Non-Contact, Mechanical Fatigue-Related ACL Injury Prevention Through Extracellular Matrix Crosslink Preservation: A Narrative Review.

Background: Anterior cruciate ligament (ACL) injuries are increasing in young athletes and many are related to non-contact, spontaneous mechanical fatigue-related ruptures. The objective of this narrative review is to identify and synthesize the anatomical, histological, physiological, and biomechanical basis of extracellular matrix (ECM) factors that contribute to ACL injuries and suggest ways to decrease their occurrence. Methods: The primary investigator searched PubMed, Web of Science, and Google Scholar database titles and abstracts using search phrases with Boolean operators: "anterior cruciate ligament" OR "ACL", OR "cranial cruciate ligament" AND "disease"; "anterior cruciate ligament" OR "ACL", OR "cranial cruciate ligament" AND "spontaneous rupture" OR "non-contact injury"; and "anterior cruciate ligament" OR ACL, OR cranial cruciate ligament" AND "crosslink", "collagen" OR "extracellular matrix"; and "anterior cruciate ligament" OR "ACL", OR "cranial cruciate ligament" AND "microtrauma", OR "sudden" OR "fatigue failure". The primary investigator and a sports orthopedic surgeon reviewed titles and abstracts of diverse evidence sources. From these identified sources, the study team performed full text reviews, selected contributing articles, performed Strength of Recommendation Taxonomy (SORT) grading, and synthesized the following themes: A Hostile Environment, ACL Strain, and Poor Nutrient Delivery; Accumulative ACL Microtrauma and Mechanical Failure; The ACL Differs From Other Ligaments; Collagen, the ECM, and ACL Mechanobiology; Crimps and ACL ECM Stretch; Crosslinks Improve ECM Mechanical Properties; The Delicate Collagen Synthesis and Degradation Balance; Exercise Training and the ACL; Can Nutraceuticals Help Restore the Balance?; Training Induced ACL Hypoxia; Estrogen and the Female Athlete; Counting Pitches or Counting Collagen Fiber Ruptures; and Restoring A Positive Anabolic-Catabolic Collagen Balance. Results: Regular exercise training within a physiologically safe loading range is vital to ACL ECM health. However, low or moderate evidence suggested that poor blood supply, slow metabolism, and a hypoxic environment may unbalance anabolic and catabolic homeostasis. Active rest and recovery concepts that prevent youth baseball shoulder and elbow injuries may help prevent non-contact ACL injuries. Conclusions: More prescriptive active rest and recovery intervals and neuromuscular control training may restore the anabolic-catabolic balance that increases mature crosslink density and improves ACL ECM strength. Confirmatory studies are needed to better establish therapeutic intervention mode(s), timing, dosage, and frequency optimization.