{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T14:49:49Z","timestamp":1773240589484,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,13]],"date-time":"2021-03-13T00:00:00Z","timestamp":1615593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoporosis is a worldwide chronic disease characterized by increasing bone fragility and fracture likelihood. In the treatment of bone defects, materials based on calcium phosphates (CaPs) are used due to their high resemblance to bone mineral, their non-toxicity, and their affinity to ionic modifications and increasing osteogenic properties. Moreover, CaPs, especially hydroxyapatite (HA), can be successfully used as a vehicle for local drug delivery. Therefore, the aim of this work was to fabricate hydroxyapatite-based composite beads for potential use as local carriers for raloxifene. HA powder, modified with magnesium and silicon ions (Mg,Si-HA) (both of which play beneficial roles in bone formation), was used to prepare composite beads. As an organic matrix, sodium alginate with chondroitin sulphate and\/or keratin was applied. Cross-linking of beads containing raloxifene hydrochloride (RAL) was carried out with Mg ions in order to additionally increase the concentration of this element on the material surface. The morphology and porosity of three different types of beads obtained in this work were characterized by scanning electron microscopy (SEM) and mercury intrusion porosimetry, respectively. The Mg and Si released from the Mg,Si-HA powder and from the beads were measured by inductively coupled plasma optical emission spectrometry (ICP-OES). In vitro RAL release profiles were investigated for 12 weeks and studied using UV\/Vis spectroscopy. The beads were also subjected to in vitro biological tests on osteoblast and osteosarcoma cell lines. All the obtained beads revealed a spherical shape with a rough, porous surface. The beads based on chondroitin sulphate and keratin (CS\/KER-RAL) with the lowest porosity resulted in the highest resistance to crushing. Results revealed that these beads possessed the most sustained drug release and no burst release effect. Based on the results, it was possible to select the optimal bead composition, consisting of a mixture of chondroitin sulphate and keratin.<\/jats:p>","DOI":"10.3390\/ijms22062933","type":"journal-article","created":{"date-parts":[[2021,3,14]],"date-time":"2021-03-14T22:13:10Z","timestamp":1615759990000},"page":"2933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Mg,Si\u2014Co-Substituted Hydroxyapatite\/Alginate Composite Beads Loaded with Raloxifene for Potential Use in Bone Tissue Regeneration"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8158-6511","authenticated-orcid":false,"given":"Katarzyna","family":"Szurkowska","sequence":"first","affiliation":[{"name":"Department of Analytical Chemistry, Chair of Analytical Chemistry and Biomaterials, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-7168","authenticated-orcid":false,"given":"Paulina","family":"Kazimierczak","sequence":"additional","affiliation":[{"name":"Chair and Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4417-5836","authenticated-orcid":false,"given":"Joanna","family":"Kolmas","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Chair of Analytical Chemistry and Biomaterials, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,13]]},"reference":[{"key":"ref_1","first-page":"2041731418776819","article-title":"Bone substitutes: A review of their characteristics, clinical use, and perspectives for large bone defects management","volume":"9","author":"Keller","year":"2018","journal-title":"J. Tissue Eng."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1007\/s10856-014-5240-2","article-title":"Bone substitutes in orthopaedic surgery: From basic science to clinical practice","volume":"25","author":"Campana","year":"2014","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Barbeck, M. (2019). Application of bone substitutes and its future prospective in regenerative medicine. Biomaterial-Supported Tissue Reconstruction or Regeneration, IntechOpen.","DOI":"10.5772\/intechopen.77756"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1186\/1479-5876-11-303","article-title":"Basic research and clinical applications of bisphosphonates in bone disease: What have we learned over the last 40 years?","volume":"11","author":"Xu","year":"2013","journal-title":"J. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Thirumalai, J. (2018). Hydroxyapatite-based materials for potential use in bone tissue infections. Hydroxyapatite\u2014Advances in Composite Nanomaterials, Biomedical Applications and Its Technological Facets, IntechOpen.","DOI":"10.5772\/intechopen.68820"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chindamo, G., Sapino, S., Peira, E., Chirio, D., Gonzalez, M.C., and Gallarate, M. (2020). Bone diseases: Current approach and future perspectives in drug delivery systems for bone targeted therapeutics. Nanomaterials, 10.","DOI":"10.3390\/nano10050875"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.2147\/IJN.S44393","article-title":"Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration","volume":"8","author":"Gu","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.copbio.2016.02.029","article-title":"Local and targeted drug delivery for bone regeneration","volume":"40","author":"Newman","year":"2016","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1111\/bcp.13759","article-title":"Side effects of drugs for osteoporosis and metastatic bone disease","volume":"85","author":"Frost","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.progsolidstchem.2004.07.001","article-title":"Calcium phosphates as substitution of bone tissues","volume":"32","year":"2004","journal-title":"Prog. Solid State Chem."},{"key":"ref_11","first-page":"317","article-title":"Bone regeneration: Molecular and cellular interactions with calcium phosphate ceramics","volume":"1","year":"2006","journal-title":"Int. J. Nanomed."