{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T04:08:06Z","timestamp":1778904486537,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T00:00:00Z","timestamp":1596153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UID\/DTP\/04138\/2019"],"award-info":[{"award-number":["UID\/DTP\/04138\/2019"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UIDB \/00100\/2020"],"award-info":[{"award-number":["UIDB \/00100\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UIDB\/50022\/2020"],"award-info":[{"award-number":["UIDB\/50022\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The development of printable hydrogel inks for extrusion-based 3D printing is opening new possibilities to the production of new and\/or improved pharmaceutical forms, specifically for topical application. Alginate and starch are natural polysaccharides that have been extensively exploited due to their biocompatibility, biodegradability, viscosity properties, low toxicity, and relatively low cost. This research work aimed to study the physicochemical and release kinetic effects of starch incorporation in alginate-based 3D hydrogel patches for topical delivery using a quality by design approach. The incorporation of a pregelatinized starch is also proposed as a way to improve the properties of the drug delivery system while maintaining the desired quality characteristics. Critical material attributes and process parameters were identified, and the sensitivity and adequacy of each parameter were statistically analyzed. The impact of alginate, starch, and CaCl2\u00b72H2O amounts on relevant quality attributes was estimated crosswise. The amount of starch revealed a synergetic impact on porosity (p = 0.0021). An evident increase in the size and quantity of open pores were detected in the as printed patches as well as after crosslinking (15.6 \u00b1 5.2 \u00b5m). In vitro drug release studies from the optimized alginate-starch 3D hydrogel patch, using the probe Rhodamine B, showed an initial high burst release, followed by a controlled release mechanism. The results obtained also showed that the viscoelastic properties, printing accuracy, gelation time, microstructure, and release rates can be modulated by varying the amount of starch added to the system. Furthermore, these results can be considered an excellent baseline for future drug release modulation strategies.<\/jats:p>","DOI":"10.3390\/pharmaceutics12080719","type":"journal-article","created":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T04:15:31Z","timestamp":1596168931000},"page":"719","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Effects of Starch Incorporation on the Physicochemical Properties and Release Kinetics of Alginate-Based 3D Hydrogel Patches for Topical Delivery"],"prefix":"10.3390","volume":"12","author":[{"given":"Sara","family":"Bom","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"PhD Trials, Avenida Maria Helena Vieira da Silva, n\u00b0 24 A, 1750-182 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8567-0032","authenticated-orcid":false,"given":"Catarina","family":"Santos","sequence":"additional","affiliation":[{"name":"EST Set\u00fabal, CDP2T, Instituto Polit\u00e9cnico de Set\u00fabal, Campus do IPS-Estefanilha, 2910-761 Set\u00fabal, Portugal"},{"name":"CQE, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal"}]},{"given":"Rita","family":"Barros","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"given":"Ana M.","family":"Martins","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2531-8499","authenticated-orcid":false,"given":"Patrizia","family":"Paradiso","sequence":"additional","affiliation":[{"name":"CQE, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal"}]},{"given":"Ricardo","family":"Cl\u00e1udio","sequence":"additional","affiliation":[{"name":"EST Set\u00fabal, CDP2T, Instituto Polit\u00e9cnico de Set\u00fabal, Campus do IPS-Estefanilha, 2910-761 Set\u00fabal, Portugal"},{"name":"IDMEC, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5723-0750","authenticated-orcid":false,"given":"Pedro Contreiras","family":"Pinto","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"PhD Trials, Avenida Maria Helena Vieira da Silva, n\u00b0 24 A, 1750-182 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-7991","authenticated-orcid":false,"given":"Helena M.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5523-5622","authenticated-orcid":false,"given":"Joana","family":"Marto","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,31]]},"reference":[{"key":"ref_1","first-page":"704","article-title":"Medical Applications for 3D printing: Current and projected uses","volume":"39","author":"Ventola","year":"2014","journal-title":"P T"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Konta, A.A., Garc\u00eda-Pi\u00f1a, M., and Serrano, D.R. (2017). Personalised 3D printed medicines: Which techniques and polymers are more successful?. Bioengineering, 4.","DOI":"10.3390\/bioengineering4040079"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ijpharm.2018.01.031","article-title":"3D printing applications for transdermal drug delivery","volume":"544","author":"Economidou","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jconrel.2016.05.034","article-title":"3D scanning and 3D printing as innovative technologies for fabricating personalized topical drug delivery systems","volume":"234","author":"Goyanes","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Azad, M.A., Olawuni, D., Kimbell, G., Badruddoza, A.Z.M., Hossain, M.S., and Sultana, T. (2020). Polymers for extrusion-based 3D printing of pharmaceuticals: A holistic materials\u2013process perspective. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020124"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Liu, Z., Jiang, Q., Zhang, Y., Li, T., and Zhang, H.C. (July, January 27). Sustainability of 3D printing: A critical review and recommendations. Proceedings of the ASME 2016 11th International Manufacturing Science and Engineering Conference, Blacksburg, VA, USA.","DOI":"10.1115\/MSEC2016-8618"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"035003","DOI":"10.1088\/1758-5090\/aa7b1d","article-title":"A bioprintable form of chitosan hydrogel for bone tissue engineering","volume":"9","author":"Irmak","year":"2017","journal-title":"Biofabrication"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100636","DOI":"10.1016\/j.mtcomm.2019.100636","article-title":"Development of alginate\/starch-based hydrogels crosslinked with different ions: Hydrophilic, kinetic and spectroscopic properties","volume":"21","author":"Fernandes","year":"2019","journal-title":"Mater. Today Commun."},{"key":"ref_9","unstructured":"Waldron, K.W. (2014). The use of biomass for packaging films and coatings. Advances in Biorefineries: Biomass and Waste Supply Chain Exploitation, Woodhead Publishing."},{"key":"ref_10","first-page":"47","article-title":"Starch-hydroxyapatite composite bone scaffold fabrication utilizing a slurry extrusion-based solid freeform fabricator","volume":"24","author":"Koski","year":"2018","journal-title":"Addit. Manuf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jfoodeng.2018.09.011","article-title":"Effect of rheological properties of potato, rice and corn starches on their hot-extrusion 3D printing behaviors","volume":"244","author":"Chen","year":"2019","journal-title":"J. Food Eng."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.ijbiomac.2019.07.124","article-title":"Hydrogels based on ozonated cassava starch: Effect of ozone processing and gelatinization conditions on enhancing 3D-printing applications","volume":"138","author":"Maniglia","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.lwt.2017.08.054","article-title":"Investigation on lemon juice gel as food material for 3D printing and optimization of printing parameters","volume":"87","author":"Yang","year":"2018","journal-title":"LWT Food Sci. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/jfpp.13993","article-title":"The characteristics of starch gels molded by 3D printing","volume":"43","author":"Zheng","year":"2019","journal-title":"J. Food Process. Preserv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.clay.2009.03.001","article-title":"Controlled release of the fungicide thiram from starch-alginate-clay based formulation","volume":"45","author":"Singh","year":"2009","journal-title":"Appl. Clay Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.carbpol.2013.03.019","article-title":"Effect of starch filler on calcium-alginate hydrogels loaded with yerba mate antioxidants","volume":"95","author":"Deladino","year":"2013","journal-title":"Carbohydr. Polym."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.carbpol.2013.12.078","article-title":"Preparation and characterization of alginate and alginate-resistant starch microparticles containing nisin","volume":"103","author":"Hosseini","year":"2014","journal-title":"Carbohydr. Polym."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.foodhyd.2015.02.032","article-title":"Effect of the weight ratio of alginate-modified tapioca starch on the physicochemical properties and release kinetics of chlorogenic acid containing beads","volume":"48","author":"Vazquez","year":"2015","journal-title":"Food Hydrocoll."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-17286-1","article-title":"Tuning alginate bioink stiffness and composition for controlled growth factor delivery and to spatially direct MSC Fate within bioprinted tissues","volume":"7","author":"Freeman","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/star.200900226","article-title":"Characteristics of pores in native and hydrolyzed starch granules","volume":"62","author":"Sujka","year":"2010","journal-title":"Starch Staerke"},{"key":"ref_21","first-page":"1","article-title":"Cross-linked alginate film pore size determination using atomic force microscopy and validation using diffusivity determinations","volume":"3","author":"Simpliciano","year":"2013","journal-title":"J. Surf. Eng. Mater. Adv. Technol."},{"key":"ref_22","first-page":"1","article-title":"Research on the printability of hydrogels in 3D bioprinting","volume":"6","author":"He","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.taap.2018.01.018","article-title":"Safety assessment of starch-based personal care products: Nanocapsules and pickering emulsions","volume":"342","author":"Marto","year":"2018","journal-title":"Toxicol. Appl. