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Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases.In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed.Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo.In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).

Robotic bronchoscopy has the potential to improve the early detection of lung cancer. For the technology to be broadly adopted, the physician needs to be able to control the robotic bronchoscope in an instinctive and effective manner. In this paper, we describe the algorithms used to manipulate/drive the Auris Monarch Platform, a 10 degree-of-freedom bronchoscope and sheath, using a 3 degree-of-freedom user input. We introduce the concept of paired driving where the devices co-insert and co-articulate depending on their relative insertion. The paper presents safety algorithms such as auto-relax on retract and tension monitoring. The drive modes were developed, optimized, and clinically tested in lung models, human cadavers and live porcine models prior to their commercial release. Clinical studies show that the physician is able to reach significantly deeper in the lung than with classic bronchoscopes.

The flexible endoscope is increasingly being considered as a surgical tool to enable innovative natural orifice or flexible access techniques. These experiences have exposed unique advantages but also significant challenges. Major current technical drawbacks in this setting relate to uncontrolled flexibility, inaccurate sustained target localization, unreliable navigation and overall platform instability. In striving to address existing technical limitations, this paper introduces a novel flexible hyper-redundant surgical robot and evaluates its clinical potential using a focused clinical application. To assess utility of the device within tight confines of the human pelvis or peritoneal cavity, detailed laboratory workspace analysis experiments were undertaken using a computer-simulated model that incorporated anatomical data obtained via pelvic magnetic resonance images of eight women. Ten participants executed ninety usability and reliability trials on an ex vivo simulator, before the robot was repeatedly trialled in an in vivo porcine model. The robot demonstrated capability of targeting >90 % of the anatomic region of interest. All 90 user trials were successfully performed without interruption or malfunction. Significant improvements in performance, time and motion were observed between first and last sets of trials (p = 0.001). In vivo feasibility testing affirmed robustness of the device when deployed within the physiological demands of a live scale appropriate model. Technologically advanced flexible operative platforms are needed to fulfil aspirations for an introductory era of flexible access surgery. This prototype is proposed as a potential future platform for robot-assisted flexible endoscopic surgery. Encouraging pre-clinical feasibility results are demonstrated for diagnostic and therapeutic applications within the pelvis.

The use of the flexible endoscope as a surgical platform potentially exposes a range of new surgical approaches and benefits yet to be fully defined. A new method using the flexible endoscope to undertake axillary dissection for breast cancer treatment is explored together with an investigation into its acceptability to the general public. Endoscopic axillary dissection via a transumbilical approach using the flexible endoscope passed subcutaneously from the umbilicus is described for four human cadaveric axillas. A questionnaire, validated by clinicians, explored the general public’s reaction to the approach and how it might be influenced by potentially serious morbidity such as an increased rate of cancer recurrence. All axillas were accessed successfully via the transumbilical approach. Levels 1 and 2 axillary dissection was attempted on four axillas. Scarring from previous axillary surgery prevented dissection in one case. In the remaining three cases, respectively 12, 11, and 14 lymph nodes were harvested. The operative times improved with each case, from 1080 to 390 min. A total of 127 people responded to the questionnaire, with 73 % preferring the described approach over the open and periareolar alternatives when morbidities were considered equivalent. When a hypothetical elevated risk of cancer recurrence was included with the transumbilical approach, one-fifth of the public still accepted the approach due to the likelihood of a superior cosmesis. The use of the flexible endoscope for oncologically safe levels 1 and 2 axillary dissection is possible and would be acceptable to the general public if it were clinically approved. However, significant challenges with the current endoscopic equipment and relevant instrumentation limit the potential of the technique. Technical innovation in terms of new instrument design with improved ergonomics will reduce long operating times and fatigue, thus ensuring surgical acceptance of the flexible endoscope.

Optical biopsy methods such as probe-based confocal laser endomicroscopy (pCLE) provide useful intraoperative real-time information, especially during minimally invasive surgery with flexible endoscopic or robotic platforms. By translating the probe at constant pressure across the target tissue, undistorted “mosaics” can be produced. However, this poses ergonomic challenges with a conventional flexible endoscope. A 100 μm confocal depth pCLE probe was integrated into a previously described seven degrees-of-freedom articulated endoscopic robot. After estimating the average workspace created by a female pneumoperitoneum, the accessibility of the peritoneal cavity by the device for robot-assisted pCLE peritoneoscopy was calculated. To demonstrate its in vivo feasibility, the robot was inserted transvaginally in a pig, under laparoscopic vision. Optical biopsy was performed of several targets within the peritoneal cavity. The workspace analysis calculated that 88 % of the surface of an estimated average female pneumoperitoneum could be contacted by the probe using the robot transvaginally. In vivo, the robot was manoeuvred to provide views of all abdominal and pelvic organs. At each target there was robotic acquisition of still pCLE images, and slowly translating images for the construction of increased field-of-view mosaics up to 2 mm in length. Optical biopsies took 1–2 min per target, and at 3.5 μm lateral resolution, the mosaic images showed characteristic features of anterior abdominal wall, liver, and spleen. In the porcine model, the robotically actuated method of performing peritoneoscopy and pCLE mosaicked optical biopsy is safe and provides a consistent means of acquiring near-histological grade images of submesothelial tissue. Clinical translation is likely to provide sufficient accessibility of the peritoneal cavity.

