{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:41:59Z","timestamp":1790167319939,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,26]],"date-time":"2021-06-26T00:00:00Z","timestamp":1624665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2017-04651"],"award-info":[{"award-number":["2017-04651"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>Due to its unique properties resembling living tissues, hydrogels are attractive carriers for the localized and targeted delivery of various drugs. Drug release kinetics from hydrogels are commonly controlled by network properties and the drug-network interactions. However, and simultaneously, the programmable delivery of multiple drugs with opposing properties (hydrophilicity, molecular weight, etc.) from hydrogels with determined network properties is still challenging. Herein, we describe the preparation of injectable self-healing hyaluronic acid (HA) hydrogels that release hydrophobic simvastatin and hydrophilic aminobisphosphonate (BP) drugs independently in response to acidic and thiol-containing microenvironments, respectively. We apply a prodrug strategy to BP by conjugating it to HA via a self-immolative disulfide linker that is stable in the blood plasma and is cleavable in the cytoplasm. Moreover, we utilize HA-linked BP ligands to reversibly bind Ca2+ ions and form coordination hydrogels. Hydrazone coupling of hydrophobic ligands to HA permits the encapsulation of simvastatin molecules in the resulting amphiphilic HA derivative and the subsequent acid-triggered release of the drug. The conjugation of BP and hydrophobic ligands to HA enables preparation of both bulk self-healing hydrogels and nanogels. Moreover, the developed hydrogel system is shown to be multi-responsive by applying orthogonally cleavable linkers. The presented hydrogel is a potential candidate for the combination treatment of osteoporosis and bone cancers as well as for bone tissue regeneration since it can deliver bone anabolic and anti-catabolic agents in response to bone diseases microenvironments.<\/jats:p>","DOI":"10.3390\/polym13132106","type":"journal-article","created":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T23:57:22Z","timestamp":1624838242000},"page":"2106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Differentiating Co-Delivery of Bisphosphonate and Simvastatin by Self-Healing Hyaluronan Hydrogel Formed by Orthogonal \u201cClicks\u201d: An In-Vitro Assessment"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2332-3665","authenticated-orcid":false,"given":"Dmitri A.","family":"Ossipov","sequence":"first","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9035-7078","authenticated-orcid":false,"given":"Mads","family":"L\u00fcchow","sequence":"additional","affiliation":[{"name":"Department of Fiber and Polymer Technology, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9200-8004","authenticated-orcid":false,"given":"Michael","family":"Malkoch","sequence":"additional","affiliation":[{"name":"Department of Fiber and Polymer Technology, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G","article-title":"Skeletal complications of malignancy","volume":"80","author":"Coleman","year":"1997","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1172\/JCI13073","article-title":"Osteolysis and cancer","volume":"107","author":"Goltzman","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/S1470-2045(16)30096-1","article-title":"Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): A randomised, multicentre, open-label, phase 3 trial","volume":"17","author":"Redini","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_4","first-page":"92","article-title":"Osteoporosis: A Review of Treatment options","volume":"43","author":"Tu","year":"2018","journal-title":"Pharm. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1210\/jcem.86.3.7366","article-title":"Anabolic Therapy for Osteoporosis","volume":"86","author":"Rosen","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","first-page":"62","article-title":"Optimizing Sequential and Combined Anabolic and Antiresorptive Osteoporosis Therapy","volume":"2","author":"Leder","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.2174\/1381612825666190801140703","article-title":"Hyaluronic Acid Modified Risedronate and Teriparatide Co-loaded Nanocarriers for Improved Osteogenic Differentiation of Osteoblasts for the Treatment of Osteoporosis","volume":"25","author":"Abourehab","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.ijbiomac.2018.05.116","article-title":"Design and development of novel hyaluronate-modified nanoparticles for combo-delivery of curcumin and alendronate: Fabrication, characterization, and cellular and molecular evidences of enhanced bone regeneration","volume":"116","author":"Dong","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16071","DOI":"10.1038\/natrevmats.2016.71","article-title":"Designing hydrogels for controlled drug delivery","volume":"1","author":"Li","year":"2016","journal-title":"Nat. Rev. Mater."