{"doi":"10.1016/j.bioactmat.2024.09.013","title":"Combinational regenerative inductive effect of bio-adhesive hybrid hydrogels conjugated with hiPSC-derived myofibers and its derived EVs for volumetric muscle regeneration","abstract":"In regenerative medicine, extracellular vesicles (EVs) possess the potential to repair injured cells by delivering modulatory factors. However, the therapeutic effect of EVs in large-scale tissue defects, which are subject to prolonged timelines for tissue architecture and functional restoration, remains poorly understood. In this study, we introduce EVs and cell-tethering hybrid hydrogels composed of tyramine-conjugated gelatin (GelTA) that can be in-situ crosslinked with EVs derived from human induced pluripotent stem cell-derived myofibers (hiPSC-myofibers) and hiPSC-muscle precursor cells. This hybrid hydrogel sustains the release of EVs and provides a beneficial nano-topography and mechanical properties for creating a favorable extracellular matrix. Secreted EVs from the hiPSC-myofibers contain specific microRNAs, potentially improving myogenesis and angiogenesis. Herein, we demonstrate increased myogenic markers and fusion/differentiation indexes through the combinatory effects of EVs and integrin-mediated adhesions in the 3D matrix. Furthermore, we observe a unique impact of EVs, which aid in maintaining the viability and phenotype of myofibers under harsh environments. The hybrid hydrogel in-situ crosslinked with hiPSCs and EVs is facilely used to fabricate large-scale muscle constructs by the stacking of micro-patterned hydrogel domains. Later, we confirmed a combinational effect, whereby muscle tissue regeneration and functional restoration were improved, via an in vivo murine volumetric muscle loss model. • EVs extrated from hiPSC-myofibers contain specific miRNAs that promote myogenic differentiation and stimulate angiogenesis. • EVs support the survival and differentiation of hiPSC-myofibers in medium without myogenic differentiation reagents. • GelTA hydrogel sustains the releases of EVs and provides a favorable ECM via their unique physicochemical properties. • GelTA hydrogel in-situ crosslinked with hiPSCs and EVs improved muscle tissue regeneration and functional restoration.","journal":"Bioactive Materials","year":2024,"id":481786,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":870232,"name":"Myung Chul Lee","orcid":"0000-0002-0566-8494","position":1,"is_corresponding":false},{"id":1322136,"name":"Jieun Jeon","orcid":null,"position":2,"is_corresponding":false},{"id":628869,"name":"Alejandra Rodríguez‐delaRosa","orcid":"0000-0002-6149-4492","position":3,"is_corresponding":false},{"id":628662,"name":"Yori Endo","orcid":"0000-0002-9282-8811","position":4,"is_corresponding":false},{"id":1238637,"name":"Da‐Seul Kim","orcid":"0000-0002-6281-0434","position":5,"is_corresponding":false},{"id":1239087,"name":"Andrea Donaxi Madrigal‐Salazar","orcid":null,"position":6,"is_corresponding":false},{"id":1239088,"name":"Jeong Wook Seo","orcid":null,"position":7,"is_corresponding":false},{"id":1232735,"name":"Hyeseon Lee","orcid":null,"position":8,"is_corresponding":false},{"id":1321722,"name":"Ki‐Tae Kim","orcid":"0000-0002-5244-2092","position":9,"is_corresponding":false},{"id":1232737,"name":"Jae-I Moon","orcid":null,"position":10,"is_corresponding":false},{"id":1232738,"name":"Seung Gwa Park","orcid":null,"position":11,"is_corresponding":false},{"id":1322137,"name":"Mariana Carolina Lopez-Pacheco","orcid":null,"position":12,"is_corresponding":false},{"id":1238640,"name":"Abdulhameed F. 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