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Breast-conserving surgery (BCS) is commonly used for the treatment of early-stage breast cancer. Following BCS, approximately 20% to 30% of patients require reexcision because postoperative histopathology identifies cancer in the surgical margins of the excised specimen. Quantitative micro-elastography (QME) is an imaging technique that maps microscale tissue stiffness and has demonstrated a high diagnostic accuracy (96%) in detecting cancer in specimens excised during surgery. However, current QME methods, in common with most proposed intraoperative solutions, cannot image cancer directly in the patient, making their translation to clinical use challenging. In this proof-of-concept study, we aimed to determine whether a handheld QME probe, designed to interrogate the surgical cavity, can detect residual cancer directly in the breast cavity in vivo during BCS. In a first-in-human study, 21 BCS patients were scanned in vivo with the QME probe by five surgeons. For validation, protocols were developed to coregister in vivo QME with postoperative histopathology of the resected tissue to assess the capability of QME to identify residual cancer. In four cavity aspects presenting cancer and 21 cavity aspects presenting benign tissue, QME detected elevated stiffness in all four cancer cases, in contrast to low stiffness observed in 19 of the 21 benign cases. The results indicate that in vivo QME can identify residual cancer by directly imaging the surgical cavity, potentially providing a reliable intraoperative solution that can enable more complete cancer excision during BCS. Significance: Optical imaging of microscale tissue stiffness enables the detection of residual breast cancer directly in the surgical cavity during breast-conserving surgery, which could potentially contribute to more complete cancer excision.

Breast-conserving surgery (BCS) is commonly used for the treatment of early-stage breast cancer. Following BCS, approximately 20% to 30% of patients require reexcision because postoperative histopathology identifies cancer in the surgical margins of the excised specimen. Quantitative micro-elastography (QME) is an imaging technique that maps microscale tissue stiffness and has demonstrated a high diagnostic accuracy (96%) in detecting cancer in specimens excised during surgery. However, current QME methods, in common with most proposed intraoperative solutions, cannot image cancer directly in the patient, making their translation to clinical use challenging. In this proof-of-concept study, we aimed to determine whether a handheld QME probe, designed to interrogate the surgical cavity, can detect residual cancer directly in the breast cavity in vivo during BCS. In a first-in-human study, 21 BCS patients were scanned in vivo with the QME probe by five surgeons. For validation, protocols were developed to coregister in vivo QME with postoperative histopathology of the resected tissue to assess the capability of QME to identify residual cancer. In four cavity aspects presenting cancer and 21 cavity aspects presenting benign tissue, QME detected elevated stiffness in all four cancer cases, in contrast to low stiffness observed in 19 of the 21 benign cases. The results indicate that in vivo QME can identify residual cancer by directly imaging the surgical cavity, potentially providing a reliable intraoperative solution that can enable more complete cancer excision during BCS.Significance:Optical imaging of microscale tissue stiffness enables the detection of residual breast cancer directly in the surgical cavity during breast-conserving surgery, which could potentially contribute to more complete cancer excision.

OCT and QME of benign stroma

Inadequate margins in breast-conserving surgery (BCS) are associated with an increased likelihood of local recurrence of breast cancer. Currently, approximately 20% of BCS patients require repeat surgery due to inadequate margins at the initial operation. Implementation of an accurate, intraoperative margin assessment tool may reduce this re-excision rate. This study determined, for the first time, the diagnostic accuracy of quantitative micro-elastography (QME), an optical coherence tomography (OCT)–based elastography technique that produces images of tissue microscale elasticity, for detecting tumor within 1 mm of the margins of BCS specimens. Simultaneous OCT and QME were performed on the margins of intact, freshly excised specimens from 83 patients undergoing BCS and on dissected specimens from 7 patients undergoing mastectomy. The resulting three-dimensional images (45 × 45 × 1 mm) were coregistered with postoperative histology to determine tissue types present in each scan. Data from 12 BCS patients and the 7 mastectomy patients served to build a set of images for reader training. One hundred and fifty-four subimages (10 × 10 × 1 mm) from the remaining 71 BCS patients were included in a blinded reader study, which resulted in 69.0% sensitivity and 79.0% specificity using OCT images, versus 92.9% sensitivity and 96.4% specificity using elasticity images. The quantitative nature of QME also facilitated development of an automated reader, which resulted in 100.0% sensitivity and 97.7% specificity. These results demonstrate high accuracy of QME for detecting tumor within 1 mm of the margin and the potential for this technique to improve outcomes in BCS.Significance:An optical imaging technology probes breast tissue elasticity to provide accurate assessment of tumor margin involvement in breast-conserving surgery.

