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

Morris, Jodie L.; Letson, Hayley L.; McEwen, Peter; Biroš, Erik; Dlaska, Constantin Edmond; Hazratwala, Kaushik; Wilkinson, Matthew; Dobson, Geoffrey P.

doi:10.1186/s41231-021-00084-3

Cited by 9 publications

(41 citation statements)

References 34 publications

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“…Surgeries were performed on 8 animals per surgery day, with equal numbers of animals per treatment group and randomisation of the order of animals undergoing surgery. Intraoperative blood loss was measured as previously described [ 28 ]. Clinical signs including body weight, temperature and weight-bearing activity were monitored daily throughout the experimental period.…”

Section: Methodsmentioning

confidence: 99%

“…Vascular injury markers (adiponectin, sE-selectin, sICAM-1, von Willebrand Factor) were measured in plasma using Milliplex® Rat Vascular Injury Magnetic Bead Panel 2 (Abacus ALS, Meadowbrook, Queensland), in combination with the Magpix® analyser (Luminex Corporation, Austin, Texas, USA). Inflammatory chemokines and cytokines (MIP-1α, IL-1α, IL-1β, MCP-1, TNF-α, IL-6, IL-12p70, IFN-γ, IL-2, IL-4, IL-10, IL-13, RANTES) were measured in plasma and joint tissue homogenates using Milliplex® Rat Cytokine/Chemokine Magnetic Bead Panel (Abacus ALS), as described previously [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

“…Following blood collection at day 28 post-surgery, animals within each treatment arm were sacrificed to assess joint tissue metrics. Macroscopic morphological analysis of the intact joint, the articular surfaces, and capsular and synovial tissue was performed using methods described previously [ 28 ]. Briefly, anteromedial capsular tissue samples from the implanted (right) and native (left) knee were dissected, snap-frozen and stored at − 80 °C for subsequent RNA/protein extraction and analysis.…”

Section: Methodsmentioning

confidence: 99%

“…ALM solution, a combination of adenosine, lidocaine and Mg 2+ , is an emerging small-volume therapy with anti-ischaemic, anti-inflammatory, coagulopathy corrective, chondroprotective and anti-fibrotic properties [ 20 – 27 ]. Recently, intra-articular (IA) administration of ALM was shown to modulate inflammatory responses in the early postoperative period and alleviate post-TKA fibrosis in a rat model of TKA [ 28 ]. In contrast to TXA, which acts downstream of coagulation pathways initiated as a result of surgery-induced inflammation, ALM appears to modulate very early coagulation, inflammatory and central nervous system (CNS) responses, favouring a permissive tissue healing environment [ 5 , 21 – 23 , 28 – 30 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, intra-articular (IA) administration of ALM was shown to modulate inflammatory responses in the early postoperative period and alleviate post-TKA fibrosis in a rat model of TKA [ 28 ]. In contrast to TXA, which acts downstream of coagulation pathways initiated as a result of surgery-induced inflammation, ALM appears to modulate very early coagulation, inflammatory and central nervous system (CNS) responses, favouring a permissive tissue healing environment [ 5 , 21 – 23 , 28 – 30 ]. We hypothesised that compared to TXA, topical administration of ALM during TKA would reduce postoperative coagulopathy and systemic inflammation, and that this would correspond to improved tissue healing in the operated knee.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of intra-articular administration of adenosine, lidocaine and magnesium solution and tranexamic acid for alleviating postoperative inflammation and joint fibrosis in an experimental model of knee arthroplasty

et al. 2021

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Background Dysregulated inflammatory responses are implicated in the pathogenesis of joint stiffness and arthrofibrosis following total knee arthroplasty (TKA). The purpose of this study was to compare the effects of intra-articular (IA) administration of tranexamic acid (TXA), an anti-fibrinolytic commonly used in TKA, and ALM chondroprotective solution on postoperative inflammation and joint tissue healing in a rat model of knee implant surgery. Methods Male Sprague–Dawley rats (n = 24) were randomly divided into TXA or ALM treatment groups. The right knee of each rat was implanted with titanium (femur) and polyethylene (tibia) implants. An IA bolus (0.1 ml) of TXA or ALM was administered after implantation and capsule closure, and before skin closure. Postoperative coagulopathy, haematology and systemic inflammatory changes were assessed. Inflammatory and fibrotic markers were assessed in joint tissue, 28 days after surgery. Results Haemostasis was comparable in animals treated with TXA or ALM after knee implant surgery. In contrast to ALM-treated animals, systemic inflammatory markers remained elevated at day 5 (IL-6, IL-12, IL-10, platelet count) and day 28 (IL-1β, IL-10) following surgery in TXA-treated animals. At day 28 following surgery, the extension range of motion of operated knees was 1.7-fold higher for ALM-treated animals compared to the TXA group. Key inflammatory mediators (NF-κB, IL-12, IL-2), immune cell infiltration (CD68+ cells) and markers of fibrosis (α-SMA, TGF-β) were also lower in capsular tissue of ALM-treated knees at day 28. Conclusion Data suggest that IA administration of ALM is superior to TXA for reducing postoperative systemic and joint inflammation and promoting restoration of healthy joint tissue architecture in a rat model of TKA. Further studies are warranted to assess the clinical translational potential of ALM IA solution to improve patient outcomes following arthroplasty.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of intra-articular administration of adenosine, lidocaine and magnesium solution and tranexamic acid for alleviating postoperative inflammation and joint fibrosis in an experimental model of knee arthroplasty

et al. 2021

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Anterior Cruciate Ligament Reconstruction Surgery: Creating a Permissive Healing Phenotype in Military Personnel and Civilians for Faster Recovery

