Dose-Response Relationship of Ambulatory Load and Cartilage - Pilot Study
Condition: Healthy
Study type: Interventional

Summary: 
      The research question is if there is a dose-response relationship between blood biomarkers
      for articular cartilage and the magnitude of physiological load. To investigate this load
      induced biomarker change, the participants will complete a 30-minute walking test under three
      loading conditions: A: 80%, B: 100% C: 120% of their respective bodyweight (Fig. 1).

      The main biomarker we are interested in is called cartilage oligomeric matrix protein (COMP).
      Serum COMP levels are increased immediately after 30-min running but there is no
      dose-response relationship shown yet.
    

Detailed description: 
      The current state of research in the field and of our own research clearly shows that the in
      vivo mechanobiology of articular cartilage is poorly understood. Previous results of changes
      in cartilage biomarker concentrations after ambulatory exercise raise the following question:

      Do load-induced changes in blood biomarkers for articular cartilage (COMP) depend on the
      physiological load magnitude? To generate initial data for answering this question, we will
      establish the experimental framework to systematically study the in vivo mechanobiology of
      human articular cartilage to address the following aims.

        -  To obtain pilot data for investigating the in vivo dose-response relationship of
           weight-bearing and blood levels of mechanosensitive biomarker of articular cartilage
           using controlled load- bearing as experimental paradigm.

        -  To provide pilot data for comparing ambulatory biomechanics between the controlled load-
           bearing conditions.

      The experimental setting consists of a 30-minutes walking stress test under three loading
      conditions: A: 80 %, B: 100% and C: 120% bodyweight. Unloading will be achieved through an
      unloading system and additional loading with an adjustable weight vest. Before and after the
      walking stress test, venous blood samples will be taken at five time points. The biomarker
      concentration is measured with a commercial available enzyme-linked immunosorbent assay
      (ELISA).

      Hypothesis Our working hypothesis is that there is a dose-response relationship between the
      temporarily increased or decreased load and the load-induced change in COMP level in the
      blood serum. We assume that serum COMP concentration increases with increasing accumulated
      load on the knee cartilage simulated through the three different loading conditions.

      Design The design of the pilot study is a controlled multimodal data collection (biological,
      biomechanical) with block randomization. Specifically, we will collect blood samples and
      biomechanical (kinematic and pressure) data. We will determine the relationship between the
      serum blood concentration and the biomechanical data.

      Because this is a cross-over study, all participants will perform the same three walking
      stress tests but in random order. Each participant of the study will be tested for 2.5 hours
      on 3 separate days.

      Method In this experiment, we will test 24 healthy participants (12 male, 12 female) on 3
      test days under three different loading conditions in a randomized block design. On each test
      day, participants will complete walking stress test for 30-minutes with A: 80%, B: 100% and
      C: 120% of their bodyweight. Through the modified bodyweight we generate higher or lower
      forces on the knee cartilage, which should affect the COMP concentration in the blood serum.

      To measure the change in serum COMP concentration, blood samples will be taken at five time
      points before and after the walking stress test. The blood samples are taken by a study
      nurse. For the venipuncture, a thin, sterile, disposable vein catheter is placed in the
      antecubital vein. The catheter stays in the vein for the entire 2.5 hours of the experiment.
      Blood samples will be collected and allowed to clot for 30-minutes. Serum will be separated
      and frozen in aliquots to -20°C within 1 hour of collection and then transferred for storage
      at -80°C until assayed. Serum biomarker concentrations will be determined using commercial
      ELISAs.
    

Intervention name(s): Increased load; Reduced load
Intervention type(s): Other; Other
Intervention description(s): Participants walk with 120% body weight achieved with a weight vest; Participants walk with 80% body weight achieved by a dynamic unloading system
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Controlled multimodal data collection (biological, biomechanical) with block randomization.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Ambulatory load; Biomarker; Articular cartilage