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Imitaz, N., Niazi, M.B.K., Fasim, F., Khan, B.A., Bano, S.A., Shah, G.M., Badshah, M., Menaa, F., and Uzair, B. (2019). Fabrication of an Original Transparent PVA\/Gelatin Hydrogel: In Vitro Antimicrobial Activity against Skin Pathogens. Int. J. Polym. Sci.","DOI":"10.1155\/2019\/7651810"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1208\/s12249-020-01866-y","article-title":"Fabrication, Physical Characterization, and In Vitro, In Vivo Evaluation of Ginger Extract-Loaded Gelatin\/Poly(Vinyl Alcohol) Hydrogel Films Against Burn Wound Healing in Animal Model","volume":"21","author":"Khan","year":"2020","journal-title":"AAPS Pharm. Sci. Tech."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.bone.2011.04.022","article-title":"Bisphosphonates: The first 40 years","volume":"49","author":"Russel","year":"2011","journal-title":"Bone"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1126\/science.286.5446.1946","article-title":"Stimulation of bone formation in vitro and in rodents by statins","volume":"286","author":"Mundy","year":"1999","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1016\/S0140-6736(00)02408-9","article-title":"Oral statins and increased bone mineral density in postmenopausal women","volume":"355","author":"Edwards","year":"2000","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s00774-014-0638-y","article-title":"The functional mechanism of simvastatin in experimental osteoporosis","volume":"34","author":"Dai","year":"2016","journal-title":"J. Bone Miner. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s10067-004-1053-x","article-title":"Effects of simvastatin on bone mineral density and remodeling parameters in postmenopausal osteopenic subjects: 1-year follow-up study","volume":"24","author":"Tikiz","year":"2005","journal-title":"Clin. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.coph.2018.03.010","article-title":"Targeting therapeutics to bone by conjugation with bisphosphonates","volume":"40","author":"Young","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.ijbiomac.2019.11.066","article-title":"Hyaluronic acid: A review on its biology, aspects of drug delivery, route of administration and a special emphasis on its approved marketed products and recent clinical studies","volume":"151","author":"Vasvani","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bayer, I.S. (2020). Hyaluronic Acid and Controlled Release: A Review. Molecules, 256.","DOI":"10.3390\/molecules25112649"},{"key":"ref_20","unstructured":"Menaa, F., Menaa, A., and Menaa, B. (2011). Hyaluronic Acid and Derivatives for Tissue Engineering. J. Biotechnol. Biomater., S3."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lee, S.Y., Kang, M.S., Jeong, W.Y., Han, D.-W., and Kim, K.S. (2020). Hyaluronic Acid-Based Theranostic Nanomedicines for Targeted Cancer Therapy. Cancers, 12.","DOI":"10.3390\/cancers12040940"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1021\/acs.bioconjchem.5b00160","article-title":"Determination of the Rat in Vivo Pharmacokinetic profile of a Bone-Targeting Dual-Action Pro-Drug for Treatment of Osteoporosis","volume":"26","author":"Chen","year":"2015","journal-title":"Bioconjugate Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7012","DOI":"10.1021\/acs.jmedchem.6b00951","article-title":"Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action prodrug for the Treatment of Osteoporosis","volume":"60","author":"Xie","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1039\/C6SC01831A","article-title":"Decoupling of stability and release in disulfide bonds with antibody-small molecule conjugates","volume":"8","author":"Pillow","year":"2017","journal-title":"Chem. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0165-022X(98)00027-X","article-title":"N-Hydroxysuccinimide carbonates and carbamates are useful reactive reagents for coupling ligands to lysines on proteins","volume":"38","author":"Morpurgo","year":"1999","journal-title":"J. Biochem. Biophys. Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4105","DOI":"10.1021\/ma400543u","article-title":"Orthogonal Chemoselective Assembly of Hyaluronic Acid Networks and Nanogels for Drug Delivery","volume":"46","author":"Ossipov","year":"2013","journal-title":"Macromolecules"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8368","DOI":"10.1039\/c0cc03055d","article-title":"Modular approach to functional hyaluronic acid hydrogels using orthogonal chemical reactions","volume":"46","author":"Ossipov","year":"2010","journal-title":"Chem. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1039\/C5BM00355E","article-title":"Control of Growth Factor Binding and Release in Bisphosphonate Functionalized Hydrogels Guides Rapid Differentiation of Precursor Cells In Vitro","volume":"4","author":"Kootala","year":"2016","journal-title":"Biomater. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8781","DOI":"10.1021\/ja902857b","article-title":"In situ Cross-Linkable High Molecular Weight Hyaluronan-Bisphosphonate Conjugate for Localized Delivery and Cell-Specific Targeting: A Hydrogel Linked Prodrug Approach","volume":"131","author":"Varghese","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6918","DOI":"10.1016\/j.biomaterials.2014.05.003","article-title":"Self-healing Hybrid Nanocomposites Consisting of Biosphosphonated Hyaluronan and Calcium Phosphate Nanoparticles","volume":"35","author":"Nejadnik","year":"2014","journal-title":"Biomaterials"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1021\/acs.chemmater.7b00128","article-title":"Dynamic Coordination Chemistry Enables Free Directional Printing of Biopolymer Hydrogel","volume":"29","author":"Shi","year":"2017","journal-title":"Chem. Mater."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11151","DOI":"10.1039\/C6CC05565F","article-title":"\u201cSmart\u201d drug loaded nanoparticle delivery from a self-healing hydrogel enabled by dynamic magnesium-biopolymer chemistry","volume":"52","author":"Shi","year":"2016","journal-title":"Chem. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shi, L., Zhao, Y., Xie, Q., Fan, C., Hilborn, J., Dai, J., and Ossipov, D. (2018). Moldable Hyaluronan Hydrogel Enabled by Dynamic Metal-Bisphosphonate Coordination Chemistry for Wound Healing. Adv. Healthc. Mater., 7.","DOI":"10.1002\/adhm.201700973"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1002\/marc.201600353","article-title":"Exploiting Bisphosphonate-Bioactive Glass Interactions for the Development of Self-Healing and Bioactive Composite Hydrogels","volume":"37","author":"Diba","year":"2016","journal-title":"Macromol. Rapid Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/s41467-020-15152-9","article-title":"Bisphosphonate nanoclay edge-site interactions facilitate hydrogel self-assembly and sustained growth factor localization","volume":"11","author":"Kim","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1002\/cmdc.201600465","article-title":"Targeting Cancer cells with Bisphosphonate Prodrug","volume":"11","author":"Matsumoto","year":"2016","journal-title":"Chem. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7477","DOI":"10.1039\/C6PY01882C","article-title":"Combination anti-HIV therapy via tandem release of prodrugs from macromolecular carriers","volume":"7","author":"Danial","year":"2016","journal-title":"Polym. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1021\/acs.bioconjchem.9b00364","article-title":"Dual-Responsive Micelles with Aggregation-Induced Emission Feature and Two-Photon Absorption for Accurate Drug Delivery and Bioimaging","volume":"30","author":"Yu","year":"2019","journal-title":"Bioconjugate Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/anie.201105565","article-title":"Sticky Nanoparticles: A Platform fore siRNA Delivery by a Bis(zinc(II)dipicolylamine)-Functionalized, Self-Assembled Nanoconjugate","volume":"51","author":"Liu","year":"2012","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Su, J. (2018). Thiol-Mediated Chemoselective Strategies for In Situ Formation of Hydrogels. Gels, 4.","DOI":"10.3390\/gels4030072"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14399","DOI":"10.1021\/acsami.8b00802","article-title":"Facile Fabrication of a Modular \u201dCatch and Release\u201d Hydrogel Iterface: Harnessing Thiol-Disulfide Exchange for Reversible Protein Capture and Cell Attachment","volume":"10","author":"Gevrek","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1002\/mabi.201400135","article-title":"A novel Crosslinked Hyaluronic Acid Nanogel for Drug Delivery","volume":"14","author":"Pedrosa","year":"2014","journal-title":"Macromol. Biosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8161","DOI":"10.1016\/j.biomaterials.2011.07.045","article-title":"Photo-cured hyaluronic acid-based hydrogels containing simvastatin as a tissue regeneration scaffold","volume":"32","author":"Bae","year":"2011","journal-title":"Biomaterials"}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/13\/13\/2106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:24:50Z","timestamp":1760163890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/13\/13\/2106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,26]]},"references-count":43,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["polym13132106"],"URL":"https:\/\/doi.org\/10.3390\/polym13132106","relation":{},"ISSN":["2073-4360"],"issn-type":[{"value":"2073-4360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,26]]}}}