PMID- 36435442 OWN - NLM STAT- MEDLINE DCOM- 20230131 LR - 20240216 IS - 1878-7568 (Electronic) IS - 1742-7061 (Print) IS - 1742-7061 (Linking) VI - 157 DP - 2023 Feb TI - Semaphorin 3A delivered by a rapidly polymerizing click hydrogel overcomes impaired implant osseointegration in a rat type 2 diabetes model. PG - 236-251 LID - S1742-7061(22)00757-7 [pii] LID - 10.1016/j.actbio.2022.11.030 [doi] AB - Semaphorin 3A (sema3A) is an osteoprotective factor that enhances bone formation while inhibiting osteoclast bone resorption. It is produced by rat calvarial osteoblasts cultured on grit-blasted/acid-etched microtextured (SLA) titanium surfaces at higher levels than on tissue culture polystyrene, suggesting that it may improve performance of titanium implants in vivo, particularly in conditions characterized by compromised bone quality. To test this, we established a clinically relevant type 2 diabetes mellitus (T2DM) rat model and used a non-toxic click hydrogel that rapidly polymerizes in situ (GEL) to provide localized controlled delivery of sema3A. In vitro studies confirmed that sema3A released from GEL was biologically active, increasing osteoblast differentiation of a pre-osteoblast cell-line. Whereas increased sema3A production was not observed in T2DM calvarial osteoblasts cultured on SLA, exogenous sema3A enhanced surface-induced osteoblast differentiation, indicating that it would be a viable candidate for in vivo use. Delivery of sema3A either by GEL or by local injection to bone defects enhanced osseointegration of SLA implants in the T2DM rats. Trabecular bone mass and bone-to-implant contact were decreased in T2DM rats compared to normal rats; sema3A delivered locally improved both parameters. These findings suggest that reduced trabecular bone contributes to poor osseointegration in T2DM patients and support GEL as a promising treatment option for sustained release of therapeutic doses of sema3A. Moreover, using this clinically translatable T2DM model and developing a biocompatible, Cu-free click chemistry hydrogel platform for the non-invasive delivery of therapeutics has major implications for regenerative medicine as a whole. STATEMENT OF SIGNIFICANCE: Osseointegration is compromised in patients with poor bone quality due to conditions like type 2 diabetes mellitus (T2DM). Previously, we showed that semaphorin 3A (sema3A) production is increased when human bone marrow stromal cells are cultured on titanium substrates that support osseointegration in vivo, suggesting it may enhance peri-implant osteogenesis in diabetes. Here we established a spontaneously developing T2DM rat model with clinical translatability and used it to assess sema3A effectiveness. Sema3A was delivered to the implant site via a novel copper-free click hydrogel, which has minimal swelling behavior and superior rheological properties. Osseointegration was successfully restored, and enhanced compared to burst release through injections. This study provides scientific evidence for using sema3A to treat impaired osseointegration in T2DM patients. CI - Copyright (c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. FAU - Deng, Jingyao AU - Deng J AD - Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23284, USA; VCU DaVinci Center for Innovation, Virginia Commonwealth University, Richmond, VA 23284, USA. FAU - Cohen, David J AU - Cohen DJ AD - Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23284, USA. FAU - Sabalewski, Eleanor L AU - Sabalewski EL AD - Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23284, USA. FAU - Van Duyn, Christine AU - Van Duyn C AD - Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23284, USA. FAU - Wilson, D Scott AU - Wilson DS AD - Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MA 21231, USA. FAU - Schwartz, Zvi AU - Schwartz Z AD - Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23284, USA; Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. FAU - Boyan, Barbara D AU - Boyan BD AD - Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23284, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: bboyan@vcu.edu. LA - eng GR - K12 AR084233/AR/NIAMS NIH HHS/United States GR - R01 AR072500/AR/NIAMS NIH HHS/United States PT - Journal Article DEP - 20221124 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Semaphorin-3A) RN - D1JT611TNE (Titanium) RN - 0 (Hydrogels) SB - IM MH - Rats MH - Humans MH - Animals MH - *Semaphorin-3A/pharmacology MH - *Diabetes Mellitus, Type 2 MH - Osseointegration MH - Titanium/pharmacology MH - Hydrogels MH - Osteogenesis MH - Osteoblasts MH - Surface Properties PMC - PMC10007856 MID - NIHMS1871851 OTO - NOTNLM OT - Bone formation OT - Bone regeneration OT - Hydrogel OT - Implants OT - Semaphorin 3A OT - Titanium OT - Type 2 diabetes COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests orpersonal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/11/27 06:00 MHDA- 2023/02/01 06:00 PMCR- 2024/02/01 CRDT- 2022/11/26 19:27 PHST- 2022/07/21 00:00 [received] PHST- 2022/11/14 00:00 [revised] PHST- 2022/11/16 00:00 [accepted] PHST- 2022/11/27 06:00 [pubmed] PHST- 2023/02/01 06:00 [medline] PHST- 2022/11/26 19:27 [entrez] PHST- 2024/02/01 00:00 [pmc-release] AID - S1742-7061(22)00757-7 [pii] AID - 10.1016/j.actbio.2022.11.030 [doi] PST - ppublish SO - Acta Biomater. 2023 Feb;157:236-251. doi: 10.1016/j.actbio.2022.11.030. Epub 2022 Nov 24.