{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T05:03:10Z","timestamp":1782622990289,"version":"3.54.5"},"reference-count":80,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100012411","name":"Alborz University of Medical Sciences","doi-asserted-by":"publisher","award":["97147"],"award-info":[{"award-number":["97147"]}],"id":[{"id":"10.13039\/501100012411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Biomater Appl"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>Although autografts and allografts remain common for bone defect repair, they entail donor-site morbidity, limited availability, and potential immune rejection. The development of tissue engineering has provided a potential solution to overcome these and facilitate effective bone regeneration. Extensive research has confirmed the osteogenic potential of bioactive molecules like Atorvastatin (ATV) and Icariin (ICA). But despite the increasing body of evidence supporting their individual merits, few studies have investigated the synergistic integration of these materials in Nanocomposite scaffolds. A novel three-dimensional scaffold composed of polycaprolactone (PCL), carboxymethyl chitosan (CMCs), and nano-hydroxyapatite (nHA), co-loaded with Icariin and Atorvastatin, and fabricated using the freeze-casting technique, is described. This study aimed to evaluate the scaffold\u2019s effectiveness in promoting calvarial bone regeneration in Wistar rats, contributing to the advancement of biomaterials in bone tissue engineering. Scaffolds containing PCL\/CMCs\/nHA with 0.1% ICA and 0.1% ATV were fabricated using the freeze-casting method. In vitro assessments were conducted to evaluate the biomechanical and physiological properties of the scaffolds. In vivo experiments involved implanting the scaffolds into calvarial bone defects in six groups of Wistar rats. After 12\u00a0weeks, histological analysis was performed to assess bone regeneration, including fibrous tissue formation, bone formation, osteon development, and osteoblast cell numbers and fibroblast cell numbers. After 72\u00a0h of incubation, the PCL\/CMCs\/nHA\/ATO\/ICA scaffold significantly enhanced cell viability compared to other groups, however, the differences observed between the other groups were not statistically significant. In vivo, results showed significantly greater bone formation, osteon development, and osteoblast numbers in the PCL\/CMCs\/nHA\/ATO\/ICA group than in the negative and other groups. The PCL\/CMCs\/nHA\/ATO\/ICA scaffold demonstrated superior bone regeneration outcomes, showing comparable performance to autografts in terms of new bone tissue formation, osteon structure, and 72-h cell viability, suggesting its potential as a viable alternative in bone tissue engineering.<\/jats:p>","DOI":"10.1177\/08853282251369228","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T18:45:20Z","timestamp":1755110720000},"page":"727-742","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigation of calvarial bone regeneration in a rat model using three-dimensional polycaprolactone\/carboxymethyl chitosan nano composite scaffolds containing hydroxyapatite nanoparticles along with the icariin and atorvastatin synthesized by the freeze-casting method"],"prefix":"10.1177","volume":"40","author":[{"given":"Nadia","family":"Sadeghi","sequence":"first","affiliation":[{"name":"Alborz University of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fereshteh","family":"Shanei","sequence":"additional","affiliation":[{"name":"Alborz University of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abouzar","family":"Moradi","sequence":"additional","affiliation":[{"name":"Alborz University of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atefeh","family":"Shamosi","sequence":"additional","affiliation":[{"name":"Alborz University of Medical Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8098-1467","authenticated-orcid":false,"given":"Sepehr","family":"Zamani","sequence":"additional","affiliation":[{"name":"Shahroud University of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6283-8181","authenticated-orcid":false,"given":"Majid","family":"Salehi","sequence":"additional","affiliation":[{"name":"Shahroud University of Medical Sciences"},{"name":"Shahroud University of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsabm.4c00362"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26103007"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1080\/09205063.2022.2127143"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtcomm.2019.100732"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pmatsci.2008.06.004"},{"key":"e_1_3_5_7_2","volume-title":"A novel concept of non-metallic orthopedic implants for load-bearing applications","author":"Plyusnin A","year":"2022","unstructured":"Plyusnin A, A novel concept of non-metallic orthopedic implants for load-bearing applications. List of Original Publications, 2022."},{"issue":"5","key":"e_1_3_5_8_2","first-page":"449","article-title":"Recent advancements in biocompatible coatings for metallic and non-metallic biomaterials: a review","volume":"23","author":"Abdulhasan AA","year":"2024","unstructured":"Abdulhasan AA, Ewe L, Mustafa AM, et al. Recent advancements in biocompatible coatings for metallic and non-metallic biomaterials: a review. Corros Sci Technol 2024; 23(5): 449\u2013469.","journal-title":"Corros Sci Technol"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.surfin.2025.107027"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202302132"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-70155-2"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2006.06.028"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s44174-022-00008-1"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-024-00307-5"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.3390\/biology10050398"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202202766"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.matt.2022.06.003"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/5584_2018_249"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03461-x"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S126505"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201403354"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1039\/c4tb00027g"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2018.04.045"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2020.102077"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.3390\/polym14010182"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1039\/D2TB02052A"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2023.1168504"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.3390\/polym13162754"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2022.02.007"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/nano11102569"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2024.105601"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00201"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00163"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2017.10.025"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/coatings9050327"},{"issue":"3","key":"e_1_3_5_36_2","first-page":"911","article-title":"A