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From the bench to the patient

The Swiss National Science Foundation is funding the National Center of Competence in Research Nanoscale Science that started in 2001. The project module “Nanotechnology in Medicine” aims to bring nanotechnology from the bench to the patient by developing a new class of diagnostic and therapeutic tools. In this project module we are working in a truly interdisciplinary team of physicists, engineers, biologists and clinicians. One of the projects is developing a novel approach, called indentation-type atomic force microscopy (IT AFM), for studying the progression of cartilage diseases (Stolz et al., 2004). IT AFM enables us to map, for example, the mechanical properties of healthy and diseased articular cartilage from the millimeter over the micrometer down to the nanometer scale, thus assessing all important scales of cartilage organization. The ultimate goal is to perform IT AFM directly in situ by developing an arthroscopic AFM which can be directly introduced into a knee or hip joint. Articular (hyaline) cartilage predominantly consists of a complex network of collagen fibers, glycosaminoglycans (GAGs) and bound water. On the one hand the GAGs act as spacers to keep the collagen fibers apart. On the other hand, by their highly negatively charged nature the GAGs bind a large amount of water (60-80 weight %) into the tissue. Osteoarthritis goes hand in hand with a degradation of the GAGs which, in turn, leads to a dehydration and therefore a collapse of the cartilage.


Fig. 1
Surface topography of (A) normal articular cartilage, (B) osteoarthritic articular cartilage, and (C) the corresponding elasticity measurements at the nanometer scale performed with a sharp pyramidal tip. (A) The 67-nm axial repeat distance of individual collagen fibers was clearly resolved by AFM. (B) In contrast to the normal cartilage that exhibited a random orientation of the collagen fiber network, in the diseased cartilage the collagen fibers coalesced on top of each other and exhibited a preferred orientation. This orientation might follow the directed movement within the joint more easily once the GAGs become digested in the course of the disease progression. (C) Comparison of the two slopes of the corresponding force displacement curves indicated stiffening of the osteoarthritic articular relative to the normal cartilage. Scale bars, 1μm (A and B).

As illustrated in Fig. 1A, articular cartilage exhibits a random orientation of the collagen fibers, which reveal a characteristic 67-nm axial repeat. For comparison, osteoarthritic cartilage exhibits a preferred orientation and bundling of the collagen fibers, as indicated by the arrows in Fig. 1B. Because of the mechanical stress, it is conceivable that upon degradation of the GAGs, the collagen fibers are no longer spaced apart and coalesce on top of each other, thereby slowly but definitely aligning themselves in a direction representing the predominant joint movement. As documented in Fig. 1C, when assessed by IT AFM at the nanometer scale the osteoarthritic cartilage appears mechanically significantly stiffer than the healthy cartilage.