Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular
ilustraciones, diagramas, fotografías, gráficos
- Autores:
-
Camargo Trujillo, Fabio Andrés
- Tipo de recurso:
- Fecha de publicación:
- 2023
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/85394
- Palabra clave:
- 615 - Farmacología y terapéutica
Polímeros
Quitosano
Antifibrinolíticos
Ácido tranexámico
Hemostáticos
Diseño de Dispositivos Médicos
Alginatos
Recursos Materiales en Salud
Materiales Biocompatibles-química
Polymers
Chitosan
Antifibrinolytic Agents
Hemostatics
Alginates
Material Resources in Health
Biocompatible Materials-chemistry
Tapón nasal
Poli (vinil alcohol)
Quitosano
Alginato de sodio
Congelamiento-descongelamiento
Ácido tranexámico
Quality by Design
Nasal pack
Poly (vinyl alcohol)
Chitosan
Sodium Alginate
Freeze-Thawing
Tranexamic Acid
- Rights
- openAccess
- License
- Atribución-NoComercial-SinDerivadas 4.0 Internacional
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| dc.title.spa.fl_str_mv |
Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular |
| dc.title.translated.eng.fl_str_mv |
Development of a nasal pack combined medical device with hemostatic activity based on the concept of modular architecture |
| title |
Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular |
| spellingShingle |
Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular 615 - Farmacología y terapéutica Polímeros Quitosano Antifibrinolíticos Ácido tranexámico Hemostáticos Diseño de Dispositivos Médicos Alginatos Recursos Materiales en Salud Materiales Biocompatibles-química Polymers Chitosan Antifibrinolytic Agents Hemostatics Alginates Material Resources in Health Biocompatible Materials-chemistry Tapón nasal Poli (vinil alcohol) Quitosano Alginato de sodio Congelamiento-descongelamiento Ácido tranexámico Quality by Design Nasal pack Poly (vinyl alcohol) Chitosan Sodium Alginate Freeze-Thawing Tranexamic Acid |
| title_short |
Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular |
| title_full |
Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular |
| title_fullStr |
Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular |
| title_full_unstemmed |
Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular |
| title_sort |
Desarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modular |
| dc.creator.fl_str_mv |
Camargo Trujillo, Fabio Andrés |
| dc.contributor.advisor.none.fl_str_mv |
Vallejo Díaz, Bibiana Margarita Rosa |
| dc.contributor.author.none.fl_str_mv |
Camargo Trujillo, Fabio Andrés |
| dc.contributor.researchgroup.spa.fl_str_mv |
Procesos de Transformación de Materiales para la Industria Farmacéutica (PTM) |
| dc.subject.ddc.spa.fl_str_mv |
615 - Farmacología y terapéutica |
| topic |
615 - Farmacología y terapéutica Polímeros Quitosano Antifibrinolíticos Ácido tranexámico Hemostáticos Diseño de Dispositivos Médicos Alginatos Recursos Materiales en Salud Materiales Biocompatibles-química Polymers Chitosan Antifibrinolytic Agents Hemostatics Alginates Material Resources in Health Biocompatible Materials-chemistry Tapón nasal Poli (vinil alcohol) Quitosano Alginato de sodio Congelamiento-descongelamiento Ácido tranexámico Quality by Design Nasal pack Poly (vinyl alcohol) Chitosan Sodium Alginate Freeze-Thawing Tranexamic Acid |
| dc.subject.decs.spa.fl_str_mv |
Polímeros Quitosano Antifibrinolíticos Ácido tranexámico Hemostáticos Diseño de Dispositivos Médicos Alginatos Recursos Materiales en Salud Materiales Biocompatibles-química |
| dc.subject.decs.eng.fl_str_mv |
Polymers Chitosan Antifibrinolytic Agents Hemostatics Alginates Material Resources in Health Biocompatible Materials-chemistry |
| dc.subject.proposal.spa.fl_str_mv |
Tapón nasal Poli (vinil alcohol) Quitosano Alginato de sodio Congelamiento-descongelamiento Ácido tranexámico |
| dc.subject.proposal.eng.fl_str_mv |
Quality by Design Nasal pack Poly (vinyl alcohol) Chitosan Sodium Alginate Freeze-Thawing Tranexamic Acid |
| description |
ilustraciones, diagramas, fotografías, gráficos |
| publishDate |
2023 |
| dc.date.issued.none.fl_str_mv |
2023 |
| dc.date.accessioned.none.fl_str_mv |
2024-01-22T17:31:05Z |
| dc.date.available.none.fl_str_mv |
2024-01-22T17:31:05Z |
| dc.type.spa.fl_str_mv |
Trabajo de grado - Maestría |
| dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| dc.type.version.spa.fl_str_mv |
info:eu-repo/semantics/acceptedVersion |
| dc.type.content.spa.fl_str_mv |
Text |
| dc.type.redcol.spa.fl_str_mv |
http://purl.org/redcol/resource_type/TM |
| status_str |
acceptedVersion |
| dc.identifier.uri.none.fl_str_mv |
https://repositorio.unal.edu.co/handle/unal/85394 |
| dc.identifier.instname.spa.fl_str_mv |
Universidad Nacional de Colombia |
| dc.identifier.reponame.spa.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
| dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.unal.edu.co/ |
| url |
https://repositorio.unal.edu.co/handle/unal/85394 https://repositorio.unal.edu.co/ |
| identifier_str_mv |
Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia |
| dc.language.iso.spa.fl_str_mv |
spa |
| language |
spa |
| dc.relation.references.spa.fl_str_mv |
Kucik, C. J., & Clenney, T. L. (2005). Management of Epistaxis. American Family Physician, 71(2), 305-311. https://www.aafp.org/afp/2005/0115/p305.html Tunkel, D. E., Anne, S., Payne, S. C., Ishman, S. L., Rosenfeld, R. M., Abramson, P. J., Alikhaani, J. D., Benoit, M. M., Bercovitz, R. S., Brown, M. D., Chernobilsky, B., Feldstein, D. A., Hackell, J. M., Holbrook, E. H., Holdsworth, S. M., Lin, K. W., Lind, M. M., Poetker, D. M., Riley, C. A., … Monjur, T. M. (2020). Clinical practice guideline: Nosebleed(Epistaxis). Otolaryngology–Head and Neck Surgery, 162(1_suppl), S1-S38. https://doi.org/10.1177/0194599819890327 Tobón, D., Jaramillo, L. A., Mejía, C., Quijano, D. (2016). Guía del manejo de Epistaxis. Asociación Colombiana de Otorrinolaringología. Guías ACORL para el manejo de las patologías más frecuentes en Otorrinolaringología (pp. 135-138). Recuperado de: https://www.acorl.org.co/resources/imagenes/visitante/medico/apoyo-al-ejercicio-profesional/guias-acorl/Epixtasis.pdf Evans, A. S., Young, D., & Adamson, R. (2004). Is the nasal tampon a suitable treatment for epistaxis in Accident & Emergency? A comparison of outcomes for ENT and A&E packed patients. The Journal of Laryngology & Otology, 118(01). doi:10.1258/002221504322731556 ISO, International Standard. (2016). ISO 1385: Medical devices: Quality management systems. Requirements for regulatory purposes. Recuperado de: http://www.bonnier.net.cn/download/d_20170812100731.pdf Gibson, M., Carmody, A., Weaver, R. (2018). Development and Manufacture of Drug Product. En: "Pharmaceutical Quality by Design: A Practical Approach". Editado por: W. S. Schlindwein, M. Gibson. Ed. John Wiley & Sons Ltd, Hoboken, USA. Vol. I. pp. 117-154. Suh, N. P. (2001). Axiomatic design: Advances and applications (pp. 1-51). New York: Oxford University Press. Aguwa, C. C., Monplaisir, L., Sylajakumari, P. A., & Muni, R. K. (2010). Integrated Fuzzy-Based Modular Architecture for Medical Device Design and Development. Journal of Medical Devices, 4(3), 031007. doi:10.1115/1.4002323 Salhieh, S. M., & Kamrani, A. K. (1999). Macro level product development using design for modularity. Robotics and Computer-Integrated Manufacturing, 15(4), 319–329. doi:10.1016/s0736-5845(99)00008-3 Hernández V., M., Hernández A., C., & Bergeret V., J. P. (2005). Epistaxis: Consideraciones generales y manejo clínico. Cuadernos de Cirugía, 19(1), 54-59. https://doi.org/10.4206/cuad.cir.2005.v19n1-09 Beule, A. G. (2011). Physiology and pathophysiology of respiratory mucosa of the nose and the paranasal sinuses. GMS Current Topics in Otorhinolaryngology, Head and Neck Surgery, 9, Doc07. https://doi.org/10.3205/cto000071 Fatakia, A., Winters, R., Amedee, R.G. (2010). Epistaxis: A Common Problem. The Ochsner Journal, 10, 176–178. INTEGRATE (The UK ENT Trainee Research Network). (2020). Nasal packs for epistaxis: Predictors of success. Clinical Otolaryngology: Official Journal of ENT-UK ; Official Journal of Netherlands Society for Oto -Rhino-Laryngology & Cervico-Facial Surgery, 45(5), 659-666. https://doi.org/10.1111/coa.13555 Moumoulidis, I., Draper, M. R., Patel, H., Jani, P., & Price, T. (2006). A prospective randomised controlled trial comparing Merocel and Rapid Rhino nasal tampons in the treatment of epistaxis. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery, 263(8), 719–722. https://doi.org/10.1007/s00405-006-0047-5 Murray, S., Mendez, A., Hopkins, A., El-Hakim, H., Jeffery, C. C., & Côté, D. W. J. (2018). Management of Persistent Epistaxis Using Floseal Hemostatic Matrix vs. traditional nasal packing: A prospective randomized control trial. Journal of Otolaryngology - Head & Neck Surgery = Le Journal D’oto-Rhino-Laryngologie Et De Chirurgie Cervico-Faciale, 47(1), 3. https://doi.org/10.1186/s40463-017-0248-5 Valtonen, O., Ormiskangas, J., Kivekäs, I., Rantanen, V., Dean, M., Poe, D., Järnstedt, J., Lekkala, J., Saarenrinne, P., & Rautiainen, M. (2020). Three-dimensional printing of the nasal cavities for clinical experiments. Scientific Reports, 10(1), 502. https://doi.org/10.1038/s41598-020-57537-2 Weber, R. (2009). Nasentamponaden und Stents. Laryngo-Rhino-Otologie, 88(S 01), S139-S155. https://doi.org/10.1055/s-0028-1119504 UpToDate. (2023). Anatomy of the medial nasal wall. Recuperado de: https://www.uptodate.com/contents/image?imageKey=PC%2F54180 MedScape. (2022). Anterior nasal packing for epistaxis: Overview, technique, preparation. Recuperado de: https://emedicine.medscape.com/article/80526-overview Widmer-von-Brugg, G.M., Brugg, A.G., Probst, R. (2007). Patientenkomfort bei postoperativer Nasentamponade: frühe (8h) versus späte (24h) Detamponade. Inaugural-Dissertation zur Erlangung der Doktorwürde der Medizinischen Fakultät der Universität Zürich. Recuperado de: https://www.uzh.ch/orl/publications/dissertations/diss_Widmer_Gian-Marco.pdf Beule, A. G., Weber, R. K., Kaftan, H., & Hosemann, W. (2004). Übersicht: Art und Wirkung geläufiger Nasentamponaden. Laryngo-Rhino-Otologie, 83(8), 534–551. Iqbal, I. Z., Jones, G. H., Dawe, N., Mamais, C., Smith, M. E., Williams, R. J., Carrie, S. (2017). Intranasal packs and haemostatic agents for the management of adult epistaxis: systematic review. The Journal of Laryngology & Otology, 131(12), 1065–1092. doi:10.1017/s0022215117002055 Thomas, I., Thekkethil, J. S., Kapoor, R. C., Thomas, T., & Thomas, P. (2018). A novel technique of using sponge as post-operative nasal packing. Bengal Journal of Otolaryngology and Head Neck Surgery, 26(1), 23-28. Recuperado de: https://bjohns.in/journal/index.php/bjohns/article/view/368 Wang, Y. P., Wang, M. C., Chen, Y. C., Leu, Y. S., Lin, H. C., & Lee, K.-S. (2011). The effects of Vaseline gauze strip, Merocel, and Nasopore on the formation of synechiae and excessive granulation tissue in the middle meatus and the incidence of major postoperative bleeding after endoscopic sinus surgery. Journal of the Chinese Medical Association, 74(1), 16–21. doi:10.1016/j.jcma.2010.09.001 Acıoğlu, E., Edizer, D. T., Yiğit, Ö., Onur, F., & Alkan, Z. (2011). Nasal septal packing: which one? European Archives of Oto-Rhino-Laryngology, 269(7), 1777–1781. doi:10.1007/s00405-011-1842-1 Akbari, E., Philpott, C. M., Ostry, A. J., Clark, A., & Javer, A. R. (2012). A double-blind randomised controlled trial of gloved versus ungloved merocel middle meatal spacers for endoscopic sinus surgery. Rhinology Journal, 50(3), 306-310. https://doi.org/10.4193/Rhin11.215 Medtronic. (2021). ENT Product Catalog. Recuperado de: https://asiapac.medtronic.com/content/dam/medtronic-com/products/ear-nosethroat/documents/ent-product-catalog.pdf Gabay, M. (2006). Absorbable hemostatic agents. American Journal of Health-System Pharmacy, 63(13), 1244–1253. doi:10.2146/ajhp060003 Wang, J., Cai, C., & Wang, S. (2014). Merocel versus nasopore for nasal packing: A metaanalysis of randomized controlled trials. PLOS ONE, 9(4), e93959. https://doi.org/10.1371/journal.pone.0093959 Selvarajah, J., Busra, M. F. M., Saim, A. B., Hj Idrus, R. B., & Lokanathan, Y. (2020). Development and Physicochemical Analysis of Genipin-Crosslinked Gelatine Sponge as a Potential Resorbable Nasal Pack. Journal of Biomaterials Science, Polymer Edition, 1–14. doi:10.1080/09205063.2020.1774841 Shikani, A., & Chahine, K. (2009). Chitosan-coated nasal packing in recalcitrant epistaxis. Otolaryngology - Head and Neck Surgery, 141(3), P109–P109. doi:10.1016/j.otohns.2009.06.341 Taulu, R. (2020). A Comparison of Drug-Eluting Stent and Intranasal Corticosteroid Spray in the Treatment of Chronic Rhinosinusitis. Tampere University Dissertations (331). Recuperado de: https://trepo.tuni.fi/bitstream/handle/10024/123745/978-952-03-1745-4.pdf?sequence=2 Adriaensen, G. F. J. P. M., Lim, K.-H., & Fokkens, W. J. (2017). Safety and efficacy of a bioabsorbable fluticasone propionate-eluting sinus dressing in postoperative management of endoscopic sinus surgery: a randomized clinical trial. International Forum of Allergy & Rhinology, 7(8), 813–820. doi:10.1002/alr.21963 Tamer, T. M., Sabet, M. M., Omer, A. M., Abbas, E., Eid, A. I., Mohy-Eldin, M. S., & Hassan, M. A. (2021). Hemostatic and antibacterial PVA/Kaolin composite sponges loaded with penicillin–streptomycin for wound dressing applications. Scientific Reports, 11(1), 3428. https://doi.org/10.1038/s41598-021-82963-1 Landsman, T. L., Touchet, T., Hasan, S. M., Smith, C., Russell, B., Rivera, J., Maitland, D. J., & Cosgriff-Hernandez, E. (2017). A shape memory foam composite with enhanced fluid uptake and bactericidal properties as a hemostatic agent. Acta Biomaterialia, 47, 91-99. https://doi.org/10.1016/j.actbio.2016.10.008 Campacci, F., Vicini, C., Ciuti G. & Ricotti, L. (2021). RhinoFit: A Bionic Nasal Device for Mitigating Post-Operative Complications After Rhinosurgery. IEEE Transactions on Medical Robotics and Bionics. 