OCT and QME of adipose tissue

OCT and QME of mucinous carcinoma

OCT and QME of invasive ductal carcinoma with stroma

OCT and QME of ductal carcinoma in situ

Supplementary Data from Quantitative Micro-Elastography Enables In Vivo Detection of Residual Cancer in the Surgical Cavity during Breast-Conserving Surgery

Reader stats, Read-Eng1, Read-Eng2, Read-Path, Read-Res, Read-Truth, Read-Son, Read-Surg1, Read-Surg2

Mechanisms of tissue deformation in OCME

Deformation is the change in size and shape of a sample in response to an applied load. Accurately measuring deformation is critical in optical coherence elastography (OCE), as along with the validity of the mechanical model of the sample, it determines the accuracy of the measurement of mechanical properties. In this chapter, we describe prominent methods to measure deformation in OCE, including phase-sensitive detection and cross-correlation-based approaches such as speckle tracking. We describe the working principles of these methods and analyze their advantages and disadvantages in the context of performance metrics including sensitivity, accuracy, and spatial resolution. In addition, we briefly describe several less prominent methods such as morphological tracking, correlation stability, digitally shifted complex cross-correlation, and Doppler spectrum detection.

Optical coherence tomography (OCT) is an imaging technique that uses low-coherence interferometry to construct 3D images with micrometer-scale resolution. It is the imaging modality used in optical coherence elastography (OCE) to measure sample deformation; as such, a detailed analysis of OCT is required to gain a clear understanding of OCE. This chapter provides an overview of the physical principles of OCT, including wave optics, coherence, and interferometry. This theory is then used to describe the main variants of OCT: time-domain OCT and Fourier-domain OCT; the latter of which can be further subdivided into swept-source OCT and spectral-domain OCT. The relationship between system parameters (such as resolution, field of view, and signal-to-noise ratio), and the specification of OCT system components (such as the light source, objectives lens, and scanning mirrors) is also discussed. The chapter concludes with a brief description of OCT variants, including optical coherence microscopy, full-field OCT, and line-field OCT.

The mechanics of tissue are exceptionally complex. They reflect the diverse composition and architecture of many tissues, and have a profound role in regulating a multitude of biochemical and molecular processes. As a consequence, the understanding and quantification of tissue mechanics has been, and still remains, an important century-long pursuit. A main challenge in this area is the formalization of biological complexity into mathematical relations that are at once simple, as to be readily interpretable, and accurate, such that they confer key information on a broad variety of tissues. In elastography, as well as in many other mechanical imaging and metrology methods, this challenge is often approached by codifying tissue mechanics using the principles of continuum mechanics. There, the biological complexity is distilled to a few relations by using assumptions that are motivated by the composition, and observed behavior of tissues, as well as the measurement method used. In this chapter, we describe and reconcile this close relationship between the tissue biology, the measurement method, and the continuum mechanics models used to quantify measurements in elastography. Specifically, we focus on those principles that have founded many of the compelling demonstrations of optical coherence elastography.

Compression optical coherence elastography (OCE) is a variant of OCE that maps mechanical parameters, or properties of a sample by measuring the deformation in response to quasi-static compressive loading. Relative to other OCE techniques, to date, compression OCE has provided higher acquisition speed, and the capability to scan over wider fields of view. In early compression OCE studies, it was not possible to estimate quantitative mechanical properties, such as elasticity, instead these early studies calculated qualitative mechanical parameters, typically strain. More recently, quantitative compression OCE has been developed to enable the estimation of elasticity, extending its use to broader applications. However, physical contact between the sample, and loading mechanism is typically required, which is a drawback in applications involving delicate tissues, such as ophthalmology. This chapter focuses on the technical development of compression OCE, beginning with the mechanical model used to determine elasticity. An overview of methods for estimating mechanical parameters, and properties; in particular, strain, stress, and elasticity, is provided. In addition, image quality metrics defined to characterize the imaging performance, such as spatial resolution, and sensitivity, are described.

