The Biology of ACL Healing: The Wild Card of Recovery

ACL Injury Healing
Ligamentization – The Wild Card After an ACL injury1, reconstruction of the ligament is often a recommended treatment.  One of the most critical steps in ACL reconstruction2 is grafting a tendon into the knee to replace the damaged ACL. Following surgery, the graft not only has to heal tightly in its new position but also transition structurally from a functioning tendon to a functioning ligament—a process known as ligamentization. Believe it or not, this process takes time! Microscopic studies, in which physicians have taken small samples of healing ligaments following ACL reconstruction to determine their rate of ligamentization, suggest that this process can take anywhere from 6 to 24 months. The ligamentization process is frustrating because it is an unseen rate-limiting step in an athlete’s recovery. Some athletes regain motion, strength, and proprioception at the six-month mark and appear outwardly healed, but the level of ligamentization of their graft is unknown and therefore a return to sport can jeopardize their recovery. For this reason, it is ideal to allow athletes recovering from ACL reconstruction as much time for rehabilitation as logistically possible, assuming it doesn’t jeopardize their return career goals.  Two studies on reinjury rates suggest that risk decreases significantly with every month until the 9-month time point.3,4  This time delay is directly related to the ligamentization process.  For this reason, in most instances, a return to cutting/pivoting sports is cautioned before the 9-month milestone.  Many instances of ACL reconstruction failure can be attributed to a failure of graft incorporation and/or the ligamentization process, so giving the athlete adequate time for recovery is best. One of Dr. Anz’s most passionate clinical research interests revolves around using biologics to improve and/or expedite the ligamentization process following ACL reconstruction. His interest is driven by how critical the ligamentization process is to the full recovery and return to the sport of injured athletes. Animal studies have suggested that slower graft incorporation correlates with increased laxity and stiffness, increasing the likelihood of re-injury, and have illustrated improved tendon healing in ACL reconstructions that incorporate the use of stem cell technologies.  We theorize that optimization of stem cell technologies for tissue regeneration requires the use of the ‘regenerative triad’—a scaffold, stem cells, and growth factors. For that reason, regenerative models with ACL reconstruction combine biologic technologies with a scaffold wrap to produce a new “sheet” of cells around the ACL graft. There are two studies that illustrate the effectiveness of biologics in improving the rate of ACL maturation. The first of these studies involved injecting leukocyte-poor platelet-rich plasma into the fascicles of ACL grafts and the other involved loading of a gelatin carrier with platelet-derived growth factors. Prior to the injury, the ACL and PCL are covered by a synovial lining—essentially a layer of collagen that ensures adequate blood and nutrient supply to the ACL. It is now believed that the lack of this synovial lining following traditional ACL reconstruction may delay the process of ligamentization. We believe that the use of a collagen membrane will protect and create a healing environment like the synovial lining of a healthy joint. At the Andrews Institute, we are interested in building a scientific body of work “brick by brick” to advance the biology of ligamentization.  In 2016, we completed a study determining how many cells can be collected from a patient’s knee, including swelling and by-products of the reconstruction surgery at the time of ACL surgery.5 This study is helping us to better understand ideal methods for collecting a patient’s stem cells.  In 2019, Dr. Anz and colleagues at Auburn University completed a study using MRI to map the ACL to develop normative values for future ACL maturation studies.6   In 2020, we completed a study that used blood concentrating devices (PRP machines) to harvest stem cells from the injury fluid at the time of ACL reconstruction for use at the time of the surgery.7  In 2021, Drs Anz, Jordan, Ostrander, and Andrews completed a study on biologic augmentation of traditional ACL reconstruction.  The theory was that collagen membranes can be used to re-establish the natural synovial lining of the ACL and that the collagen would serve as a container to hold biologic adjuncts around the ACL. This study combined collagen-wrapped graft tissue with cells from the patient’s bone marrow fluid.  This study found that wrapping a graft with an amnion collagen matrix and injecting bone marrow aspirate concentrate was associated with lower MRI T2* values, a surrogate measure of improved graft maturation and collagen content. While early studies are promising, further development is needed to determine if the ligamentization process can be sped up.  At this time, no change in rehab protocols or strong recommendations can be recommended, but the future looks bright.  It is important at this time, even with biologic adjuncts available, to stick to 9-month return to sport timelines.  There is a significant risk of reinjury if athletes push too fast too soon based on exciting theories.  With more time and study, evidence will emerge as to whether biologics can improve ligamentization.  In the meantime, we continue to work on the science to find the truth- “brick by brick”. As an Orthopedic Surgeon and Sports Medicine Specialist, Dr. Adam W. Anz is dedicated to providing individuals and athletes from all over the world with the highest possible quality of care. He serves his patients at the world-class Andrews Institute in Gulf Breeze, Florida. Sources: 1.) https://adamanzmd.com/acl-knee-injuries/ 2.) https://adamanzmd.com/acl-reconstruction/ 3.) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912389/pdf/nihms782171.pdf 4.) https://www.jospt.org/doi/full/10.2519/jospt.2020.9071 5.) https://adamanzmd.com/wp-content/uploads/2021/11/2017-Viable-Stem-Cells-Are-in-the-Injury-Effusion-Fluid-and-Arthroscopic-Byproducts-From-Knee-Cruciate-Ligament-Surgery.pdf 6.) https://adamanzmd.com/wp-content/uploads/2021/11/2019-3T-MRI-mapping-is-a-valid-in-vivo-method-of-quantitatively-evaluating-the-anterior-cruciate-ligament-rater-reliability-and-comparison-across-age.pdf 7.) http://box5216.temp.domains/~adamanzm/wp-content/uploads/2021/11/2021-Synovial-Stem-Cells-Harvested-with-PRP-Device.pdf   Additional ACL blog articles: 1. ACL Knee Injuries 2. When is an athlete ready for contact sports after ACL surgery? 3. ACL Reconstruction 4. Revision ACL Reconstruction 5.ACL Knee Injuries 6. Save the Menisci: Meniscal Root Tears 7. Meniscus Repair Paper Published in the American Journal of Sports Medicine 8. FCL Reconstruction 9. PCL Reconstruction 10. Multi-Ligament Knee Reconstruction 11. MCL Reconstruction 12. PCL Reconstruction 13. FCL/LCL Knee Injuries
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