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mucalo, M. (2015). Structure and properties of hydroxyapatite for biomedical applications. Hydroxyapatite (Hap) for Biomedical Applications, Woodhead Publishing.","DOI":"10.1016\/B978-1-78242-033-0.00014-6"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1002\/jbm.b.33651","article-title":"Substituted hydroxyapatites for bone regeneration: A review of current trends","volume":"105","author":"Ratnayake","year":"2017","journal-title":"J. Biomed. Mater. Res. B"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9203","DOI":"10.1016\/j.ceramint.2015.03.316","article-title":"Substituted hydroxyapatites for biomedical applications: A review","volume":"41","author":"Supova","year":"2015","journal-title":"Ceram. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1016\/j.ceramint.2015.10.048","article-title":"Synthetic hydroxyapatite in pharmaceutical applications","volume":"42","author":"Kolmas","year":"2016","journal-title":"Ceram. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101131","DOI":"10.1016\/j.jddst.2019.101131","article-title":"3D hydroxyapatite scaffold for bone regeneration and local drug delivery applications","volume":"53","author":"Mondal","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.actbio.2011.11.017","article-title":"Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: A review","volume":"8","author":"Bose","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.3390\/nu5083022","article-title":"Magnesium and osteoporosis: Current state of knowledge and future research directions","volume":"5","author":"Castiglioni","year":"2013","journal-title":"Nutrients"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1038\/nm.4162","article-title":"Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats","volume":"22","author":"Zhang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s10856-006-0032-y","article-title":"Biomimetic Mg-substituted hydroxyapatite: From synthesis to in vivo behaviour","volume":"19","author":"Landi","year":"2008","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S8756-3282(02)00950-X","article-title":"Orthosilicic acid stimulates collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro","volume":"32","author":"Reffitt","year":"2003","journal-title":"Bone"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1023\/A:1021114710076","article-title":"A comparative study on the in vivo behavior of hydroxyapatite and silicon substituted hydroxyapatite granules","volume":"13","author":"Patel","year":"2002","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.pnsc.2017.08.009","article-title":"Hydroxyapatites enriched in silicon\u2013Bioceramic materials for biomedical and pharmaceutical applications","volume":"27","author":"Szurkowska","year":"2017","journal-title":"Prog. Nat. Sci. Mater. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/S8756-3282(01)00685-8","article-title":"The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro","volume":"30","author":"Taranta","year":"2002","journal-title":"Bone"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.jsbmb.2009.01.010","article-title":"Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: Estrogen receptor dependent or independent pathways of raloxifene","volume":"113","author":"Miki","year":"2009","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14","DOI":"10.2174\/1874325000903010014","article-title":"Raloxifene: Mechanism of action, effects on bone tissue, and applicability in clinical traumatology practice","volume":"3","author":"Rey","year":"2009","journal-title":"Open Orthop. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.maturitas.2006.05.007","article-title":"Raloxifene therapy interacts with serum osteoprotegerin in postmenopausal women","volume":"56","author":"Messalli","year":"2007","journal-title":"Maturitas"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.psyneuen.2018.10.001","article-title":"Raloxifene as a treatment for cognition in women with schizophrenia: The influence of menopause status","volume":"100","author":"Gurvich","year":"2019","journal-title":"Psychoneuroendocrinology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1088\/1361-6528\/abaf81","article-title":"Nanostructured lipid carrier potentiated oral delivery of raloxifene for breast cancer treatment","volume":"31","author":"Soni","year":"2020","journal-title":"Nanotechnology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.21873\/invivo.12135","article-title":"Raloxifene and Bazedoxifene Could Be Promising Candidates for Preventing the COVID-19 Related Cytokine Storm, ARDS and Mortality","volume":"34","author":"Smetana","year":"2020","journal-title":"In Vivo"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ijpharm.2009.05.044","article-title":"Intestinal glucuronidation metabolism may have a greater impact on oral bioavailability than hepatic glucuronidation metabolism in humans: A study with raloxifene, substrate for UGT1A1, 1A8, 1A9, and 1A10","volume":"378","author":"Mizuma","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1080\/03639040802438365","article-title":"Solid State Interactions of Raloxifene HCl with Different Hydrophilic Carriers During Co-grinding and its Effect on Dissolution Rate","volume":"35","author":"Garg","year":"2009","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1248\/cpb.58.293","article-title":"Enhanced dissolution and bioavailability of raloxifene by co-grinding with different superdisintegrants","volume":"58","author":"Jagadish","year":"2010","journal-title":"Chem. Pharm. Bull."