et al. 2022

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Introduction Anterior cruciate ligament (ACL) rupture in military personnel and civilians can be a devastating injury. A service member is 10 times more likely to suffer an ACL injury than their civilian counterparts, and despite successful surgical stabilization, 4%-35% will develop arthrofibrosis, over 50% will not return to full active duty, and up to 50% will develop post-traumatic osteoarthritis (PTOA) within 15 years. Equally concerning, woman are 2 to 8 times more likely to experience ACL injuries than men, which represents a major knowledge gap. Materials and Methods A comprehensive literature search was performed in December 2021 using structured search terms related to prevalence, risk factors, disease progression, and treatment of ACL injury and reconstruction. The literature search was conducted independently by two researchers using PubMed, Cochrane, and Embase databases, with inclusion of articles with military, civilian, and sex relevance, and exclusion of most papers with a publication date greater than 10 years. The resources used for the review reflect the most current data, knowledge, and recommendations associated with research and clinical findings from reliable international sources. Results Currently, there is no effective system-based drug therapy that creates a “permissive environment” to reduce synovial and cartilage stress after ACL injury and reconstruction and prevent secondary complications. We argue that progress in this area has been hampered by researchers and clinicians failing to recognize that (1) an ACL injury is a system’s failure that affects the whole joint, (2) the early molecular events define and perpetuate different injury phenotypes, (3) male and female responses may be different and have a molecular basis, (4) the female phenotype continues to be under-represented in basic and clinical research, and (5) the variable outcomes may be perpetuated by the trauma of surgery itself. The early molecular events after ACL injury are characterized by an overexpression of joint inflammation, immune dysfunction, and trauma-induced synovial stress. We are developing an upstream adenosine, lidocaine, and magnesium therapy to blunt these early molecular events and expedite healing with less arthrofibrosis and early PTOA complications. Conclusions ACL injuries continue to be a major concern among military personnel and civilians and represent a significant loss in command readiness and quality of life. The lack of predictability in outcomes after ACL repair or reconstruction underscores the need for new joint protection therapies. The male–female disparity requires urgent investigation.

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RANTES Concentration at the Time of Surgery Is Associated With Postoperative Stiffness in Patients Undergoing ACL Reconstruction

et al. 2022

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Background: Patients undergoing anterior cruciate ligament (ACL) reconstruction have been shown to be at risk for postoperative arthrofibrosis. Diagnostic biomarkers associated with the development of postoperative stiffness are unknown. Hypothesis: Biomarkers found in the synovial fluid at the time of surgery are associated with the development of postoperative arthrofibrosis in a cohort of patients undergoing ACL reconstruction. Study Design: Case-control study; Level of evidence, 3. Methods: Patients undergoing ACL reconstruction were prospectively enrolled. Synovial fluid was collected before surgical incision. A cohort of patients with postoperative stiffness requiring manipulation under anesthesia (MUA) and/or lysis of adhesions (LOA) was retrospectively identified. Matching of cases to controls was performed using a 1:2 pair matching algorithm. Risk factor–adjusted single-biomarker and multivariable models were used to assess the association of synovial fluid biomarkers with postoperative stiffness requiring MUA/LOA. Stepwise logistic regression controlling for clinical risk factors was used to identify biomarkers that are possible predictors of postoperative stiffness. Results: A total of 11 cases (3 male, 8 female) were identified and matched with 21 controls (6 male, 15 female) with no significant differences in age, sex, smoking history, or days from injury to surgery. Concentrations of the biomarker regulated upon activation, normal T-cell expressed and presumably secreted (RANTES) were significantly higher in patients requiring MUA/LOA versus controls (694.20 pg/mL [interquartile range, 214.75-3428.79] vs 113.04 pg/mL [interquartile range, 32.81-517.91], respectively; P = .034). On single-biomarker models, RANTES (odds ratio, 2.28; 95% CI, 1.29-5.37; P = .019) and basic fibroblast growth factor (bFGF) (odds ratio, 1.91; 95% CI, 1.07-3.99; P = .047) were associated with increased risk of postoperative stiffness requiring MUA/LOA after ACL reconstruction. Stepwise logistic regression identified 3 biomarkers that are possible predictors of postoperative stiffness, which were included in the final model: Interleukin 1 receptor antagonist (IL-1RA) ( P = .198), bFGF ( P = .157), and RANTES ( P = .046). Conclusion: Higher concentrations of synovial fluid biomarkers bFGF and RANTES were associated with increased risk for stiffness requiring intervention after ACL reconstruction. Interleukin 6 (IL-6), vascular endothelial growth factor A (VEGF-A), tissue inhibitor of metalloproteinases 1 (TIMP-1), interleukin 1 receptor antagonist (IL-1RA), matrix metalloproteinase 3 (MMP-3), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 1B (MIP-1B) were not associated with the development of postoperative arthrofibrosis.

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

Cited by 9 publications

References 34 publications

Comparison of intra-articular administration of adenosine, lidocaine and magnesium solution and tranexamic acid for alleviating postoperative inflammation and joint fibrosis in an experimental model of knee arthroplasty

Comparison of intra-articular administration of adenosine, lidocaine and magnesium solution and tranexamic acid for alleviating postoperative inflammation and joint fibrosis in an experimental model of knee arthroplasty

Anterior Cruciate Ligament Reconstruction Surgery: Creating a Permissive Healing Phenotype in Military Personnel and Civilians for Faster Recovery

RANTES Concentration at the Time of Surgery Is Associated With Postoperative Stiffness in Patients Undergoing ACL Reconstruction

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