In Vitro, In Compost, and In Vivo Assessment of Chitosan-Polyethylene Glycol as an Intravaginal Insert for Progesterone Delivery in Sheep
Abstract
In estrous synchronization, the hormone progesterone is an important element. Various hormone preparations currently available have limitations, especially those related to environmental impact issues. Various alternatives are being studied, and using biodegradable polymeric materials (chitosan-polyethylene glycol combination) to develop new devices is considered one of the solutions. This contribution aims to design and evaluate intravaginal implants that can release progesterone and be degraded in the body and the environment. Implants are made by melting and molding techniques. In vitro drug release studies using dyes as drug models. Implant degradation studies tested in compost. Changes in the shape of the implant, while it is in the vagina, are observed by ultrasound. Blood collection was performed three days before and during implantation to obtain a blood progesterone profile. In vitro drug release studies using dye as a drug model showed a chitosan-PEG profile that released the drug faster at first, then slowed down. Implant degradation studies in compost and vagina demonstrated a gradual degradation process. The blood progesterone profile increased during implantation, as high as 15 ng/mL on the third day. In conclusion, the chitosan-PEG intravaginal implant formulation designed using the melting and molding technique proved to be degraded in the compost environment. It released the hormone progesterone for four days according to the degradation period of the implant in the vagina.
References
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Corteel, J. M., B. Leboeuf, & G. Baril. 1988. Artificial breeding of adult goats and kids induced with hormones to ovulate outside the breeding season. Small Rumin. Res. 1:19–35. https://doi.org/10.1016/0921-4488(88)90041-7
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Dodero, A., M. Alloisio, M. Castellano, & S. Vicini. 2020. Multilayer alginate-polycaprolactone electrospun membranes as skin wound patches with drug delivery abilities. ACS Appl. Mater. Interfaces. 12:31162–31171. https://doi.org/10.1021/acsami.0c07352
dos Santos, A. M., S. G. Carvalho, V. H. S. Araujo, G. C. Carvalho, M. P. D. Gremião, & M. Chorilli. 2020. Recent advances in hydrogels as strategy for drug delivery intended to vaginal infections. Int. J. Pharm. 590:119867. https://doi.org/10.1016/j.ijpharm.2020.119867
Fernandes, L., R. Costa, M. Henriques, & M. E. Rodrigues. 2023. Simulated vaginal fluid: Candida resistant strains’ biofilm characterization and vapor phase of essential oil effect. J. Med. Mycol. 33:101329. https://doi.org/10.1016/j.mycmed.2022.101329
Gobikrushanth, M., R. J. Mapletoft, & M. G. Colazo. 2023. Estrous activity and pregnancy outcomes in Holstein heifers subjected to a progesterone based 5-d CO-Synch protocol with or without administration of initial GnRH. Theriogenology 202:36–41. https://doi.org/10.1016/j.theriogenology.2023.02.024
Gonzalez-Bulnes, A., A. Menchaca, G. B. Martin, & P. Martinez-Ros. 2020. Seventy years of progestagen treatments for management of the sheep oestrous cycle: Where we are and where we should go. Reprod. Fertil. Dev. 32:441–452. https://doi.org/10.1071/RD18477
Gore, D. L. M., J. N. Mburu, T. O. Okeno, & T. K. Muasya. 2020. Short-term oestrous synchronisation protocol following single fixed-time artificial insemination and natural mating as alternative to long-term protocol in dairy goats. Small Rumin. Res. 192:106207. https://doi.org/10.1016/j.smallrumres.2020.106207
Helbling, I. M., F. Karp, A. Cappadoro, & J. A. Luna. 2020. Design and evaluation of a recyclable intravaginal device made of ethylene vinyl acetate copolymer for bovine estrus synchronization. Drug Deliv. Transl. Res. 10:1255–1266. https://doi.org/10.1007/s13346-020-00717-4
Macmillan, K. & C. Burke. 1996. Effects of oestrous cycle control on reproductive efficiency. Anim. Reprod. Sci. 42:307–320. https://doi.org/10.1016/0378-4320(96)01512-6
Martinez-Ros, P., S. Astiz, E. Garcia-Rosello, A. Rios-Abellan, & A. Gonzalez-Bulnes. 2019. Onset of estrus and preovulatory LH surge and ovulatory efficiency in sheep after short-term treatments with progestagen-sponges and progesterone-CIDRs. Reprod. Domest. Anim. 54:408–411. https://doi.org/10.1111/rda.13317
Martinez-Ros, P., M. Lozano, F. Hernandez, A. Tirado, A. Rios-Abellan, M. C. López-Mendoza, & A. Gonzalez-Bulnes. 2018. Intravaginal device-type and treatment-length for ovine estrus synchronization modify vaginal mucus and microbiota and affect fertility. Animals. 8:1–8. https://doi.org/10.3390/ani8120226
Menchaca, A., P. Dos, & S. Neto. 2017. Estrous synchronization treatments in sheep : Brief update. Rev. bras. reprod. anim. supl. 41:340–344.
