Atomic force stiffness imaging: capturing differences in mechanical properties to identify and localize areas of prostate cancer tissue

Prostate cancer is now the most commonly diagnosed cancer in men in western countries. Due to the difficulty for early detection, there are an estimated 10000 deaths a year in the UK from prostate cancer alone; whereby the only curative option is interventional treatment that aims to excise all diseased cells while preserving the neurovascular bundle. To date, several studies have shown that the mechanical properties of cancer cells and tissues i.e. adhesion, stiffness, roughness and viscoelasticity are significantly different from benign cells and regions of tissue that are healthy. Building upon these results, we believe novel methods of imaging the mechanical properties of prostate cancer samples can provide new surgical intervention opportunities beyond what is possible through vision alone. In this paper, we used an Atomic Force Microscope (AFM) to measure the stiffness and topography variations correlating to regions of prostate cancer at the surface of an excised sample at a cellular level. Preliminary results show that by using an AFM we can detect structural differences in non-homogeneous tissue samples, confirming previous results that cancerous tissues appear stiffer than benign areas. Through these results, we aim to develop a stiffness imaging protocol to aid the early detection of prostate cancer, in addition to force sensing surgical tools.


Saliency Detection as a Reactive Process: Unexpected Sensory Events Evoke Corticomuscular Coupling

Survival in a fast-changing environment requires animals not only to detect unexpected sensory events, but also to react. In humans, these salient sensory events generate large electrocortical responses, which have been traditionally interpreted within the sensory domain. Here we describe a basic physiological mechanism coupling saliency-related cortical responses with motor output. In four experiments conducted on 70 healthy participants, we show that salient substartle sensory stimuli modulate isometric force exertion by human participants, and that this modulation is tightly coupled with electrocortical activity elicited by the same stimuli. We obtained four main results. First, the force modulation follows a complex triphasic pattern consisting of alternating decreases and increases of force, time-locked to stimulus onset. Second, this modulation occurs regardless of the sensory modality of the eliciting stimulus. Third, the magnitude of the force modulation is predicted by the amplitude of the electrocortical activity elicited by the same stimuli. Fourth, both neural and motor effects are not reflexive but depend on contextual factors. Together, these results indicate that sudden environmental stimuli have an immediate effect on motor processing, through a tight corticomuscular coupling. These observations suggest that saliency detection is not merely perceptive but reactive, preparing the animal for subsequent appropriate actions.


Determining the biomechanics of touch sensation in C. elegans

The sense of touch is a fundamental mechanism that nearly all organisms use to interact with their surroundings. However, the process of mechanotransduction whereby a mechanical stimulus gives rise to a neuronal response is not well understood. In this paper we present an investigation of the biomechanics of touch using the model organism C. elegans. By developing a custom micromanipulation and force sensing system around a high resolution optical microscope, we measured the spatial deformation of the organism’s cuticle and force response to controlled uniaxial indentations. We combined these experimental results with anatomical data to create a multilayer computational biomechanical model of the organism and accurately derive its material properties such as the elastic modulus and poisson’s ratio. We demonstrate the utility of this model by combining it with previously published electrophysiological data to provide quantitative insights into different biomechanical states for mechanotransduction, including the first estimate of the sensitivity of an individual mechanoreceptor to an applied stimulus (parameterised as strain energy density). We also interpret empirical behavioural data to estimate the minimum number of mechanoreceptors which must be activated to elicit a behavioural response.



£1.5 million EPSRC Global Challenges Research Funding to Tackle Malaria Diagnosis in sub-Saharan Africa using robotics, computer vision and machine learning

A multidisciplinary team led by Delmiro Fernandez-Reyes, Reader in Digital Health & Intelligent Systems at UCL Computer Science, in equal collaboration with the College of Medicine of the University of Ibadan (COMUI), Nigeria, has been carrying outresearchto produce a novel fast robotic-automated computational system capable of reliably diagnosing malaria in sub-Saharan West-Africa.