study on PLGA sustained release icariin\/titanium dioxide nanotube composite coating","volume":"23","author":"Wang F-F","year":"2019","unstructured":"Wang F-F, Li Y, Liu H-C. A study on PLGA sustained release icariin\/titanium dioxide nanotube composite coating. Eur Rev Med Pharmacol Sci 2019; 23(3): 911\u2013917.","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S203859"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.3904\/kjim.2015.244"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5446.1946"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.892247"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.3390\/ma13204679"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mser.2016.01.001"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075322"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1177\/08853282251329901"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmbbm.2021.104717"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-024-01357-y"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/iwj.14878"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfa.2021.126503"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.3390\/polym14163397"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceramint.2022.02.085"},{"issue":"11","key":"e_1_3_5_51_2","first-page":"43","article-title":"The effect of processing physical parameters on the mechanical, microstructure, and porosity of Gelatin-HA scaffolds produced by freeze-drying technique for biomedical applications","volume":"66","author":"Elhelw A","year":"2023","unstructured":"Elhelw A, El-Henawy M, Mandour R, et al. The effect of processing physical parameters on the mechanical, microstructure, and porosity of Gelatin-HA scaffolds produced by freeze-drying technique for biomedical applications. Egypt J Chem 2023; 66(11): 43\u201352.","journal-title":"Egypt J Chem"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1177\/2041731420967791"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.b.35553"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.036525"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1177\/08853282241292144"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.msec.2018.04.080"},{"issue":"9","key":"e_1_3_5_57_2","first-page":"1134","article-title":"Injectable multifunctional hydrogel containing Sphingosine 1-phosphate and human acellular amniotic membrane for skin wound healing","volume":"27","author":"Doudi S","year":"2024","unstructured":"Doudi S, Kamalabadi-Farahani M, Atashi A, et al. Injectable multifunctional hydrogel containing Sphingosine 1-phosphate and human acellular amniotic membrane for skin wound healing. Iranian journal of basic medical sciences. 2024; 27(9): 1134\u201347.","journal-title":"Iranian journal of basic medical sciences"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules19044256"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/bip.22359"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceramint.2021.11.206"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2020.01.012"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.msec.2016.10.084"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1208\/s12249-022-02419-1"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.msec.2020.111158"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2008.07.030"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomaterials.9b01381"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.3390\/nano11102569"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1002\/adem.202100463"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1039\/D2TB00546H"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1177\/08853282241238581"},{"key":"e_1_3_5_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2021.06.014"},{"key":"e_1_3_5_72_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-26163-3_2"},{"key":"e_1_3_5_73_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12232719"},{"key":"e_1_3_5_74_2","doi-asserted-by":"publisher","DOI":"10.3390\/ma15093376"},{"key":"e_1_3_5_75_2","doi-asserted-by":"publisher","DOI":"10.3390\/ma12182992"},{"key":"e_1_3_5_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2019.05.005"},{"key":"e_1_3_5_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2020.124895"},{"key":"e_1_3_5_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.compositesb.2022.109625"},{"key":"e_1_3_5_79_2","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12185"},{"key":"e_1_3_5_80_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13018-020-01841-0"},{"key":"e_1_3_5_81_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40729-023-00508-9"}],"container-title":["Journal of Biomaterials Applications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/08853282251369228","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/08853282251369228","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/08853282251369228","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T19:53:04Z","timestamp":1777492384000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/08853282251369228"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":80,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1177\/08853282251369228"],"URL":"https:\/\/doi.org\/10.1177\/08853282251369228","relation":{},"ISSN":["0885-3282","1530-8022"],"issn-type":[{"value":"0885-3282","type":"print"},{"value":"1530-8022","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,13]]}}}