Nakasaki, K., H. Hirai, H. Mimoto, T. N. M. Quyen, M. Koyama, & K. Takeda. 2019. Succession of microbial community during vigorous organic matter degradation in the primary fermentation stage of food waste composting. Sci. Total Environ. 671:1237–1244. https://doi.org/10.1016/j.scitotenv.2019.03.341
Omontese, B. O., P. I. Rekwot, I. U. Ate, J. O. Ayo, M. U. Kawu, J. S. Rwuaan, A. I. Nwannenna, R. A. Mustapha, & A. A. Bello. 2016. An update on oestrus synchronisation of goats in Nigeria. Asian Pacific J. Reprod. 5:96–101. https://doi.org/10.1016/j.apjr.2016.01.002
Othman, S. H., N. D. A. Ronzi, R. A. Shapi’i, M. Dun, S. H. Ariffin, & M. A. P. Mohammed. 2023. Biodegradability of starch nanocomposite films containing different concentrations of chitosan nanoparticles in compost and planting soils. Coatings. 13:777. https://doi.org/10.3390/coatings13040777
Owen, D. H. & D. F. Katz. 1999. A vaginal fluid simulant. Contraception 59:91–95. https://doi.org/10.1016/S0010-7824(99)00010-4
Poshina, D. N., S. V. Raik, A. N. Poshin, & Y. A. Skorik. 2018. Accessibility of chitin and chitosan in enzymatic hydrolysis: A review. Polym. Degrad. Stab. 156:269–278. https://doi.org/10.1016/j.polymdegradstab.2018.09.005
Rathbone, M. J., C. R. Bunt, C. R. Ogle, S. Burggraaf, K. L. Macmillan, C. R. Burke, & K. L. Pickering. 2002a. Reengineering of a commercially available bovine intravaginal insert (CIDR insert) containing progesterone. J. Control. Release. 85:105–115. https://doi.org/10.1016/S0168-3659(02)00288-2
Rathbone, M. J., C. R. Bunt, C. R. Ogle, S. Burggraaf, K. L. Macmillan, & K. Pickering. 2002b. Development of an injection molded poly(ε-caprolactone) intravaginal insert for the delivery of progesterone to cattle. J. Control. Release. 85:61–71. https://doi.org/10.1016/S0168-3659(02)00272-9
Roche, J. F. & J. J. Ireland. 1981. Effect of exogenous progesterone on time of occurrence of the LH surge in heifers. J. Anim. Sci. 52:580–586. https://doi.org/10.2527/jas1981.523580x
Roman, D. L., V. Ostafe, & A. Isvoran. 2020. Deeper inside the specificity of lysozyme when degrading chitosan. A structural bioinformatics study. J. Mol. Graph. Model. 100:107676. https://doi.org/10.1016/j.jmgm.2020.107676
Say, E., S. Çoban, Y. Nak, D. Nak, U. Kara, S. White, V. Kasimanickam, & R. Kasimanickam. 2016. Fertility of Holstein heifers after two doses of PGF2α in 5-day CO-Synch progesterone-based synchronization protocol. Theriogenology 86:988–993. https://doi.org/10.1016/j.theriogenology.2016.03.026
Shockley, M. F. & A. H. Muliana. 2020. Modeling temporal and spatial changes during hydrolytic degradation and erosion in biodegradable polymers. Polym. Degrad. Stab. 180:109298. https://doi.org/10.1016/j.polymdegradstab.2020.109298
Silva, B. D. M., T. A. S. N. Silva, N. H. Moreira, H. C. A. Teixeira, M. A. Paiva Neto, J. P. Neves, & A. F. Ramos. 2015. Ovulation induction in ewes using GnRH in long and short-term synchronization protocols. Anim. Reprod. 12:312–315