The team, comprising Delmiro Fernandez-Reyes, Mandayam A. Srinivasan, Vijay Pawar, Mike Shaw and John Shawe-Taylor (UCL Department of Computer Science) and Biobele J. Brown, Ikeoluwa Lagunju and Olugbemiro Sodeinde (COMUI Department of Paediatrics), has now been awarded a £1.5 million EPSRC Global Challenges Research Fund (GCRF) grant. The funding will be used to carry-out engineering (robotics), computational research (computer vision and machine learning) and digital health clinical research (paediatrics infectious diseases) to design, implement, deploy and test a fully automated system capable of tackling the challenges posed by human-operated light-microscopy currently used in the diagnosis of malaria.

Investigation of mechanosensation in C. elegans using light field calcium imaging

We describe a new experimental approach to investigate touch sensation in the model organism C. elegans using light field deconvolution microscopy. By combining fast volumetric image acquisition with controlled indentation of the organism using a high sensitivity force transducer, we are able to simultaneously measure activity in multiple touch receptor neurons expressing the calcium ion indicator GCaMP6s. By varying the applied mechanical stimulus we show how this method can be used to quantify touch sensitivity in C. elegans. We describe some of the challenges of performing light field calcium imaging in moving samples and demonstrate that they can be overcome by simple data processing.

Nano-mechanical single-cell sensing of cell–matrix contacts

Extracellular protein matrices provide a rigidity interface exhibiting nano-mechanical cues that guide cell growth and proliferation. Cells sense such cues using actin-rich filopodia extensions which encourage favourable cell–matrix contacts to recruit more actin-mediated local forces into forming stable focal adhesions. A challenge remains in identifying and measuring these local cellular forces and in establishing empirical relationships between them, cell adhesion and filopodia formation. Here we investigate such relationships using a micromanipulation system designed to operate at the time scale of focal contact dynamics, with the sample frequency of a force probe being 0.1 ms, and to apply and measure forces at nano-to-micro Newton ranges for individual mammalian cells. We explore correlations between cell biomechanics, cell–matrix attachment forces and the spread areas of adhered cells as well as their relative dependence on filopodia formation using synthetic protein matrices with a proven ability to induce enhanced filopodia numbers in adherent cells. This study offers a basis for engineering exploitable cell–matrix contacts in situ at the nanoscale and single-cell levels.

In-vivo high resolution AFM topographic imaging of Caenorhabditis elegans reveals previously unreported surface structures of cuticle mutants

Atomic force microscopy (AFM) is a powerful method for topographic imaging of surfaces with nanometer resolution. AFM offers significant advantages over scanning electron microscopy (SEM) including the acquisition of quantitative 3D-images and biomechanical information. More importantly, for in-vivo biological imaging, AFM does not require sample dehydration/labeling. We show for the first time high-resolution topographical images of the cuticle of the model organism C. elegans under physiological conditions using AFM. C. elegans is used extensively for drug screening and to study pathogen adherence in innate immunity; both applications highly depend on the integrity of the nematode’s cuticle. Mutations affecting both drug adsorption and pathogen clearance have been proposed to relate to changes in the cuticle structure, but never visually examined in high resolution. In this study we use AFM to visualize the topography of wild-type adult C. elegans as well as several cuticle collagen mutants and describe previously unseen anatomical differences.



Robotics and Autonomous Systems work showcased

As part of a recent showcase briefing and networking event for Robotics and Autonomous Systems (RAS) in Horizon 2020, scientists from the National Physical Laboratory (NPL), UCL and MIT gave a presentation on multi-scale robotic teleoperation to the Rt Hon Greg Clark, Minister for Universities and Science.

Prof Mandayam Srinivasan, co-founder of the field of haptics who leads the work at MIT and UCL TouchLabs, started with an overview of teleoperation and haptics at multiple scales from industrial engineering to human scale applications, including robot assisted and remote surgery. The minister was also able to try a hands-on demonstration of micromanipulation with haptic (force) feedback that allows the operator to feel and touch objects at the size of cell developed by Dr Vijay Pawar and Prof Srinivasan.