Development of Nanotools for Imaging, Measuring and Manipulating Soft Matter in the Human Body

Osteoarthritis (OA) is a painful and disabling progressive joint disease that is characterized by degradation of the articular cartilage and affects millions of people. OA poses a dilemma: it usually begins attacking different joints long before middle age, but cannot be diagnosed until it becomes symptomatic decades later, at which point the structure and biomechanical properties of the affected cartilage are usually irreversibly altered. Currently available clinical devices typically work at the millimeter scale or above and hence cannot resolve the cellular and molecular features of cartilage, i.e. the scale at which biochemical processes occur and pathological lesions start. In contrast, the scanning force microscope (SFM) - the prototype of a nanotool - can readily image cartilage morphology and measure its biomechanical properties at the micrometer scale and beyond. Thus, the SFM opens the exciting possibility to detect pathological features of articular cartilage long before they become symptomatic and cause a functional impairment of the affected joint. Detection of OA at a presymptomatic stage might be key to develop effective therapies to slow down or stop its progression.

Fig. 1: Investigating the age-related changes of the elastic modulus of healthy cartilage in mice. Typically, a two-year-old mouse corresponds to an 80-year-old human. (A) The photo depicts a top view of a mouse femoral head simultaneously with the cantilever of an SFM (arrow) viewed through a stereo microscope. By monitoring the cantilever deflection while pushing the femur by a controlled displacement against the SFM tip, the elastic modulus of the cartilage covering the femoral head surface can be determined. (B) The red curve displays the age-dependent increase of the mouse cartilage’s elastic modulus as measured with a 20-nm-size tip, while the green curve reveals the concommitant loss of the proteoglycan moiety as measured by biochemical analysis.

In parallel with the systematic ex vivo characterization of the biomechanical and biochemical properties of normal and pathological mouse and human articular cartilage, we are also developing an arthroscopic SFM, i.e. a clinical nanodevice for direct in situ inspection of articular cartilage morphology and stiffness at the sub-micrometer scale by a minimally invasive intervention. One potential use of the arthroscopic SFM may be for quality control during follow-ups after cartilage transplantations. Ultimately, this novel nanotool might enable the orthopaedic surgeon to quickly and reliably assess the health status of articular cartilage profilactically and, if necessary, to prescribe therapeutic steps that interfere with disease progression at a presymptomatic stage.

Fig. 2: Arthroscopic SFM. (A) Testing of the arthroscopic SFM (arrows) in a knee phantom. (B) Prototype of an arthroscopic SFM. (C) The arthroscopic SFM will be a diagnostic tool that can be introduced into the knee joint via an arthroscopic instrument tubus

The arthroscopic SFM might become the prototype of a new generation of nanotools for minimally invasive diagnostic interventions in other parts of the human body for example, to detect vulnerable plaques in the coronary arteries of the heart by a catheter-based approach. Also, it is conceivable that the mechanical properties of healthy and cancerous cells might differ when measured at the sub-micrometer scale. This difference could be used for the development of an SFM-based tool for the early recognition, for example, of chest or laryngeal cancer. The realization of such goals would be the step out of the “stone age” of scanning probe-based clinical tools. However, while some of the most important achievements made in science may cover all aspects of science and technology, the key technologies will also improve the quality of our life.

Investigating native coronary artery endothelium in situ and cell culture by scanning force microscopy
Tobias Reichlin, Andreas Wild, Markus Dürrenberger, A.U. Daniels, Ueli Aebi, Patrick R. Hunziker and Martin Stolz
Journal of Structural Biology Volume 152, Issue 1 , October 2005, Pages 52-63

Contact:

Martin Stolz	Ueli Aebi	Urs Staufer
M.E. Müller Institute for Structural Biology Biozentrum, University of Basel Switzerland		University of Neuchâtel Switzerland

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