Silva, L. O., N. P. Folchini, R. L. O. R. Alves, G. Madureira, C. E. C. Consentini, J. C. L. Motta, M. C. Wiltbank, & R. Sartori. 2023. Effect of progesterone from corpus luteum, intravaginal implant, or both on luteinizing hormone release, ovulatory response, and subsequent luteal development after gonadotropin-releasing hormone treatment in cows. J. Dairy Sci. 106:4413–4428. https://doi.org/10.3168/jds.2022-22618
Suárez, G., P. Zunino, H. Carol, & R. Ungerfeld. 2006. Changes in the aerobic vaginal bacterial mucous load and assessment of the susceptibility to antibiotics after treatment with intravaginal sponges in anestrous ewes. Small Rumin. Res. 63: 39–43. https://doi.org/10.1016/j.smallrumres.2005.01.011
Thai, H., C. Thuy Nguyen, L. Thi Thach, M. Thi Tran, H. Duc Mai, T. Thi Thu Nguyen, G. Duc Le, M. Van Can, L. Dai Tran, G. Long Bach, K. Ramadass, C. I. Sathish, & Q. Van Le. 2020. Characterization of chitosan/alginate/lovastatin nanoparticles and investigation of their toxic effects in vitro and in vivo. Sci. Rep. 10:1–15. https://doi.org/10.1038/s41598-020-57666-8
Wang, X., S. Liu, Y. Guan, J. Ding, C. Ma, & Z. Xie. 2021. Vaginal drug delivery approaches for localized management of cervical cancer. Adv. Drug Deliv. Rev. 174:114–126. https://doi.org/10.1016/j.addr.2021.04.009
Xu, Q., Y. Ji, Q. Sun, Y. Fu, Y. Xu, & L. Jin. 2019. Fabrication of cellulose nanocrystal/chitosan hydrogel for controlled drug release. Nanomaterials 9:253. https://doi.org/10.3390/nano9020253
Zeng, S. H., P. P. Duan, M. X. Shen, Y. J. Xue, & Z. Y. Wang. 2016. Preparation and degradation mechanisms of biodegradable polymer: A review. IOP Conf. Ser. Mater. Sci. Eng. 137:012003. https://doi.org/10.1088/1757-899X/137/1/012003
Arya, D., R. Goswami, & M. Sharma. 2023. Estrous synchronization in cattle , sheep and goat. Multidiscip. Rev. 6:2023001. https://doi.org/10.31893/multirev.2023001
Biehl, M. V., M. V. C. de Ferraz Junior, J. P. R. Barroso, I. Susin, E. M. Ferreira, D. M. Polizel, & A. V. Pires. 2019. The reused progesterone device has the same effect on short or long estrus synchronization protocols in tropical sheep. Trop. Anim. Health Prod. 51:1545–1549. https://doi.org/10.1007/s11250-019-01841-1
Bilbao, M. G., L. O. Zapata, H. Romero Harry, S. Perez Wallace, M. F. Farcey, L. Gelid, R. A. Palomares, M. S. Ferrer, & J. A. Bartolome. 2019. Comparison between the 5-day cosynch and 7-day estradiol-based protocols for synchronization of ovulation and timed artificial insemination in suckled BOS taurus BEEF cows. Theriogenology 131:72–78. https://doi.org/10.1016/j.theriogenology.2019.01.027
Bonacker, R. C., K. S. Stoecklein, J. W. C. Locke, J. N. Ketchum, E. R. Knickmeyer, C. M. Spinka, S. E. Poock, & J. M. Thomas. 2020. Treatment with prostaglandin F2α and an intravaginal progesterone insert promotes follicular maturity in advance of gonadotropin-releasing hormone among postpartum beef cows. Theriogenology 157:350–359. https://doi.org/10.1016/j.theriogenology.2020.08.018
