Introduction
Anterior cruciate ligament (ACL) tears are a common and devastating injury among young
athletes, and re-injury poses significant threats to both successful return to play and
long term outcomes. Graft healing during ACL reconstruction (ACLR) is a slow biologic
process, that involves graft incorporation into bone tunnel sites, as well as
intra-articular graft remodeling . The intra-articular graft remodeling process is known
as ligamentization, and occurs in three phases after ACLR. The first phase of early
healing occurs between 0 and three months, the second phase occurs between 6 months and
one year, and the final phase of maturation occurs after 1 year when the graft appears
very similar to the native ACL. The studies that defined these time points biopsied human
bone-patella tendon-bone (BTB) ACL autografts at different postoperative points, and
described changes occurring over time in regards to vascularization, cellular aspects,
and appearance of the extracellular matrix in comparison to control ACLs . Unlike animal
models which display a necrotic stage, grafts in human models undergo an early vascular
invasion, associated with fibroblasts that are converted to a hyper-cellular matrix with
only focalized areas of necrosis . This process occurs as early as 3 weeks
postoperatively, and increases over time as areas similar to the native patellar tendon
with mature collagen and metabolically quiescent cells decrease . This process is the
limiting factor in graft healing for bone-patella tendon-bone (BTB) grafts, as
osteointegration occurs earlier .
The processes of osteointegration and ligamentization are responses to the new
intrasynovial milieu and physical forces that the new graft is exposed to. During these
healing and restructuring processes, failure load and stiffness of grafts decreases by up
to 24% at 7 weeks, before strengthening to their potential . This contributes to the long
recovery period for ACLR, and the risk of re-rupture during this period. Advances in
biologic adjuncts to accelerate and improve this healing process would have a significant
impact on the management of ACL injuries.
Recently, biologic preparations of various growth factors have been developed to safely
and effectively treat a variety of musculoskeletal conditions, including tendinopathies
and arthritis . Bone marrow aspirate concentrate (BMAC) consists of undifferentiated
mesenchymal stem cells that are concentrated and applied to the injury site . Previous
studies have demonstrated this treatment to offer the pluripotent potential of the cells
to impact healing, regeneration, biomechanical strength, and reducing bone-tunnel
enlargement . Investigators have demonstrated that mesenchymal stem cell reinforced
grafts had a significantly higher failure load and stiffness as early as 8 week
post-operation in a rabbit model, suggesting an added benefit of advanced healing . Using
BMSCs can offer a novel method to enhance tendon graft osteointegration. While there have
been numerous laboratory studies researching the effect of mesenchymal stem cells, there
lacks evidence in translation to the clinical setting. Silva et al performed a study
where they injected bone marrow derived stem cells (BMSCs) into patellar tendon grafts to
examine for increased graft-to-bone tunnel integration. They did not find a significant
difference of tunnel integration on MRI imaging, but they did not examine the
intra-articular portions for the effect on the ligamentization process, nor did they
examine the effect on clinical examination and patient reported outcomes .
Quantitative MRI is a non-invasive method to interrogate tissue properties and evaluate
the biochemical composition of tissues. The T2* sequence gives information regarding
tissue graft volume, water content, fiber alignment, and tissue density. Median grayscale
values (a measure to determine tissue quality)can also be correlated to maximum failure
load, yield load, and linear stiffness of grafts in a porcine model. Increases in MRI
signals in ACL grafts have been found to be time dependent, becoming well established by
three months, particularly at the distal intra-articular portion near the tibial tunnel .
These changes have not been shown previously to be predictive of graft failure, but
Investigators have recently also confirmed that normalized T2* signal intensity values of
ACL grafts have significant correlation with knee instability related to ligamentization
and tunnel healing.
A recent study examined intra-articular graft maturation after platelet-rich plasma gel
(PRPG) application, with MRI at month intervals from 3-12 months postoperatively. The
intra-articular segment was divided in a proximal, middle, and distal segment, on a scale
from 0-3 ranging from completely homogenous to severely heterogeneous. The mean time to
obtain completely homogenous bone-patella tendon-bone (BTB) graft was 109 days for the
PRPG group, and 363 for the control group 8.
We propose using quantitative magnetic resonance (MR) imaging with T2* mapping to
investigate if BMAC treatment at time of ACL reconstruction can accelerate the graft
maturation and healing process. We will perform a randomized controlled trial of patients
undergoing ACL reconstruction with bone-patellar tendon-bone allograft evaluating the T2*
weighted MRI changes of the graft at 3 and 9 months after surgical reconstruction.
Additionally, we will obtain patient-reported outcome measures from this cohort to
evaluate if BMAC treatment imparts a clinically-significant effect on ACL reconstruction.
Study Rationale
This study will evaluate the efficacy of biologic augmentation of ACL reconstruction with
BMSCs as measured by magnetic resonance imaging to detect graft healing and integration.
Secondary endpoints will include validated patient reported outcome measures, as well as
functional outcome using objective examination findings.
Hypothesis
The hypotheses of this study are that there will be improved graft healing and
integration at three and nine months as measured by decreased signal intensity and
heterogeneity on T2* MRI following administration of BMAC during ACL reconstruction
compared to the control group. Additionally, patient reported outcomes and physical
examination findings will be significantly improved at an earlier time in those who
receive the BMAC treatment to their allograft compared to the control group.
Study Plan
This study will be a prospective randomized trial of patients undergoing arthroscopic
reconstruction of full thickness anterior cruciate ligament (ACL) tears. All patients who
sign consent and undergo full thickness ACL reconstruction will be enrolled in the study.
Enrollment will continue until 32 patients, 16 in each group, are enrolled. Follow-up
will take place at 6 weeks, 3 months, 6 months, 9 months, 12 months, and 24 months.
