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However, stem cell treatment of SCI has been severely impaired by the increased generation of reactive oxygen species in the lesion microenvironment, which can lead to a high level of stem cell death and dysfunction. Herein, a MnO2 nanoparticle (NP)-dotted hydrogel is prepared through dispersion of MnO2 NPs in a PPFLMLLKGSTR peptide modified hyaluronic acid hydrogel. The peptide-modified hydrogel enables the adhesive growth of mesenchymal stem cells (MSCs) and nerve tissue bridging. The MnO2 NPs alleviate the oxidative environment, thereby effectively improving the viability of MSCs. Transplantation of MSCs in the multifunctional gel generates a significant motor function restoration on a long-span rat spinal cord transection model and induces an in vivo integration as well as neural differentiation of the implanted MSCs, leading to a highly efficient regeneration of central nervous spinal cord tissue. Therefore, the MnO2 NP-dotted hydrogel represents a promising strategy for stem-cell-based therapies of central nervous system diseases through the comprehensive regulation of pathological microenvironment complications.<\/jats:p>","DOI":"10.1021\/acsnano.9b07598","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T12:52:46Z","timestamp":1574772766000},"page":"14283-14293","source":"Crossref","is-referenced-by-count":280,"title":["A MnO2 Nanoparticle-Dotted Hydrogel Promotes\nSpinal Cord Repair\n                    <i>via<\/i>\n                    Regulating Reactive Oxygen\nSpecies Microenvironment and Synergizing with Mesenchymal Stem Cells"],"prefix":"10.1021","volume":"13","author":[{"given":"Liming","family":"Li","sequence":"first","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Xiao","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiafu","family":"Mu","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongcui","family":"Cao","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8133-5472","authenticated-orcid":true,"given":"Rongjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Imperial College London , , South Kensington Campus , , ,","place":["London, United Kingdom, SW7 2AZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6142-5489","authenticated-orcid":true,"given":"Hirak Kumar","family":"Patra","sequence":"additional","affiliation":[{"name":"University of Cambridge , , , ,","place":["Cambridge, United Kingdom, CB2 0SP"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqing","family":"Feng","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Ministry of Education and Tianjin City , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiko","family":"Tabata","sequence":"additional","affiliation":[{"name":"Kyoto University , , ,","place":["Kyoto, Japan, 606-8501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel K. H.","family":"Slater","sequence":"additional","affiliation":[{"name":"University of Cambridge , , , ,","place":["Cambridge, United Kingdom, CB2 0SP"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4498-5705","authenticated-orcid":true,"given":"Jianbin","family":"Tang","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1837-7976","authenticated-orcid":true,"given":"Youqing","family":"Shen","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1052-7060","authenticated-orcid":true,"given":"Jianqing","family":"Gao","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,11,26]]},"reference":[{"key":"2026081718230857200_cit1","doi-asserted-by":"publisher","first-page":"S193","DOI":"10.1038\/nature16035","article-title":"Global Neurotrauma\nResearch Challenges and Opportunities","volume":"527","author":"Rubiano","year":"2015","journal-title":"Nature"},{"key":"2026081718230857200_cit2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002322","article-title":"Long-Term Health Status and Trajectories\nof Seriously\nInjured Patients: A Population-Based Longitudinal Study","volume":"14","author":"Gabbe","year":"2017","journal-title":"PLoS Med."},{"key":"2026081718230857200_cit3","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/S1474-4422(18)30415-0","article-title":"Global, Regional,\nand National Burden\nof Traumatic Brain Injury and Spinal Cord Injury, 1990\u20132016:\nA Systematic Analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Badhiwala","year":"2019","journal-title":"Lancet Neurol."