Bragança, J. F. M., J. M. Maciel, L. K. Girardini, S. A. Machado, J. F. X. da Rocha, A. A. Tonin, & R. X. da Rocha. 2017. Influence of a device intravaginal to synchronization/induction of estrus and its reuse in sheep vaginal flora. Comp. Clin. Path. 26:1369–1373. https://doi.org/10.1007/s00580-017-2542-z
Chaudhari, A., N. Haque, N. Jamnesha, N. Bhalakiya, G. Patel, M. Madhavatar, D. Patel, & P. Patel. 2018. Synchronization of estrus: A reproductive management tool in veterinary practice. Int. J. Curr. Microbiol. Appl. Sci. 7:1511–1519
Collado-González, M., Y. G. Espinosa, & F. M. Goycoolea. 2019. Interaction between chitosan and mucin: Fundamentals and applications. Biomimetics 4:1–20. https://doi.org/10.3390/biomimetics4020032
Corteel, J. M., B. Leboeuf, & G. Baril. 1988. Artificial breeding of adult goats and kids induced with hormones to ovulate outside the breeding season. Small Rumin. Res. 1:19–35. https://doi.org/10.1016/0921-4488(88)90041-7
de Graaff, W. & B. Grimard. 2018. Progesterone-releasing devices for cattle estrus induction and synchronization: Device optimization to anticipate shorter treatment durations and new device developments. Theriogenology 112:34–43. https://doi.org/10.1016/j.theriogenology.2017.09.025
Dodero, A., M. Alloisio, M. Castellano, & S. Vicini. 2020. Multilayer alginate-polycaprolactone electrospun membranes as skin wound patches with drug delivery abilities. ACS Appl. Mater. Interfaces. 12:31162–31171. https://doi.org/10.1021/acsami.0c07352
dos Santos, A. M., S. G. Carvalho, V. H. S. Araujo, G. C. Carvalho, M. P. D. Gremião, & M. Chorilli. 2020. Recent advances in hydrogels as strategy for drug delivery intended to vaginal infections. Int. J. Pharm. 590:119867. https://doi.org/10.1016/j.ijpharm.2020.119867
Fernandes, L., R. Costa, M. Henriques, & M. E. Rodrigues. 2023. Simulated vaginal fluid: Candida resistant strains’ biofilm characterization and vapor phase of essential oil effect. J. Med. Mycol. 33:101329. https://doi.org/10.1016/j.mycmed.2022.101329
Gobikrushanth, M., R. J. Mapletoft, & M. G. Colazo. 2023. Estrous activity and pregnancy outcomes in Holstein heifers subjected to a progesterone based 5-d CO-Synch protocol with or without administration of initial GnRH. Theriogenology 202:36–41. https://doi.org/10.1016/j.theriogenology.2023.02.024
Gonzalez-Bulnes, A., A. Menchaca, G. B. Martin, & P. Martinez-Ros. 2020. Seventy years of progestagen treatments for management of the sheep oestrous cycle: Where we are and where we should go. Reprod. Fertil. Dev. 32:441–452. https://doi.org/10.1071/RD18477
Gore, D. L. M., J. N. Mburu, T. O. Okeno, & T. K. Muasya. 2020. Short-term oestrous synchronisation protocol following single fixed-time artificial insemination and natural mating as alternative to long-term protocol in dairy goats. Small Rumin. Res. 192:106207. https://doi.org/10.1016/j.smallrumres.2020.106207
Helbling, I. M., F. Karp, A. Cappadoro, & J. A. Luna. 2020. Design and evaluation of a recyclable intravaginal device made of ethylene vinyl acetate copolymer for bovine estrus synchronization. Drug Deliv. Transl. Res. 10:1255–1266. https://doi.org/10.1007/s13346-020-00717-4
