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Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra\u2010conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory\u2010polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4\u2010ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1\u00a0\u00b1\u00a03.5\u00a0MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein\u2010based conduits. Moreover, the NGC can gradually regulate the intra\u2010conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF\/RSF\/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.<\/jats:p>","DOI":"10.1002\/advs.202302988","type":"journal-article","created":{"date-parts":[[2024,3,2]],"date-time":"2024-03-02T14:35:01Z","timestamp":1709390101000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Remodeling of the Intra\u2010Conduit Inflammatory Microenvironment to Improve Peripheral Nerve Regeneration with a Neuromechanical Matching Protein\u2010Based Conduit"],"prefix":"10.1002","volume":"11","author":[{"given":"Jia\u2010Yi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"},{"name":"Department of Rehabilitation Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu\u2010Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Centre for Biomedical Materials of Ministry of Education Frontiers Science Center for Materiobiology and Dynamic Chemistry School of Materials Science and Engineering East China University of Science and Technology  Shanghai 200237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun\u2010Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guan\u2010Jie","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng\u2010Xuan","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"huang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De\u2010Hua","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di\u2010Han","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Xiao","sequence":"additional","affiliation":[{"name":"School of Mechanical Medical and Process Engineering Centre for Biomedical Technologies Queensland University of Technology  Brisbane 4059 Australia"},{"name":"Australia\u2010China Centre for Tissue Engineering and Regenerative Medicine Queensland University of Technology  Brisbane 4059 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Xiao","sequence":"additional","affiliation":[{"name":"School of Mechanical Medical and Process Engineering Centre for Biomedical Technologies Queensland University of Technology  Brisbane 4059 Australia"},{"name":"Australia\u2010China Centre for Tissue Engineering and Regenerative Medicine Queensland University of Technology  Brisbane 4059 Australia"},{"name":"School of Medicine and Dentistry &amp; 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