},{"key":"2026081718230857200_cit4","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/s41586-018-0068-4","article-title":"Dissecting\nSpinal Cord Regeneration","volume":"557","author":"Sofroniew","year":"2018","journal-title":"Nature"},{"key":"2026081718230857200_cit5","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1093\/brain\/awt262","article-title":"Restoration of Sensorimotor\nFunctions after Spinal Cord Injury","volume":"137","author":"Dietz","year":"2014","journal-title":"Brain"},{"key":"2026081718230857200_cit6","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nn.4541","article-title":"Cell Transplantation\nTherapy for Spinal Cord Injury","volume":"20","author":"Assinck","year":"2017","journal-title":"Nat. Neurosci."},{"key":"2026081718230857200_cit7","doi-asserted-by":"publisher","first-page":"3330","DOI":"10.1021\/acsami.6b12829","article-title":"Peptide-Tethered\nHydrogel Scaffold Promotes Recovery from Spinal Cord Transection via Synergism with Mesenchymal Stem Cells","volume":"9","author":"Li","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"2026081718230857200_cit8","doi-asserted-by":"publisher","first-page":"046033","DOI":"10.1088\/1741-2560\/8\/4\/046033","article-title":"High Molecular Weight\nHyaluronic Acid Limits Astrocyte\nActivation and Scar Formation after Spinal Cord Injury","volume":"8","author":"Khaing","year":"2011","journal-title":"J. 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Neurosurg\nSpine"},{"key":"2026081718230857200_cit11","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/sj.sc.3101674","article-title":"Increased Production of Reactive\nOxygen Species Contributes to Motor Neuron Death in a Compression\nMouse Model of Spinal Cord Injury","volume":"43","author":"Xu","year":"2005","journal-title":"Spinal Cord"},{"key":"2026081718230857200_cit12","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1002\/stem.1579","article-title":"Concise Review:\nSpinal Cord Injuries: How Could Adult\nMesenchymal and Neural Crest Stem Cells Take up the Challenge?","volume":"32","author":"Neirinckx","year":"2014","journal-title":"Stem Cells"},{"key":"2026081718230857200_cit13","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.redox.2015.12.011","article-title":"Cellular\nand Subcellular Oxidative Stress Parameters Following Severe Spinal\nCord Injury","volume":"8","author":"Visavadiya","year":"2016","journal-title":"Redox Biol."},{"key":"2026081718230857200_cit14","doi-asserted-by":"publisher","first-page":"134","DOI":"10.3109\/10799893.2012.672994","article-title":"Molecular\nRole of Catalase on Oxidative Stress-Induced Ca2+ Signaling\nand Trp Cation Channel Activation in Nervous System","volume":"32","author":"Naziroglu","year":"2012","journal-title":"J. Recept. Signal Transduction Res."},{"key":"2026081718230857200_cit15","doi-asserted-by":"publisher","first-page":"7129","DOI":"10.1002\/adma.201601902","article-title":"Intelligent\nAlbumin-MnO2 Nanoparticles as pH-\/H2O2-Responsive Dissociable\nNanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy","volume":"28","author":"Chen","year":"2016","journal-title":"Adv. Mater."},{"key":"2026081718230857200_cit16","doi-asserted-by":"publisher","first-page":"3202","DOI":"10.1021\/nn405773r","article-title":"Multifunctional\nAlbumin-MnO2 Nanoparticles Modulate Solid Tumor Microenvironment\nby Attenuating Hypoxia, Acidosis, Vascular Endothelial Growth Factor\nand Enhance Radiation Response","volume":"8","author":"Prasad","year":"2014","journal-title":"ACS Nano"},{"key":"2026081718230857200_cit17","doi-asserted-by":"publisher","first-page":"12682","DOI":"10.1021\/acsnano.8b07584","article-title":"Integration of Polymerization and\nBiomineralization as a Strategy\nto Facilely Synthesize Nanotheranostic Agents","volume":"12","author":"Xiao","year":"2018","journal-title":"ACS Nano"},{"key":"2026081718230857200_cit18","doi-asserted-by":"publisher","first-page":"4698","DOI":"10.1016\/j.biomaterials.2006.04.043","article-title":"In Situ Cross-Linkable\nHyaluronic Acid Hydrogels Prevent Post-Operative Abdominal Adhesions\nin a Rabbit Model","volume":"27","author":"Yeo","year":"2006","journal-title":"Biomaterials"},{"key":"2026081718230857200_cit19","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1016\/j.biomaterials.2006.10.021","article-title":"The Prevention\nof Peritoneal Adhesions by In Situ Cross-Linking\nHydrogels of Hyaluronic Acid and Cellulose Derivatives","volume":"28","author":"Ito","year":"2007","journal-title":"Biomaterials"},{"key":"2026081718230857200_cit20","doi-asserted-by":"publisher","first-page":"14896","DOI":"10.1021\/ja507626y","article-title":"Cell