The sites where graft healing occurs within the bone tunnel and where the intra-articular ligamentization process takes place are the two most important sites of biological incorporation after anterior cruciate ligament (ACL) reconstruction, since they help to determine the mechanical behavior of the femur-ACL graft-tibia complex. Graft-tunnel healing is a complex process influenced by several factors, such as type of graft, preservation of remnants, bone quality, tunnel length and placement, fixation techniques and mechanical stress. In recent years, numerous experimental and clinical studies have been carried out to evaluate potential strategies designed to enhance and optimize the biological environment of the graft-tunnel interface.Modulation of inflammation, tissue engineering and gene transfer techniques have been applied in order to obtain a direct-type fibrocartilaginous insertion of the ACL graft, similar to that of native ligament, and to accelerate the healing process of tendon grafts within the bone tunnel. Although animal studies have given encouraging results, clinical studies are lacking and their results do not really support the use of the various strategies in clinical practice. Further investigations are therefore needed to optimize delivery techniques, therapeutic concentrations, maintenance of therapeutic effects over time, and to reduce the risk of undesirable effects in clinical practice.
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