Tissue mechanical properties determine the relationship between an applied mechanical load and the resulting deformation of the sample. In optical coherence elastography (OCE), the objective is to spatially resolve tissue mechanical properties from often incomplete and noisy measurements of the load and deformation. This is achieved by solving an inverse problem, using a model of elasticity that reasonably describes the behavior of tissue. Incorporating more parameters into the model (such as heterogeneity, anisotropy, nonlinearity, or viscoelasticity) than are needed in a given application can unnecessarily complicate the inverse problem. Also, how the load is applied can enhance certain tissue responses, and the validity of an elasticity model, and, thus, allow for the characterization of tissue in different regimes. A successful OCE technique offers a good match between the load application method, and the tissue mechanical properties of interest, and employs a reasonably complete but simplified mechanical model that provides a noise-robust inversion. OCE techniques can be classified into two broad categories: those inducing and subsequently tracking propagating mechanical waves, and those applying and assuming a uniaxial load, and tracking the deformation in response. With a brief introduction to the former, this chapter focuses on the latter group, describes the most prominent of these techniques, and presents an overview of studies that have successfully extracted mechanical properties in tissue-like media.

Funding: Australian Research Council; Department of Health, Australian Government; Cancer Council Western Australia; Oncores Medical; The William and Marlene Schrader Trust of the University of Western Australia; Royal Society. Phase-sensitive optical coherence tomography (OCT) is used to measure motion in a range of techniques, such as Doppler OCT and optical coherence elastography (OCE). In phase-sensitive OCT, motion is typically estimated using a model of the OCT signal derived from a single reflector. However, this approach is not representative of turbid samples, such as tissue, which exhibit speckle. In this study, for the first time, we demonstrate, through theory and experiment that speckle significantly lowers the accuracy of phase-sensitive OCT in a manner not accounted for by the OCT signal-to-noise ratio (SNR). We describe how the inaccuracy in speckle reduces phase difference sensitivity and introduce a new metric, speckle brightness, to quantify the amount of constructive interference at a given location in an OCT image. Experimental measurements show an almost three-fold degradation in sensitivity between regions of high and low speckle brightness at a constant OCT SNR. Finally, we apply these new results in compression OCE to demonstrate a ten-fold improvement in strain sensitivity, and a five-fold improvement in contrast-to-noise by incorporating independent speckle realizations. Our results show that speckle introduces a limit to the accuracy of phase-sensitive OCT and that speckle brightness should be considered to avoid erroneous interpretation of experimental data. Publisher PDF

Compression optical coherence elastography forms images based on the mechanical properties of tissue by mapping the local strain in response to a compressive load. Strain is described by a second-order tensor, comprising six independent components. The majority of compression elastography methods, however, measure and form their analyses from a single axial component, which relies on the assumption that the stress in tissue is uniform and uniaxial. However, in general, tissues are complex and heterogeneous, and rarely comply with this assumption. This can lead to inaccuracies and misinterpretation of image contrast in compression optical coherence elastography. Here, we image the full strain tensor and demonstrate its utility in unambiguously characterizing deformation in structured phantoms and ex vivo tissues. We derive additional parameters from the strain tensor, and map the local compressibility, anisotropy of deformation, and total equivalent strain. Such analysis is enabled by an efficient non-iterative approach to measuring the three-dimensional displacement field via a closed-form solution to a collection of the amplitude of complex correlation coefficients across multiple digitally shifted images. Strain tensor imaging is likely to lead to more accurate estimation of tissue mechanical properties, improving the utility of compression optical coherence elastography in clinical and biological applications.

The importance of cellular-scale mechanical properties is well-established, yet it is challenging to map subcellular elasticity in three dimensions. We present subcellular mechano-microscopy, an optical coherence microscopy (OCM)-based variant of three-dimensional (3-D) compression optical coherence elastography (OCE) that provides an elasticity system resolution of 5 × 5 × 5 µm: a 7-fold improvement in system resolution over previous OCE studies of cells. The improved resolution is achieved through a ∼5-fold improvement in optical resolution, refinement of the strain estimation algorithm, and demonstration that mechanical deformation of subcellular features provides feature resolution far greater than that demonstrated previously on larger features with diameter >250 µm. We use mechano-microscopy to image adipose-derived stem cells encapsulated in gelatin methacryloyl. We compare our results with compression OCE and demonstrate that mechano-microscopy can provide contrast from subcellular features not visible using OCE.