Macmillan, K. & C. Burke. 1996. Effects of oestrous cycle control on reproductive efficiency. Anim. Reprod. Sci. 42:307–320. https://doi.org/10.1016/0378-4320(96)01512-6
Martinez-Ros, P., S. Astiz, E. Garcia-Rosello, A. Rios-Abellan, & A. Gonzalez-Bulnes. 2019. Onset of estrus and preovulatory LH surge and ovulatory efficiency in sheep after short-term treatments with progestagen-sponges and progesterone-CIDRs. Reprod. Domest. Anim. 54:408–411. https://doi.org/10.1111/rda.13317
Martinez-Ros, P., M. Lozano, F. Hernandez, A. Tirado, A. Rios-Abellan, M. C. López-Mendoza, & A. Gonzalez-Bulnes. 2018. Intravaginal device-type and treatment-length for ovine estrus synchronization modify vaginal mucus and microbiota and affect fertility. Animals. 8:1–8. https://doi.org/10.3390/ani8120226
Menchaca, A., P. Dos, & S. Neto. 2017. Estrous synchronization treatments in sheep : Brief update. Rev. bras. reprod. anim. supl. 41:340–344.
Nakasaki, K., H. Hirai, H. Mimoto, T. N. M. Quyen, M. Koyama, & K. Takeda. 2019. Succession of microbial community during vigorous organic matter degradation in the primary fermentation stage of food waste composting. Sci. Total Environ. 671:1237–1244. https://doi.org/10.1016/j.scitotenv.2019.03.341
Omontese, B. O., P. I. Rekwot, I. U. Ate, J. O. Ayo, M. U. Kawu, J. S. Rwuaan, A. I. Nwannenna, R. A. Mustapha, & A. A. Bello. 2016. An update on oestrus synchronisation of goats in Nigeria. Asian Pacific J. Reprod. 5:96–101. https://doi.org/10.1016/j.apjr.2016.01.002
Othman, S. H., N. D. A. Ronzi, R. A. Shapi’i, M. Dun, S. H. Ariffin, & M. A. P. Mohammed. 2023. Biodegradability of starch nanocomposite films containing different concentrations of chitosan nanoparticles in compost and planting soils. Coatings. 13:777. https://doi.org/10.3390/coatings13040777
Owen, D. H. & D. F. Katz. 1999. A vaginal fluid simulant. Contraception 59:91–95. https://doi.org/10.1016/S0010-7824(99)00010-4
Poshina, D. N., S. V. Raik, A. N. Poshin, & Y. A. Skorik. 2018. Accessibility of chitin and chitosan in enzymatic hydrolysis: A review. Polym. Degrad. Stab. 156:269–278. https://doi.org/10.1016/j.polymdegradstab.2018.09.005
Rathbone, M. J., C. R. Bunt, C. R. Ogle, S. Burggraaf, K. L. Macmillan, C. R. Burke, & K. L. Pickering. 2002a. Reengineering of a commercially available bovine intravaginal insert (CIDR insert) containing progesterone. J. Control. Release. 85:105–115. https://doi.org/10.1016/S0168-3659(02)00288-2
Rathbone, M. J., C. R. Bunt, C. R. Ogle, S. Burggraaf, K. L. Macmillan, & K. Pickering. 2002b. Development of an injection molded poly(ε-caprolactone) intravaginal insert for the delivery of progesterone to cattle. J. Control. Release. 85:61–71. https://doi.org/10.1016/S0168-3659(02)00272-9
Roche, J. F. & J. J. Ireland. 1981. Effect of exogenous progesterone on time of occurrence of the LH surge in heifers. J. Anim. Sci. 52:580–586. https://doi.org/10.2527/jas1981.523580x
