Getgood, A. | Search bioRxiv

bioRxiv2022

Development of Multi-Bundle Virtual Ligaments to Simulate Knee Mechanics after Total Knee Arthroplasty

Preclinical evaluation of total knee arthroplasty (TKA) components is essential to understanding their mechanical behavior and developing strategies for improving joint stability. While preclinical testing of TKA components has been useful in quantifying their effectiveness, such testing can be criticized for lacking clinical relevance, as the important contributions of surrounding soft tissues are either neglected or greatly simplified. The purpose of our study was to develop and determine if subject-specific virtual ligaments reproduce the same kinematics as native ligaments surrounding TKA joints. Five TKA knees were mounted to a motion simulator. Each was subjected to tests of anterior-posterior (AP), internal-external (IE), and varus-valgus (VV) laxity. The forces transmitted through major ligaments were measured using a sequential resection technique. By tuning the measured ligament forces and elongations to a generic non-linear elastic ligament model, virtual ligaments were designed and used to simulate the soft tissue envelope around isolated TKA components. The average root mean square error (RMSE) between the laxity results of TKA joints with native versus virtual ligaments was 2.9 mm during AP translation, 6.5{degrees} during IE rotations, and 2.0{degrees} during VV rotations, and there was no statistically significant difference between the results of both methods. Interclass correlation coefficients (ICCs) indicated a good level of reliability for AP and IE laxity (0.85 and 0.84). To conclude, a virtual ligament envelope around TKA joints can mimic natural knee behavior and is an effective method for the preclinical testing of TKA components.

bioengineering↗

bioRxiv2020

Identification of Proteinase Activated Receptor (PAR) cleaving enzymes in human osteoarthritis knee joint synovial fluids.

ObjectiveOsteoarthritis (OA) is the most prevalent joint disorder with incidence increasing worldwide. Mechanistic insights into OA pathophysiology are still evolving and there are currently no disease-modifying OA drugs available. It is well established that an increase in proteolytic enzyme activity is linked to progressive degradation of the cartilage in OA. Proteolytic enzymes can also trigger inflammation through activation of a family of G-protein coupled receptors (GPCRs) called the Proteinase Activated Receptors (PARs). Here we sought to characterize the PAR activating enzyme repertoire in human OA knee joint fluids. MethodsHuman knee joint synovial fluids derived from twenty-five OA patients and four healthy donors were screened for PAR cleavage activity using novel genetically encoded human PAR biosensor expressing cells. The class or type of enzymes cleaving the PARs was further characterized using enzyme-selective inhibitors and enzyme-specific fluorogenic substrates. ResultsActivity of PAR1, PAR2 and PAR4 activating enzymes were identified at substantially different levels in OA patients relative to healthy knee joint synovial fluids. Using enzyme class or type selective inhibitors and fluorogenic substrates we found that serine proteinases, including thrombin-like enzymes, trypsin-like enzymes, and matrix metalloproteinases are the major PAR activating enzymes present in the OA knee synovial fluids. ConclusionsMultiple enzymes activating PAR1, PAR2 and PAR4 are present in OA joint fluids. PAR signalling can trigger pro-inflammatory responses and targeting PARs has been proposed as a therapeutic approach in OA. Knowledge of the PAR activators present in the human knee joint will guide study of relevant signaling events and enable future development of novel PAR targeted therapies for OA and other inflammatory joint diseases.

pharmacology and toxicology↗