We demonstrate a convolutional neural network (CNN) for multi-class breast tissue classification as adipose tissue, benign dense tissue, or malignant tissue, using multi-channel optical coherence tomography (OCT) and attenuation images, and a novel Matthews correlation coefficient (MCC)-based loss function that correlates more strongly with performance metrics than the commonly used cross-entropy loss. We hypothesized that using multi-channel images would increase tumor detection performance compared to using OCT alone. 5,804 images from 29 patients were used to fine-tune a pre-trained ResNet-18 network. Adding attenuation images to OCT images yields statistically significant improvements in several performance metrics, including benign dense tissue sensitivity (68.0% versus 59.6%), malignant tissue positive predictive value (PPV) (79.4% versus 75.5%), and total accuracy (85.4% versus 83.3%), indicating that the additional contrast from attenuation imaging is most beneficial for distinguishing between benign dense tissue and malignant tissue.

Quantitative micro-elastography (QME), a variant of compression optical coherence elastography (OCE), is a technique to image tissue elasticity on the microscale. QME has been proposed for a range of applications, most notably tumor margin assessment in breast-conserving surgery. However, QME sensitivity, a key imaging metric, has yet to be systematically analyzed. Consequently, it is difficult to optimize imaging performance and to assess the potential of QME in new application areas. To address this, we present a framework for analyzing sensitivity that incorporates the three main steps in QME image formation: mechanical deformation, its detection using optical coherence tomography (OCT), and signal processing used to estimate elasticity. Firstly, we present an analytical model of QME sensitivity, validated by experimental data, and demonstrate that sub-kPa elasticity sensitivity can be achieved in QME. Using silicone phantoms, we demonstrate that sensitivity is dependent on friction, OCT focus depth, and averaging methods in signal processing. For the first time, we show that whilst lubrication of layer improves accuracy by reducing surface friction, it reduces sensitivity due to the time-dependent effect of lubricant exudation from the layer boundaries resulting in increased friction. Furthermore, we demonstrate how signal processing in QME provides a trade-off between sensitivity and resolution that can be used to optimize imaging performance. We believe that our framework to analyze sensitivity can help to sustain the development of QME and, also, that it can be readily adapted to other OCE techniques.

Supplementary material to: Speckle-dependent accuracy in phase-sensitive optical coherence tomography

Intraoperative margin assessment is needed to reduce the re-excision rate of breast-conserving surgery. One possibility is optical palpation, a tactile imaging technique that maps stress (force applied across the tissue surface) as an indicator of tissue stiffness. Images (optical palpograms) are generated by compressing a transparent silicone layer on the tissue and measuring the layer deformation using optical coherence tomography (OCT). This paper reports, for the first time, the diagnostic accuracy of optical palpation in identifying tumor within 1 mm of the excised specimen boundary using an automated classifier. Optical palpograms from 154 regions of interest (ROIs) from 71 excised tumor specimens were obtained. An automated classifier was constructed to predict the ROI margin status by first choosing a circle diameter, then searching for a location within the ROI where the circle was ≥ 75% filled with high stress (indicating a positive margin). A range of circle diameters and stress thresholds, as well as the impact of filtering out non-dense tissue regions, were tested. Sensitivity and specificity were calculated by comparing the automated classifier results with the true margin status, determined from co-registered histology. 83.3% sensitivity and 86.2% specificity were achieved, compared to 69.0% sensitivity and 79.0% specificity obtained with OCT alone on the same dataset using human readers. Representative optical palpograms show that positive margins containing a range of cancer types tend to exhibit higher stress compared to negative margins. These results demonstrate the potential of optical palpation for margin assessment.

Effective intraoperative tumor margin assessment is needed to reduce re-excision rates in breast-conserving surgery (BCS). Mapping the attenuation coefficient in optical coherence tomography (OCT) throughout a sample to create an image (attenuation imaging) is one promising approach. For the first time, three-dimensional OCT attenuation imaging of human breast tissue microarchitecture using a wide-field (up to ~45 × 45 × 3.5 mm) imaging system is demonstrated. Representative results from three mastectomy and one BCS specimen (from 31 specimens) are presented with co-registered postoperative histology. Attenuation imaging is shown to provide substantially improved contrast over OCT, delineating nuanced features within tumors (including necrosis and variations in tumor cell density and growth patterns) and benign features (such as sclerosing adenosis). Additionally, quantitative micro-elastography (QME) images presented alongside OCT and attenuation images show that these techniques provide complementary contrast, suggesting that multimodal imaging could increase tissue identification accuracy and potentially improve tumor margin assessment.

