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Determination of the microstructural extracellular and cellular response of young and aged anterior cruciate ligaments in the mammalian knee joint to mechanical load

   Institute of Life Course and Medical Sciences

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  Prof E Comerford, Dr B Geraghty, Prof Hazel Screen  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The human anterior cruciate ligament (ACL) is one of the most frequently injured structures of the knee joint resulting in osteoarthritis, pain and morbidity for the affected individual. It is an important stabiliser of the knee joint preventing forward movement of the tibia with respect to the femur and internal rotation of the joint. In a healthy knee joint, the ACL will exhibit altering loads with different activities and functions. It has been found that during mid-stance when the knee is near full extension the strain in the ACL peaks at 13%, whilst during the swing phase of the limb the ACL reaches 10% strain. This strain can further be increased during activities such as running and football and the influence of age on the mechanical responsiveness of the ACL to these activities is currently unknown. Therefore, detailed knowledge of how mechanical strain is associated with minor ACL injury, damage and eventual tearing at a microstructural level has not yet been determined. 

It is our hypothesis that the mechanisms of cellular injury and resultant responses in the associated extracellular matrix (ECM) of the mammalian ACL following mechanical load will differ in both young and aged ACL tissue. Determination of injury mechanism and the tissue’s response will be vital in terms of future prevention of tissue injury and regeneration associated with healthy ageing.

We will examine injury and deformation at a microstructural level, in both young and aged ACL tissue, using fast and slow cyclic loading, followed by histological and immunohistochemical staining to look at structural and inflammatory/degradative changes. We will then use confocal microscopy to further identify where the structural and cellular changes occur following different cyclic loading regimes.

Fresh femoral-ACL-tibia complexes (FATC), will be collected from paired young (<5 years old) and aged (>7 years old) canine cadaveric knee joints (n=10 (2 aims x 5 knee pairs)) for each age group). The canine knee model is well recognised for simulating ACL injury and disease. Both FATCs will be put into a mechanical testing rig, allowing a resting grip-to-grip distance of 10 mm. One FATC from each stifle pair will be subjected to fast cyclic loading at 10HZ for 1800 cycles and the other at slow cyclic loading (0.1HZ) for 1800 cycles from 1-10% uniaxial strain (Spiesz, 2015). Following loading, the FATCs will be removed from the rig and will be either:

1)     Snap frozen in OCT over isopentane, cryosectioned at 20um and stained for structural deformation using hematoxylin and eosin, for protein degradation (MMP-3 and 13, MMP-1, the collagen degradation marker C1,2C) and for inflammatory markers such as IL6 and cyclo-oxygenase-2 (COX-2)

2)     Examined immediately following loading using confocal microscopy, with a custom designed rig, to further determine where structural damage is occurring and its effect in detail in two different age groups.

This project will deliver excellent interdisciplinary training in answering the proposed research question, on the response of structure to function in the ACL with ageing, by using biological and mechanical methods. Training in histology and immunostaining and measurement of the biological markers of tissue damage will be provided and mechanical skills acquired by the student will include rig design and cyclic testing of bone-ligament-bone as well as computational modelling of actual and simulated tissue changes within the ACL. Training will also be provided in confocal microscopy following loading of the ACLs to examine ex vivo structural damage to cells and the extracellular matrix.  

As part of their degree registration, the student will have access to the Liverpool Doctoral College and its training resources including lectures on time management, team building, career development as well as thesis writing support and viva practice. Other modules such as study design and statistical training are available through the Department of Biostatistics at Liverpool. The student will be a member of the Comparative Musculoskeletal disease and Evolutionary Morphology and Biomechanics groups, Institute of Life Course and Medical Sciences. This research environment will provide a great opportunity for the PhD student to learn new skills in study design, participate in veterinary clinical research, gait data acquisition and analysis and preparing work for publication.

An Undergraduate Degree in Biological Sciences or Biomedical/Mechanical Engineering; 2:1 is required.

Informal enquiries or to express an interest in applying to Professor Eithne Comerford on [Email Address Removed] or Dr. Brendan Geraghty on [Email Address Removed]

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