Lee, Myung Chul Lee, Jae Seo Kim, Seongsoo Jamaiyar, Anurag Wu, Winona Gonzalez, Montserrat Legorreta Duran, Tania Carolina Acevedo Madrigal-Salazar, Andrea Donaxi Bassous, Nicole Carvalho, Violeta Choi, Cholong Kim, Da-Seul Seo, Jeong Wook Rodrigues, Nelson Teixeira, Senhorinha F. C. F. Alkhateeb, Abdulhameed F. Soto, Javier Alejandro Lozano Hussain, Mohammad Asif Leijten, Jeroen Feinberg, Mark W. Shin, Su Ryon 2024-10-16T16:30:09Z 2024-10-16T16:30:09Z 2024-10-17 2025-01 0935-9648 https://pubs.kist.re.kr/handle/201004/150807 Microporous hydrogels have been widely used for delivering therapeutic cells. However, several critical issues, such as the lack of control over the harsh environment they are subjected to under pathological conditions and rapid egression of cells from the hydrogels, have produced limited therapeutic outcomes. To address these critical challenges, cell-tethering and hypoxic conditioning colloidal hydrogels containing mesenchymal stem cells (MSCs) are introduced to increase the productivity of paracrine factors locally and in a long-term manner. Cell-tethering colloidal hydrogels that are composed of tyramine-conjugated gelatin prevent cells from egressing through on-cell oxidative phenolic crosslinks while providing mechanical stimulation and interconnected microporous networks to allow for host-implant interactions. Oxygenating microparticles encapsulated in tyramine-conjugated colloidal microgels continuously generated oxygen for 2 weeks with rapid diffusion, resulting in maintaining a mild hypoxic condition while MSCs consumed oxygen under severe hypoxia. Synergistically, local retention of MSCs within the mild hypoxic-conditioned and mechanically robust colloidal hydrogels significantly increased the secretion of various angiogenic cytokines and chemokines. The oxygenating colloidal hydrogels induced anti-inflammatory responses, reduced cellular apoptosis, and promoted numerous large blood vessels in vivo. Finally, mice injected with the MSC-tethered oxygenating colloidal hydrogels significantly improved blood flow restoration and muscle regeneration in a hindlimb ischemia (HLI) model. This study introduces cell-tethering and oxygenating colloidal hydrogels that prevent cell egression and maintain mild hypoxic conditions while providing mechanical stimulation and interconnected microporous networks. These synergistic multiple factors significantly increase the productivity of paracrine factors of mesenchymal stem cells locally and in a long-term manner, improving blood flow restoration and muscle regeneration in response to hindlimb ischemia. image English WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Synergistic effect of Hypoxic Conditioning and Cell-Tethering Colloidal Gels enhanced Productivity of MSC Paracrine Factors and Accelerated Vessel Regeneration Article 10.1002/adma.202408488 1 Advanced Materials, v.37, no.3 Advanced Materials 37 3 N scie scopus 001409912800036 2-s2.0-85205940879 Chemistry, Multidisciplinary Chemistry, Physical Nanoscience & Nanotechnology Materials Science, Multidisciplinary Physics, Applied Physics, Condensed Matter Chemistry Science & Technology - Other Topics Materials Science Physics Article MECHANISMS EXPRESSION SCAFFOLDS APOPTOSIS PLACENTA IMPROVES SURVIVAL ANGIOGENESIS STEM-CELLS REPAIR oxygenating microparticles paracrine effect vessel regeneration colloidal gel hMSC hypoxic conditioning ischemic disease mechanical stimulation