This presentation reports a comparison between two handheld quantitative micro elastography (QME) methods: PZT actuated compression QME and manual compression QME. PZT actuated compression QME utilizes a PZT actuator to provide a periodic compression against the scanned sample, whilst manual compression QME utilizes the continuous motion of the user’s hand holding the probe to create compression against the sample. From our results, each method has its own advantages, and both methods are capable of measuring elasticity of the sample and distinguishing stiff tumor from regions of soft benign tissue on excised human breast specimens.

13 pags., 7 figs., Compression optical coherence elastography (OCE) typically requires a mechanical actuator to impart a controlled uniform strain to the sample. However, for handheld scanning, this adds complexity to the design of the probe and the actuator stroke limits the amount of strain that can be applied. In this work, we present a new volumetric imaging approach that utilizes bidirectional manual compression via the natural motion of the user's hand to induce strain to the sample, realizing compact, actuator-free, handheld compression OCE. In this way, we are able to demonstrate rapid acquisition of three-dimensional quantitative microelastography (QME) datasets of a tissue volume (6 × 6 × 1 mm) in 3.4 seconds. We characterize the elasticity sensitivity of this freehand manual compression approach using a homogeneous silicone phantom and demonstrate comparable performance to a benchtop mounted, actuator-based approach. In addition, we demonstrate handheld volumetric manual compression-based QME on a tissue-mimicking phantom with an embedded stiff inclusion and on freshly excised human breast specimens from both mastectomy and wide local excision (WLE) surgeries. Tissue results are coregistered with postoperative histology, verifying the capability of our approach to measure the elasticity of tissue and to distinguish stiff tumor from surrounding soft benign tissue., This research was supported by grants and fellow shipsfrom the Australian Research Council, the National Health and Medical Research Council (Australia), the National Breast Cancer Foundation (Australia), the Department of Health, Western Australia, the Cancer Council, Western Australia and through a research con-tract with OncoRes Medical, Australia

Inadequate margins in breast-conserving surgery (BCS) are associated with an increased likelihood of local recurrence of breast cancer. Currently, approximately 20% of BCS patients require repeat surgery due to inadequate margins at the initial operation. Implementation of an accurate, intraoperative margin assessment tool may reduce this re-excision rate. This study determined, for the first time, the diagnostic accuracy of quantitative micro-elastography (QME), an optical coherence tomography (OCT)–based elastography technique that produces images of tissue microscale elasticity, for detecting tumor within 1 mm of the margins of BCS specimens. Simultaneous OCT and QME were performed on the margins of intact, freshly excised specimens from 83 patients undergoing BCS and on dissected specimens from 7 patients undergoing mastectomy. The resulting three-dimensional images (45 × 45 × 1 mm) were coregistered with postoperative histology to determine tissue types present in each scan. Data from 12 BCS patients and the 7 mastectomy patients served to build a set of images for reader training. One hundred and fifty-four subimages (10 × 10 × 1 mm) from the remaining 71 BCS patients were included in a blinded reader study, which resulted in 69.0% sensitivity and 79.0% specificity using OCT images, versus 92.9% sensitivity and 96.4% specificity using elasticity images. The quantitative nature of QME also facilitated development of an automated reader, which resulted in 100.0% sensitivity and 97.7% specificity. These results demonstrate high accuracy of QME for detecting tumor within 1 mm of the margin and the potential for this technique to improve outcomes in BCS. Significance: An optical imaging technology probes breast tissue elasticity to provide accurate assessment of tumor margin involvement in breast-conserving surgery.

14 pags., 7 figs., We present a finger-mounted quantitative micro-elastography (QME) probe, capable of measuring the elasticity of biological tissue in a format that avails of the dexterity of the human finger. Finger-mounted QME represents the first demonstration of a wearable elastography probe. The approach realizes optical coherence tomography-based elastography by focusing the optical beam into the sample via a single-mode fiber that is fused to a length of graded-index fiber. The fiber is rigidly affixed to a 3D-printed thimble that is mounted on the finger. Analogous to manual palpation, the probe compresses the tissue through the force exerted by the finger. The resulting deformation is measured using optical coherence tomography. Elasticity is estimated as the ratio of local stress at the sample surface, measured using a compliant layer, to the local strain in the sample. We describe the probe fabrication method and the signal processing developed to achieve accurate elasticity measurements in the presence of motion artifact. We demonstrate the probe’s performance in motion-mode scans performed on homogeneous, bi-layer and inclusion phantoms and its ability to measure a thermally-induced increase in elasticity in ex vivo muscle tissue. In addition, we demonstrate the ability to acquire 2D images with the finger-mounted probe where lateral scanning is achieved by swiping the probe across the sample surface., Australian Research Council (ARC); the Cancer Council, Western Australia; OncoRes Medical; War Widows' Guild of Western Australia Scholarship.