},{"key":"ref_34","first-page":"3787","article-title":"Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: Optimization and in vivo appraisal","volume":"7","author":"Elsheikh","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ijpharm.2013.01.013","article-title":"Preparation and evaluation of raloxifene-loaded solid dispersion nanoparticle by spray-drying technique without an organic solvent","volume":"443","author":"Tran","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1089\/adt.2020.990","article-title":"Melt Dispersion Adsorbed onto Porous Carriers: An Effective Method to Enhance the Dissolution and Flow Properties of Raloxifene Hydrochloride","volume":"18","author":"Mahajan","year":"2020","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1177\/039463201402700315","article-title":"Novel hydroxyapatite biomaterial covalently linked to raloxifene","volume":"27","author":"Meme","year":"2014","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.ijpharm.2016.12.031","article-title":"Raloxifene microsphere-embedded collagen\/chitosan\/\u03b2-tricalcium phosphate scaffold for effective bone tissue engineering","volume":"518","author":"Zhang","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18551","DOI":"10.1016\/j.ceramint.2018.07.077","article-title":"Novel hybrid material based on Mg2+ and SiO44\u2212 co-substituted nano-hydroxyapatite, alginate and chondroitin sulphate for potential use in biomaterials engineering","volume":"44","author":"Szurkowska","year":"2018","journal-title":"Ceram. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1098\/rsta.2011.0258","article-title":"Structure and functionalization of mesoporous bioceramics for bone tissue regeneration and local drug delivery","volume":"370","author":"Montserrat","year":"2012","journal-title":"Phil. Trans. R. Soc. A"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1166\/jnn.2014.9127","article-title":"Scaffold design for bone regeneration","volume":"14","year":"2014","journal-title":"J. Nanosci. Nanotechnol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.actbio.2009.07.001","article-title":"In situ generation of sodium alginate\/hydroxyapatite nanocomposite beads as drug- controlled release matrices","volume":"6","author":"Zhang","year":"2010","journal-title":"Acta Biomater."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.reactfunctpolym.2013.07.014","article-title":"Aglinate\/BSA\/montmorillonite composites with enhanced protein entrapment and controlled release efficiency","volume":"73","author":"Kaygusuz","year":"2013","journal-title":"React. Funct. Polym."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ijpharm.2007.12.038","article-title":"Impact of cross-linker on alginate matrix integrity and drug release","volume":"335","author":"Ching","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_45","first-page":"277","article-title":"Do novel cement-type biomaterials reveal ion reactivity that affects cell viability in vitro?","volume":"9","author":"Przekora","year":"2014","journal-title":"Cent. Eur. J. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.actbio.2008.09.017","article-title":"Bilayered chitosan-based scaffolds for osteochondral tissue engineering: Influence of hydroxyapatite on in vitro cytotoxicity and dynamic bioactivity studies in a specific double-chamber bioreactor","volume":"5","author":"Malafaya","year":"2009","journal-title":"Acta Biomater."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4242","DOI":"10.1016\/j.actbio.2011.07.016","article-title":"Ion reactivity of calcium-deficient hydroxyapatite in standard cell culture media","volume":"7","author":"Gustavsson","year":"2011","journal-title":"Acta Biomater."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijbiomac.2010.03.015","article-title":"Biocomposites containing natural polymers and hydroxyapatite for bone tissue engineering","volume":"47","author":"Swetha","year":"2010","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.ijbiomac.2014.07.008","article-title":"Alginate composites for bone tissue engineering: A review","volume":"72","author":"Venkatesan","year":"2015","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"115650","DOI":"10.1016\/j.carbpol.2019.115650","article-title":"Recent advance in delivery system and tissue engineering applications of chondroitin sulfate","volume":"230","author":"Yang","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1039\/C2TB00460G","article-title":"Strategy to introduce an hydroxyapatite\u2013keratin nanocomposite into a fibrous membrane for bone tissue engineering","volume":"1","author":"Li","year":"2013","journal-title":"J. Mater. Chem. B"},{"key":"ref_52","first-page":"2979","article-title":"Controlled release of raloxifene by nanoencapsulation: Effect on in vitro antiproliferative activity of human breast cancer cells","volume":"9","author":"Fontana","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_53","first-page":"4331","article-title":"Experimental desing and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application","volume":"9","author":"Mahmood","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.3390\/molecules14072410","article-title":"Novel biodegradable polyesters. Synthesis and application as drug carriers for the preparation of raloxifene HCl loaded nanoparticles","volume":"14","author":"Bikiaris","year":"2009","journal-title":"Molecules"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5633","DOI":"10.2147\/IJN.S140935","article-title":"Fabrication and physicochemical characterization of porous composite microgranules with selenium oxyanions and risedronate sodium for potential applications in bone tumors","volume":"12","author":"Kolmas","year":"2017","journal-title":"Int. J. Nanomed."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/2933\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:35:19Z","timestamp":1760160919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/2933"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,13]]},"references-count":55,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22062933"],"URL":"https:\/\/doi.org\/10.3390\/ijms22062933","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,13]]}}}