Protective,\nAbc Triblock Polymer-Based Thermoresponsive\nHydrogels with Ros-Triggered Degradation and Drug Release","volume":"136","author":"Gupta","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"2026081718230857200_cit21","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1016\/j.cell.2012.08.020","article-title":"Long-Distance Growth and Connectivity of Neural Stem\nCells after Severe Spinal Cord Injury","volume":"150","author":"Lu","year":"2012","journal-title":"Cell"},{"key":"2026081718230857200_cit22","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1172\/JCI59251","article-title":"Human Dental Pulp-Derived\nStem Cells\nPromote Locomotor Recovery after Complete Transection of the Rat Spinal\nCord by Multiple Neuro-Regenerative Mechanisms","volume":"122","author":"Sakai","year":"2011","journal-title":"J. Clin. Invest."},{"key":"2026081718230857200_cit23","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.biomaterials.2015.02.073","article-title":"Integration of Donor Mesenchymal Stem Cell-Derived\nNeuron-Like Cells into Host Neural Network after Rat Spinal Cord Transection","volume":"53","author":"Zeng","year":"2015","journal-title":"Biomaterials"},{"key":"2026081718230857200_cit24","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s41467-017-00583-8","article-title":"An Injectable Hydrogel\nEnhances Tissue Repair after\nSpinal Cord Injury by Promoting Extracellular Matrix Remodeling","volume":"8","author":"Hong","year":"2017","journal-title":"Nat. Commun."},{"key":"2026081718230857200_cit25","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/s41593-018-0093-5","article-title":"Cortico-Reticulo-Spinal\nCircuit Reorganization Enables Functional Recovery after Severe Spinal\nCord Contusion","volume":"21","author":"Asboth","year":"2018","journal-title":"Nat. Neurosci."},{"key":"2026081718230857200_cit26","doi-asserted-by":"publisher","first-page":"1706032","DOI":"10.1002\/adma.201706032","article-title":"Biodegradable Spheres\nProtect Traumatically Injured Spinal Cord by Alleviating the Glutamate-Induced\nExcitotoxicity","volume":"30","author":"Liu","year":"2018","journal-title":"Adv. Mater."},{"key":"2026081718230857200_cit27","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.biomaterials.2016.08.005","article-title":"Transplantation\nof Tissue Engineering Neural Network and Formation of Neuronal Relay\ninto the Transected Rat Spinal Cord","volume":"109","author":"Lai","year":"2016","journal-title":"Biomaterials"},{"key":"2026081718230857200_cit28","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.clineuro.2011.11.002","article-title":"Correlational Study\nof the Serum Levels of the Glial Fibrillary Acidic Protein and Neurofilament\nProteins in Parkinson\u2019s Disease Patients","volume":"114","author":"Su","year":"2012","journal-title":"Clin Neurol Neurosurg"},{"key":"2026081718230857200_cit29","doi-asserted-by":"publisher","first-page":"4797","DOI":"10.1016\/j.biomaterials.2003.12.012","article-title":"Prolongation\nof Sciatic Nerve Blockade by In Situ Cross-Linked\nHyaluronic Acid","volume":"25","author":"Jia","year":"2004","journal-title":"Biomaterials"},{"key":"2026081718230857200_cit30","doi-asserted-by":"publisher","first-page":"1900603","DOI":"10.1002\/adfm.201900603","article-title":"Ferrimagnetic\nNanochains-Based Mesenchymal\nStem Cell Engineering for Highly Efficient Post-Stroke Recovery","volume":"29","author":"Zhang","year":"2019","journal-title":"Adv. Funct. Mater."}],"container-title":["ACS Nano"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsnano.9b07598","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancac3\/article-pdf\/13\/12\/14283\/8360115\/nn9b07598.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancac3\/article-pdf\/13\/12\/14283\/8360115\/nn9b07598.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:26:35Z","timestamp":1787005595000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancac3\/article\/13\/12\/14283\/808861\/A-MnO2-Nanoparticle-Dotted-Hydrogel-Promotes"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,26]]},"references-count":30,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,11,26]]},"published-print":{"date-parts":[[2019,12,24]]}},"URL":"https:\/\/doi.org\/10.1021\/acsnano.9b07598","relation":{},"ISSN":["1936-0851","1936-086X"],"issn-type":[{"value":"1936-0851","type":"print"},{"value":"1936-086X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,26]]}}}