Biochemical markers of type II collagen breakdown and synthesis are positioned at specific sites in human osteoarthritic knee cartilage

SummaryObjectiveTo investigate whether type II collagen turnover markers used for osteoarthritis (OA) activity evaluation in body fluids can be detected at the level of specific histological features of OA cartilage tissue, as well as how they relate with each other at this level.MethodsAdjacent sections were obtained from full-depth cartilage biopsies from 32 OA knees. Immunohistochemistry was performed for Helix-II and CTX-II, which are type II collagen fragments originating from the triple helix and the telopeptide region, respectively, and believed to reflect distinct breakdown events, as well as for type IIA N propeptide (PIIANP), a biochemical marker reflecting synthesis of type IIA collagen.ResultsHelix-II and CTX-II were detected in areas where collagen damage was reported previously, most frequently around chondrocytes, but also frequently in regions not previously investigated such as the margin area and close to subchondral bone, including vascularization sites and bone–cartilage interface. The latter is CTX-II's prevailing position and shows rarely Helix-II. PIIANP co-localized with Helix-II and CTX-II on a limited number of features, mainly in deep zone cartilage. Overall, our analysis highlights clear patterns of association of the markers with specific histological features, and shows that they spread to these features in an ordered way.ConclusionHelix-II and CTX-II show to some degree differential selectivity for specific features in cartilage tissue. CTX-II detection close to bone may be relevant to the possible role of subchondral bone in OA. The restricted co-localization of breakdown markers and PIIANP suggests that collagen fragments can result only partially from newly synthesized collagen. Our study strengthens the interest for the question whether combining several markers reflecting different regional cartilage contributions or metabolic processes should allow a broader detection of OA activity

Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices)

In the European Union (EU), the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, while authorising the placing on the market of medical devices is decentralised to independent 'conformity assessment' organisations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the Medical Device Directive, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre-and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024. Here, we describe how it may contribute to the development of regulatory science in Europe.Orthopaedics, Trauma Surgery and Rehabilitatio

EFORT recommendations for off-label use, mix & match and mismatch in hip and knee arthroplasty

Off-label use is frequently practiced in primary and revision arthroplasty, as there may be indications for the application of implants for purposes outside the one the manufacturers intended.Under certain circumstances, patients may benefit from selective application of mix & match. This can refer to primary hip arthroplasty (if evidence suggests that the combination of devices from different manufacturers has superior results) and revision hip or knee arthroplasty (when the exchange of one component only is necessary and the invasiveness of surgery can be reduced).Within the EFORT 'Implant and Patient Safety Initiative', evidence-and consensus-based recommendations have been developed for the safe application of off-label use and mix & match in primary as well as revision hip and knee arthroplasty.Prior to the application of a medical device for hip or knee arthroplasty off-label and within a mix & match situation, surgeons should balance the risks and benefits to the patient, obtain informed consent, and document the decision process appropriately.Nevertheless, it is crucial for surgeons to only combine implants that are compatible. Mismatch of components, where their sizes or connections do not fit, may have catastrophic effects and is a surgical mistake.Surgeons must be fully aware of the features of the components that they use in off-label indications or during mix & match applications, must be appropriately trained and must audit their results.Considering the frequent practice of off-label and mix & match as well as the potential medico-legal issues, further research is necessary to obtain more data about the appropriate indications and outcomes for those procedures.Orthopaedics, Trauma Surgery and Rehabilitatio

A classification method for neurogenic heterotopic ossification of the hip

Background: Existing classifications for heterotopic ossification (HO) do not include all HO types; nor do they consider the anatomy of the involved joint or the neurological injury. Therefore, we performed this study to propose and evaluate a classification according to the location of neurogenic HO and the neurological injury. Materials and methods: We studied the files of 24 patients/33 hips with brain or spinal cord injury and neurogenic HO of the hip treated with excision, indomethacin, and radiation therapy. We classified patients according to the Brooker classification scheme as well as ours. Four types of neurogenic HO were distinguished according to the anatomical location of HO: type 1, anterior; type 2, posterior; type 3, anteromedial; type 4, circumferential. Subtypes of each type were added based on the neurological injury: a, spinal cord; b, brain injury. Mean follow-up was 2.5 years (1-8 years). Results: The Brooker classification scheme was misleading - all hips were class III or IV, corresponding to ankylosis, even though only 14 hips had ankylosis. On the other hand, our classification was straightforward and easy to assign in all cases. It corresponded better to the location of the heterotopic bone, and allowed for preoperative planning of the appropriate surgical approach and evaluation of the prognosis; recurrence of neurogenic HO was significantly higher in patients with brain injury (subtype b), while blood loss was higher for patients with anteromedial (type 3) and circumferential (type 4) neurogenic HO. Conclusions: Our proposed classification may improve the management and evaluation of the prognosis for patients with neurogenic HO