PMID- 35006932 OWN - NLM STAT- MEDLINE DCOM- 20220408 LR - 20220408 IS - 2576-6422 (Electronic) IS - 2576-6422 (Linking) VI - 4 IP - 9 DP - 2021 Sep 20 TI - Injectable Multifunctional Drug Delivery System for Hard Tissue Regeneration under Inflammatory Microenvironments. PG - 6993-7006 LID - 10.1021/acsabm.1c00620 [doi] AB - Engineering multifunctional hydrogel systems capable of amplifying the regenerative capacity of endogenous progenitor cells via localized presentation of therapeutics under tissue inflammation is central to the translation of effective strategies for hard tissue regeneration. Here, we loaded dexamethasone (DEX), a pleotropic drug with anti-inflammatory and mineralizing abilities, into aluminosilicate clay nanotubes (halloysite clay nanotubes (HNTs)) to engineer an injectable multifunctional drug delivery system based on photo-cross-linkable gelatin methacryloyl (GelMA) hydrogel. In detail, a series of hydrogels based on GelMA formulations containing distinct amounts of DEX-loaded nanotubes was analyzed for physicochemical and mechanical properties and kinetics of DEX release as well as compatibility with mesenchymal stem cells from human exfoliated deciduous teeth (SHEDs). The anti-inflammatory response and mineralization potential of the engineered hydrogels were determined in vitro and in vivo. DEX conjugation with HNTs was confirmed by FTIR analysis. The incorporation of DEX-loaded nanotubes enhanced the mechanical strength of GelMA with no effect on its degradation and swelling ratio. Scanning electron microscopy (SEM) images demonstrated the porous architecture of GelMA, which was not significantly altered by DEX-loaded nanotubes' (HNTs/DEX) incorporation. All GelMA formulations showed cytocompatibility with SHEDs (p < 0.05) regardless of the presence of HNTs or HNTs/DEX. However, the highest osteogenic cell differentiation was noticed with the addition of HNT/DEX 10% in GelMA formulations (p < 0.01). The controlled release of DEX over 7 days restored the expression of alkaline phosphatase and mineralization (p < 0.0001) in lipopolysaccharide (LPS)-stimulated SHEDs in vitro. Importantly, in vivo data revealed that DEX-loaded nanotube-modified GelMA (5.0% HNT/DEX 10%) led to enhanced bone formation after 6 weeks (p < 0.0001) compared to DEX-free formulations with a minimum localized inflammatory response after 7 days. Altogether, our findings show that the engineered DEX-loaded nanotube-modified hydrogel may possess great potential to trigger in situ mineralized tissue regeneration under inflammatory conditions. FAU - Bordini, Ester A F AU - Bordini EAF AUID- ORCID: 0000-0002-4178-5794 AD - Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, Michigan 48109, United States. FAU - Ferreira, Jessica A AU - Ferreira JA AUID- ORCID: 0000-0002-9669-4339 AD - Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, Michigan 48109, United States. FAU - Dubey, Nileshkumar AU - Dubey N AUID- ORCID: 0000-0002-6664-1375 AD - Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, Michigan 48109, United States. FAU - Ribeiro, Juliana S AU - Ribeiro JS AUID- ORCID: 0000-0002-6847-6262 AD - Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, Michigan 48109, United States. FAU - de Souza Costa, Carlos A AU - de Souza Costa CA AUID- ORCID: 0000-0002-7455-6867 AD - Department of Physiology and Pathology, Araraquara School of Dentistry, Universidade Estadual Paulista (UNESP), 1680 Humaita Street, Araraquara, Sao Paulo 14801-903, Brazil. FAU - Soares, Diana G AU - Soares DG AUID- ORCID: 0000-0002-1485-6104 AD - Department of Operative Dentistry, Endodontics and Dental Materials, Bauru School of Dentistry, Sao Paulo University (USP), Al. Dr. Octavio Pinheiro Brizola, 9-75, Bauru, Sao Paulo 17012-901, Brazil. FAU - Bottino, Marco C AU - Bottino MC AUID- ORCID: 0000-0001-8740-2464 AD - Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, Michigan 48109, United States. AD - Department of Biomedical Engineering, College of Engineering, University of Michigan, Carl A. Gerstacker Building, 2200 Bonisteel Blvd., Ann Arbor, Michigan 48109, United States. LA - eng GR - K08 DE023552/DE/NIDCR NIH HHS/United States GR - R01 DE026578/DE/NIDCR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20210827 PL - United States TA - ACS Appl Bio Mater JT - ACS applied bio materials JID - 101729147 RN - 0 (Hydrogels) RN - 0 (Methacrylates) RN - 0 (gelatin methacryloyl) RN - 9000-70-8 (Gelatin) RN - T1FAD4SS2M (Clay) SB - IM MH - Clay/chemistry MH - Drug Delivery Systems MH - Gelatin MH - Humans MH - *Hydrogels/pharmacology MH - Methacrylates MH - *Tissue Engineering/methods OTO - NOTNLM OT - bone OT - dentin OT - dexamethasone OT - gelatin methacryloyl OT - hydrogel OT - regeneration EDAT- 2022/01/11 06:00 MHDA- 2022/04/09 06:00 CRDT- 2022/01/10 17:13 PHST- 2022/01/10 17:13 [entrez] PHST- 2022/01/11 06:00 [pubmed] PHST- 2022/04/09 06:00 [medline] AID - 10.1021/acsabm.1c00620 [doi] PST - ppublish SO - ACS Appl Bio Mater. 2021 Sep 20;4(9):6993-7006. doi: 10.1021/acsabm.1c00620. Epub 2021 Aug 27.