yang, Y. M., Zhao, H. J., Li, M. Z., Lu, S. Z., & Kaplan, D. L. (2012). Preparation of uniaxial multichannel silk fibroin scaffolds for guiding primary neurons. Acta Biomaterialia, 8(7), 2628-2638. https://doi.org/10.1016/j.actbio.2012.03.033
There are 32 citations in total.

Details

Primary Language Turkish
Subjects Engineering
Journal Section Articles
Authors

İlyas Özçiçek 0000-0002-4495-7395

Project Number BİDEB-2211-C
Early Pub Date October 2, 2022
Publication Date November 30, 2022
Published in Issue Year 2022 Issue: 41

Cite

APA Özçiçek, İ. (2022). Nöral Doku Mühendisliği Uygulamalarına Yönelik Mikro-oluklu İpek Fibroin/Polietilen Oksit Film İskelelerin Geliştirilmesi. Avrupa Bilim Ve Teknoloji Dergisi(41), 343-348. https://doi.org/10.31590/ejosat.1123769