Proof-of-concept for the detection of early osteoarthritis pathology by clinically applicable endomicroscopy and quantitative AI-supported optical biopsy

Abstract

Objective: Clinical trials for osteoarthritis (OA), the leading cause of global disability, are unable to pinpoint the early, potentially reversible disease with clinical technology. Hence, disease-modifying drug candidates cannot be tested early in the disease. To overcome this obstacle, we asked whether early OApathology detection is possible with current clinical technology. Methods: We determined the relationship between two sensitive early OA markers, atomic force microscopy (AFM)-measured human articular cartilage (AC) surface stiffness, and location-matched superficial zone chondrocyte spatial organizations (SCSOs), asking whether a significant loss of surface stiffness can be detected in early OA SCSO stages. We then tested whether current clinical technology can visualize and accurately diagnose the SCSOs using an approved probe-based confocal laser-endomicroscope and a random forest (RF) model. Results: We demonstrated a correlation between AC surface stiffness and the SCSO (r rm ¼ À0.91; 95% CI: À0.97, À0.73), and an extensive loss of surface stiffness specifically in those ACs with early OA-typical SCSO (95%CIs: string SCSO: 269-173 kPa, double string SCSO: 77-46 kPa). This established the SCSO as a visualizable, functionally relevant surrogate marker of early OA AC surface pathology. Moreover, SCSObased stiffness discrimination worked well in each patient's AC. We then demonstrated feasibility of visualizing the SCSO by clinical laser-endomicroscopy and, importantly, accurate SCSO diagnosis using RF. Conclusion: We present the proof-of-concept of early OA-pathology detection with available clinical technology, introducing a future-oriented, AI-supported, non-destructive quantitative optical biopsy for early disease detection. Operationalizing SCSO recognition, this approach allows testing for correlations between local tissue architectures with other experimental and clinical read-outs, but needs clinical validation and a larger sample size for defining diagnostic thresholds.

Engeletin Protects Against TNF-α-Induced Apoptosis and Reactive Oxygen Species Generation in Chondrocytes and Alleviates Osteoarthritis in vivo

“…OA has become a worldwide medical burden, and thus far, there have been no available preventive or therapeutic biological interventions. 29 This study aimed to discover a therapeutic drug for OA. Chondrocytes were treated with TNF-α to mimic the inflammatory environment, and engeletin was then administered.…”

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

“…Another approach is to focus on other diagnostic imaging techniques to diagnose the early and potentially reversible disease pathology, especially since methods, such as X-ray and MRI cannot yet statistically discriminate between healthy vs. early OA [239]. We recently showed that a clinically available confocal laser endomicroscope could be used to image a surrogate marker of otherwise clinically, but not yet detectable, early OA functional pathology prior to cell clustering [240]. Specifically, we showed that characteristics of the spatial organization of the superficial zone chondrocytes (SCSO) are indicative of early pathology [94,[107][108][109][110]136,241] and can be imaged clinically using a confocal laser endomicroscope.…”

“…Specifically, we showed that characteristics of the spatial organization of the superficial zone chondrocytes (SCSO) are indicative of early pathology [94,[107][108][109][110]136,241] and can be imaged clinically using a confocal laser endomicroscope. Combined with random forest modelling, this artificial intelligence (AI)-based non-destructive quantitative optical biopsy was capable of accurately differentiating between a healthy vs. early OA architectural fingerprint, suggesting that early OA pathology detection is indeed possible with current clinical technology [240]. Thus, such new imaging approaches, combined with modern analysis and/or predictive tools, such as AI, could be used with measurements of multiple easily measurable biochemical biomarker candidates (e.g., MMP-3 and possibly IL-17) from blood samples and combined with patient-related parameters over time and in parallel.…”

“…This group also suggested that, when possible, samples including serum/plasma, urine and SF should be collected at all available time points, such as preoperatively, at the time of surgery, clinical aspiration, and treatment which, in terms of clinical treatment outcomes, could help identify relationships between early (e.g., 1-2 years) and later outcomes (e.g., 5-10 years). Thus, inclusion of easily measurable biomarkers, combined with imaging technologies, e.g., AI-supported endomicroscopy-assisted optical biopsy, that correlate local tissue architectures [240] with biomarkers and other parameters, such as clinical symptoms, age, sex, BMI and, e.g., the type of injury, could also better stratify joint-or injury-specific progression and improve our understanding of early disease pathology and detection.…”

Articular Chondrocyte Phenotype Regulation through the Cytoskeleton and the Signaling Processes That Originate from or Converge on the Cytoskeleton: Towards a Novel Understanding of the Intersection between Actin Dynamics and Chondrogenic Function

“…Articular cartilage (AC) is an autonomously functioning connective tissue that absorbs and distributes the occurring mechanical joint loads. The resident cells of AC, the chondrocytes (CHs), are sparsely distributed within species-, joint type-, surface-specific [ 5 , 6 , 7 ] and diagnostically relevant [ 8 , 9 ] arrangements that are termed the superficial chondrocyte spatial organization (SCSO) and that can be used for spatial [ 10 ] and predictive modelling [ 11 ] in the context of a non-destructive quantitative optical biopsy for early disease detection. The CHs are quiescent, fully differentiated cells whose chondrogenic phenotype ensures a fine-tuned balance between anabolism and catabolism to maintain tissue homeostasis [ 12 ].…”