Approximately a quarter of patients undergoing breast conserving surgery will need further surgery as close or involved surgical margins suggest they may have residual tumour in the breast. Handheld imaging probes capable of scanning the surgical cavity during the surgery have the potential to improve intraoperative assessment of surgical margins in breast conserving surgery thus allow real time assessment of completeness of tumour excision. In this paper, we present a handheld optical coherence elastography (OCE) probe, allowing us to acquire a 3D quantitative elastogram of a 6×6×1.5 mm volume in 3.4 seconds. Our technique is based on a compression OCE technique, referred to as quantitative micro-elastography (QME), where a compliant silicone layer is incorporated to measure stress at the tissue surface. To perform handheld scanning, we implemented a rapid scan pattern to enable B-scan rates of 215 Hz using a microelectromechanical system (MEMS) scanner: minimizing the time difference between B-scan pairs used to generate displacement maps thus minimizing the motion artefact caused by hand motion. We present handheld scans acquired from silicone phantoms where the motion artefact is barely noticeable. In addition, freshly dissected human breast tissue from a mastectomy was scanned with the handheld probe. The breast tissue elastograms are validated using standard histology and demonstrate our ability to distinguish stiff regions of tumour from benign tissue using this probe.

Variations in the mechanical properties of the extracellular environment can alter important aspects of cell function such as proliferation, migration, differentiation and survival. However, many of the techniques available to study these effects lack the ability to characterise cell-to-cell and cell-to-environment interactions on the microscopic scale in three dimensions (3D). Quantitative micro-elastography (QME) is an extension of compression optical coherence elastography that utilizes a compliant layer with known mechanical properties to estimate the axial stress at the tissue surface, which combined with axial strain, is used to map the 3D microscale elasticity of tissue into an image. Despite being based on OCT, limitations in post-processing techniques used to determine axial strain prevented QME to quantify the elasticity of individual cells. In this study we extend the capability of QME to present, to the best of our knowledge, the first images of the elasticity of cells and their environment in 3D over millimeter field-of-views. We improve the accuracy and resolution of QME by incorporating an efficient, iterative solution to the inverse elasticity problem using adjoint elasticity equations to enable QME to visualize individual cells for the first time. We present images of human stem cells embedded in soft gelatin methacryloyl (GelMa) hydrogels and demonstrate these cells elevate the stiffness of the GelMa from 3-kPa to approximately 25-kPa. Our QME system is developed using commercially available components that can be readily made available to biologists, highlighting the potential for QME to emerge as an important tool in the field of mechanobiology.

16 pags., 7 figs., 1 tab., Optical coherence elastography (OCE) has been proposed for a range of clinical applications. However, the majority of these studies have been performed using bulky, lab-based imaging systems. A compact, handheld imaging probe would accelerate clinical translation, however, to date, this had been inhibited by the slow scan rates of compact devices and the motion artifact induced by the user’s hand. In this paper, we present a proof-of-concept, handheld quantitative micro-elastography (QME) probe capable of scanning a 6 × 6 × 1 mm volume of tissue in 3.4 seconds. This handheld probe is enabled by a novel QME acquisition protocol that incorporates a custom bidirectional scan pattern driving a microelectromechanical system (MEMS) scanner, synchronized with the sample deformation induced by an annular PZT actuator. The custom scan pattern reduces the total acquisition time and the time difference between B-scans used to generate displacement maps, minimizing the impact of motion artifact. We test the feasibility of the handheld QME probe on a tissue-mimicking silicone phantom, demonstrating comparable image quality to a bench-mounted setup. In addition, we present the first handheld QME scans performed on human breast tissue specimens. For each specimen, quantitative micro-elastograms are co-registered with, and validated by, histology, demonstrating the ability to distinguish stiff cancerous tissue from surrounding soft benign tissue., Australian Research Council (ARC); Department of Health, Western Australia; Cancer Council, Western Australia; OncoRes Medical.

