Soft Tissue-to-Bone Healing in Anterior Cruciate Ligament Reconstruction - Structural Interfaces and Attachments in Biology - page 279

13.5.4 Biologic Modulation
Opportunities exist for modulating several biologically active agents that have
been shown to play a role in the healing process after ACL reconstruction.
Following ACL injury [ 112 ] and reconstruction [ 113 ], the level of MMPs
increases in the intra-articular environment. In a rabbit model, the use of an
intra-articular injection of alpha-2-macroglobulin (a known MMP inhibitor)
after ACL reconstruction was evaluated [ 27 ]. The control group demonstrated
an increased concentration of intra-articular MMPs and less organized and vascu-
lar connective tissue at the bone-tendon interface. The treatment group had more
mature interface tissue, more Sharpey's fibers between the graft and bone, and a
significantly higher load-to-failure at both 2 and 5 weeks.
Given that healing of the graft within the tunnel is dependent on bone ingrowth,
it is believed that excessive osteoclast activity within the tunnel may contribute to
bone resorption, tunnel widening, and poor healing. Rodeo et al. evaluated the
effects of osteoprotegerin (OPG), an inhibitor of osteoclast activity, and receptor
activator of nuclear factor-kappa B ligand [ 114 ], an osteoclast activator in a rabbit
ACL reconstruction model [ 115 ]. In the OPG-treated limbs, there were significantly
fewer osteoclasts and significantly more bone at the tendon-bone interface when
compared to controls and the receptor activator of nuclear factor-kappa B ligand
(RANKL)-treated limbs. The OPG group also had a smaller average tunnel area and
significantly increased stiffness compared to the RANKL group. Other techniques
of biomodulation, including macrophage inhibition [ 116 ] and enhanced angiogen-
esis using hyperbaric oxygen [ 117 ], have shown promise in improving histologic
and biomechanical parameters of graft healing.
13.5.5 Biophysical Modalities
Mechanical stimulation, electrical stimulation, pulsed electric magnetic fields, and
ultrasound therapy have been applied in various clinical settings to augment soft
tissue and fracture healing. Ultrasound therapy is a noninvasive mechanism of
delivering mechanical energy transcutaneously. It has been shown to promote
osteoblast proliferation and angiogenesis in the lab setting [ 118 - 120 ]. Clinically
it has been shown to accelerate delayed fracture healing and soft tissue repair [ 121 ,
122 ]. In an ovine ACL model, Walsh et al. demonstrated that low-intensity pulsed
ultrasound (LIPUS) could improve tendon osteointegration, vascularity, stiffness,
and peak load [ 71 ]. Furthermore, other studies have shown similar promise in
applying LIPUS to tendon-bone healing in animal models [ 123 ].