Roman, D. L., V. Ostafe, & A. Isvoran. 2020. Deeper inside the specificity of lysozyme when degrading chitosan. A structural bioinformatics study. J. Mol. Graph. Model. 100:107676. https://doi.org/10.1016/j.jmgm.2020.107676
Say, E., S. Çoban, Y. Nak, D. Nak, U. Kara, S. White, V. Kasimanickam, & R. Kasimanickam. 2016. Fertility of Holstein heifers after two doses of PGF2α in 5-day CO-Synch progesterone-based synchronization protocol. Theriogenology 86:988–993. https://doi.org/10.1016/j.theriogenology.2016.03.026
Shockley, M. F. & A. H. Muliana. 2020. Modeling temporal and spatial changes during hydrolytic degradation and erosion in biodegradable polymers. Polym. Degrad. Stab. 180:109298. https://doi.org/10.1016/j.polymdegradstab.2020.109298
Silva, B. D. M., T. A. S. N. Silva, N. H. Moreira, H. C. A. Teixeira, M. A. Paiva Neto, J. P. Neves, & A. F. Ramos. 2015. Ovulation induction in ewes using GnRH in long and short-term synchronization protocols. Anim. Reprod. 12:312–315
Silva, L. O., N. P. Folchini, R. L. O. R. Alves, G. Madureira, C. E. C. Consentini, J. C. L. Motta, M. C. Wiltbank, & R. Sartori. 2023. Effect of progesterone from corpus luteum, intravaginal implant, or both on luteinizing hormone release, ovulatory response, and subsequent luteal development after gonadotropin-releasing hormone treatment in cows. J. Dairy Sci. 106:4413–4428. https://doi.org/10.3168/jds.2022-22618
Suárez, G., P. Zunino, H. Carol, & R. Ungerfeld. 2006. Changes in the aerobic vaginal bacterial mucous load and assessment of the susceptibility to antibiotics after treatment with intravaginal sponges in anestrous ewes. Small Rumin. Res. 63: 39–43. https://doi.org/10.1016/j.smallrumres.2005.01.011
Thai, H., C. Thuy Nguyen, L. Thi Thach, M. Thi Tran, H. Duc Mai, T. Thi Thu Nguyen, G. Duc Le, M. Van Can, L. Dai Tran, G. Long Bach, K. Ramadass, C. I. Sathish, & Q. Van Le. 2020. Characterization of chitosan/alginate/lovastatin nanoparticles and investigation of their toxic effects in vitro and in vivo. Sci. Rep. 10:1–15. https://doi.org/10.1038/s41598-020-57666-8
Wang, X., S. Liu, Y. Guan, J. Ding, C. Ma, & Z. Xie. 2021. Vaginal drug delivery approaches for localized management of cervical cancer. Adv. Drug Deliv. Rev. 174:114–126. https://doi.org/10.1016/j.addr.2021.04.009
Xu, Q., Y. Ji, Q. Sun, Y. Fu, Y. Xu, & L. Jin. 2019. Fabrication of cellulose nanocrystal/chitosan hydrogel for controlled drug release. Nanomaterials 9:253. https://doi.org/10.3390/nano9020253
Zeng, S. H., P. P. Duan, M. X. Shen, Y. J. Xue, & Z. Y. Wang. 2016. Preparation and degradation mechanisms of biodegradable polymer: A review. IOP Conf. Ser. Mater. Sci. Eng. 137:012003. https://doi.org/10.1088/1757-899X/137/1/012003
Authors
YessaE. Y., TumbelakaL. I. T. A., WientarsihI., UlumM. F., PurwantaraB., & Amrozi. (2023). In Vitro, In Compost, and In Vivo Assessment of Chitosan-Polyethylene Glycol as an Intravaginal Insert for Progesterone Delivery in Sheep. Tropical Animal Science Journal, 46(3), 295-305. https://doi.org/10.5398/tasj.2023.46.3.295
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