Funding: Australian Research Council; the Cancer Council Western Australia; OncoRes Medical; William and Marlene Schrader Trust of the University of Western Australia scholarship. Optical coherence elastography (OCE) is emerging as a method to image the mechanical properties of tissue on the microscale. However, the spatial resolution, a main advantage of OCE, has not been investigated and is not trivial to evaluate. To address this, we present a framework to analyze resolution in phase-sensitive compression OCE that incorporates the three main determinants of resolution: mechanical deformation of the sample, detection of this deformation using optical coherence tomography (OCT), and signal processing to estimate local axial strain. We demonstrate for the first time, through close correspondence between experiment and simulation of structured phantoms, that resolution in compression OCE is both spatially varying and sample dependent, which we link to the discrepancies between the model of elasticity and the mechanical deformation of the sample. We demonstrate that resolution is dependent on factors such as feature size and mechanical contrast. We believe that the analysis of image formation provided by our framework can expedite the development of compression OCE. Publisher PDF

We demonstrate the use of the near-infrared attenuation coefficient, measured using optical coherence tomography (OCT), in longitudinal assessment of hypertrophic burn scars undergoing fractional laser treatment. The measurement method incorporates blood vessel detection by speckle decorrelation and masking, and a robust regression estimator to produce 2D en face parametric images of the attenuation coefficient of the dermis. Through reliable co-location of the field of view across pre- and post-treatment imaging sessions, the study was able to quantify changes in the attenuation coefficient of the dermis over a period of ~20 weeks in seven patients. Minimal variation was observed in the mean attenuation coefficient of normal skin and control (untreated) mature scars, as expected. However, a significant decrease (13 ± 5%, mean ± standard deviation) was observed in the treated mature scars, resulting in a greater distinction from normal skin in response to localized damage from the laser treatment. By contrast, we observed an increase in the mean attenuation coefficient of treated (31 ± 27%) and control (27 ± 20%) immature scars, with numerical values incrementally approaching normal skin as the healing progressed. This pilot study supports conducting a more extensive investigation of OCT attenuation imaging for quantitative longitudinal monitoring of scars. (Figure presented.) En face 2D OCT attenuation coefficient map of a treated immature scar derived from the pre-treatment (top) and the post-treatment (bottom) scans. (Vasculature (black) is masked out.) The scale bars are 0.5 mm.

"Strain tensor imaging in compression optical coherence elastography."Fig. S1: Displacement sensitivity at varying OCT signal to noise ratios (SNR) along the z axis (a), and the x and y axes (b). Normal strain sensitivity at varying OCT SNR along the z axis (c), and the x and y axes (d). P. Wijesinghe, L. Chin and B. F. Kennedy, "Strain Tensor Imaging in Compression Optical Coherence Elastography," in IEEE Journal of Selected Topics in Quantum Electronics.doi: 10.1109/JSTQE.2018.2871596URL: http://ieeexplore.ieee.org/stamp/stamp.jsp?tp=&arnumber=8470111&isnumber=4481213

An accurate intraoperative identification of malignant tissue is a challenge in the surgical management of breast cancer. Imaging techniques that help address this challenge could contribute to more complete and accurate tumor excision, and thereby help reduce the current high reexcision rates without resorting to the removal of excess healthy tissue. Optical coherence microelastography (OCME) is a three-dimensional, high-resolution imaging technique that is sensitive to microscale variations of the mechanical properties of tissue. As the tumor modifies the mechanical properties of breast tissue, OCME has the potential to identify, on the microscale, involved regions of fresh, unstained tissue. OCME is based on the use of optical coherence tomography (OCT) to measure tissue deformation in response to applied mechanical compression. In this feasibility study on 58 ex vivo samples from patients undergoing mastectomy or wide local excision, we demonstrate the performance of OCME as a means to visualize tissue microarchitecture in benign and malignant human breast tissues. Through a comparison with corresponding histology and OCT images, OCME is shown to enable ready visualization of features such as ducts, lobules, microcysts, blood vessels, and arterioles and to identify invasive tumor through distinctive patterns in OCME images, often with enhanced contrast compared with OCT. These results lay the foundation for future intraoperative studies. Cancer Res; 75(16); 3236–45. ©2015 AACR.

Compression optical coherence elastography (OCE) enables rapid acquisition with high resolution over fields of view relevant to many clinical applications. Compression OCE typically provides a relative measure of mechanical properties; however, we have recently demonstrated a technique which quantifies stiffness via a compliant layer, termed quantitative OCE. In quantitative OCE, stiffness is reported as a tangent modulus, which is a surrogate for Young’s modulus at a given preload in non-linear elastic material. In biological tissues, which are typically non-linear elastic, values of stiffness reported through quantitative OCE could be over- or under-estimated, and are heavily biased by the arbitrary bulk preload applied to that region. We present a method to measure tissue nonlinearity locally, by preforming compression OCE at multiple preloads ranging from 2% to 40%. We show, through presentation of 2D quantitative elastograms, that compression OCE has the potential to measure the non-linear stiffness in tissue mimicking phantoms and biological tissue. Further, intrinsic mechanical contrast in tissue is dependent upon its preload. By tailoring tissue preload, we demonstrate improved contrast between benign and tumor tissue in a murine liver carcinoma model.

