Institute of Physical Chemistry, Albert-Ludwigs-University Freiburg, Albertstr. 21, 79104, Freiburg, Germany; G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Medical Center - Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Germany.
G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Medical Center - Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Germany.
Osteoarthritis Cartilage. 2021 Feb;29(2):269-279. doi: 10.1016/j.joca.2020.10.003. Epub 2020 Nov 19.
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 OA-pathology detection is possible with current clinical technology.
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.
We demonstrated a correlation between AC surface stiffness and the SCSO (r = -0.91; 95%CI: -0.97, -0.73), 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, SCSO-based 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.
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.
骨关节炎（OA）是全球致残的主要原因，针对其开展的临床试验无法利用临床技术准确识别早期、潜在可逆转的疾病。因此，无法在疾病早期阶段对疾病修饰药物候选物进行测试。为了克服这一障碍，我们研究了利用现有临床技术是否能够早期检测 OA 病变。
我们通过原子力显微镜（AFM）测量的人关节软骨（AC）表面硬度和位置匹配的浅层区软骨细胞空间组织（SCSO）这两个敏感的早期 OA 标志物，确定了两者之间的关系，以确定在早期 OA SCSO 阶段是否可以检测到表面硬度的显著降低。然后，我们使用经过批准的基于探针的共聚焦激光内窥显微镜和随机森林（RF）模型，测试了现有临床技术是否能够可视化和准确诊断 SCSO。
我们证实了 AC 表面硬度与 SCSO 之间存在相关性（r=-0.91；95%CI：-0.97，-0.73），并且在那些具有早期 OA 典型 SCSO 的 AC 中，表面硬度会出现广泛降低（95%CI：string SCSO：269-173 kPa，double string SCSO：77-46 kPa）。这确立了 SCSO 是早期 OA AC 表面病理学的可视化、具有功能相关性的替代标志物。此外，基于 SCSO 的硬度区分在每位患者的 AC 中均表现良好。然后，我们通过临床激光内窥镜检查证实了可视化 SCSO 的可行性，并且利用 RF 进行了重要的 SCSO 准确诊断。
我们利用现有的临床技术提供了早期 OA 病变检测的概念验证，为早期疾病检测引入了一种面向未来、基于人工智能、无损定量光学活检方法。该方法可以通过识别 SCSO，允许对局部组织结构与其他实验和临床检测结果之间的相关性进行测试，但需要临床验证和更大的样本量来定义诊断阈值。
