Investigating the Role of Mechanobiology in ACL Injury and Reconstruction
Restricted (Penn State Only)
- Author:
- Paschall, Lauren
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 14, 2024
- Committee Members:
- Daniel Hayes, Program Head/Chair
Esther Gomez, Outside Field Member
Justin Brown, Major Field Member
Spencer Szczesny, Chair & Dissertation Advisor
Braden Fleming, Special Member
Erdem Tabdanov, Outside Unit Member - Keywords:
- ACL
ACL reconstruction
Mechanobiology
Sex-Differences
Estrogen
Immune cells - Abstract:
- The anterior cruciate ligament (ACL) is one of the most commonly torn ligaments affecting more than 200,000 people in the United States each year. Furthermore, females are more at risk of sustaining an ACL injury given that female athletes are 2-8 times more likely to tear their ACL compared to their male counterparts. Reconstruction of the ACL is the gold-standard treatment following rupture. However, even after surgery, reconstruction failures occur in 10% of the patient population. Furthermore, while the outcomes are comparable in the general patient population, active individuals are 3-4 times more likely to tear their allografts compared to autografts. Therefore, autografts are recommended for these individuals. However, harvesting autogenous tendon from patients leads to other complications that negatively impact postoperative rehabilitation and may limit full recovery after reconstruction surgery. Furthermore, autogenous tendon is often not an option for revision surgery given the limited tendons available for harvest. Given these difficulties in treating ACL tears, there is significant clinical interest in preventing ACL tears and improving allograft reconstruction outcomes. Prior work has suggested that ACL ruptures and increased allograft reconstruction ruptures are due to an impaired remodeling response to load. While historically noncontact ACL tears have been thought to be due to a single traumatic event, recent studies suggest that ACLs are susceptible to fatigue failure where repetitive subfailure loading leads to an accumulation of microtrauma thereby predisposing the ACL to injury. Furthermore, females may be more susceptible to fatigue failure making them more prone to ACL injury compared to males. Similarly in reconstructions, previous data suggest that increased allograft rerupture rate in active individuals is due to an impaired remodeling response. While the mechanics are identical between autografts and allografts prior to surgical implantation, after the grafts go through ligamentization (a remodeling phase) allografts have inferior stiffness and strength compared to autografts. However, despite these data, to the best of our knowledge, no study has directly investigated the role of mechanical loading on the mechanobiological response of primary ACLs and ACLRs. The overall objective of this work is to understand the role of mechanical loading on primary ACL tears and ACL reconstruction (ACLR) reruptures. Specifically, we aim to understand how mechanical loading predisposes high risk patients for primary ACL tears (females) and ACLR reruptures (patients with allografts) and the mechanisms driving these differences. To achieve this, the dissertation will be broken down into three main objectives. Specifically, I investigated the mechanobiological response of male and female ACL explants to load, investigated the mechanobiological response of autograft and allograft ACLRs, and investigated mechanisms driving these mechanobiological differences between high-risk groups (males vs females and autografts vs allografts). To accomplish this, we utilized a custom-made tensile bioreactor that cyclically loaded ACLs and ACLR explants and gene expression was quantified. First, we investigated the biological response of male and female rabbit ACLs to cyclic loading and found that the remodeling response of ACLs is dependent on the magnitude of cyclic loading and is sex specific. We then wanted to compare the mechanobiological response of autografts and allografts to cyclic load. Interestingly, we found that there were no differences in the remodeling response between autografts and allografts. Given that we found no differences in the mechanobiological response of autografts and allografts to mechanical load, the final objective was to investigate potential mechanisms driving the impaired remodeling response in female ACLs compared to male ACLs. RNA-sequencing was than utilized to identify potential biological processes responsible for the impaired remodeling response observed in female ACLs. We found that female ACLs have an impaired mechanobiological and mechanotransduction response to load. Specifically, we identified estrogen and PI3K/AKT signaling as potential mediators of this impaired mechanobiological response observed in female ACLs in response to load. Interestingly, when treating male ACLs with estrogen and SC79, an AKT activator, preliminary data suggest that they do not affect the ACLs remodeling response to load. Collectively, our data demonstrates that primary ACL injury may be a consequence of failed tissue remodeling and inadequate repair of microtrauma resulting from fatigue loading. Furthermore, the increased susceptibility of female ACL tears could be partially attributed to an impaired mechanobiological response corresponding to a reduced capacity to repair ACL tissue damage due to cyclic loading. Together, this work provides critical insight into the mechanism of primary ACL injury and will aid in future development of therapeutics to prevent ACL rupture.