Breast cancer has the second highest mortality rate of all cancers in females. Surgical excision of malignant tissue forms a central component of breast-conserving surgery (BCS) procedures. Incomplete excision of malignant tissue is a major issue in BCS with typically 20 – 30% cases requiring a second surgical procedure due to postoperative detection of tumor in the margin. A major challenge for surgeons during BCS is the lack of effective tools to assess the surgical margin intraoperatively. Such tools would enable the surgeon to more effectively remove all tumor during the initial surgery, hence reducing re-excision rates. We report advances in the development of a new tool, optical coherence micro-elastography, which forms images, known as elastograms, based on mechanical contrast within the tissue. We demonstrate the potential of this technique to increase contrast between malignant tumor and healthy stroma in elastograms over OCT images. We demonstrate a key advance toward clinical translation by conducting wide-field imaging in intraoperative time frames with a wide-field scanning system, acquiring mosaicked elastograms with overall dimensions of ~50 × 50 mm, large enough to image an entire face of most lumpectomy specimens. We describe this wide-field imaging system, and demonstrate its operation by presenting wide-field optical coherence tomography images and elastograms of a tissue mimicking silicone phantom and a number of representative freshly excised human breast specimens. Our results demonstrate the feasibility of scanning large areas of lumpectomies, which is an important step towards practical intraoperative margin assessment.

In this paper, we demonstrate in vivo volumetric quantitative micro-elastography of human skin. Elasticity is estimated at each point in the captured volume by combining local axial strain measured in the skin with local axial stress estimated at the skin surface. This is achieved by utilizing phase-sensitive detection to measure axial displacements resulting from compressive loading of the skin and an overlying, compliant, transparent layer with known stress/strain behavior. We use an imaging probe head that provides optical coherence tomography imaging and compression from the same direction. We demonstrate our technique on a tissue phantom containing a rigid inclusion, and present in vivo elastograms acquired from locations on the hand, wrist, forearm and leg of human volunteers.

Incomplete excision of malignant tissue is a major issue in breast-conserving surgery, with typically 20 - 30% of cases requiring a second surgical procedure arising from postoperative detection of an involved margin. We report advances in the development of a new intraoperative tool, optical coherence micro-elastography, for the assessment of tumor margins on the micro-scale. We demonstrate an important step by conducting whole specimen imaging in intraoperative time frames with a wide-field scanning system acquiring mosaicked elastograms with overall dimensions of ~50 × 50 mm, large enough to image an entire face of most lumpectomy specimens. This capability is enabled by a wide-aperture annular actuator with an internal diameter of 65 mm. We demonstrate feasibility by presenting elastograms recorded from freshly excised human breast tissue, including from a mastectomy, lumpectomies and a cavity shaving.

Optical coherence elastography (OCE) is emerging as a potentially useful tool in the identification of a number of diseases. In our group, we are developing OCE techniques based on compressive loading. Typically, these techniques employ a quasi-static mechanical load introduced by uniaxially compressing a sample with a rigid plate. The resulting deformation of the sample is measured using phase-sensitive detection and the local axial strain is estimated from the slope of displacement over a finite depth in the sample, providing qualitative mechanical contrast. In this talk, an overview of our work will be given and some of the outstanding challenges described. Our group’s work in OCE can broadly be divided into four streams, each of which will be described in detail in the talk: system development; techniques; quantification; and applications. • System development: The phase-sensitive OCE method we have developed will be described, as well as a high resolution optical coherence microscopy-based elastography system suitable for imaging cellular-scale mechanical properties. • Techniques: In addition to presenting techniques to estimate strain, our approaches to imaging tissue viscoelasticity and nonlinearity will be described. A technique to segment elastograms based on strain heterogeneity will be presented. • Quantification: Methods under development to quantify tissue stiffness in compression OCE will be described. This work is enabled by optical palpation and solutions to the forward and inverse elasticity problems. • Applications: Three applications areas will be described: intraoperative assessment of tumour margins, mapping stiffness in tumour biology and assessing the stiffness of cardiovascular tissue in an animal model.