Indiana University-Purdue University Indianapolis (IUPUI) / Ligament injury is one of the most prevalent musculoskeletal disorders that may lead to disability or disease, such as osteoarthritis. Conservative interventions which accelerate or augment ligament healing are needed to enhance therapeutic outcomes. The purpose of this research agenda was to investigate the tissue level effects of a type of manual therapy, cross fiber massage (CFM), in particular instrument-assisted CFM (IACFM), on ligament healing. Bilateral knee medial collateral ligament (MCL) injuries were created using an established rodent model where one MCL received IACFM treatment and the other untreated MCL served as a within subjects control. The short and long term effects of IACFM on the biomechanical and histological properties of repairing ligaments were investigated. Tensile mechanical testing was performed to determine ligament mechanical properties. Ligament histology was examined under light microscopy and scanning electron microscopy. IACFM was found to accelerate early ligament healing (4 weeks post-injury), possibly via favorable effects on collagen formation and organization, but minimal improvement was demonstrated in later healing (12 weeks post-injury). Regional blood flow and angiogenesis were investigated as possible mechanisms underlying the accelerated healing found in IACFM-treated ligaments. Laser Doppler perfusion imaging was used to investigate vascular function. Micro-computed tomography was used to determine vascular structural parameters. Compared to untreated contralateral injured controls, IACFM-treated injured knees demonstrated a delayed increase in blood flow and altered microvascular structure, possibly suggesting angiogenesis. Mechanotransduction is discussed as a mechanism for the beneficial effects of CFM in that application of a mechanical force was found to enhance biomechanical and histological properties as well as vascular function and structure acutely in healing ligaments. Although this thesis focused on IACFM treatment of injured knee ligaments, it is plausible for concepts to apply to other manual modalities that offer conservative alternatives to invasive procedures or pharmaceuticals in the treatment of soft tissue injuries.