Intra-articular Adenosine, Lidocaine and Magnesium (ALM) solution decreases postoperative joint fibrosis in an experimental knee implant model

Jodie L Morris,Hayley L Letson,Constantin Dlaska,Geoffrey P Dobson,Matthew Wilkinson,Peter Mcewen,Kaushik Hazratwala,Erik Biros

doi:10.1186/s41231-021-00084-3

Jodie L Morris, Hayley L Letson + Show 6 more

Open Access

https://doi.org/10.1186/s41231-021-00084-3

Copy DOI

Abstract

BackgroundThere is currently no drug therapy to prevent arthrofibrosis following knee surgery. We aimed to determine if the anti-ischemic and anti-inflammatory drug adenosine, lidocaine and Mg2+ (ALM), reduces surgery-related arthrofibrosis in a rat model of knee implant surgery.MethodsMale Sprague-Dawley rats (n = 24) were randomly divided into ALM or saline groups. The right knee of each animal was implanted with custom titanium (femur) and polyethylene (tibia) implants, and the left knee served as a non-operated control. An intra-articular ALM or saline bolus (0.1 ml) was administered at the end of surgery, and animals monitored for 4 weeks. Fibrotic changes were assessed by macroscopic examination, histopathology, and expression of key inflammatory and fibrotic markers in the joint capsule and infrapatellar fat pad (IFP).ResultsKnee swelling was evident in both groups at 4 weeks. However, range of motion was 2-fold higher in the ALM-treated knees, and differences in macroscopic pathology indicated improved healing, compared to the control group. Histologically, ALM treatment also led to significantly decreased synovitis and fibrotic pathology in the joint capsule and IFP compared to saline controls. RNA and protein expression profiles of pro-fibrotic mediators (α-SMA, TGF-β1, FGF1, PDGFA) were also significantly lower in knees from ALM-treated animals. In addition, the expression of inflammatory mediators was lower in plasma (IL-1β, IL-10) and joint tissue (NFκB, IL-1β, IL-12), 4 weeks after surgery.ConclusionWe show that intra-articular administration of a single ALM bolus significantly decreased fibrotic pathology and synovitis in an experimental model of knee implant surgery, by blunting inflammation and modulating essential genes of fibrosis. ALM has the therapeutic potential for translation into humans undergoing knee replacement surgery.

Highlights

There is currently no drug therapy to prevent arthrofibrosis following knee surgery
We report that IA administration of ALM at the end of knee implant surgery in the rat appears to increase Range of motion (ROM) and to improve healing after 4 weeks, with the macroscopic restoration of healthy joint tissue architecture
ALM therapy reduces fibrotic changes in the infrapatellar fat pad The finding that ALM significantly reduced the expression of α-SMA, a marker for myofibroblasts which are the critical cell mediators of fibrosis [22], suggests that the drug therapy may have reduced fibrosis in the IFP in our total knee arthroplasty (TKA) model

Summary

Introduction

We aimed to determine if the anti-ischemic and anti-inflammatory drug adenosine, lidocaine and Mg2+ (ALM), reduces surgeryrelated arthrofibrosis in a rat model of knee implant surgery. The key drivers of postoperative joint stiffness and fibrosis are believed to be excessive inflammation, the proliferation of metaplastic fibroblasts, increased extracellular matrix (ECM) proteins, and fibrous scar tissue that leads to restricted joint motion and pain [1, 2, 5] These secondary complications arise primarily from the trauma of surgery and involve the synovial membrane, extracapsular structures (e.g. medial and lateral ligaments) and the infrapatellar fat pad (IFP) [1, 2, 4,5,6,7]. Based on ALM’s anti-inflammatory, anti-ischemic, and coagulopathy correction properties, we hypothesized that an intra-articular bolus administered before skin closure may reduce arthrofibrosis in a rat model of knee implant surgery

Objectives

Methods

Results

Conclusion