{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T00:01:15Z","timestamp":1792886475653,"version":"4.5.0"},"reference-count":124,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Government program of basic research at the Koltzov Institute of Developmental Biology of the Russian Academy of Sciences","award":["0088-2025-0004"],"award-info":[{"award-number":["0088-2025-0004"]}],"id":[{"id":"https:\/\/ror.org\/02mh2cd26","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Reconstruction of large and complex hard tissue defects remains a major clinical challenge, as conventional autografts and allografts are often limited in availability, biological compatibility, and long-term efficacy, particularly for extensive defects or poor bone quality. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a potent osteoinductive factor capable of initiating the complete cascade of bone formation. However, its clinical use is restricted by dose-dependent complications such as inflammation, ectopic ossification, and osteolysis. This review synthesizes current evidence on the safety profile of rhBMP-2 and examines strategies to enhance its therapeutic index. Preclinical and clinical data indicate that conventional collagen-based carriers frequently cause rapid burst release and uncontrolled diffusion, aggravating adverse outcomes. It is noteworthy that low doses of rhBMP-2 (0.5\u20130.7 mg\/level in anterior cervical discectomy and fusion (ACDF) or 0.5\u20131.0 mg\/level in transforaminal lumbar interbody fusion (TLIF)) provide the optimal balance of efficacy and safety. Advanced biomaterial-based platforms, such as bioceramic\u2013polymer composites, injectable hydrogels, and 3D-printed scaffolds, enable spatially and temporally controlled release while maintaining osteogenic efficacy. Molecular delivery approaches, including chemically modified messenger RNA (cmRNA) and regional gene therapy, provide transient, site-specific rhBMP-2 expression with reduced dosing and minimal systemic exposure. By integrating mechanistic insights with translational advances, this review outlines a framework for optimizing rhBMP-2-based regenerative protocols, emphasizing their potential role in multidisciplinary strategies for reconstructing complex hard tissue defects.<\/jats:p>","DOI":"10.3390\/ijms262110723","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T11:11:16Z","timestamp":1762254676000},"page":"10723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Optimizing rhBMP-2 Therapy for Bone Regeneration: From Safety Concerns to Biomaterial-Guided Delivery Systems"],"prefix":"10.3390","volume":"26","author":[{"given":"Maria","family":"Chernysheva","sequence":"first","affiliation":[{"name":"Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 119334 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1361-666X","authenticated-orcid":false,"given":"Evgenii","family":"Ruchko","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 119334 Moscow, Russia"},{"name":"Lopukhin Federal Research and Clinical Center of Physical\u2013Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artem","family":"Eremeev","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 119334 Moscow, Russia"},{"name":"Lopukhin Federal Research and Clinical Center of Physical\u2013Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e29292","DOI":"10.1097\/MD.0000000000029292","article-title":"Induced Membrane Technique for Large Bone Defects: A Systematic Review and Individual Participant Data Meta-Analysis","volume":"101","author":"Sun","year":"2022","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hoveidaei, A.H., Ghaseminejad-Raeini, A., Esmaeili, S., Sharafi, A., Ghaderi, A., Pirahesh, K., Azarboo, A., Nwankwo, B.O., and Conway, J.D. 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