Anterior Cruciate Ligament Tissue Engineering: Biological Principles, Engineered Substitutes, and Preclinical Outcomes

The rising popularity of sports practiced without adequate preparation has increased the incidence of anterior cruciate ligament (ACL) injuries, particularly among young individuals. Because the ACL has a very limited intrinsic healing capacity, surgical reconstruction—most often using autologous grafts—remains the standard of care. However, current techniques frequently lead to donor-site morbidity and do not consistently restore long-term joint stability, contributing to early post-traumatic osteoarthritis in active patients. Over the past decades, tissue engineering (TE) has opened promising avenues for developing biological substitutes capable of overcoming these limitations. Despite substantial progress, no strategy has yet demonstrated reliable and clinically validated functional regeneration of the human ACL. Meanwhile, artificial intelligence is emerging as a complementary tool for diagnosis, surgical planning, biomechanical assessment, and personalized reconstruction strategies. This review aims to provide a comprehensive overview of current TE-based approaches for ACL repair and reconstruction, analyzes their biological and biomechanical limitations, and discusses emerging concepts that may enhance future clinical outcomes. We first summarize the fundamental principles of tissue engineering, then examine the major strategies proposed for ACL regeneration—highlighting their respective strengths and shortcomings—and finally outline perspectives for a novel approach currently under development.