3 (2), 297-305. doi: 10.1109/TMRB.2021.3063852 Friedland, Y., Bagot d'Arc, M. B. D., Ha, J., & Delin, C. (2022). The Use of Self-Assembling Peptides (PuraStat™ ) in Functional Endoscopic Sinus Surgery for Haemostasis and Reducing Adhesion Formation. A Case Series of 94 Patients. Surgical technology international, 41,sti41/1594. Advance online publication. https://doi.org/10.52198/22.STI.41.GS1694 Lee, M. F., Ma, Z., & Ananda, A. (2017). A novel haemostatic agent based on self-assembling peptides in the setting of nasal endoscopic surgery, a case series. International journal of surgery case reports, 41, 461–464. https://doi.org/10.1016/j.ijscr.2017.11.024 Kar, M., Cetinkaya, E. A., & Konşuk-Ünlü, H. (2022). Comparison of the ankaferd blood stopper tampon and the merocel nasal tampon after septoplasty surgery. Aesthetic Plastic Surgery. https://doi.org/10.1007/s00266-022-03031-1 Jimenez-Martin, J., Las Heras, K., Etxabide, A., Uranga, J., de la Caba, K., Guerrero, P., Igartua, M., Santos-Vizcaino, E., & Hernandez, R. M. (2022). Green hemostatic sponge-like scaffold composed of soy protein and chitin for the treatment of epistaxis. Materials Today Bio, 15, 100273. https://doi.org/10.1016/j.mtbio.2022.100273 Li, M., Pan, G., Yang, Y., & Guo, B. (2023). Smart aligned multi-layered conductive cryogels with hemostasis and breathability for coagulopathy epistaxis, nasal mucosal repair and bleeding monitoring. Nano Today, 48, 101720. https://doi.org/10.1016/j.nantod.2022.101720 Sasmal, P., & Datta, P. (2019). Tranexamic acid-loaded chitosan electrospun nanofibers as drug delivery system for hemorrhage control applications. Journal of Drug Delivery Science and Technology, 52, 559-567. https://doi.org/10.1016/j.jddst.2019.05.018 Tran, Q. K., Rehan, M. A., Haase, D. J., Matta, A., & Pourmand, A. (2020). Prophylactic antibiotics for anterior nasal packing in emergency department: A systematic review and meta-analysis of clinically-significant infections. The American Journal of Emergency Medicine, 38(5), 983-989. https://doi.org/10.1016/j.ajem.2019.11.037 Lange, J. L., Peeden, E. H., & Stringer, S. P. (2017). Are prophylactic systemic antibiotics necessary with nasal packing? A systematic review. American Journal of Rhinology & Allergy, 31(4), 240-247. https://doi.org/10.2500/ajra.2017.31.4454 Schouten, E. S., van de Pol, A. C., Schouten, A. N. J., Turner, N. M., Jansen, N. J. G., & Bollen, C. W. (2009). The effect of aprotinin, tranexamic acid, and aminocaproic acid on blood loss and use of blood products in major pediatric surgery: A meta-analysis. Pediatric Critical Care Medicine, 10(2), 182–190. Akkan, S., Çorbacıoğlu, Ş. K., Aytar, H., Emektar, E., Dağar, S., & Çevik, Y. (2019). Evaluating effectiveness of nasal compression with tranexamic acid compared with simple nasal compression and merocel packing: A randomized controlled trial. Annals of Emergency Medicine, 74(1), 72-78. https://doi.org/10.1016/j.annemergmed.2019.03.030 U.S. Food and Drug Administration (2018). Overview of regulatory requirements: Medical devices - transcript. FDA. https://www.fda.gov/training-and-continuing-education/cdrh-learn/overview-regulatory-requirements-medical-devices-transcript Ministerio de Salid y Protección Social. (2013). ABC de Dispositivos Médicos. Recuperado de: https://www.invima.gov.co/documents/20143/442916/abc_dispositivos-medicos.pdf/d32f6922-0c50-bcaa-6b53-066edfb98274 U.S. Food and Drug Administration (2022). Principles of Premarket Pathways for Combination Products. Guidance for Industry and FDA Staff. Recuperado de: https://www.fda.gov/media/119958/download Antich-Isern, P., Caro-Barri, J., & Aparicio-Blanco, J. (2021). The combination of medical devices and medicinal products revisited from the new European legal framework. International Journal of Pharmaceutics, 607, 120992. doi:10.1016/j.ijpharm.2021.120992 Bodenberger, N., Kubiczek, D., Abrosimova, I., Scharm, A., Kipper, F., Walther, P., & Rosenau, F. (2016). Evaluation of methods for pore generation and their influence on physio-chemical properties of a protein based hydrogel. Biotechnology Reports, 12, 6–12. doi:10.1016/j.btre.2016.09.001 Redaelli, F., Sorbona, M., & Rossi, F. (2017). Synthesis and processing of hydrogels for medical applications. Bioresorbable Polymers for Biomedical Applications, 205–228. doi:10.1016/b978-0-08-100262-9.00010-0 Udenni-Gunathilake, T. M. S., Ching, Y. C., Ching, K. Y., Chuah, C. H., & Abdullah, L. C. (2017). Biomedical and Microbiological Applications of Bio-Based Porous Materials: A Review. Polymers, 9(5), 160. https://doi.org/10.3390/polym9050160 Joardder, M. U. H., Karim, A., Kumar, C., & Brown, R. J. (2016). Porosity. SpringerBriefs in Food, Health, and Nutrition. doi:10.1007/978-3-319-23045-0 Ganji, F., Vasheghani-Farahani, S., Vasheghani-Farahani, E. (2010). Theoretical Description of Hydrogel Swelling: A Review. Iranian Polymer Journal 19(5). 375-398. Drozdov, A. D., & deClaville Christiansen, J. (2015). Modeling the effects of pH and ionic strength on swelling of polyelectrolyte gels. The Journal of Chemical Physics, 142(11), 114904. doi:10.1063/1.4914924 Borges, F. T. P., Papavasiliou, G., & Teymour, F. (2020). Characterizing the Molecular Architecture of Hydrogels and Crosslinked Polymer Networks beyond Flory–Rehner—I. Theory. Biomacromolecules, 21(12), 5104–5118. doi:10.1021/acs.biomac.0c01256 Korsmeyer, R. W., Von Meerwall, E., & Peppas, N. A. (1986). Solute and penetrant diffusion in swellable polymers. II. Verification of theoretical models. Journal of Polymer Science Part B: Polymer Physics, 24(2), 409–434. doi:10.1002/polb.1986.090240215 Aguilar M. R. & San Román J. (2019). Polymers pH-responsive polymers: properties, synthesis and applications. En: “Smart and their Applications.” Woodhead Publishing Ltd., Cambridge, UK. pp. 45-66,240-254. Young, R. J ., & Lovell, P. A. (1991). Introduction to Polymers. 2nd Edition. Springer Science+Business Media B.V. Hong Kong. pp. 310-318. Boardman, P. (2020). Modelling the Mechanical Properties of Hydrogel. iGEM 2020, Boston, E.E.U.U. Afghan, N., (2016) Mechanical Properties of Poly (vinyl alcohol) Based Blends and Composites. Electronic Thesis and Dissertation Repository. 3746. The University of Western Ontario, London, Canadá. Recuperado de: https://ir.lib.uwo.ca/cgi/viewcontent.cgi?article=5353&context=etd Stauffer, S. R., & Peppas, N. A. (1992). Poly(Vinyl alcohol) hydrogels prepared by freezing thawing cyclic processing. Polymer, 33(18), 3932-3936. https://doi.org/10.1016/0032-3861(92)90385-A Liu, X., Steiger, C., Lin, S., Parada, G. A., Liu, J., Chan, H. F., Yuk, H., Phan, N. V., Collins, J., Tamang, S., Traverso, G., & Zhao, X. (2019). Ingestible hydrogel device. Nature Communications, 10(1), 493. https://doi.org/10.1038/s41467-019-08355-2 Okay, O. (Ed.). (2014). Polymeric cryogels: Macroporous gels with remarkable properties (Vol. 263). Springer International Publishing. https://doi.org/10.1007/978-3-319-05846-7 Willcox, P. J., Howie, D. W., Schmidt-Rohr, K., Hoagland, D. A., Gido, S. P., Pudjijanto, S., … Venkatraman, S. (1999). Microstructure of poly(vinyl alcohol) hydrogels produced by freeze/thaw cycling. Journal of Polymer Science Part B: Polymer Physics, 37(24), 3438–3454. doi:10.1002/(sici)1099-0488(19991215)37:24<3438::aid-polb6>3.0.co;2-9 Ricciardi, R., Auriemma, F., Gaillet, C., De Rosa, C., & Lauprêtre, F. (2004). Investigation of the Crystallinity of Freeze/Thaw Poly(vinyl alcohol) Hydrogels by Different Techniques. Macromolecules, 37(25), 9510–9516. doi:10.1021/ma048418v Lozinsky, V.I., Vainerman, E.S., Domotenko, L.V. (1986). Study of cryostructurization of polymer systems VII. Structure formation under freezing of poly(vinyl alcohol) aqueous solutions. Colloid & Polymer Sci 264, 19–24. https://doi.org/10.1007/BF01410304 Damshkaln, L. G., Simenel, I. A., & Lozinsky, V. I. (1999). Study of cryostructuration of polymer systems. XV. Freeze-Thaw-induced formation of cryoprecipitate matter from low-concentrated aqueous solutions of poly(vinyl alcohol). Journal of Applied Polymer Science, 74(8), 1978–1986. doi:10.1002/(sici)1097-4628(19991121)74:8<1978::aid-app11>3.0.co;2-l Auriemma, F., De Rosa, C., & Triolo, R. (2006). Slow Crystallization Kinetics of Poly(vinyl alcohol) in Confined Environment during Cryotropic Gelation of Aqueous Solutions. Macromolecules, 39(26), 9429–9434. doi:10.1021/ma061955q Hassan, C. M., & Peppas, N. A. (2000). Structure and morphology of freeze/thawed pva hydrogels. Macromolecules, 33(7), 2472-2479. https://doi.org/10.1021/ma9907587 Hickey, A. S., & Peppas, N. A. (1995). Mesh size and diffusive characteristics of semicrystalline poly(vinyl alcohol) membranes prepared by freezing/thawing techniques. Journal of Membrane Science, 107(3), 229–237. doi:10.1016/0376-7388(95)00119-0 Qian, L., & Zhang, H. (2010). Controlled freezing and freeze drying: a versatile route for porous and micro-/nano-structured materials. Journal of Chemical Technology & Biotechnology, 86(2), 172–184. doi:10.1002/jctb.2495 Coria-Hernández, J., Méndez-Albores, A., Meléndez-Pérez, R., Rosas-Mendoza, M., & Arjona-Román, J. (2018). Thermal, Structural, and Rheological Characterization of Waxy Starch as a Cryogel for Its Application in Food Processing. Polymers, 10(4), 359. doi:10.3390/polym10040359 Fukumori, T., & Nakaoki, T. (2014). High-tensile-strength polyvinyl alcohol films prepared from freeze/thaw cycled gels. Journal of Applied Polymer Science, 131(15), n/a–n/a. doi:10.1002/app.40578 Chee, B. S., de Lima, G. G., Devine, D. M., & Nugent, M. J. D. (2018). Investigation of the effects of orientation on freeze/thawed Polyvinyl alcohol hydrogel properties. Materials Today Communications. doi:10.1016/j.mtcomm.2018.08.005 Kim, T. H., An, D. B., Oh, S. H., Kang, M. K., Song, H. H., & Lee, J. H. (2015). Creating stiffness gradient polyvinyl alcohol hydrogel using a simple gradual freezing–thawing method to investigate stem cell differentiation behaviors. Biomaterials, 40, 51–60. doi:10.1016/j.biomaterials.2014.11.017 Isa, I. Classifying physical models and prototypes in the design process (s.f.). Norwegian University of Science and Technology. Recuperado de: https://www.ntnu.no/documents/10401/1264433962/SitiArtikkel.pdf/e39fd03a-de17-4a13-97c6-19fadfda49e0#:~:text=An%20analytical%20prototype%20is%20a,similar%20to%20the%20final%20product. Kiemle Trindade, I. E., Oliveira Camargo Gomes, A. de, Martins Sampaio-Teixeira, A. C., & Kiemle Trindade, S. H. (2007). Adult nasal volumes assessed by acoustic rhinometry. Brazilian Journal of Otorhinolaryngology, 73(1), 32-39. https://doi.org/10.1016/S1808-8694(15)31119-8 Kjærgaard, T., Cvancarova, M., & Steinsvåg, S. K. (2009). Relation of nasal air flow to nasal cavity dimensions. Archives of Otolaryngology–Head & Neck Surgery, 135(6), 565. https://doi.org/10.1001/archoto.2009.50 Samoliński, B. K., Grzanka, A., & Gotlib, T. (2007). Changes in nasal cavity dimensions in children and adults by gender and age. The Laryngoscope, 117(8), 1429–1433. https://doi.org/10.1097/MLG.0b013e318064e837 Araújo, L. L. de, Silva, A. S. C. da, Araújo, B. M. A. M., Yamashita, R. P., Trindade, I. E. K., & Fukushiro, A. P. (2016). Dimensões nasofaríngeas em indivíduos sem anomalias craniofaciais: Dados normativos. CoDAS, 28(4), 403-408. https://doi.org/10.1590/2317-1782/20162015020 R. Stone and K. Wood, Development of a Functional Basis for Design, Journal of Mechanical Design, vol. 122, no. 4, pp. 359-370, (2000). Camargo-Trujillo, F.A., Rincon-Duarte, O.F., Barbosa H., Vallejo, B. (2020). Aplicación del Diseño Axiomático y Quality by Design (QbD) en el Diseño de un Prototipo Analítico, para un Dispositivo Hemostático Intranasal. Trabajo de Grado, pregrado. Universidad Nacional de Colombia, Bogotá, Colombia. Nguyen, Q. (2022). Epistaxis: Otolaryngology and Facial Plastic Surgery. Medscape. Recuperado de: https://emedicine.medscape.com/article/863220-overview#a3. Leadon, M., & Hohman, M. H. (2023). Posterior epistaxis nasal pack. StatPearls Publishing. Recuperado de: http://www.ncbi.nlm.nih.gov/books/NBK576436/ Vallejo Díaz, B. M., Perilla, J. E. (2008). Elementos conceptuales para estudiar el comportamiento bioadhesivo en polímeros, Rev. Colomb. Cienc. Quím. Farm. 37(1) Pendolino, A. L., Scarpa, B., & Ottaviano, G. (2019). Relationship Between Nasal Cycle, Nasal Symptoms and Nasal Cytology. American journal of rhinology & allergy, 33(6), 644–649. https://doi.org/10.1177/1945892419858582 Joseph, J., Martinez-Devesa, P., Bellorini, J., & Burton, M. J. (2018). Tranexamic acid for patients with nasal haemorrhage (epistaxis). The Cochrane database of systematic reviews, 12(12), CD004328. https://doi.org/10.1002/14651858.CD004328.pub3 Picetti, R., Shakur-Still, H., Medcalf, R. L., Standing, J. F., & Roberts, I. (2019). What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies. Blood Coagulation & Fibrinolysis, 30(1), 1–10. doi:10.1097/mbc.0000000000000789 Beer, H. L., Duvvi, S., Webb, C. J., & Tandon, S. (2005). Blood loss estimation in epistaxis scenarios. The Journal of Laryngology & Otology, 119(01). doi:10.1258/0022215053222752 Venturato, A., MacFarlane, G., Geng, J., & Bradley, M. (2016). Understanding Polymer-Cell Attachment. Macromolecular bioscience, 16(12), 1864–1872. https://doi.org/10.1002/mabi.201600253 Li, T., Shi, Z., He, X., Jiang, P., Lu, X., Zhang, R., & Wang, X. (2018). Aging-Resistant Functionalized LDH–SAS/Nitrile-Butadiene Rubber Composites: Preparation and Study of Aging Kinetics/Anti-Aging Mechanism. Materials, 11(5), 836. doi:10.3390/ma11050836 Chen, L., Yan, C., & Zheng, Z. (2018). Functional polymer surfaces for controlling cell behaviors. Materials Today, 21(1), 38–59. doi:10.1016/j.mattod.2017.07.002 Ino, J. M., Chevallier, P., Letourneur, D., Mantovani, D., & Le Visage, C. (2013). Plasma functionalization of poly(vinyl alcohol) hydrogel for cell adhesion enhancement. Biomatter, 3(4), e25414. https://doi.org/10.4161/biom.25414 Gupta, S., T, G., Basu, B., Goswami, S., & Sinha, A. (2012). Stiffness- and wettability-dependent myoblast cell compatibility of transparent poly(vinyl alcohol) hydrogels. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 101B(2), 346–354. doi:10.1002/jbm.b.32845 Peppas, N., & Stauffer, S. (1991). Reinforced uncrosslinked poly (Vinyl alcohol) gels produced by cyclic freezing-thawing processes: A short review. https://doi.org/10.1016/0168-3659(91)90007-Z Kumar, A., Behl, T., & Chadha, S. (2020). Synthesis of physically crosslinked PVA/Chitosan loaded silver nanoparticles hydrogels with tunable mechanical properties and antibacterial effects. International Journal of Biological Macromolecules. doi:10.1016/j.ijbiomac.2020.02.048 Figueroa-Pizano, M. D., Vélaz, I., Peñas, F. J., Zavala-Rivera, P., Rosas-Durazo, A. J., Maldonado-Arce, A. D., & Martínez-Barbosa, M. E. (2018). Effect of freeze-thawing conditions for preparation of chitosan-poly (Vinyl alcohol) hydrogels and drug release studies. Carbohydrate Polymers, 195, 476-485. https://doi.org/10.1016/j.carbpol.2018.05.004 Krutzer, B., Ros, M., Smit, J., de Jong W. (2011). A review of synthetic latices in surgical glove use. Kraton Innovation Center Amsterdam. Recuperado de: https://www.kraton.com/jp/products/pdf/synthetic_latices.pdf Yilmaz-Atay, H. (2020). Antibacterial Activity of Chitosan-Based Systems. Functional Chitosan: Drug Delivery and Biomedical Applications, 457–489. https://doi.org/10.1007/978-981-15-0263-7_15 Abdel-Mohsen, A. M., Aly, A. S., Hrdina, R., Montaser, A. S., & Hebeish, A. (2011). Eco-Synthesis of PVA/Chitosan Hydrogels for Biomedical Application. Journal of Polymers and the Environment, 19(4), 1005–1012. doi:10.1007/s10924-011-0334-0 Lim, L. Y., & Wan, L. S. C. (1994). The effect of plasticizers on the properties of polyvinyl alcohol films. Drug Development and Industrial Pharmacy, 20(6), 1007-1020. https://doi.org/10.3109/03639049409038347 Xie, L., Jiang, M., Dong, X., Bai, X., Tong, J., & Zhou, J. (2011). Controlled mechanical and swelling properties of poly(vinyl alcohol)/sodium alginate blend hydrogels prepared by freeze-thaw followed by Ca2+ crosslinking. Journal of Applied Polymer Science, 124(1), 823–831. doi:10.1002/app.35083 Muangsri, R., Chuysinuan, P., Thanyacharoen, T., Techasakul, S., Sukhavattanakul, P., & Ummartyotin, S. (2022). Utilization of freeze thaw process for polyvinyl alcohol/sodium alginate (Pva/sa) hydrogel composite. Journal of Metals, Materials and Minerals, 32(2), 34-41. https://doi.org/10.55713/jmmm.v32i2.1257 Matyash, M., Despang, F., Ikonomidou, C., Gelinsky M. (2014). Swelling and mechanical properties of alginate hydrogels with respect to promotion of neural growth. Repository of the Max Delbrück Center for Molecular Medicine (MDC) Berlin (Germany). Recuperado de: https://core.ac.uk/download/pdf/300323656.pdf Kamoun, E. A., Kenawy, E.-R. S., Tamer, T. M., El-Meligy, M. A., & Mohy Eldin, M. S. (2015). Poly (vinyl alcohol)-alginate physically crosslinked hydrogel membranes for wound dressing applications: Characterization and bio-evaluation. Arabian Journal of Chemistry, 8(1), 38–47. doi:10.1016/j.arabjc.2013.12.003 Zhang, S., Han, D., Ding, Z., Wang, X., Zhao, D., Hu, Y., & Xiao, X. (2019). Fabrication and Characterization of One Interpenetrating Network Hydrogel Based on Sodium Alginate and Polyvinyl Alcohol. Journal of Wuhan University of Technology-Mater. Sci. Ed., 34(3), 744–751. doi:10.1007/s11595-019-2112-0 Jiang, X., Xiang, N., Zhang, H., Sun, Y., Lin, Z., & Hou, L. (2018). Preparation and characterization of poly(vinyl alcohol)/sodium alginate hydrogel with high toughness and electric conductivity. Carbohydrate Polymers, 186, 377–383. doi:10.1016/j.carbpol.2018.01.061 Ostroha, J., Pong, M., Lowman, A., & Dan, N. (2004). Controlling the collapse/swelling transition in charged hydrogels. Biomaterials, 25(18), 4345–4353. doi:10.1016/j.biomaterials.2003.11.019 Daza Agudelo, J. I., Badano, J. M., & Rintoul, I. (2018). Kinetics and thermodynamics of swelling and dissolution of PVA gels obtained by freeze-thaw technique. Materials Chemistry and Physics, 216, 14–21. doi:10.1016/j.matchemphys.2018.05.038 Aranaz, I., Alcántara, A. R., Civera, M. C., Arias, C., Elorza, B., Heras Caballero, A., & Acosta, N. (2021). Chitosan: An Overview of Its Properties and Applications. Polymers, 13(19), 3256. https://doi.org/10.3390/polym13193256 Lee, K. Y., & Mooney, D. J. (2012). Alginate: properties and biomedical applications. Progress in polymer science, 37(1), 106–126. https://doi.org/10.1016/j.progpolymsci.2011.06.003 Ben-Halima, N. (2016). Poly(vinyl alcohol): review of its promising applications and insights into biodegradation. RSC Advances, 6(46), 39823–39832. doi:10.1039/c6ra05742j Minagawa, T., Okamura, Y., Shigemasa, Y., Minami, S., & Okamoto, Y. (2007). Effects of molecular weight and deacetylation degree of chitin/chitosan on wound healing. Carbohydrate Polymers, 4(67), 640-644. https://doi.org/10.1016/j.carbpol.2006.07.007 Pillai, C. K. S., Paul, W., & Sharma, C. P. (2009). Chitin and chitosan polymers: Chemistry, solubility and fiber formation. Progress in Polymer Science, 34(7), 641-678. https://doi.org/10.1016/j.progpolymsci.2009.04.001 Goy, R. C., Britto, D. de, & Assis, O. B. G. (2009). A review of the antimicrobial activity of chitosan. Polímeros, 19, 241-247. https://doi.org/10.1590/S0104-14282009000300013 Wu, J., Gong, X., Fan, Y., & Xia, H. (2011). Physically crosslinked poly(vinyl alcohol) hydrogels with magnetic field controlled modulus. Soft Matter, 7(13), 6205. doi:10.1039/c1sm05386h Zhou, Q., Kang, H., Bielec, M., Wu, X., Cheng, Q., Wei, W., & Dai, H. (2018). Influence of different divalent ions cross-linking sodium alginate-polyacrylamide hydrogels on antibacterial properties and wound healing. Carbohydrate Polymers, 197, 292–304. doi:10.1016/j.carbpol.2018.05.078 FDA (Center for Drug Evaluation and Research). (2009). Environmental Assessment, 22-430. Recuperado de: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022430s000ea.pdf Holloway, J. L., Lowman, A. M., & Palmese, G. R. (2013). The role of crystallization and phase separation in the formation of physically cross-linked PVA hydrogels. Soft Matter, 9(3), 826–833. doi:10.1039/c2sm26763b Lozinsky, V. I. (2008). Polymeric cryogels as a new family of macroporous and supermacroporous materials for biotechnological purposes. Russian Chemical Bulletin, 57(5), 1015–1032. doi:10.1007/s11172-008-0131-7 Hetzner, H., Schmid, C., Tremmel, S., Durst, K., & Wartzack, S. (2014). Empirical-statistical study on the relationship between deposition parameters, process variables, deposition rate and mechanical properties of a-c:h:w coatings. Coatings, 4(4), 772-795. https://doi.org/10.3390/coatings4040772 Zurovac, J. & Brown, R. (2012). Orthogonal Design: A Powerful Method for Comparative Effectiveness Research with Multiple Interventions. Issue Brief, Mathematica Policy Research. Recuperado de: https://mathematica.org/~/media/publications/PDFs/health/orthogonaldesign_ib.pdf ASTM, D20 Committee. (2018). Test method for tensile properties of thin plastic sheeting. ASTM International. https://doi.org/10.1520/D0882-18 Sher, N., Fatima, N., Perveen, S., Siddiqui, F. A., & Wafa Sial, A. (2015). Pregabalin and tranexamic Acid evaluation by two simple and sensitive spectrophotometric methods. International journal of analytical chemistry, 2015, 241412. https://doi.org/10.1155/2015/241412 ICH, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (2022). Validation of Analytical Procedures Q2(R2). ICH Harmonised Guideline. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-q2r2-validation-analytical-procedures-step-2b_en.pdf Fong, R., Robertson, A., Mallon, P., & Thompson, R. (2018). The Impact of Plasticizer and Degree of Hydrolysis on Free Volume of Poly(vinyl alcohol) Films. Polymers, 10(9), 1036. https://doi.org/10.3390/polym10091036 Koosha, M., Aalipour, H., Sarraf Shirazi, M. J., Jebali, A., Chi, H., Hamedi, S., Wang, N., Li, T., & Moravvej, H. (2021). Physically Crosslinked Chitosan/PVA Hydrogels Containing Honey and Allantoin with Long-Term Biocompatibility for Skin Wound Repair: An In Vitro and In Vivo Study. Journal of functional biomaterials, 12(4), 61. https://doi.org/10.3390/jfb12040061 Podorozhko, E. A., Ul’yabaeva, G. R., Kil’deeva, N. R., Tikhonov, V. E., Antonov, Y. A., Zhuravleva, I. L., & Lozinsky, V. I. (2016). A Study of cryostructuring of polymer systems. 41. Complex and composite poly(vinyl alcohol) cryogels containing soluble and insoluble forms of chitosan, respectively. Colloid Journal, 78(1), 90–101. doi:10.1134/s1061933x16010130 Gupta, S., Goswami, S., & Sinha, A. (2012). A combined effect of freeze—Thaw cycles and polymer concentration on the structure and mechanical properties of transparent PVA gels. Biomedical Materials, 7(1), 015006. https://doi.org/10.1088/1748-6041/7/1/015006 Lotfipour, F., Alami-Milani, M., Salatin, S., Hadavi, A., & Jelvehgari, M. (2019). Freeze-thaw-induced cross-linked PVA/chitosan for oxytetracycline-loaded wound dressing: the experimental design and optimization. Research in pharmaceutical sciences, 14(2), 175–189. https://doi.org/10.4103/1735-5362.253365 Ödeen, S. (1993). Determination of Viscoelastic Material Properties and Impact Force from Measurements on Impacted Bodies. Luleå University of Technology. Luleå, Suecia. Schick, C., & Androsch, R. (2018). Nucleation‐controlled semicrystalline morphology of bulk polymers. Polymer crystallization, 1(4). https://doi.org/10.1002/pcr2.10036 Su, Y., Wu, Y., Liu, M., Qing, Y., Zhou, J., & Wu, Y. (2020). Ferric Ions Modified Polyvinyl Alcohol for Enhanced Molecular Structure and Mechanical Performance. Materials, 13(6), 1412. https://doi.org/10.3390/ma13061412 Muthu, S., & Prabhakaran, A. (2014). Vibrational spectroscopic study and NBO analysis on tranexamic acid using DFT method. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 129, 184–192. doi:10.1016/j.saa.2014.03.050 Shaikh, T., Nafady, A., Talpur, F. N., Sirajuddin, Agheem, M. H., Shah, M. R., … Siddiqui, S. (2015). Tranexamic acid derived gold nanoparticles modified glassy carbon electrode as sensitive sensor for determination of nalbuphine. Sensors and Actuators B: Chemical, 211, 359–369. doi:10.1016/j.snb.2015.01.096 Tretinnikov, O. N., & Zagorskaya, S. A. (2012). Determination of the degree of crystallinity of poly(vinyl alcohol) by FTIR spectroscopy. Journal of Applied Spectroscopy, 79(4), 521–526. doi:10.1007/s10812-012-9634-y Waresindo, W. X., Luthfianti, H. R., Edikresnha, D., Suciati, T., Noor, F. A., & Khairurrijal, K. (2021). A freeze–thaw PVA hydrogel loaded with guava leaf extract: Physical and antibacterial properties. RSC Advances, 11(48), 30156-30171. https://doi.org/10.1039/D1RA04092H Lotfipour, F., Alami-Milani, M., Salatin, S., Hadavi, A., & Jelvehgari, M. (2019). Freeze-thaw-induced cross-linked PVA/chitosan for oxytetracycline-loaded wound dressing: the experimental design and optimization. Research in pharmaceutical sciences, 14(2), 175–189. https://doi.org/10.4103/1735-5362.253365 Sethi, A., Ahmad, M., Huma, T., Khalid, I., & Ahmad, I. (2021). Evaluation of Low Molecular Weight Cross Linked Chitosan Nanoparticles, to Enhance the Bioavailability of 5-Flourouracil. Dose-Response, 19(2). doi:10.1177/15593258211025353 Arafa, M. G., Mousa, H. A., & Afifi, N. N. (2020). Preparation of PLGA-chitosan based nanocarriers for enhancing antibacterial effect of ciprofloxacin in root canal infection. Drug delivery, 27(1), 26–39. https://doi.org/10.1080/10717544.2019.1701140 ChemSpider. (2023). Tranexamic acid | C8H15NO2 | chemspider. Recuperado de: http://www.chemspider.com/Chemical-Structure.10482000.html PubChem. (2023). Tranexamic acid. Recuperado de: https://pubchem.ncbi.nlm.nih.gov/compound/5526 Su, Y., Wu, Y., Liu, M., Qing, Y., Zhou, J., & Wu, Y. (2020). Ferric Ions Modified Polyvinyl Alcohol for Enhanced Molecular Structure and Mechanical Performance. Materials, 13(6), 1412. https://doi.org/10.3390/ma13061412 Andrade, J., González-Martínez, C., & Chiralt, A. (2020). The Incorporation of Carvacrol into Poly (vinyl alcohol) Films Encapsulated in Lecithin Liposomes. Polymers, 12(2), 497. doi:10.3390/polym12020497 Lozinsky, V. I., Damshkaln, L. G., Shaskol’skii, B. L., Babushkina, T. A., Kurochkin, I. N., & Kurochkin, I. I. (2007). Study of cryostructuring of polymer systems: 27. Physicochemical properties of poly(Vinyl alcohol) cryogels and specific features of their macroporous morphology. Colloid Journal, 69(6), 747-764. https://doi.org/10.1134/S1061933X07060117 Nakano, T., & Nakaoki, T. (2011). Coagulation size of freezable water in poly(Vinyl alcohol) hydrogels formed by different freeze/thaw cycle periods. Polymer Journal, 43(11), 875-880. https://doi.org/10.1038/pj.2011.92 Wahab, A. H. A., Kadir, M. R. A., Harun, M. N., Ramlee, M. H., Syahrom, A., Sulong, M. A., & Saad, A. P. M. (2018). Developing Functionally Graded PVA Hydrogel using Simple Freeze-Thaw Method for Artificial Glenoid Labrum. Journal of the Mechanical Behavior of Biomedical Materials. doi:10.1016/j.jmbbm.2018.12.033 Gherman, S. P., Biliuță, G., Bele, A., Ipate, A. M., Baron, R. I., Ochiuz, L., Șpac, A. F., et al. (2023). Biomaterials Based on Chitosan and Polyvinyl Alcohol as a Drug Delivery System with Wound-Healing Effects. Gels, 9(2), 122. MDPI AG. Retrieved from http://dx.doi.org/10.3390/gels9020122 Simões, M. M. de S. G., & de Oliveira, M. G. (2010). Poly(vinyl alcohol) films for topical delivery of S-nitrosoglutathione: Effect of freezing-thawing on the diffusion properties. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 93B(2), 416–424. doi:10.1002/jbm.b.31598 Takamura, A., Ishii, F., & Hidaka, H. (1992). Drug release from poly(vinyl alcohol) gel prepared by freeze-thaw procedure. Journal of Controlled Release, 20(1), 21–27. doi:10.1016/0168-3659(92)90135-e Chang, C., Lue, A., & Zhang, L. (2008). Effects of Crosslinking Methods on Structure and Properties of Cellulose/PVA Hydrogels. Macromolecular Chemistry and Physics, 209(12), 1266–1273. doi:10.1002/macp.200800161 Li, H., & Xiao, R. (2021). Glass Transition Behavior of Wet Polymers. Materials (Basel, Switzerland), 14(4), 730. https://doi.org/10.3390/ma14040730 Li, L., Xu, X., Liu, L., Song, P., Cao, Q., Xu, Z., … Wang, H. (2021). Water governs the mechanical properties of poly(vinyl alcohol). Polymer, 213, 123330. doi:10.1016/j.polymer.2020.123330 Qiao, C., Ma, X., Zhang, J., & Yao, J. (2018). Effect of hydration on water state, glass transition dynamics and crystalline structure in chitosan films. Carbohydrate Polymers. doi:10.1016/j.carbpol.2018.11.045 Bunn, C. W. (1948). Crystal Structure of Polyvinyl Alcohol. Nature, 161(4102), 929–930. doi:10.1038/161929a0 Ricciardi, R., Auriemma, F., De Rosa, C., & Lauprêtre, F. (2004). X-ray Diffraction Analysis of Poly(vinyl alcohol) Hydrogels, Obtained by Freezing and Thawing Techniques. Macromolecules, 37(5), 1921–1927. doi:10.1021/ma035663q Drambei, P., Nakano, Y., Bin, Y., Okuno, T., & Matsuo, M. (2006). Characterization of PVA and Chitosan/PVA Blends Prepared from Aqueous Solutions of Various Na2SO4 Concentrations. Macromolecular Symposia, 242(1), 146–156. doi:10.1002/masy.200651022 Chung, F. H., & Scott, R. W. (1973). A new approach to the determination of crystallinity of polymers by X-ray diffraction. Journal of Applied Crystallography, 6(3), 225–230. doi:10.1107/s0021889873008514 Kawano, Y., Tanaka, Y., Hata, N., Yoshiike, Y., Nakajima, M., Yonemochi, E., & Ishihara, N. (2022). Swelling and Salt Formation in Ibuprofen and Tranexamic Acid-Containing Tablets during High-Temperature Storage. Crystals, 12(10), 1420. MDPI AG. Retrieved from http://dx.doi.org/10.3390/cryst12101420 El-Habeeb, A. A., & Refat, M. S. (2019). Synthesis, structure interpretation, antimicrobial and anticancer studies of tranexamic acid complexes towards Ga(III), W(VI), Y(III) and Si(IV) metal ions. Journal of Molecular Structure, 1175, 65–72. doi:10.1016/j.molstruc.2018.07.099 Yang, X., Dargaville, B., & Hutmacher, D. (2021). Elucidating the molecular mechanisms for the interaction of water with polyethylene glycol-based hydrogels: Influence of ionic strength and gel network structure. Polymers, 13(6), 845. https://doi.org/10.3390/polym13060845 Ritger, P. L., & Peppas, N. A. (1987). A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. Journal of Controlled Release, 5(1), 37–42. doi:10.1016/0168-3659(87)90035-6 Zhao, S. (2014). Osmotic pressure versus swelling pressure: Comment on “bifunctional polymer hydrogel layers as forward osmosis draw agents for continuous production of fresh water using solar energy”. Environmental Science & Technology, 48(7), 4212-4213. https://doi.org/10.1021/es5006994 Wang, H., Wei, J., & Simon, G. P. (2014). Response to osmotic pressure versus swelling pressure: Comment on “bifunctional polymer hydrogel layers as forward osmosis draw agents for continuous production of fresh water using solar energy”. Environmental Science & Technology, 48(7), 4214-4215. https://doi.org/10.1021/es5011016 Flory, P. J. (1953). Principles of polymer chemistry (19. print). Cornell Univ. Press. Ithaca, New York. pp. 434 - 451. Zmora, S., Glicklis, R., & Cohen, S. (2002). Tailoring the pore architecture in 3-D alginate scaffolds by controlling the freezing regime during fabrication. Biomaterials, 23(20), 4087–4094. doi:10.1016/s0142-9612(02)00146-1 Chhatri, A., Bajpai, J., Bajpai, A. K., Sandhu, S. S., Jain, N., & Biswas, J. (2011). Cryogenic fabrication of savlon loaded macroporous blends of alginate and polyvinyl alcohol (PVA). Swelling, deswelling and antibacterial behaviors. Carbohydrate Polymers, 83(2), 876–882. doi:10.1016/j.carbpol.2010.08.077 Gurikov, P., & Smirnova, I. (2018). Non-Conventional Methods for Gelation of Alginate. Gels (Basel, Switzerland), 4(1), 14. https://doi.org/10.3390/gels4010014 Kumar, A., & Gupta, R. K. (2018). Theory of rubber elasticity. En A. Kumar & R. K. Gupta, Fundamentals of Polymer Engineering (3.a ed., pp. 357-379). CRC Press. https://doi.org/10.1201/9780429398506-10 Schoof, H., Apel, J., Heschel, I., & Rau, G. (2001). Control of pore structure and size in freeze-dried collagen sponges. Journal of Biomedical Materials Research, 58(4), 352–357. doi:10.1002/jbm.1028 Schoof, H., Bruns, L., Fischer, A., Heschel, I., & Rau, G. (2000). Dendritic ice morphology in unidirectionally solidified collagen suspensions. Journal of Crystal Growth, 209(1), 122–129. doi:10.1016/s0022-0248(99)00519-9 Shapiro, L., & Cohen, S. (1997). Novel alginate sponges for cell culture and transplantation. Biomaterials, 18(8), 583–590. doi:10.1016/s0142-9612(96)00181-0 Lammens, J., Goudarzi, N. M., Leys, L., Nuytten, G., Van Bockstal, P. J., Vervaet, C., Boone, M. N., & De Beer, T. (2021). Spin Freezing and Its Impact on Pore Size, Tortuosity and Solid State. Pharmaceutics, 13(12), 2126. https://doi.org/10.3390/pharmaceutics13122126 Y. Sánchez-Cardona, C. E. Echeverri-Cuartas, M. E. Londoño López and N. Moreno-Castellanos, "Preparation and characterization of chitosan/gelatin /PVA scaffolds for tissue engineering application," 2021 IEEE 2nd International Congress of Biomedical Engineering and Bioengineering (CI-IB&BI), Bogota D.C., Colombia, 2021, pp. 1-4, doi: 10.1109/CI-IBBI54220.2021.9626060 Hong, K. H. (2016). Polyvinyl alcohol/tannic acid hydrogel prepared by a freeze-thawing process for wound dressing applications. Polymer Bulletin, 74(7), 2861–2872. doi:10.1007/s00289-016-1868-z Cascone, M. G., Lazzeri, L., Sparvoli, E., Scatena, M., Serino, L. P., & Danti, S. (2004). Morphological evaluation of bioartificial hydrogels as potential tissue engineering scaffolds. Journal of Materials Science: Materials in Medicine, 15(12), 1309–1313. doi:10.1007/s10856-004-5739-z Kenawy, E.-R., El-Newehy, M. H., & Al-Deyab, S. S. (2010). Controlled release of atenolol from freeze/thawed poly(vinyl alcohol) hydrogel. Journal of Saudi Chemical Society, 14(2), 237–240. doi:10.1016/j.jscs.2010.02.014 Bruschi, M. L. (2015). Mathematical models of drug release. En Strategies to Modify the Drug Release from Pharmaceutical Systems, 63–86. doi:10.1016/b978-0-08-100092-2.00005-9 Lane, L. B. (1925). Freezing Points of Glycerol and Its Aqueous Solutions. Industrial & Engineering Chemistry, 17(9), 924–924. doi:10.1021/ie50189a017 Bretz, K. J., Jobbágy, Á., & Bretz, K. (2010). Force measurement of hand and fingers. Biomechanica Hungarica. https://doi.org/10.17489/biohun/2010/1/07 Nkhwa, S., Kemal, E., Gurav, N., & Deb, S. (2019). Dual polymer networks: a new strategy in expanding the repertoire of hydrogels for biomedical applications. Journal of Materials Science: Materials in Medicine, 30(10). doi:10.1007/s10856-019-6316-9 Zhang, R., Zhao, W., Ning, F., Zhen, J., Qiang, H., Zhang, Y., Liu, F., & Jia, Z. (2022). Alginate Fiber-Enhanced Poly(vinyl alcohol) Hydrogels with Superior Lubricating Property and Biocompatibility. Polymers, 14(19), 4063. https://doi.org/10.3390/polym14194063 Szekalska, M., Sosnowska, K., Wróblewska, M., Basa, A., & Winnicka, K. (2022). Does the Freeze–Thaw Technique Affect the Properties of the Alginate/Chitosan Glutamate Gels with Posaconazole as a Model Antifungal Drug? International Journal of Molecular Sciences, 23(12), 6775. https://doi.org/10.3390/ijms23126775 Li, X., Shu, M., Li, H., Gao, X., Long, S., Hu, T., & Wu, C. (2018). Strong, tough and mechanically self-recoverable poly(Vinyl alcohol)/alginate dual-physical double-network hydrogels with large cross-link density contrast. RSC Advances, 8(30), 16674-16689. https://doi.org/10.1039/C8RA01302K Singh, R., Sood, N., Kerai, S., & Puri, A. (2017). Use of Merocel® aids in prevention of nasal pressure ulcers following nasal intubation: Case series of 33 patients. Indian journal of anaesthesia, 61(6), 513–515. https://doi.org/10.4103/ija.IJA_26_17 U.S. Food and Drug Administration (FDA). (2020). The device development process. FDA. https://www.fda.gov/patients/learn-about-drug-and-device-approvals/device-development-process Xu, Jian, et al. «Preparation and Characterization of Chitosan/Polyvinyl Porous Alcohol Aerogel Microspheres with Stable Physicochemical Properties». International Journal of Biological Macromolecules, vol. 187, septiembre de 2021, pp. 614-23. DOI.org (Crossref), https://doi.org/10.1016/j.ijbiomac.2021.07.127. Jipa, I., Stoica, A., Stroescu, M., Dobre, L.-M., Dobre, T., Jinga, S., & Tardei, C. (2012). Potassium sorbate release from poly(vinyl alcohol)-bacterial cellulose films. Chemical Papers, 66(2). Fernandes Queiroz, M., Melo, K., Sabry, D., Sassaki, G., & Rocha, H. (2014). Does the Use of Chitosan Contribute to Oxalate Kidney Stone Formation? Marine Drugs, 13(1), 141–158. doi:10.3390/md13010141 |
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Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Vallejo Díaz, Bibiana Margarita Rosad0ac0cbc2685cf4b90b0d2f35b7bf2ecCamargo Trujillo, Fabio Andrés73f331e0223771a49e64a8aec3e71bfaProcesos de Transformación de Materiales para la Industria Farmacéutica (PTM)2024-01-22T17:31:05Z2024-01-22T17:31:05Z2023https://repositorio.unal.edu.co/handle/unal/85394Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramas, fotografías, gráficosLos tapones nasales son sistemas de uso frecuente en el ámbito clínico, empleados usualmente para el control de sangrados nasales copiosos, o de difícil control. A pesar de su uso frecuente, las alternativas disponibles de este tipo de dispositivos suelen evidenciar inconvenientes asociados con la incomodidad del paciente, la nula contención del sangrado, la inducción de complicaciones como infección, y necrosis por sobrepresiones en el tejido mucoso de la cavidad nasal, entre las más referenciadas. En el presente estudio, se emplearon, el QbD (Quality by Design), y el AD (Diseño Axiomático), como metodologías de diseño para el planteamiento de una nueva alternativa de tipo tapón nasal, que busca resolver los problemas que atañen con mayor frecuencia al uso de estos dispositivos. De esta manera, se abarcó el diseño y desarrollo, desde etapas primarias (identificación de necesidades y atributos de usuario mediante encuestas sobre las características de uso, y problemas recurrentes en el uso de tapones nasales), planteando un desarrollo conceptual que involucró la definición del perfil objetivo de producto, sus especificaciones, atributos funcionales, y requerimientos materiales y de proceso. Consecuentemente se planteó el desarrollo de un prototipo funcional bimodular. Conformado por un módulo interno, el cual consta de un sistema monolítico de forma cilíndrica con terminación en punta cónica, con la virtud de hincharse de manera controlada y reversible, para facilitar el control del sangrado mediante contención mecánica. Sobre este módulo con características de esponja obtenida por liofilización, se evaluó la respuesta al hinchamiento, y contracción por exposición a agua purificada y soluciones saturadas de cloruro de calcio; como respuesta a la proporción de los polímeros presentes en el mismo (polivinil alcohol (PVA), y alginato de sodio (SA)). La concentración de la mezcla de los polímeros en la solución de trabajo a partir del cual se obtuvieron los sistemas (variable entre el 5%w/w y el 15%w/w), y el número de ciclos de congelamiento y descongelamiento mediante el uso de nitrógeno líquido, fueron estudiados como mecanismo para alcanzar un sistema con adecuada integridad estructural. De manera análoga, se propuso el desarrollo de un segundo módulo, con características de película delgada, capaz de entregar de manera controlada un fármaco hemostático (ácido tranexámico), con la facultad de resistir deformaciones evidenciando un comportamiento elástico, y con baja porosidad superficial. Sobre este sistema se determinó la influencia que tenían sobre las propiedades mecánicas del sistema, variables como la proporción de los polímeros componentes (polivinil alcohol, y quitosano), la concentración de agente plastificante (glicerina entre el 2%w/w y el 8%w/w), y el número de ciclos de congelamiento por exposición a nitrógeno líquido, y su posterior descongelamiento; proceso empleado como mecanismo para la obtención de sistemas con adecuadas propiedades mecánicas, caracterizando propiedades que influyen en esta respuesta, desde su perfil calorimétrico, espectro infrarrojo, y morfología. La evaluación de ambos módulos fue ejecutada empleando un diseño experimental compuesto rotable, que permitió identificar superficies de respuesta que, para el caso del módulo interno, la variable de mayor incidencia sobre el hinchamiento fue la concentración de los polímeros en la solución de trabajo, la cual determina el tamaño de poro de los sistemas (sistemas microporosos). Así mismo, se identificó que la recuperación del hinchamiento es conducida principalmente por la inducción de fenómenos de entrecruzamiento físico asociados a la interacción de las cadenas de alginato de sodio, con los cationes divalentes del cloruro de calcio. Para el caso del módulo externo, se determinó que, el aumento en la proporción de PVA, las bajas concentraciones de glicerina en la formulación, y un alto número de ciclos de congelamiento y descongelamiento, son factores que pueden actuar como promotores de la formación de nodos cristalinos favoreciendo la formación de regiones de entrecruzamiento polimérico, que aumentaron la resistencia a la fractura de los productos obtenidos. Congruentemente, se corroboró