Bioengineered Constructs as a Tissue Engineering-Based Therapy for Volumetric Muscle Loss

Severe skeletal muscle injuries involving substantial tissue loss can significantly impair muscle strength and functionality, reducing the quality of life for affected individuals. Such injuries, termed volumetric muscle loss, require extensive clinical intervention, as the body's innate healing mechanisms are insufficient to regenerate functional muscle. The current standard of care primarily involves autologous muscle tissue transfer, with some consideration of acellular synthetic constructs. However, both approaches have limited therapeutic efficacy, presenting challenges such as donor-site morbidity, infection risks, and suboptimal functional recovery. Over the past decade, skeletal muscle tissue engineering (SMTE) has emerged as a promising strategy for regenerating functional muscle through bioengineered constructs. Advanced biofabrication techniques, including bioprinting, have further enabled the development of synthetic constructs that closely mimic native muscle architecture. Given these advancements, a critical review of recent therapeutic strategies, their achievements, and limitations is necessary. This review examines the spectrum of bioengineered constructs developed from various biomaterials and evaluates their therapeutic potential. Special emphasis is placed on 3D bioprinting strategies and their role in creating physiologically relevant constructs for functional muscle restoration. In addition, the integration of machine learning in optimizing construct design, predicting cellular behavior, and enhancing tissue integration is discussed. The review indicates that despite significant progress in SMTE, key challenges remain, including replicating the complex structural organization of muscle tissue, minimizing fibrosis, and achieving vascularization and innervation to regenerate functional, strengthened muscle. Future research should address these barriers while prioritizing the development of translational, clinically relevant regenerative constructs. In addition, efforts should focus on advancing scalable, construct-based regenerative treatments that are readily available at the point of care and easily managed in surgical settings. Impact Statement This review highlights key advancements in skeletal muscle tissue engineering (SMTE) for treating volumetric muscle loss (VML), a condition that severely impairs muscle function and quality of life. By exploring the advancements in bioengineered constructs and the role of 3D bioprinting, this review underscores innovative strategies that closely replicate native muscle tissue, offering new prospects for functional muscle regeneration. In addition, the review discusses machine learning integration in SMTE to optimize construct design and predict cellular behavior, presenting a promising avenue for developing constructs with high therapeutic value. This review also highlights essential insights into the existing limitations in constructs and proposes future directions that should be undertaken to advance construct-based regenerative medicine toward more effective and clinically viable solutions in VML therapy.