{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:44:17Z","timestamp":1790624657330,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["HI20C0625"],"award-info":[{"award-number":["HI20C0625"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["P0015342"],"award-info":[{"award-number":["P0015342"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003661","name":"Korea Institute for Advancement of Technology","doi-asserted-by":"publisher","award":["HI20C0625"],"award-info":[{"award-number":["HI20C0625"]}],"id":[{"id":"10.13039\/501100003661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003661","name":"Korea Institute for Advancement of Technology","doi-asserted-by":"publisher","award":["P0015342"],"award-info":[{"award-number":["P0015342"]}],"id":[{"id":"10.13039\/501100003661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003661","name":"Korea Institute for Advancement of Technology","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100003661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CGBio Co., Ltd","award":["HI20C0625"],"award-info":[{"award-number":["HI20C0625"]}]},{"name":"CGBio Co., Ltd","award":["P0015342"],"award-info":[{"award-number":["P0015342"]}]},{"name":"CGBio Co., Ltd","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bone morphogenetic protein-2 (BMP-2) is used in the treatment of degenerative spinal disease and vertebral fractures, spine fusion, dental surgery, and facial surgery. However, high doses are associated with side effects such as inflammation and osteophytes. In this study, we performed spinal fusion surgery on mini-pigs using BMP-2 and a HA\/\u03b2-TCP hydrogel carrier, and evaluated the degree of fusion and osteophyte growth according to time and dosage. Increasing the dose of BMP-2 led to a significantly higher fusion rate than was observed in the control group, and there was no significant difference between the 8-week and 16-week samples. We also found that the HA + \u03b2-TCP hydrogel combination helped maintain the rate of BMP-2 release. In conclusion, the BMP-2-loaded HA\/\u03b2-TCP hydrogel carrier used in this study overcame the drawback of potentially causing side effects when used at high concentrations by enabling the sustained release of BMP-2. This method is also highly efficient, since it provides mineral matter to accelerate the fusion rate of the spine and improve bone quality.<\/jats:p>","DOI":"10.3390\/ijms24010892","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T04:28:17Z","timestamp":1672806497000},"page":"892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Concentration-Dependent Efficacy of Recombinant Human Bone Morphogenetic Protein-2 Using a HA\/\u03b2-TCP Hydrogel Carrier in a Mini-Pig Vertebral Oblique Lateral Interbody Fusion Model"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2935-4975","authenticated-orcid":false,"given":"Hye-Yeong","family":"Lee","sequence":"first","affiliation":[{"name":"Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-In","family":"Kang","sequence":"additional","affiliation":[{"name":"Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea"},{"name":"Department of Neurosurgery, Yongin Severance Hospital, Yonsei University College of Medicine, 363, Yongin-si 16995, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7274-391X","authenticated-orcid":false,"given":"Hye-Lan","family":"Lee","sequence":"additional","affiliation":[{"name":"Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwang-Yong","family":"Hwang","sequence":"additional","affiliation":[{"name":"Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keung-Nyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon","family":"Ha","sequence":"additional","affiliation":[{"name":"Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea"},{"name":"POSTECH Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1006\/excr.1996.0005","article-title":"Human osteogenic protein-1 induces chondroblastic, osteoblastic, and\/or adipocytic differentiation of clonal murine target cells","volume":"222","author":"Asahina","year":"1996","journal-title":"Exp. Cell Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1016\/j.biomaterials.2009.01.031","article-title":"Effect of local sequential vegf and bmp-2 delivery on ectopic and orthotopic bone regeneration","volume":"30","author":"Kempen","year":"2009","journal-title":"Biomaterials"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"838","DOI":"10.14245\/ns.2244464.232","article-title":"Safety and efficacy of recombinant human bone morphogenetic protein-2 in multilevel posterolateral lumbar fusion in a prospective, randomized, controlled trial","volume":"19","author":"Choi","year":"2022","journal-title":"Neurospine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"524","DOI":"10.14245\/ns.2244140.070","article-title":"Comparison between 3-dimensional-printed titanium and polyetheretherketone cages: 1-year outcome after minimally invasive transforaminal interbody fusion","volume":"19","author":"Kim","year":"2022","journal-title":"Neurospine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"299","DOI":"10.14245\/ns.2244038.019","article-title":"Genetic odyssey to ossification of the posterior longitudinal ligament in the cervical spine: A systematic review","volume":"19","author":"Won","year":"2022","journal-title":"Neurospine"},{"key":"ref_6","first-page":"423","article-title":"A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery","volume":"62","author":"Benglis","year":"2008","journal-title":"Neurosurgery"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1002\/jor.22160","article-title":"Bmp induced inflammation: A comparison of rhbmp-7 and rhbmp-2","volume":"30","author":"Lee","year":"2012","journal-title":"J. Orthop. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1007\/s10856-013-4967-5","article-title":"Effects of porous beta-tricalcium phosphate-based ceramics used as an e. Coli-derived rhbmp-2 carrier for bone regeneration","volume":"24","author":"Lee","year":"2013","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1126\/science.3201241","article-title":"Novel regulators of bone formation: Molecular clones and activities","volume":"242","author":"Wozney","year":"1988","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1054\/bjom.2000.0533","article-title":"Bone induction by Escherichia coli-derived recombinant human bone morphogenetic protein-2 compared with chinese hamster ovary cell-derived recombinant human bone morphogenetic protein-2","volume":"38","author":"Bessho","year":"2000","journal-title":"Br. J. Oral Maxillofac. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s00774-009-0040-3","article-title":"Osteoinductive capacity and heat stability of recombinant human bone morphogenetic protein-2 produced by Escherichia coli and dimerized by biochemical processing","volume":"27","author":"Yano","year":"2009","journal-title":"J. Bone Miner. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1016\/j.biomaterials.2013.11.029","article-title":"The effect of dose on rhbmp-2 signaling, delivered via collagen sponge, on osteoclast activation and in vivo bone resorption","volume":"35","author":"Kim","year":"2014","journal-title":"Biomaterials"},{"key":"ref_13","first-page":"1205","article-title":"Use of rhbmp-2 in combination with structural cortical allografts: Clinical and radiographic outcomes in anterior lumbar spinal surgery","volume":"87","author":"Burkus","year":"2005","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/00024720-200304000-00001","article-title":"Is infuse bone graft superior to autograft bone? An integrated analysis of clinical trials using the lt-cage lumbar tapered fusion device","volume":"16","author":"Burkus","year":"2003","journal-title":"J. Spinal Disord. Tech."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1007\/s11095-017-2147-x","article-title":"Formulation, delivery and stability of bone morphogenetic proteins for effective bone regeneration","volume":"34","author":"Jiskoot","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/ten.teb.2015.0357","article-title":"A review of the clinical side effects of bone morphogenetic protein-2","volume":"22","author":"James","year":"2016","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1023\/A:1013382832091","article-title":"Enhancement of bone growth by sustained delivery of recombinant human bone morphogenetic protein-2 in a polymeric matrix","volume":"18","author":"Woo","year":"2001","journal-title":"Pharm. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1089\/ten.2006.12.1305","article-title":"Enhanced bone regeneration at a segmental bone defect by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel","volume":"12","author":"Yamamoto","year":"2006","journal-title":"Tissue Eng."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1016\/j.biomaterials.2008.12.046","article-title":"The effect of an rhbmp-2 absorbable collagen sponge-targeted system on bone formation in vivo","volume":"30","author":"Visser","year":"2009","journal-title":"Biomaterials"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4856","DOI":"10.1016\/j.biomaterials.2005.01.012","article-title":"Enhanced osteoinduction by controlled release of bone morphogenetic protein-2 from biodegradable sponge composed of gelatin and beta-tricalcium phosphate","volume":"26","author":"Takahashi","year":"2005","journal-title":"Biomaterials"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1097\/01.brs.0000217650.90861.99","article-title":"Controlling bone morphogenetic protein diffusion and bone morphogenetic protein-stimulated bone growth using fibrin glue","volume":"31","author":"Patel","year":"2006","journal-title":"Spine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1007\/s10856-009-3914-y","article-title":"Developments in injectable multiphasic biomaterials. The performance of microporous biphasic calcium phosphate granules and hydrogels","volume":"21","author":"Daculsi","year":"2010","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.addr.2020.10.005","article-title":"Synthetic peptide hydrogels as 3D scaffolds for tissue engineering","volume":"160","author":"Ding","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7814","DOI":"10.1038\/s41598-017-08412-0","article-title":"3d biomimetic artificial bone scaffolds with dual-cytokines spatiotemporal delivery for large weight-bearing bone defect repair","volume":"7","author":"Bao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.addr.2007.03.016","article-title":"Matrices and scaffolds for delivery of bioactive molecules in bone and cartilage tissue engineering","volume":"59","author":"Lee","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115544","DOI":"10.1016\/j.bone.2020.115544","article-title":"Evaluation of synthetic ceramics as compression resistant matrix to promote osteogenesis of autologous blood coagulum containing recombinant human bone morphogenetic protein 6 in rabbit posterolateral lumbar fusion model","volume":"140","author":"Stokovic","year":"2020","journal-title":"Bone"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16924","DOI":"10.1038\/s41598-021-96484-4","article-title":"A novel bmp-2-loaded hydroxyapatite\/beta-tricalcium phosphate microsphere\/hydrogel composite for bone regeneration","volume":"11","author":"Tateiwa","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.msec.2016.09.074","article-title":"Strategies for delivering bone morphogenetic protein for bone healing","volume":"70","author":"Begam","year":"2017","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1111\/clr.12473","article-title":"Capability