la ausencia de poros superficiales atribuido a las condiciones de secado, y al uso de nitrógeno líquido como sistema de congelamiento. Esto permitió ampliar el espacio de conocimiento disponible actualmente, concerniente a la expresión de propiedades mecánicas de sistemas compuestos de PVA (89-98 KDa) y quitosano (Bajo peso molecular), fabricados por ciclos de congelamiento y descongelamiento alcanzados por exposición a nitrógeno líquido, posicionándose como una matriz de composición y diseño originales, con respecto a las películas poliméricas publicadas hasta el momento. Finalmente, se evaluó el desempeño global del dispositivo, ensamblando módulos con las variables de estudio optimizadas: módulo interno (proporción PVA:SA - 30:70; número de ciclos de congelamiento y descongelamiento - 4; concentración de la mezcla de polímeros en la solución de trabajo - 10%w/w); módulo externo (proporción PVA:CH - 80:20; número de ciclos de congelamiento y descongelamiento - 3; concentración de glicerina en la formulación - 8%w/w). A partir de estas, se obtuvo un prototipo sobre el que se identificaron, la cinética de liberación de ácido tranexámico, señalando un comportamiento bimodal, que incluye la liberación de cerca del 25% del fármaco cargado en los primeros 15 minutos; así como la liberación sostenida a lo largo de 48 horas del fármaco remanente; las propiedades de hinchamiento en las condiciones de uso previstas, evidenciando una capacidad de hinchamiento dependiente de la cantidad de agua inyectada, alcanzando un hinchamiento volumétrico global del 181,5% con respecto a su volumen inicial al inyectar 10 mL de agua purificada y sus propiedades de rigidez y resistencia a la fatiga, representando un comportamiento idóneo para el cumplimiento de su funciones, a partir de la comparación con los datos existentes en literatura referentes a tapones nasales convencionales. De manera general, se presenta como producto, la obtención de un sistema bimodular capaz de expresar propiedades mecánicas, de hinchamiento, y liberación de fármaco hemostático, con idóneo potencial para ser utilizado en el tratamiento de sangrados nasales de difícil manejo, cuyo diseño plantea una alternativa para la resolución de un grupo de problemas recurrentes en episodios de epistaxis de difícil control. (Texto tomado de la fuente)Nasal packs are frequently used medical devices in the clinical setting, usually employed to control ample or tough-to-control nosebleeds. Despite its frequent use, the alternatives available for this type of device tend to show drawbacks associated with patient discomfort, lack of efficient containment of bleeding, as well as induction of complications such as infection, necrosis due to overpressure in the mucous tissue of the nasal cavity, among the most commonly reported. By means of this study, QbD (Quality by Design) and AD (Axiomatic Design) were handled as design methodologies to engage a new nasal pack alternative, which seeks to solve the problems that most frequently concern the use of this kind of device. Thus, the design and development were covered, from the primary stages (identification of user needs and attributes through surveys on the regular use, and recurring problems in the use of nasal packs), proposing a conceptual approach that involved the definition of the Target Product Profile, its specifications, functional attributes, and material and process requirements and controls. Consequently, the development of a bimodular functional prototype was proposed. Made up of an internal matrix, which consists of a monolithic cylindrical system with a conical tip ending, which exhibits swelling behavior in a controlled and reversible fashion, to facilitate bleeding control through mechanical containment. In this module, which comprises sponge characteristics obtained by lyophilization, the response to swelling and contraction by exposure to purified water and saturated solutions of calcium chloride was evaluated; as an outcome subjected to the proportion of polymers present in it (Poly (vinyl alcohol) (PVA), and sodium alginate (SA)). The concentration of the mixture of the polymers in the whole formulation, from which the systems were obtained (variable between 5%w/w and 15%w/w), and the number of cycles of freezing and thawing by using liquid nitrogen, were studied as mechanisms to achieve a system with proper structural integrity. Similarly, the development of a second module was proposed, with thin film features, capable of delivering a haemostatic drug (tranexamic acid) in a controlled way, with the ability to resist deformations, evidencing elastic behavior, and with low surface porosity. In this system, the influence the critical variables of process, and composition had on the mechanical properties of the system was determined, those variables were, the proportion of the compositional polymers (polyvinyl alcohol, and chitosan), the concentration of plasticizing agent (glycerin between 2%w/w and 8%w/w), and freezing cycles number due to exposure to liquid nitrogen, and its subsequent thawing. Some mechanical properties (young modulus, and tensile strength), were characterized along with the understanding of this response, achieved by recognizing of the calorimetric profile, infrared spectrum, and morphological appearance. Both module's assessment was carried out using a circumscribed central composite experimental design, which allowed the identification of surface responses, on which, it was determined that in the case of the internal matrix, the variable with the highest incidence on swelling, was the concentration of the polymers in the whole formulation, which determines the systems pore size. Likewise, it was identified that the recovery from swelling is mainly driven by the induction of physical crosslinking phenomena associated with the interaction of the sodium alginate chains with the divalent cations from calcium chloride. In the case of the external matrix, it was determined that increases in the proportion of PVA, low concentrations of glycerin in the formulation, and a high number of freezing and thawing cycles are factors that can serve as promoters on the formation of crystalline nodes auspicing polymeric crosslinking regions, which increased the films breaking strength. Congruently, the absence of surface pores attributed to the drying conditions and the use of liquid nitrogen as a freezing system was corroborated. This allowed the expansion of the currently available knowledge space, concerning the expression of mechanical properties of systems composed of PVA (89-98 KDa) and chitosan (Low molecular weight), manufactured by freezing and thawing cycles achieved by exposure to liquid nitrogen. displaying as a matrix of original composition and design, regarding to the polymeric films published to this date. Finally, the device global performance was assessed, assembling matrices with the optimized study variables: Internal matrix (PVA:SA ratio - 30:70; Number of freeze-thawing cycles - 4; Concentration of the polymer mixture in the whole system - 10%w/w); external matrix (PVA:CH Ratio - 80:20; number of freeze-thaw cycles - 3; glycerin concentration in the formulation - 8%w/w). From these, a prototype was obtained on which the release kinetics of tranexamic acid were identified, indicating a bimodal behavior, which includes the release of about 25% of the loaded drug in the first 15 minutes; as well as the sustained release over 48 hours of the remaining drug; the swelling properties under the expected conditions of use, evidencing a swelling capacity dependent on the amount of water injected, reaching an overall volumetric swelling of 181.5% with respect to its initial volume when injecting 10 mL of purified water, and its properties of stiffness and fatigue, representing ideal behavior for the fulfillment of its functionality. In general, it is presented as a product, obtained from a bimodular system able to express mechanical behavior, swelling, and release of hemostatic drug, with optimal potential to be used in the management of epistaxis, whose design fulfills a set of recurring problems in the treatment of difficult-to-control episodes of epistaxis, positioning itself as a potential alternative for the treatment of this condition.MaestríaMagíster en Ciencias Farmacéuticas106 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Ciencias FarmacéuticasFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá615 - Farmacología y terapéuticaPolímerosQuitosanoAntifibrinolíticosÁcido tranexámicoHemostáticosDiseño de Dispositivos MédicosAlginatosRecursos Materiales en SaludMateriales Biocompatibles-químicaPolymersChitosanAntifibrinolytic AgentsHemostaticsAlginatesMaterial Resources in HealthBiocompatible Materials-chemistryTapón nasalPoli (vinil alcohol)QuitosanoAlginato de sodioCongelamiento-descongelamientoÁcido tranexámicoQuality by DesignNasal packPoly (vinyl alcohol)ChitosanSodium AlginateFreeze-ThawingTranexamic AcidDesarrollo de un dispositivo médico combinado con actividad hemostática tipo tapón nasal a partir del concepto de arquitectura modularDevelopment of a nasal pack combined medical device with hemostatic activity based on the concept of modular architectureTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMColombiaKucik, C. J., & Clenney, T. L. (2005). Management of Epistaxis. American Family Physician, 71(2), 305-311. https://www.aafp.org/afp/2005/0115/p305.htmlTunkel, D. E., Anne, S., Payne, S. C., Ishman, S. L., Rosenfeld, R. M., Abramson, P. J., Alikhaani, J. D., Benoit, M. M., Bercovitz, R. S., Brown, M. D., Chernobilsky, B., Feldstein, D. A., Hackell, J. M., Holbrook, E. H., Holdsworth, S. M., Lin, K. W., Lind, M. M., Poetker, D. M., Riley, C. A., … Monjur, T. M. (2020). Clinical practice guideline: Nosebleed(Epistaxis). Otolaryngology–Head and Neck Surgery, 162(1_suppl), S1-S38. https://doi.org/10.1177/0194599819890327Tobón, D., Jaramillo, L. A., Mejía, C., Quijano, D. (2016). Guía del manejo de Epistaxis. Asociación Colombiana de Otorrinolaringología. Guías ACORL para el manejo de las patologías más frecuentes en Otorrinolaringología (pp. 135-138). Recuperado de: https://www.acorl.org.co/resources/imagenes/visitante/medico/apoyo-al-ejercicio-profesional/guias-acorl/Epixtasis.pdfEvans, A. S., Young, D., & Adamson, R. (2004). Is the nasal tampon a suitable treatment for epistaxis in Accident & Emergency? A comparison of outcomes for ENT and A&E packed patients. The Journal of Laryngology & Otology, 118(01). doi:10.1258/002221504322731556ISO, International Standard. (2016). ISO 1385: Medical devices: Quality management systems. Requirements for regulatory purposes. Recuperado de: http://www.bonnier.net.cn/download/d_20170812100731.pdfGibson, M., Carmody, A., Weaver, R. (2018). Development and Manufacture of Drug Product. En: "Pharmaceutical Quality by Design: A Practical Approach". Editado por: W. S. Schlindwein, M. Gibson. Ed. John Wiley & Sons Ltd, Hoboken, USA. Vol. I. pp. 117-154.Suh, N. P. (2001). Axiomatic design: Advances and applications (pp. 1-51). New York: Oxford University Press.Aguwa, C. C., Monplaisir, L., Sylajakumari, P. A., & Muni, R. K. (2010). Integrated Fuzzy-Based Modular Architecture for Medical Device Design and Development. Journal of Medical Devices, 4(3), 031007. doi:10.1115/1.4002323Salhieh, S. M., & Kamrani, A. K. (1999). Macro level product development using design for modularity. Robotics and Computer-Integrated Manufacturing, 15(4), 319–329. doi:10.1016/s0736-5845(99)00008-3Hernández V., M., Hernández A., C., & Bergeret V., J. P. (2005). Epistaxis: Consideraciones generales y manejo clínico. Cuadernos de Cirugía, 19(1), 54-59. https://doi.org/10.4206/cuad.cir.2005.v19n1-09Beule, A. G. (2011). Physiology and pathophysiology of respiratory mucosa of the nose and the paranasal sinuses. GMS Current Topics in Otorhinolaryngology, Head and Neck Surgery, 9, Doc07. https://doi.org/10.3205/cto000071Fatakia, A., Winters, R., Amedee, R.G. (2010). Epistaxis: A Common Problem. The Ochsner Journal, 10, 176–178.INTEGRATE (The UK ENT Trainee Research Network). (2020). Nasal packs for epistaxis: Predictors of success. Clinical Otolaryngology: Official Journal of ENT-UK ; Official Journal of Netherlands Society for Oto -Rhino-Laryngology & Cervico-Facial Surgery, 45(5), 659-666. https://doi.org/10.1111/coa.13555Moumoulidis, I., Draper, M. R., Patel, H., Jani, P., & Price, T. (2006). A prospective randomised controlled trial comparing Merocel and Rapid Rhino nasal tampons in the treatment of epistaxis. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery, 263(8), 719–722. https://doi.org/10.1007/s00405-006-0047-5Murray, S., Mendez, A., Hopkins, A., El-Hakim, H., Jeffery, C. C., & Côté, D. W. J. (2018). Management of Persistent Epistaxis Using Floseal Hemostatic Matrix vs. traditional nasal packing: A prospective randomized control trial. Journal of Otolaryngology - Head & Neck Surgery = Le Journal D’oto-Rhino-Laryngologie Et De Chirurgie Cervico-Faciale, 47(1), 3. https://doi.org/10.1186/s40463-017-0248-5Valtonen, O., Ormiskangas, J., Kivekäs, I., Rantanen, V., Dean, M., Poe, D., Järnstedt, J., Lekkala, J., Saarenrinne, P., & Rautiainen, M. (2020). Three-dimensional printing of the nasal cavities for clinical experiments. Scientific Reports, 10(1), 502. https://doi.org/10.1038/s41598-020-57537-2Weber, R. (2009). Nasentamponaden und Stents. Laryngo-Rhino-Otologie, 88(S 01), S139-S155. https://doi.org/10.1055/s-0028-1119504UpToDate. (2023). Anatomy of the medial nasal wall. Recuperado de: https://www.uptodate.com/contents/image?imageKey=PC%2F54180MedScape. (2022). Anterior nasal packing for epistaxis: Overview, technique, preparation. Recuperado de: https://emedicine.medscape.com/article/80526-overviewWidmer-von-Brugg, G.M., Brugg, A.G., Probst, R. (2007). Patientenkomfort bei postoperativer Nasentamponade: frühe (8h) versus späte (24h) Detamponade. Inaugural-Dissertation zur Erlangung der Doktorwürde der Medizinischen Fakultät der Universität Zürich. Recuperado de: https://www.uzh.ch/orl/publications/dissertations/diss_Widmer_Gian-Marco.pdfBeule, A. G., Weber, R. K., Kaftan, H., & Hosemann, W. (2004). Übersicht: Art und Wirkung geläufiger Nasentamponaden. Laryngo-Rhino-Otologie, 83(8), 534–551.Iqbal, I. Z., Jones, G. H., Dawe, N., Mamais, C., Smith, M. E., Williams, R. J., Carrie, S. (2017). Intranasal packs and haemostatic agents for the management of adult epistaxis: systematic review. The Journal of Laryngology & Otology, 131(12), 1065–1092. doi:10.1017/s0022215117002055Thomas, I., Thekkethil, J. S., Kapoor, R. C., Thomas, T., & Thomas, P. (2018). A novel technique of using sponge as post-operative nasal packing. Bengal Journal of Otolaryngology and Head Neck Surgery, 26(1), 23-28. Recuperado de: https://bjohns.in/journal/index.php/bjohns/article/view/368Wang, Y. P., Wang, M. C., Chen, Y. C., Leu, Y. S., Lin, H. C., & Lee, K.