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1208\/s12248-010-9185-1","article-title":"DDSolver: An add-in program for modeling and comparison of drug dissolution profiles","volume":"12","author":"Zhang","year":"2010","journal-title":"AAPS J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.colsurfb.2016.03.039","article-title":"A quality by design (QbD) approach on starch-based nanocapsules: A promising platform for topical drug delivery","volume":"143","author":"Marto","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_26","first-page":"676","article-title":"Improved quality of 3D-printed tissue constructs through enhanced mixing of alginate hydrogels","volume":"1","author":"Cohen","year":"2008","journal-title":"Res. Gate"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/mame.201100008","article-title":"The effect of mixing on the mechanical properties of hyaluronan-based injectable hydrogels","volume":"296","author":"Piskounova","year":"2011","journal-title":"Macromol. Mater. Eng."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1088\/1758-5090\/aa6370","article-title":"3D printing PLGA: A quantitative examination of the effects of polymer composition and printing parameters on print resolution","volume":"9","author":"Guo","year":"2017","journal-title":"Biofabrication"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8320","DOI":"10.1016\/j.ceramint.2015.03.004","article-title":"Effect of layer printing delay on mechanical properties and dimensional accuracy of 3D printed porous prototypes in bone tissue engineering","volume":"41","author":"Farzadi","year":"2015","journal-title":"Ceram. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.foodhyd.2014.02.005","article-title":"Formation kinetics and rheology of alginate fluid gels produced by in-situ calcium release","volume":"40","author":"Norton","year":"2014","journal-title":"Food Hydrocoll."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S0142-9612(00)00201-5","article-title":"Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: Part 1. Structure, gelation rate and mechanical properties","volume":"22","author":"Kuo","year":"2001","journal-title":"Biomaterials"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.1467-2494.2004.00250.x","article-title":"Development of hydrogel patch for controlled release of alpha-hydroxy acid contained in tamarind fruit pulp extract","volume":"27","author":"Viyoch","year":"2005","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.jhazmat.2019.03.037","article-title":"Rheological characterization of starch gels: A biomass based sorbent for removal of polycyclic aromatic hydrocarbons (PAHs)","volume":"371","author":"Abdurrahmanoglu","year":"2019","journal-title":"J. Hazard. Mater."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.carbpol.2015.07.037","article-title":"Structure and properties of semi-interpenetrating network hydrogel based on starch","volume":"133","author":"Zhu","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"36687","DOI":"10.1039\/C5RA03862F","article-title":"Production of ultra-high concentration calcium alginate beads with prolonged dissolution profile","volume":"5","author":"Voo","year":"2015","journal-title":"RSC Adv."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.foodhyd.2018.03.014","article-title":"Physicochemical properties of alginate-based films: Effect of ionic crosslinking and mannuronic and guluronic acid ratio","volume":"81","author":"Costa","year":"2018","journal-title":"Food Hydrocoll."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.4236\/jep.2012.39127","article-title":"Environmentally friendly formulations of trifluralin based on alginate modified starch","volume":"03","author":"Onyido","year":"2012","journal-title":"J. Environ. Prot."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Szekalska, M., Sosnowska, K., K\u00f3snik, A.C., and Winnicka, K. (2018). Calcium chloride modified alginate microparticles formulated by the spray drying process: A strategy to prolong the release of freely soluble drugs. Materials, 11.","DOI":"10.3390\/ma11091522"},{"key":"ref_39","unstructured":"Bruschi, M.L. (2015). Mathematical models of drug release. Strategies to Modify Drug Release from Pharmaceutical Systems, Woodhead Publishing."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6373","DOI":"10.1063\/1.1603731","article-title":"Fractal kinetics in drug release from finite fractal matrices","volume":"119","author":"Kosmidis","year":"2003","journal-title":"J. Chem. Phys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ijpharm.2005.10.044","article-title":"On the use of the Weibull function for the discernment of drug release mechanisms","volume":"309","author":"Papadopoulou","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5909","DOI":"10.1063\/1.449622","article-title":"On controlled diffusion-limited drug release from a leaky matrix","volume":"83","author":"Bunde","year":"1985","journal-title":"J. Chem. Phys."},{"key":"ref_43","first-page":"656","article-title":"Formulation and evaluation of in vitro release kinetics of na3cadtpa decorporation agent embedded in microemulsion-based gel formulation for topical delivery","volume":"63","author":"Cojocaru","year":"2015","journal-title":"Farmacia"},{"key":"ref_44","first-page":"118","article-title":"Design and development of oral transmucosal film for delivery of salbutamol sulphate","volume":"2","author":"Gupta","year":"2014","journal-title":"J. Pharm. Chem. Biol. Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/8\/719\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:53:13Z","timestamp":1760176393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/8\/719"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,31]]},"references-count":44,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["pharmaceutics12080719"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12080719","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,31]]}}}