Research paperTowards Optical Coherence Tomography-based elastographic evaluation of human cartilage
Graphical abstract
Introduction
Cartilage degenerative changes are a major cause of disability in humans. Their prevalence and socioeconomic impact is expected to further increase in our aging population (Uchio et al., 2002). In the clinical context, cartilage degeneration is the central hallmark of osteoarthritis (OA), a complex musculoskeletal disorder with numerous contributory genetic, constitutional and biomechanical factors. Early cartilage degeneration is marked by progressive extracellular matrix degeneration and decreased resistance to load deformation (Akizuki et al., 1987), while the macroscopic appearance of the tissue remains intact (Franz et al., 2001). The initial degenerative changes are reversible due to the tissue׳s limited intrinsic repair capabilities; however, the persistence of an unfavourable mechanical environment combined with tissue susceptibility leads to progressive and irreversible matrix degradation and structural damage in terms of fibrillation, fissuring and subsequent cartilage tissue loss (Johnson et al., 2012). Therefore, preventive interventions, including surgery or pharmaceutical agents, have to be initiated as long as the pathology is reversible (Bay-Jensen et al., 2010). The reliable detection of the very earliest evidence of cartilage degeneration is a prerequisite for such timely intervention. Current clinical imaging modalities such as radiography, arthroscopy and clinical routine Magnetic Resonance Imaging (MRI) are characterized by numerous limitations in resolution, sensitivity/specificity, inter-observer reliability, objectivity and cannot differentiate normal from early degenerative cartilage (Brismar et al., 2002, Marx et al., 2005, Palmer et al., 2013, Spahn et al., 2009). Furthermore, they do not properly assess mechanical properties, which may further limit these modalities׳ diagnostic performance as cartilage softening is regarded the first and most reliable sign of OA (Haapala et al., 2000).
Conventional biomechanical assessment of cartilage relies on the measurement of tissue deformation by indentation. In the past, arthroscopically available hand-held indentation devices have been developed and investigated for their clinical potential (Franz et al., 2001, Toyras et al., 2005). Amongst other reasons, their use has been restricted due to limited measurement accuracy: First, measurement of tissue thickness, an important parameter to calculate intrinsic biomechanical properties, was not possible using these devices. Second, reproducibility was low due to the difficult overall handling of the probe (Garcia-Seco et al., 2009). Also, these devices were not capable of assessing tissue structure or morphology.
Therefore, the comprehensive non-destructive micro-scale assessment of cartilage functional and structural properties with clinical potential remains elusive. Optical Coherence Tomography (OCT)-based imaging may provide a potential solution to this problem. As an imaging technique that has received considerable scientific and clinical attention since its first thorough description in 1991 (Huang et al., 1991), OCT is based on the measurement of near-infra-red light scattering and reflection and allows imaging of surface and subsurface tissue regions in real time and at high spatial resolution. High degrees of correlation between OCT and reference histology have been demonstrated (Chu et al., 2004, Nebelung et al., 2014). Although OCT-based parameterisation and quantification of morphological and optical parameters have been investigated recently, quantitative approaches so far cannot differentiate early disease stages (Nebelung et al., 2014, Saarakkala et al., 2009, Viren et al., 2012). Therefore, the present paper aims to evaluate whether loading-induced changes in human cartilage by means of OCT are to be assessed qualitatively. This feasibility study is thus meant to provide the basis for the comprehensive quantitative assessment of cartilage by Optical Coherence Elastography (OCE), which is classically used to determine tissue biomechanical properties by acquisition of tissue strain maps (i.e. elastograms) using OCT (Wang and Larin, 2015). Scientific evidence on OCE in the assessment of cartilage is sparse at present. Huang et al. (2011) pioneered the field in developing an OCT-based air-jet indentation system, which uses a pressurised air jet for standardized cartilage indentation. In comparison to alternative evaluation methods such as ultrasound elastography or magnetic resonance elastography, which allow spatial resolutions of hundred of micrometres and organ-size fields of view (Wang and Larin, 2015), OCE provides micrometre-scale resolution (<15 µm) and millimetre-scale imaging depth of cartilage (Kennedy et al., 2014a, Wang and Larin, 2015). The exquisite displacement sensitivity may allow for the determination of very small changes in mechanical properties at the resolution of the OCT system (i.e. 5–20 µm) (Kennedy et al., 2013). Furthermore, high acquisition speeds in combination with real-time imaging make OCT-based approaches an interesting technique for cartilage evaluation.
Therefore, the present study introduces a new in vitro indentation device for the assessment of structural and functional cartilage tissue properties by means of OCT imaging under simultaneous indentation by quasistatic external loading. Its system design and subsequent validation are described as well as the subsequent qualitative evaluation of human cartilage samples and their response to loading. As MR imaging is the clinical workhorse in the non-invasive evaluation of cartilage damage, the indentation device was made compatible with MRI to allow for comprehensive inter-method cross referencing. After assessing the device׳s MRI-compatibility, comparative evaluation was performed using analogous loading conditions and T2 weighted gradient echo sequences.
Section snippets
Systemdesign
The indentation device consists of a centre plate driven by a threaded drive rod and framed by an upper and lower base plate (displayed in detail in Fig. 1). Indentation loading is brought about by the upward movement (against the indenter piston) of a sample container with the sample that rests on the centre plate. The 8 mm-diameter 10 mm-long cylindrical plane-ended and bevelled-edged (bevel of 1 mm) indenter piston is fully made of Poly-methyl-methacrylate (PMMA). The piston itself is threaded,
Results
Upon biomechanical validation of the indentation device a total of 5 human cartilage samples were included in the comprehensive assessment. Prior to measurements, individual samples׳ thickness was determined and found to vary substantially despite being commonly classified as Outerbridge grade 0. More specifically, substantial data variability in relation to the measurement technique was found (needle-probe technique: 2.770±0.697 [range, min/max: 1.883/3.430]; MR imaging: 2.600±0.602 [range,
Discussion
The most important findings of the present study are that 1) the developed contact indentation device may be used for both structural and compositional assessment of human cartilage by OCT as well as MRI and 2) loading-induced morphological changes were observed in either imaging modality although these were found to be heterogeneous within, and inconsistent between, samples.
Early cartilage degeneration is characterized by tissue softening (Haapala et al., 2000), collagen breakdown,
Conclusions
We presented an indentation device that may be useful for the combined structural and functional assessment of human cartilage by OCT and MRI. Although further refinements are required and the present evaluation method is yet merely qualitative, the complementary assessment of human articular cartilage in vitro by OCT and MRI is feasible and promising. Future modifications should include more quantitative techniques to investigate spatially resolved and depth-dependent mechanical properties of
Acknowledgements/funding
The authors would like to thank Ms. Sophie Lecouturier, Mr. Simon Oehrl and Mr. Björn Sondern for their overall technical assistance. Furthermore, they would like to acknowledge the support granted by Dr. Yi from the Institute of General Mechanics of the RWTH Aachen. This study was supported by the START-Program of the Faculty of Medicine, RWTH Aachen - Germany (696600). HJ is a member of the D-Board Consortium. The D-Board project has received funding from the European Union׳s Seventh
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