-S. (2011). The effects of Vaseline gauze strip, Merocel, and Nasopore on the formation of synechiae and excessive granulation tissue in the middle meatus and the incidence of major postoperative bleeding after endoscopic sinus surgery. Journal of the Chinese Medical Association, 74(1), 16–21. doi:10.1016/j.jcma.2010.09.001Acıoğlu, E., Edizer, D. T., Yiğit, Ö., Onur, F., & Alkan, Z. (2011). Nasal septal packing: which one? European Archives of Oto-Rhino-Laryngology, 269(7), 1777–1781. doi:10.1007/s00405-011-1842-1Akbari, E., Philpott, C. M., Ostry, A. J., Clark, A., & Javer, A. R. (2012). A double-blind randomised controlled trial of gloved versus ungloved merocel middle meatal spacers for endoscopic sinus surgery. Rhinology Journal, 50(3), 306-310. https://doi.org/10.4193/Rhin11.215Medtronic. (2021). ENT Product Catalog. Recuperado de: https://asiapac.medtronic.com/content/dam/medtronic-com/products/ear-nosethroat/documents/ent-product-catalog.pdfGabay, M. (2006). Absorbable hemostatic agents. American Journal of Health-System Pharmacy, 63(13), 1244–1253. doi:10.2146/ajhp060003Wang, J., Cai, C., & Wang, S. (2014). Merocel versus nasopore for nasal packing: A metaanalysis of randomized controlled trials. PLOS ONE, 9(4), e93959. https://doi.org/10.1371/journal.pone.0093959Selvarajah, J., Busra, M. F. M., Saim, A. B., Hj Idrus, R. B., & Lokanathan, Y. (2020). Development and Physicochemical Analysis of Genipin-Crosslinked Gelatine Sponge as a Potential Resorbable Nasal Pack. Journal of Biomaterials Science, Polymer Edition, 1–14. doi:10.1080/09205063.2020.1774841Shikani, A., & Chahine, K. (2009). Chitosan-coated nasal packing in recalcitrant epistaxis. Otolaryngology - Head and Neck Surgery, 141(3), P109–P109. doi:10.1016/j.otohns.2009.06.341Taulu, R. (2020). A Comparison of Drug-Eluting Stent and Intranasal Corticosteroid Spray in the Treatment of Chronic Rhinosinusitis. Tampere University Dissertations (331). Recuperado de: https://trepo.tuni.fi/bitstream/handle/10024/123745/978-952-03-1745-4.pdf?sequence=2Adriaensen, G. F. J. P. M., Lim, K.-H., & Fokkens, W. J. (2017). Safety and efficacy of a bioabsorbable fluticasone propionate-eluting sinus dressing in postoperative management of endoscopic sinus surgery: a randomized clinical trial. International Forum of Allergy & Rhinology, 7(8), 813–820. doi:10.1002/alr.21963Tamer, T. M., Sabet, M. M., Omer, A. M., Abbas, E., Eid, A. I., Mohy-Eldin, M. S., & Hassan, M. A. (2021). Hemostatic and antibacterial PVA/Kaolin composite sponges loaded with penicillin–streptomycin for wound dressing applications. Scientific Reports, 11(1), 3428. https://doi.org/10.1038/s41598-021-82963-1Landsman, T. L., Touchet, T., Hasan, S. M., Smith, C., Russell, B., Rivera, J., Maitland, D. J., & Cosgriff-Hernandez, E. (2017). A shape memory foam composite with enhanced fluid uptake and bactericidal properties as a hemostatic agent. Acta Biomaterialia, 47, 91-99. https://doi.org/10.1016/j.actbio.2016.10.008Campacci, F., Vicini, C., Ciuti G. & Ricotti, L. (2021). RhinoFit: A Bionic Nasal Device for Mitigating Post-Operative Complications After Rhinosurgery. IEEE Transactions on Medical Robotics and Bionics. 3 (2), 297-305. doi: 10.1109/TMRB.2021.3063852Friedland, Y., Bagot d'Arc, M. B. D., Ha, J., & Delin, C. (2022). The Use of Self-Assembling Peptides (PuraStat™ ) in Functional Endoscopic Sinus Surgery for Haemostasis and Reducing Adhesion Formation. A Case Series of 94 Patients. Surgical technology international, 41,sti41/1594. Advance online publication. https://doi.org/10.52198/22.STI.41.GS1694Lee, M. F., Ma, Z., & Ananda, A. (2017). A novel haemostatic agent based on self-assembling peptides in the setting of nasal endoscopic surgery, a case series. International journal of surgery case reports, 41, 461–464. https://doi.org/10.1016/j.ijscr.2017.11.024Kar, M., Cetinkaya, E. A., & Konşuk-Ünlü, H. (2022). Comparison of the ankaferd blood stopper tampon and the merocel nasal tampon after septoplasty surgery. Aesthetic Plastic Surgery. https://doi.org/10.1007/s00266-022-03031-1Jimenez-Martin, J., Las Heras, K., Etxabide, A., Uranga, J., de la Caba, K., Guerrero, P., Igartua, M., Santos-Vizcaino, E., & Hernandez, R. M. (2022). Green hemostatic sponge-like scaffold composed of soy protein and chitin for the treatment of epistaxis. Materials Today Bio, 15, 100273. https://doi.org/10.1016/j.mtbio.2022.100273Li, M., Pan, G., Yang, Y., & Guo, B. (2023). Smart aligned multi-layered conductive cryogels with hemostasis and breathability for coagulopathy epistaxis, nasal mucosal repair and bleeding monitoring. Nano Today, 48, 101720. https://doi.org/10.1016/j.nantod.2022.101720Sasmal, P., & Datta, P. (2019). Tranexamic acid-loaded chitosan electrospun nanofibers as drug delivery system for hemorrhage control applications. Journal of Drug Delivery Science and Technology, 52, 559-567. https://doi.org/10.1016/j.jddst.2019.05.018Tran, Q. K., Rehan, M. A., Haase, D. J., Matta, A., & Pourmand, A. (2020). Prophylactic antibiotics for anterior nasal packing in emergency department: A systematic review and meta-analysis of clinically-significant infections. The American Journal of Emergency Medicine, 38(5), 983-989. https://doi.org/10.1016/j.ajem.2019.11.037Lange, J. L., Peeden, E. H., & Stringer, S. P. (2017). Are prophylactic systemic antibiotics necessary with nasal packing? A systematic review. American Journal of Rhinology & Allergy, 31(4), 240-247. https://doi.org/10.2500/ajra.2017.31.4454Schouten, E. S., van de Pol, A. C., Schouten, A. N. J., Turner, N. M., Jansen, N. J. G., & Bollen, C. W. (2009). The effect of aprotinin, tranexamic acid, and aminocaproic acid on blood loss and use of blood products in major pediatric surgery: A meta-analysis. Pediatric Critical Care Medicine, 10(2), 182–190.Akkan, S., Çorbacıoğlu, Ş. K., Aytar, H., Emektar, E., Dağar, S., & Çevik, Y. (2019). Evaluating effectiveness of nasal compression with tranexamic acid compared with simple nasal compression and merocel packing: A randomized controlled trial. Annals of Emergency Medicine, 74(1), 72-78. https://doi.org/10.1016/j.annemergmed.2019.03.030U.S. Food and Drug Administration (2018). Overview of regulatory requirements: Medical devices - transcript. FDA. https://www.fda.gov/training-and-continuing-education/cdrh-learn/overview-regulatory-requirements-medical-devices-transcriptMinisterio de Salid y Protección Social. (2013). ABC de Dispositivos Médicos. Recuperado de: https://www.invima.gov.co/documents/20143/442916/abc_dispositivos-medicos.pdf/d32f6922-0c50-bcaa-6b53-066edfb98274U.S. Food and Drug Administration (2022). Principles of Premarket Pathways for Combination Products. Guidance for Industry and FDA Staff. Recuperado de: https://www.fda.gov/media/119958/downloadAntich-Isern, P., Caro-Barri, J., & Aparicio-Blanco, J. (2021). The combination of medical devices and medicinal products revisited from the new European legal framework. International Journal of Pharmaceutics, 607, 120992. doi:10.1016/j.ijpharm.2021.120992Bodenberger, N., Kubiczek, D., Abrosimova, I., Scharm, A., Kipper, F., Walther, P., & Rosenau, F. (2016). Evaluation of methods for pore generation and their influence on physio-chemical properties of a protein based hydrogel. Biotechnology Reports, 12, 6–12. doi:10.1016/j.btre.2016.09.001Redaelli, F., Sorbona, M., & Rossi, F. (2017). Synthesis and processing of hydrogels for medical applications. Bioresorbable Polymers for Biomedical Applications, 205–228. doi:10.1016/b978-0-08-100262-9.00010-0Udenni-Gunathilake, T. M. S., Ching, Y. C., Ching, K. Y., Chuah, C. H., & Abdullah, L. C. (2017). Biomedical and Microbiological Applications of Bio-Based Porous Materials: A Review. Polymers, 9(5), 160. https://doi.org/10.3390/polym9050160Joardder, M. U. H., Karim, A., Kumar, C., & Brown, R. J. (2016). Porosity. SpringerBriefs in Food, Health, and Nutrition. doi:10.1007/978-3-319-23045-0Ganji, F., Vasheghani-Farahani, S., Vasheghani-Farahani, E. (2010). Theoretical Description of Hydrogel Swelling: A Review. Iranian Polymer Journal 19(5). 375-398.Drozdov, A. D., & deClaville Christiansen, J. (2015). Modeling the effects of pH and ionic strength on swelling of polyelectrolyte gels. The Journal of Chemical Physics, 142(11), 114904. doi:10.1063/1.4914924Borges, F. T. P., Papavasiliou, G., & Teymour, F. (2020). Characterizing the Molecular Architecture of Hydrogels and Crosslinked Polymer Networks beyond Flory–Rehner—I. Theory. Biomacromolecules, 21(12), 5104–5118. doi:10.1021/acs.biomac.0c01256Korsmeyer, R. W., Von Meerwall, E., & Peppas, N. A. (1986). Solute and penetrant diffusion in swellable polymers. II. Verification of theoretical models. Journal of Polymer Science Part B: Polymer Physics, 24(2), 409–434. doi:10.1002/polb.1986.090240215Aguilar M. R. & San Román J. (2019). Polymers pH-responsive polymers: properties, synthesis and applications. En: “Smart and their Applications.” Woodhead Publishing Ltd., Cambridge, UK. pp. 45-66,240-254.Young, R. J ., & Lovell, P. A. (1991). Introduction to Polymers. 2nd Edition. Springer Science+Business Media B.V. Hong Kong. pp. 310-318.Boardman, P. (2020). Modelling the Mechanical Properties of Hydrogel. iGEM 2020, Boston, E.E.U.U.Afghan, N., (2016) Mechanical Properties of Poly (vinyl alcohol) Based Blends and Composites. Electronic Thesis and Dissertation Repository. 3746. The University of Western Ontario, London, Canadá. Recuperado de: https://ir.lib.uwo.ca/cgi/viewcontent.cgi?article=5353&context=etdStauffer, S. R., & Peppas, N. A. (1992). Poly(Vinyl alcohol) hydrogels prepared by freezing thawing cyclic processing. Polymer, 33(18), 3932-3936. https://doi.org/10.1016/0032-3861(92)90385-ALiu, X., Steiger, C., Lin, S., Parada, G. A., Liu, J., Chan, H. F., Yuk, H., Phan, N. V., Collins, J., Tamang, S., Traverso, G., & Zhao, X. (2019). Ingestible hydrogel device. Nature Communications, 10(1), 493. https://doi.org/10.1038/s41467-019-08355-2Okay, O. (Ed.). (2014). Polymeric cryogels: Macroporous gels with remarkable properties (Vol. 263). Springer International Publishing. https://doi.org/10.1007/978-3-319-05846-7Willcox, P. J., Howie, D. W., Schmidt-Rohr, K., Hoagland, D. A., Gido, S. P., Pudjijanto, S., … Venkatraman, S. (1999). Microstructure of poly(vinyl alcohol) hydrogels produced by freeze/thaw cycling. Journal of Polymer Science Part B: Polymer Physics, 37(24), 3438–3454. doi:10.1002/(sici)1099-0488(19991215)37:24<3438::aid-polb6>3.0.co;2-9Ricciardi, R., Auriemma, F., Gaillet, C., De Rosa, C., & Lauprêtre, F. (2004). Investigation of the Crystallinity of Freeze/Thaw Poly(vinyl alcohol) Hydrogels by Different Techniques. Macromolecules, 37(25), 9510–9516. doi:10.1021/ma048418vLozinsky, V.I., Vainerman, E.S., Domotenko, L.V. (1986). Study of cryostructurization of polymer systems VII. Structure formation under freezing of poly(vinyl alcohol) aqueous solutions. Colloid & Polymer Sci 264, 19–24. https://doi.org/10.1007/BF01410304Damshkaln, L. G., Simenel, I. A., & Lozinsky, V. I. (1999). Study of cryostructuration of polymer systems. XV. Freeze-Thaw-induced formation of cryoprecipitate matter from low-concentrated aqueous solutions of poly(vinyl alcohol). Journal of Applied Polymer Science, 74(8), 1978–1986. doi:10.1002/(sici)1097-4628(19991121)74:8<1978::aid-app11>3.0.co;2-lAuriemma, F., De Rosa, C., & Triolo, R. (2006). Slow Crystallization Kinetics of Poly(vinyl alcohol) in Confined Environment during Cryotropic Gelation of Aqueous Solutions. Macromolecules, 39(26), 9429–9434. doi:10.1021/ma061955qHassan, C. M., & Peppas, N. A. (2000). Structure and morphology of freeze/thawed pva hydrogels. Macromolecules, 33(7), 2472-2479. https://doi.org/10.1021/ma9907587Hickey, A. S., & Peppas, N. A. (1995). Mesh size and diffusive characteristics of semicrystalline poly(vinyl alcohol) membranes prepared by freezing/thawing techniques. Journal of Membrane Science, 107(3), 229–237. doi:10.1016/0376-7388(95)00119-0Qian, L., & Zhang, H. (2010). Controlled freezing and freeze drying: a versatile route for porous and micro-/nano-structured materials. Journal of Chemical Technology & Biotechnology, 86(2), 172–184. doi:10.1002/jctb.2495Coria-Hernández, J., Méndez-Albores, A., Meléndez-Pérez, R., Rosas-Mendoza, M., & Arjona-Román, J. (2018). Thermal, Structural, and Rheological Characterization of Waxy Starch as a Cryogel for Its Application in Food Processing. Polymers, 10(4), 359. doi:10.3390/polym10040359Fukumori, T., & Nakaoki, T. (2014). High-tensile-strength polyvinyl alcohol films prepared from freeze/thaw cycled gels. Journal of Applied Polymer Science, 131(15), n/a–n/a. doi:10.1002/app.40578Chee, B. S., de Lima, G. G., Devine, D. M., & Nugent, M. J. D. (2018). Investigation of the effects of orientation on