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Tissue engineering strategies are being pursued to treat neuromuscular injuries by mimicking aspects of native myofascicular architecture; however, the critical role of innervation in myofiber development is often overlooked. Our group previously developed a pre\u2010innervated tissue\u2010engineered muscle on nanofiber sheets, demonstrating that innervation facilitated myofiber maturation and function in vitro. The current study builds on this framework to biofabricate pre\u2010innervated three\u2010dimensional (3D) bundles of individual myofibers that more closely replicate in vivo architecture. Specifically, we established a methodology to generate centimeter\u2010scale Tissue Engineered Motor Units (TEMUs) comprising aligned myofiber bundles within a collagenous hydrogel and innervated by axons projecting from discrete population(s) of spinal motor neurons. A custom\u2010built polydimethylsiloxane micro\u2010scale channel system facilitated the alignment and self\u2010assembly of myoblasts. The presence of aggregated motor neurons and axonal integration significantly enhanced myofiber maturation and contractility compared to non\u2010innervated controls. We also evaluated the effects of media constituents on myofiber maturation, as assessed by myocyte fusion and sarcomere formation. Importantly, this TEMU biofabrication protocol is fully scalable, generating modular myofiber bundles at least 8 cm in length that can be aligned in parallel to achieve large\u2010scale myofiber macro\u2010bundles. TEMUs address key challenges in muscle tissue engineering by providing a 3D biofidelic platform to study the role of innervation in muscle development and function in vitro, as well as an implantable composite tissue to facilitate muscle replacement after severe trauma.<\/jats:p>","DOI":"10.1002\/mabi.202500660","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T14:36:56Z","timestamp":1786631816000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modular Tissue\u2010Engineered Motor Units Featuring Spinal Motor Neurons Innervating Self\u2010Assembled Myofiber Bundles"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5163-3663","authenticated-orcid":false,"given":"Melanie C.","family":"Hilman","sequence":"first","affiliation":[{"name":"Center For Brain Injury &amp; Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia Pennsylvania USA"},{"name":"Department of Bioengineering School of Engineering and Applied Science University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8529-587X","authenticated-orcid":false,"given":"Elizabeth N.","family":"Krizman","sequence":"additional","affiliation":[{"name":"Center For Brain Injury &amp; Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Foteini","family":"Mourkioti","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Cell and Developmental Biology Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Institute For Regenerative Medicine Musculoskeletal Program Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suradip","family":"Das","sequence":"additional","affiliation":[{"name":"Center For Brain Injury &amp; Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5355-5216","authenticated-orcid":false,"given":"D. 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