{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T15:48:03Z","timestamp":1782143283964,"version":"3.54.5"},"reference-count":41,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"unspecified","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2027473"],"award-info":[{"award-number":["2027473"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,5,10]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Knee osteoarthritis is a leading cause of pain and disability and frequently results in total knee arthroplasty (TKA). Decisions about surgery and postoperative management rely largely on subjective pain scales and patient-reported outcome measures (PROMs), and 10\u201315% of patients remain dissatisfied after TKA despite technically successful surgery. Evidence suggests that pain is partly reflected in peripheral immune signalling, yet this neuroimmune interface has not been studied in patients with joint pain due to knee osteoarthritis. This study will explore whether peripheral immune responses (interleukin-1 beta, IL-1\u03b2) are associated with pain and may serve as objective pain biomarkers in patients with painful knee osteoarthritis compared with pain-free controls and how these markers relate to pain and psychological (anxiety, depression and pain catastrophising) PROMs. This will be the first study to correlate pain markers (peripheral immune responses) with subjective pain levels in orthopaedic patients with symptomatic knee osteoarthritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This is a protocol for a prospective cross-sectional matched-subject observational study. We will include 20 adults undergoing unilateral primary TKA for painful advanced knee osteoarthritis, their contralateral pain-free knees as internal controls and 20 age and sex matched healthy controls without joint pain or functional limitation. All participants will undergo standardised clinical assessment and complete pain and psychological PROMs. In patients with TKA, venous blood will be collected pre-operatively. During TKA surgery, synovial fluid will be aspirated from the painful operated knee and the contralateral pain-free knee. Healthy controls will provide a single venous blood sample at a hospital visit. Peripheral blood mononuclear cells and synovial fluid mononuclear cells will be stimulated ex vivo with toll-like receptor 2 and 4 agonists to quantify IL-1\u03b2 release. In parallel, hyperspectral imaging will characterise unstimulated immune cell phenotypes. Multivariable statistical and machine-learning approaches will relate biomarker profiles to pain and psychological PROMs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study has been approved by the Southern Adelaide Local Health Network (SALHN) HREC (references: 2024\/HRE00253, SSA 2024\/SSA00641). Written informed consent will be obtained from all participants. Study results will be disseminated through peer-reviewed publications and presentations at national and international scientific conferences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial number registration<\/jats:title>\n                    <jats:p>ACTRN12626000084381.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2026-117858","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T14:57:10Z","timestamp":1782140230000},"page":"e117858","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Protocol for assessment of pain biomarkers in orthopaedic patients undergoing total knee arthroplasty in a tertiary care hospital and neuroimmunopharmacology laboratory in South Australia: a cross-sectional matched-subject observational 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Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel G","family":"Evans","sequence":"additional","affiliation":[{"name":"School of Biomedicine, The University of Adelaide Faculty of Health and Medical Sciences, Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D-Yin (Indy)","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia and Perioperative Care, Flinders Medical Centre, Flinders Dr, Flinders University, Bedford Park, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Trauma and Orthopaedic Surgery, Flinders Medical Centre, Flinders Dr, Flinders University, Bedford Park, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan W","family":"Verjans","sequence":"additional","affiliation":[{"name":"Division of Research and Innovation, Australian Institute for Machine Learning (AIML), University of Adelaide Press, Adelaide, South Australia, Australia"},{"name":"(SAHMRI), South Australian Health and Medical Research Institute Limited, Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Job N","family":"Doornberg","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R","family":"Hutchinson","sequence":"additional","affiliation":[{"name":"School of Biomedicine, The University of Adelaide Faculty of Health and Medical Sciences, Adelaide, South Australia, Australia"},{"name":"Institute for Photonics and Advanced Sensing (IPAS), University of Adelaide, Adelaide, South Australia, 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