freeze/thawed Polyvinyl alcohol hydrogel properties. Materials Today Communications. doi:10.1016/j.mtcomm.2018.08.005Kim, T. H., An, D. B., Oh, S. H., Kang, M. K., Song, H. H., & Lee, J. H. (2015). Creating stiffness gradient polyvinyl alcohol hydrogel using a simple gradual freezing–thawing method to investigate stem cell differentiation behaviors. Biomaterials, 40, 51–60. doi:10.1016/j.biomaterials.2014.11.017Isa, I. Classifying physical models and prototypes in the design process (s.f.). Norwegian University of Science and Technology. Recuperado de: https://www.ntnu.no/documents/10401/1264433962/SitiArtikkel.pdf/e39fd03a-de17-4a13-97c6-19fadfda49e0#:~:text=An%20analytical%20prototype%20is%20a,similar%20to%20the%20final%20product.Kiemle Trindade, I. E., Oliveira Camargo Gomes, A. de, Martins Sampaio-Teixeira, A. C., & Kiemle Trindade, S. H. (2007). Adult nasal volumes assessed by acoustic rhinometry. Brazilian Journal of Otorhinolaryngology, 73(1), 32-39. https://doi.org/10.1016/S1808-8694(15)31119-8Kjærgaard, T., Cvancarova, M., & Steinsvåg, S. K. (2009). Relation of nasal air flow to nasal cavity dimensions. Archives of Otolaryngology–Head & Neck Surgery, 135(6), 565. https://doi.org/10.1001/archoto.2009.50Samoliński, B. K., Grzanka, A., & Gotlib, T. (2007). Changes in nasal cavity dimensions in children and adults by gender and age. The Laryngoscope, 117(8), 1429–1433. https://doi.org/10.1097/MLG.0b013e318064e837Araújo, L. L. de, Silva, A. S. C. da, Araújo, B. M. A. M., Yamashita, R. P., Trindade, I. E. K., & Fukushiro, A. P. (2016). Dimensões nasofaríngeas em indivíduos sem anomalias craniofaciais: Dados normativos. CoDAS, 28(4), 403-408. https://doi.org/10.1590/2317-1782/20162015020R. Stone and K. Wood, Development of a Functional Basis for Design, Journal of Mechanical Design, vol. 122, no. 4, pp. 359-370, (2000).Camargo-Trujillo, F.A., Rincon-Duarte, O.F., Barbosa H., Vallejo, B. (2020). Aplicación del Diseño Axiomático y Quality by Design (QbD) en el Diseño de un Prototipo Analítico, para un Dispositivo Hemostático Intranasal. Trabajo de Grado, pregrado. Universidad Nacional de Colombia, Bogotá, Colombia.Nguyen, Q. (2022). Epistaxis: Otolaryngology and Facial Plastic Surgery. Medscape. Recuperado de: https://emedicine.medscape.com/article/863220-overview#a3.Leadon, M., & Hohman, M. H. (2023). Posterior epistaxis nasal pack. StatPearls Publishing. Recuperado de: http://www.ncbi.nlm.nih.gov/books/NBK576436/Vallejo Díaz, B. M., Perilla, J. E. (2008). Elementos conceptuales para estudiar el comportamiento bioadhesivo en polímeros, Rev. Colomb. Cienc. Quím. Farm. 37(1)Pendolino, A. L., Scarpa, B., & Ottaviano, G. (2019). Relationship Between Nasal Cycle, Nasal Symptoms and Nasal Cytology. American journal of rhinology & allergy, 33(6), 644–649. https://doi.org/10.1177/1945892419858582Joseph, J., Martinez-Devesa, P., Bellorini, J., & Burton, M. J. (2018). Tranexamic acid for patients with nasal haemorrhage (epistaxis). The Cochrane database of systematic reviews, 12(12), CD004328. https://doi.org/10.1002/14651858.CD004328.pub3Picetti, R., Shakur-Still, H., Medcalf, R. L., Standing, J. F., & Roberts, I. (2019). What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies. Blood Coagulation & Fibrinolysis, 30(1), 1–10. doi:10.1097/mbc.0000000000000789Beer, H. L., Duvvi, S., Webb, C. J., & Tandon, S. (2005). Blood loss estimation in epistaxis scenarios. The Journal of Laryngology & Otology, 119(01). doi:10.1258/0022215053222752Venturato, A., MacFarlane, G., Geng, J., & Bradley, M. (2016). Understanding Polymer-Cell Attachment. Macromolecular bioscience, 16(12), 1864–1872. https://doi.org/10.1002/mabi.201600253Li, T., Shi, Z., He, X., Jiang, P., Lu, X., Zhang, R., & Wang, X. (2018). Aging-Resistant Functionalized LDH–SAS/Nitrile-Butadiene Rubber Composites: Preparation and Study of Aging Kinetics/Anti-Aging Mechanism. Materials, 11(5), 836. doi:10.3390/ma11050836Chen, L., Yan, C., & Zheng, Z. (2018). Functional polymer surfaces for controlling cell behaviors. Materials Today, 21(1), 38–59. doi:10.1016/j.mattod.2017.07.002Ino, J. M., Chevallier, P., Letourneur, D., Mantovani, D., & Le Visage, C. (2013). Plasma functionalization of poly(vinyl alcohol) hydrogel for cell adhesion enhancement. Biomatter, 3(4), e25414. https://doi.org/10.4161/biom.25414Gupta, S., T, G., Basu, B., Goswami, S., & Sinha, A. (2012). Stiffness- and wettability-dependent myoblast cell compatibility of transparent poly(vinyl alcohol) hydrogels. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 101B(2), 346–354. doi:10.1002/jbm.b.32845Peppas, N., & Stauffer, S. (1991). Reinforced uncrosslinked poly (Vinyl alcohol) gels produced by cyclic freezing-thawing processes: A short review. https://doi.org/10.1016/0168-3659(91)90007-ZKumar, A., Behl, T., & Chadha, S. (2020). Synthesis of physically crosslinked PVA/Chitosan loaded silver nanoparticles hydrogels with tunable mechanical properties and antibacterial effects. International Journal of Biological Macromolecules. doi:10.1016/j.ijbiomac.2020.02.048Figueroa-Pizano, M. D., Vélaz, I., Peñas, F. J., Zavala-Rivera, P., Rosas-Durazo, A. J., Maldonado-Arce, A. D., & Martínez-Barbosa, M. E. (2018). Effect of freeze-thawing conditions for preparation of chitosan-poly (Vinyl alcohol) hydrogels and drug release studies. Carbohydrate Polymers, 195, 476-485. https://doi.org/10.1016/j.carbpol.2018.05.004Krutzer, B., Ros, M., Smit, J., de Jong W. (2011). A review of synthetic latices in surgical glove use. Kraton Innovation Center Amsterdam. Recuperado de: https://www.kraton.com/jp/products/pdf/synthetic_latices.pdfYilmaz-Atay, H. (2020). Antibacterial Activity of Chitosan-Based Systems. Functional Chitosan: Drug Delivery and Biomedical Applications, 457–489. https://doi.org/10.1007/978-981-15-0263-7_15Abdel-Mohsen, A. M., Aly, A. S., Hrdina, R., Montaser, A. S., & Hebeish, A. (2011). Eco-Synthesis of PVA/Chitosan Hydrogels for Biomedical Application. Journal of Polymers and the Environment, 19(4), 1005–1012. doi:10.1007/s10924-011-0334-0Lim, L. Y., & Wan, L. S. C. (1994). The effect of plasticizers on the properties of polyvinyl alcohol films. Drug Development and Industrial Pharmacy, 20(6), 1007-1020. https://doi.org/10.3109/03639049409038347Xie, L., Jiang, M., Dong, X., Bai, X., Tong, J., & Zhou, J. (2011). Controlled mechanical and swelling properties of poly(vinyl alcohol)/sodium alginate blend hydrogels prepared by freeze-thaw followed by Ca2+ crosslinking. Journal of Applied Polymer Science, 124(1), 823–831. doi:10.1002/app.35083Muangsri, R., Chuysinuan, P., Thanyacharoen, T., Techasakul, S., Sukhavattanakul, P., & Ummartyotin, S. (2022). Utilization of freeze thaw process for polyvinyl alcohol/sodium alginate (Pva/sa) hydrogel composite. Journal of Metals, Materials and Minerals, 32(2), 34-41. https://doi.org/10.55713/jmmm.v32i2.1257Matyash, M., Despang, F., Ikonomidou, C., Gelinsky M. (2014). Swelling and mechanical properties of alginate hydrogels with respect to promotion of neural growth. Repository of the Max Delbrück Center for Molecular Medicine (MDC) Berlin (Germany). Recuperado de: https://core.ac.uk/download/pdf/300323656.pdfKamoun, E. A., Kenawy, E.-R. S., Tamer, T. M., El-Meligy, M. A., & Mohy Eldin, M. S. (2015). Poly (vinyl alcohol)-alginate physically crosslinked hydrogel membranes for wound dressing applications: Characterization and bio-evaluation. Arabian Journal of Chemistry, 8(1), 38–47. doi:10.1016/j.arabjc.2013.12.003Zhang, S., Han, D., Ding, Z., Wang, X., Zhao, D., Hu, Y., & Xiao, X. (2019). Fabrication and Characterization of One Interpenetrating Network Hydrogel Based on Sodium Alginate and Polyvinyl Alcohol. Journal of Wuhan University of Technology-Mater. Sci. Ed., 34(3), 744–751. doi:10.1007/s11595-019-2112-0Jiang, X., Xiang, N., Zhang, H., Sun, Y., Lin, Z., & Hou, L. (2018). Preparation and characterization of poly(vinyl alcohol)/sodium alginate hydrogel with high toughness and electric conductivity. Carbohydrate Polymers, 186, 377–383. doi:10.1016/j.carbpol.2018.01.061Ostroha, J., Pong, M., Lowman, A., & Dan, N. (2004). Controlling the collapse/swelling transition in charged hydrogels. Biomaterials, 25(18), 4345–4353. doi:10.1016/j.biomaterials.2003.11.019Daza Agudelo, J. I., Badano, J. M., & Rintoul, I. (2018). Kinetics and thermodynamics of swelling and dissolution of PVA gels obtained by freeze-thaw technique. Materials Chemistry and Physics, 216, 14–21. doi:10.1016/j.matchemphys.2018.05.038Aranaz, I., Alcántara, A. R., Civera, M. C., Arias, C., Elorza, B., Heras Caballero, A., & Acosta, N. (2021). Chitosan: An Overview of Its Properties and Applications. Polymers, 13(19), 3256. https://doi.org/10.3390/polym13193256Lee, K. Y., & Mooney, D. J. (2012). Alginate: properties and biomedical applications. Progress in polymer science, 37(1), 106–126. https://doi.org/10.1016/j.progpolymsci.2011.06.003Ben-Halima, N. (2016). Poly(vinyl alcohol): review of its promising applications and insights into biodegradation. RSC Advances, 6(46), 39823–39832. doi:10.1039/c6ra05742jMinagawa, T., Okamura, Y., Shigemasa, Y., Minami, S., & Okamoto, Y. (2007). Effects of molecular weight and deacetylation degree of chitin/chitosan on wound healing. Carbohydrate Polymers, 4(67), 640-644. https://doi.org/10.1016/j.carbpol.2006.07.007Pillai, C. K. S., Paul, W., & Sharma, C. P. (2009). Chitin and chitosan polymers: Chemistry, solubility and fiber formation. Progress in Polymer Science, 34(7), 641-678. https://doi.org/10.1016/j.progpolymsci.2009.04.001Goy, R. C., Britto, D. de, & Assis, O. B. G. (2009). A review of the antimicrobial activity of chitosan. Polímeros, 19, 241-247. https://doi.org/10.1590/S0104-14282009000300013Wu, J., Gong, X., Fan, Y., & Xia, H. (2011). Physically crosslinked poly(vinyl alcohol) hydrogels with magnetic field controlled modulus. Soft Matter, 7(13), 6205. doi:10.1039/c1sm05386hZhou, Q., Kang, H., Bielec, M., Wu, X., Cheng, Q., Wei, W., & Dai, H. (2018). Influence of different divalent ions cross-linking sodium alginate-polyacrylamide hydrogels on antibacterial properties and wound healing. Carbohydrate Polymers, 197, 292–304. doi:10.1016/j.carbpol.2018.05.078FDA (Center for Drug Evaluation and Research). (2009). Environmental Assessment, 22-430. Recuperado de: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022430s000ea.pdfHolloway, J. L., Lowman, A. M., & Palmese, G. R. (2013). The role of crystallization and phase separation in the formation of physically cross-linked PVA hydrogels. Soft Matter, 9(3), 826–833. doi:10.1039/c2sm26763bLozinsky, V. I. (2008). Polymeric cryogels as a new family of macroporous and supermacroporous materials for biotechnological purposes. Russian Chemical Bulletin, 57(5), 1015–1032. doi:10.1007/s11172-008-0131-7Hetzner, H., Schmid, C., Tremmel, S., Durst, K., & Wartzack, S. (2014). Empirical-statistical study on the relationship between deposition parameters, process variables, deposition rate and mechanical properties of a-c:h:w coatings. Coatings, 4(4), 772-795. https://doi.org/10.3390/coatings4040772Zurovac, J. & Brown, R. (2012). Orthogonal Design: A Powerful Method for Comparative Effectiveness Research with Multiple Interventions. Issue Brief, Mathematica Policy Research. Recuperado de: https://mathematica.org/~/media/publications/PDFs/health/orthogonaldesign_ib.pdfASTM, D20 Committee. (2018). Test method for tensile properties of thin plastic sheeting. ASTM International. https://doi.org/10.1520/D0882-18Sher, N., Fatima, N., Perveen, S., Siddiqui, F. A., & Wafa Sial, A. (2015). Pregabalin and tranexamic Acid evaluation by two simple and sensitive spectrophotometric methods. International journal of analytical chemistry, 2015, 241412. https://doi.org/10.1155/2015/241412ICH, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (2022). Validation of Analytical Procedures Q2(R2). ICH Harmonised Guideline. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-q2r2-validation-analytical-procedures-step-2b_en.pdfFong, R., Robertson, A., Mallon, P., & Thompson, R. (2018). The Impact of Plasticizer and Degree of Hydrolysis on Free Volume of Poly(vinyl alcohol) Films. Polymers, 10(9), 1036. https://doi.org/10.3390/polym10091036Koosha, M., Aalipour, H., Sarraf Shirazi, M. J., Jebali, A., Chi, H., Hamedi, S., Wang, N., Li, T., & Moravvej, H. (2021). Physically Crosslinked Chitosan/PVA Hydrogels Containing Honey and Allantoin with Long-Term Biocompatibility for Skin Wound Repair: An In Vitro and In Vivo Study. Journal of functional biomaterials, 12(4), 61. https://doi.org/10.3390/jfb12040061Podorozhko, E. A., Ul’yabaeva, G. R., Kil’deeva, N. R., Tikhonov, V. E., Antonov, Y. A., Zhuravleva, I. L., & Lozinsky, V. I. (2016). A Study of cryostructuring of polymer systems. 41. Complex and composite poly(vinyl alcohol) cryogels containing soluble and insoluble forms of chitosan, respectively. Colloid Journal, 78(1), 90–101. doi:10.1134/s1061933x16010130Gupta, S., Goswami, S., & Sinha, A. (2012). A combined effect of freeze—Thaw cycles and polymer concentration on the structure and mechanical properties of transparent PVA gels. Biomedical Materials, 7(1), 015006. https://doi.org/10.1088/1748-6041/7/1/015006Lotfipour, F., Alami-Milani, M., Salatin, S., Hadavi, A., & Jelvehgari, M. (2019). Freeze-thaw-induced cross-linked PVA/chitosan for oxytetracycline-loaded wound dressing: the experimental design and optimization. Research in pharmaceutical sciences, 14(2), 175–189. https://doi.org/10.4103/1735-5362.253365Ödeen, S. (1993). Determination of Viscoelastic Material Properties and Impact Force from Measurements on Impacted Bodies. Luleå University of Technology. Luleå, Suecia.Schick, C., & Androsch, R. (2018). Nucleation‐controlled semicrystalline morphology of bulk polymers. Polymer crystallization, 1(4). https://doi.org/10.1002/pcr2.10036Su, Y., Wu, Y., Liu, M., Qing, Y., Zhou, J., & Wu, Y. (2020). Ferric Ions Modified Polyvinyl Alcohol for Enhanced Molecular Structure and Mechanical Performance. Materials, 13(6), 1412. https://doi.org/10.3390/ma13061412Muthu, S., & Prabhakaran, A. (2014). Vibrational spectroscopic study and NBO analysis on tranexamic acid using DFT method. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 129, 184–192. doi:10.1016/j.saa.2014.03.050Shaikh, T., Nafady, A., Talpur, F. N., Sirajuddin, Agheem, M. H., Shah, M. R., … Siddiqui, S. (2015). Tranexamic acid derived gold nanoparticles modified glassy carbon electrode as sensitive sensor for determination of nalbuphine. Sensors and Actuators B: Chemical, 211, 359–369. doi:10.1016/j.snb.2015.01.096Tretinnikov, O. N., & Zagorskaya, S. A. (2012). Determination of the degree of crystallinity of poly(vinyl alcohol) by FTIR spectroscopy. Journal of Applied Spectroscopy, 79(4), 521–526. doi:10.1007/s10812-012-9634-yWaresindo, W. X., Luthfianti, H. R., Edikresnha, D., Suciati, T., Noor, F. A., & Khairurrijal, K. (2021). A freeze–thaw PVA hydrogel loaded with guava leaf extract: Physical and antibacterial properties. RSC Advances, 11(48), 30156-30171. https://doi.org/10.1039/D1RA04092HLotfipour, F., Alami-Milani, M., Salatin, S., Hadavi, A., & Jelvehgari, M. (2019). Freeze-thaw-induced cross-linked PVA/chitosan for oxytetracycline-loaded wound dressing: the experimental design and optimization. Research in pharmaceutical sciences, 14(2), 175–189. https://doi.org/10.4103/1735-5362.253365Sethi, A., Ahmad, M., Huma, T., Khalid, I., & Ahmad, I. (2021). Evaluation of Low Molecular Weight Cross Linked Chitosan Nanoparticles, to Enhance the Bioavailability of 5-Flourouracil. Dose-Response, 19(2). doi:10.1177/15593258211025353Arafa, M. G., Mousa, H. A., & Afifi, N. N. (2020). Preparation of PLGA-chitosan based nanocarriers for enhancing antibacterial effect of ciprofloxacin in root canal infection. Drug delivery, 27(1), 26–39. https://doi.org/10.1080/10717544.2019.1701140ChemSpider. (2023). Tranexamic acid | C8H15NO2 | chemspider. Recuperado de: http://www.chemspider.com/Chemical-Structure.10482000.htmlPubChem. (2023). Tranexamic acid. Recuperado de: https://pubchem.ncbi.nlm.nih.gov/compound/5526Su, Y., Wu, Y., Liu, M., Qing, Y., Zhou, J., & Wu, Y. (2020). Ferric Ions Modified Polyvinyl Alcohol for Enhanced Molecular Structure and Mechanical Performance. Materials, 13(6), 1412. https://doi.org/10.3390/ma13061412Andrade, J., González-Martínez, C., & Chiralt, A. (2020). The Incorporation of Carvacrol into Poly (vinyl alcohol) Films Encapsulated in Lecithin Liposomes. Polymers, 12(2), 497. doi:10.3390/polym12020497Lozinsky, V. I., Damshkaln, L. G., Shaskol’skii, B. L., Babushkina, T. A., Kurochkin, I. N., & Kurochkin, I. I. (2007). Study of cryostructuring of polymer systems: 27. Physicochemical properties of poly(Vinyl alcohol) cryogels and specific features of their macroporous morphology. Colloid Journal, 69(6), 747-764. https://doi.org/10.1134/S1061933X07060117Nakano, T., & Nakaoki, T. (2011). Coagulation size of freezable water in poly(Vinyl alcohol) hydrogels formed by different freeze/thaw cycle periods. Polymer Journal, 43(11), 875-880. https://doi.org/10.1038/pj.2011.92Wahab, A. H. A., Kadir, M. R. A., Harun, M. N., Ramlee, M. H., Syahrom, A., Sulong, M. A., & Saad, A. P. M. (2018). Developing Functionally Graded PVA Hydrogel using Simple Freeze-Thaw Method for Artificial Glenoid Labrum. Journal of the Mechanical Behavior of Biomedical Materials. doi:10.1016/j.jmbbm.2018.12.033Gherman, S. P., Biliuță, G., Bele, A., Ipate, A. M., Baron, R. I., Ochiuz, L., Șpac, A. F., et al. (2023). Biomaterials Based on Chitosan and Polyvinyl Alcohol as a Drug Delivery System with Wound-Healing Effects. Gels, 9(2), 122. MDPI AG. Retrieved from http://dx.doi.org/10.3390/gels9020122Simões, M. M. de S. G., & de Oliveira, M. G. (2010). Poly(vinyl alcohol) films for topical delivery of S-nitrosoglutathione: Effect of freezing-thawing on the diffusion properties. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 93B(2), 416–424. doi:10.1002/jbm.b.31598Takamura, A., Ishii, F., & Hidaka, H. (1992). Drug release from poly(vinyl alcohol) gel prepared by freeze-thaw procedure. Journal of Controlled Release, 20(1), 21–27. doi:10.1016/0168-3659(92)90135-eChang, C., Lue, A., & Zhang, L. (2008). Effects of Crosslinking Methods on Structure and Properties of Cellulose/PVA Hydrogels. Macromolecular Chemistry and Physics, 209(12), 1266–1273. doi:10.1002/macp.200800161Li, H., & Xiao, R. (2021). Glass Transition Behavior of Wet Polymers. Materials (Basel, Switzerland), 14(4), 730. https://doi.org/10.3390/ma14040730Li, L., Xu, X., Liu, L., Song, P., Cao, Q., Xu, Z., … Wang, H. (2021). Water governs the mechanical properties of poly(vinyl alcohol). Polymer, 213, 123330. doi:10.1016/j.polymer.2020.123330Qiao, C., Ma, X., Zhang, J., & Yao, J. (2018). Effect of hydration on water state, glass transition dynamics and crystalline structure in chitosan films. Carbohydrate Polymers. doi:10.1016/j.carbpol.2018.11.045Bunn, C. W. (1948). Crystal Structure of Polyvinyl Alcohol. Nature, 161(4102), 929–930. doi:10.1038/161929a0Ricciardi, R., Auriemma, F., De Rosa, C., & Lauprêtre, F. (2004). X-ray Diffraction Analysis of Poly(vinyl alcohol) Hydrogels, Obtained by Freezing and Thawing Techniques. Macromolecules, 37(5), 1921–1927. doi:10.1021/ma035663qDrambei, P., Nakano, Y., Bin, Y., Okuno, T., & Matsuo, M. (2006). Characterization of PVA and Chitosan/PVA Blends Prepared from Aqueous Solutions of Various Na2SO4 Concentrations. Macromolecular Symposia, 242(1), 146–156. doi:10.1002/masy.200651022Chung, F. H., & Scott, R. W. (1973). A new approach to the determination of crystallinity of polymers by X-ray diffraction. Journal of Applied Crystallography, 6(3), 225–230. doi:10.1107/s0021889873008514Kawano, Y., Tanaka, Y., Hata, N., Yoshiike, Y., Nakajima, M., Yonemochi, E., & Ishihara, N. (2022). Swelling and Salt Formation in Ibuprofen and Tranexamic Acid-Containing Tablets during High-Temperature Storage. Crystals, 12(10), 1420. MDPI AG. Retrieved from http://dx.doi.org/10.3390/cryst12101420El-Habeeb, A. A., & Refat, M. S. (2019). Synthesis, structure interpretation, antimicrobial and anticancer studies of tranexamic acid complexes towards Ga(III), W(VI), Y(III) and Si(IV) metal ions. Journal of Molecular Structure, 1175, 65–72. doi:10.1016/j.molstruc.2018.07.099Yang, X., Dargaville, B., & Hutmacher, D. (2021). Elucidating the molecular mechanisms for the interaction of water with polyethylene glycol-based hydrogels: Influence of ionic strength and gel network structure. Polymers, 13(6), 845. https://doi.org/10.3390/polym13060845Ritger, P. L., & Peppas, N. A. (1987). A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. Journal of Controlled Release, 5(1), 37–42. doi:10.1016/0168-3659(87)90035-6Zhao, S. (2014). Osmotic pressure versus swelling pressure: Comment on “bifunctional polymer hydrogel layers as forward osmosis draw agents for continuous production of fresh water using solar energy”. Environmental Science & Technology, 48(7), 4212-4213. https://doi.org/10.1021/es5006994Wang, H., Wei, J., & Simon, G. P. (2014). Response to osmotic pressure versus swelling pressure: Comment on “bifunctional polymer hydrogel layers as forward osmosis draw agents for continuous production of fresh water using solar energy”. Environmental Science & Technology, 48(7), 4214-4215. https://doi.org/10.1021/es5011016Flory, P. J. (1953). Principles of polymer chemistry (19. print). Cornell Univ. Press. Ithaca, New York. pp. 434 - 451.Zmora, S., Glicklis, R., & Cohen, S. (2002). Tailoring the pore architecture in 3-D alginate scaffolds by controlling the freezing regime during fabrication. Biomaterials, 23(20), 4087–4094. doi:10.1016/s0142-9612(02)00146-1Chhatri, A., Bajpai, J., Bajpai, A. K., Sandhu, S. S., Jain, N., & Biswas, J. (2011). Cryogenic fabrication of savlon loaded macroporous blends of alginate and polyvinyl alcohol (PVA). Swelling, deswelling and antibacterial behaviors. Carbohydrate Polymers, 83(2), 876–882. doi:10.1016/j.carbpol.2010.08.077Gurikov, P., & Smirnova, I. (2018). Non-Conventional Methods for Gelation of Alginate. Gels (Basel, Switzerland), 4(1), 14. https://doi.org/10.3390/gels4010014Kumar, A., & Gupta, R. K. (2018). Theory of rubber elasticity. En A. Kumar & R. K. Gupta, Fundamentals of Polymer Engineering (3.a ed., pp. 357-379). CRC Press. https://doi.org/10.1201/9780429398506-10Schoof, H., Apel, J., Heschel, I., & Rau, G. (2001). Control of pore structure and size in freeze-dried collagen sponges. Journal of Biomedical Materials Research, 58(4), 352–357. doi:10.1002/jbm.1028Schoof, H., Bruns, L., Fischer, A., Heschel, I., & Rau, G. (2000). Dendritic ice morphology in unidirectionally solidified collagen suspensions. Journal of Crystal Growth, 209(1), 122–129. doi:10.1016/s0022-0248(99)00519-9Shapiro, L., & Cohen, S. (1997). Novel alginate sponges for cell culture and transplantation. Biomaterials, 18(8), 583–590. doi:10.1016/s0142-9612(96)00181-0Lammens, J., Goudarzi, N. M., Leys, L., Nuytten, G., Van Bockstal, P. J., Vervaet, C., Boone, M. N., & De Beer, T. (2021). Spin Freezing and Its Impact on Pore Size, Tortuosity and Solid State. Pharmaceutics, 13(12), 2126. https://doi.org/10.3390/pharmaceutics13122126Y. Sánchez-Cardona, C. E. Echeverri-Cuartas, M. E. Londoño López and N. Moreno-Castellanos, "Preparation and characterization of chitosan/gelatin /PVA scaffolds for tissue engineering application," 2021 IEEE 2nd International Congress of Biomedical Engineering and Bioengineering (CI-IB&BI), Bogota D.C., Colombia, 2021, pp. 1-4, doi: 10.1109/CI-IBBI54220.2021.9626060Hong, K. H. (2016). Polyvinyl alcohol/tannic acid hydrogel prepared by a freeze-thawing process for wound dressing applications. Polymer Bulletin, 74(7), 2861–2872. doi:10.1007/s00289-016-1868-zCascone, M. G., Lazzeri, L., Sparvoli, E., Scatena, M., Serino, L. P., & Danti, S. (2004). Morphological evaluation of bioartificial hydrogels as potential tissue engineering scaffolds. Journal of Materials Science: Materials in Medicine, 15(12), 1309–1313. doi:10.1007/s10856-004-5739-zKenawy, E.-R., El-Newehy, M. H., & Al-Deyab, S. S. (2010). Controlled release of atenolol from freeze/thawed poly(vinyl alcohol) hydrogel. Journal of Saudi Chemical Society, 14(2), 237–240. doi:10.1016/j.jscs.2010.02.014Bruschi, M. L. (2015). Mathematical models of drug release. En Strategies to Modify the Drug Release from Pharmaceutical Systems, 63–86. doi:10.1016/b978-0-08-100092-2.00005-9Lane, L. B. (1925). Freezing Points of Glycerol and Its Aqueous Solutions. Industrial & Engineering Chemistry, 17(9), 924–924. doi:10.1021/ie50189a017Bretz, K. J., Jobbágy, Á., & Bretz, K. (2010). Force measurement of hand and fingers. Biomechanica Hungarica. https://doi.org/10.17489/biohun/2010/1/07Nkhwa, S., Kemal, E., Gurav, N., & Deb, S. (2019). Dual polymer networks: a new strategy in expanding the repertoire of hydrogels for biomedical applications. Journal of Materials Science: Materials in Medicine, 30(10). doi:10.1007/s10856-019-6316-9Zhang, R., Zhao, W., Ning, F., Zhen, J., Qiang, H., Zhang, Y., Liu, F., & Jia, Z. (2022). Alginate Fiber-Enhanced Poly(vinyl alcohol) Hydrogels with Superior Lubricating Property and Biocompatibility. Polymers, 14(19), 4063. https://doi.org/10.3390/polym14194063Szekalska, M., Sosnowska, K., Wróblewska, M., Basa, A., & Winnicka, K. (2022). Does the Freeze–Thaw Technique Affect the Properties of the Alginate/Chitosan Glutamate Gels with Posaconazole as a Model Antifungal Drug? International Journal of Molecular Sciences, 23(12), 6775. https://doi.org/10.3390/ijms23126775Li, X., Shu, M., Li, H., Gao, X., Long, S., Hu, T., & Wu, C. (2018). Strong, tough and mechanically self-recoverable poly(Vinyl alcohol)/alginate dual-physical double-network hydrogels with large cross-link density contrast. RSC Advances, 8(30), 16674-16689. https://doi.org/10.1039/C8RA01302KSingh, R., Sood, N., Kerai, S., & Puri, A. (2017). Use of Merocel® aids in prevention of nasal pressure ulcers following nasal intubation: Case series of 33 patients. Indian journal of anaesthesia, 61(6), 513–515. https://doi.org/10.4103/ija.IJA_26_17U.S. Food and Drug Administration (FDA). (2020). The device development process. FDA. https://www.fda.gov/patients/learn-about-drug-and-device-approvals/device-development-processXu, Jian, et al. «Preparation and Characterization of Chitosan/Polyvinyl Porous Alcohol Aerogel Microspheres with Stable Physicochemical Properties». International Journal of Biological Macromolecules, vol. 187, septiembre de 2021, pp. 614-23. DOI.org (Crossref), https://doi.org/10.1016/j.ijbiomac.2021.07.127.Jipa, I., Stoica, A., Stroescu, M., Dobre, L.-M., Dobre, T., Jinga, S., & Tardei, C. (2012). Potassium sorbate release from poly(vinyl alcohol)-bacterial cellulose films. Chemical Papers, 66(2).Fernandes Queiroz, M., Melo, K., Sabry, D., Sassaki, G., & Rocha, H. (2014). Does the Use of Chitosan Contribute to Oxalate Kidney Stone Formation? Marine Drugs, 13(1), 141–158. doi:10.3390/md13010141EstudiantesInvestigadoresPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/85394/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1032496108.2023.pdf1032496108.2023.pdfTesis de Maestría en Ciencias Farmacéuticasapplication/pdf7934762https://repositorio.unal.edu.co/bitstream/unal/85394/2/1032496108.2023.pdfc87ddb75ea27b01124a049f877adf6f3MD52THUMBNAIL1032496108.2023.pdf.jpg1032496108.2023.pdf.jpgGenerated Thumbnailimage/jpeg5445https://repositorio.unal.edu.co/bitstream/unal/85394/3/1032496108.2023.pdf.jpge445b486a0fd93a4accd1cfce41174faMD53unal/85394oai:repositorio.unal.edu.co:unal/853942024-01-22 23:03:37.761Repositorio Institucional Universidad Nacional de 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