of new bone formation with a mixture of hydroxyapatite and beta-tricalcium phosphate granules","volume":"26","author":"Sanda","year":"2015","journal-title":"Clin. Oral Implants Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s10856-016-5734-1","article-title":"Microsphere-based scaffolds encapsulating tricalcium phosphate and hydroxyapatite for bone regeneration","volume":"27","author":"Gupta","year":"2016","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/aor.12275","article-title":"The effects of recombinant human bone morphogenetic protein-2-loaded tricalcium phosphate microsphere-hydrogel composite on the osseointegration of dental implants in minipigs","volume":"38","author":"Lee","year":"2014","journal-title":"Artif. Organs"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e28095","DOI":"10.1097\/MD.0000000000028095","article-title":"Neurologic deficit due to vertebral body osteophytes after oblique lumbar interbody fusion: A case report","volume":"100","author":"Lee","year":"2021","journal-title":"Medicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1089\/ten.tea.2010.0555","article-title":"High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo","volume":"17","author":"Zara","year":"2011","journal-title":"Tissue Eng. Part A"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.22203\/eCM.v023a02","article-title":"Osteogenic differentiation of mesenchymal stem cells is regulated by osteocyte and osteoblast cells in a simplified bone niche","volume":"23","author":"Birmingham","year":"2012","journal-title":"Eur. Cell Mater."},{"key":"ref_35","first-page":"4910399","article-title":"Bmp-2 enhances osteogenic differentiation of human adipose-derived and dental pulp stem cells in 2D and 3D in vitro models","volume":"2022","author":"Milian","year":"2022","journal-title":"Stem Cells Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15794","DOI":"10.1073\/pnas.1313898110","article-title":"Ca2+ channel nanodomains boost local Ca2+ amplitude","volume":"110","author":"Tadross","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"38035","DOI":"10.1038\/srep38035","article-title":"The complex nature of calcium cation interactions with phospholipid bilayers","volume":"6","author":"Melcrova","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hasegawa, T., Hongo, H., Yamamoto, T., Abe, M., Yoshino, H., Haraguchi-Kitakamae, M., Ishizu, H., Shimizu, T., Iwasaki, N., and Amizuka, N. (2022). Matrix vesicle-mediated mineralization and osteocytic regulation of bone mineralization. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179941"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2220\/biomedres.32.259","article-title":"Morphological assessment of bone mineralization in tibial metaphyses of ascorbic acid-deficient ods rats","volume":"32","author":"Hasegawa","year":"2011","journal-title":"Biomed. Res."},{"key":"ref_40","first-page":"133","article-title":"The osteocyte as a wiring transmission system","volume":"1","author":"Marotti","year":"2000","journal-title":"J. Musculoskelet. Neuron. Interact."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jsb.2017.07.004","article-title":"Coalignment of osteocyte canaliculi and collagen fibers in human osteonal bone","volume":"199","author":"Repp","year":"2017","journal-title":"J. Struct. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yao, H., Guo, J., Zhu, W., Su, Y., Tong, W., Zheng, L., Chang, L., Wang, X., Lai, Y., and Qin, L. (2022). Controlled release of bone morphogenetic protein-2 augments the coupling of angiogenesis and osteogenesis for accelerating mandibular defect repair. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112397"},{"key":"ref_43","first-page":"175","article-title":"Advanced hydrogel systems for mandibular reconstruction","volume":"21","author":"Guo","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"111782","DOI":"10.1016\/j.msec.2020.111782","article-title":"Injectable composite hydrogel promotes osteogenesis and angiogenesis in spinal fusion by optimizing the bone marrow mesenchymal stem cell microenvironment and exosomes secretion","volume":"123","author":"Zhang","year":"2021","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7906","DOI":"10.1038\/s41598-022-12082-y","article-title":"Effects of rhbmp-2-loaded hydroxyapatite granules\/beta-tricalcium phosphate hydrogel (ha\/beta-tcp\/hydrogel) composite on a rat model of caudal intervertebral fusion","volume":"12","author":"Nakagawa","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Brambilla, E., Locarno, S., Gallo, S., Orsini, F., Pini, C., Farronato, M., Thomaz, D.V., Lenardi, C., Piazzoni, M., and Tartaglia, G. (2022). Poloxamer-based hydrogel as drug delivery system: How polymeric excipients influence the chemical-physical properties. Polymers, 14.","DOI":"10.3390\/polym14173624"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hirun, N., and Kraisit, P. (2022). Drug-polymers composite matrix tablets: Effect of hydroxypropyl methylcellulose (hpmc) k-series on porosity, compatibility, and release behavior of the tablet containing a bcs class i drug. Polymers, 14.","DOI":"10.3390\/polym14163406"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jddst.2019.05.028","article-title":"Controlled release tablets based on hpmc:Lactose blends","volume":"52","author":"Moussa","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/892\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:58:03Z","timestamp":1760119083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/892"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,3]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24010892"],"URL":"https:\/\/doi.org\/10.3390\/ijms24010892","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,3]]}}}