This paper describes a multitasking robotic platform for Minimally Invasive Surgery (MIS). The device is designed to be introduced through a standard trocar port. Once the device is inserted to the desired surgical site, it can be reconfigured by lifting an articulated section, and protruding two tendon driven flexible arms. Each of the arms holds an interchangeable surgical instrument. The articulated section features a 2 Degrees-of-Freedom (DoF) universal joint followed by a single DoF yaw joint. It incorporates an on-board camera and LED light source at the distal end, leaving a Ø3mm channel for an additional instrument. The main shaft of the robot is largely hollow, leaving ample space for the insertion of two tendon driven flexible arms integrated with surgical instruments. The ex-vivo and in-vivo experiments demonstrate the potential clinical value of the device for performing surgical tasks through single incision or natural orifice transluminal procedures.

Background. Minimally invasive surgical techniques such as single access and natural orifice translumenal endoscopic surgery (NOTES) aim to reduce the number of external scars on the patient but impose restrictions on the space available for the light source within the endoscope and, therefore, the size of the field of view that can be sufficiently illuminated. Materials and Methods. This article presents and compares a number of illumination methods (xenon, light-emitting diodes, laser/phosphor, supercontinuum laser) that could be applied in single-access, robotic, and NOTES procedures. The luminance, spectral content, and intensity profile of each source was measured. Standardized images of each illuminating an abdominal simulator were assessed by a group of surgeons to provide an initial clinical impression. Results. The xenon source was found to have the highest luminance when used with a standard laparoscopic light cable, but this was significantly reduced when used with a small cable suitable for single-access applications. The supercontinuum laser–based light source had brightness comparable to the xenon, which was supported by the surgical test group observations. Conclusions. The supercontinuum fiber probe is a potential alternative to xenon light sources for use in single-access surgery with its comparable luminance, small diameter, flexibility, and even illumination. An initial in vivo test is described, providing a guide for future development.

Introduction: Natural orifice translumenal endoscopic surgery (NOTES) is moving into the clinical arena with multiple feasibility trials taking place around the world. Early results appear...

This paper introduces a modular, mechatronic joint design for a flexible access minimally invasive surgical platform. The design features a hybrid tendon-micromotor actuation scheme coupled via an internal “ring gear”. This configuration transmits the rotary motion of the embedded micromotor to joint rotation in an efficient manner while also providing a hollow lumen through the centre of the joint unit. Detailed analyses of the joint design including tendon path length, positional accuracy and force/torque transmission characteristics are presented. The design has been incorporated into a dexterous, seven degree-of-freedom flexible access platform and its clinical efficacy for performing a Natural Orifice Translumenal Endoscopic Surgery (NOTES) diagnostic peritoneoscopy in an in-vivo environment is presented.

Probe-based confocal laser endomicroscopy (pCLE) provides high-resolution in vivo imaging for intraoperative tissue characterization. Maintaining a desired contact force between target tissue and the pCLE probe is important for image consistency, allowing large area surveillance to be performed. A hand-held instrument that can provide a predetermined contact force to obtain consistent images has been developed. The main components of the instrument include a linear voice coil actuator, a donut load-cell, and a pCLE probe. In this paper, detailed mechanical design of the instrument is presented and system level modeling of closed-loop force control of the actuator is provided. The performance of the instrument has been evaluated in bench tests as well as in hand-held experiments. Results demonstrate that the instrument ensures a consistent predetermined contact force between pCLE probe tip and tissue. Furthermore, it compensates for both simulated physiological movement of the tissue and involuntary movements of the operator's hand. Using pCLE video feature tracking of large colonic crypts within the mucosal surface, the steadiness of the tissue images obtained using the instrument force control is demonstrated by confirming minimal crypt translation.

This paper introduces an articulated robotic device based on universal joints with embedded micro motors for minimally invasive surgery. The device features an articulated distal tip with seven independently controllable degrees-of-freedom (DoF), arranged as two universal joints (intersecting pitch and yaw) and three single DoF joints (yaw only); two O3mm internal channels, one for an on-board camera for visualization and the other for passing interventional instruments. The design allows the robot to explore the entire peritoneal cavity from a chosen single incision point. A trans-vaginal procedure using the device to locate the uterine horn, as a model of a human fallopian tube, and apply an endoscopic clip was carried out during a live porcine trial to demonstrate the potential for performing a Natural Orifice Translumenal Endoscopic Surgery (NOTES) tubal ligation procedure.

New surgical approaches based on natural orifice transluminal surgery (NOTES) have the potential to further decrease morbidity and hospital stay. However, a number of key challenges have been identified preventing its clinical adoption, including inadequate instrument design and spatial disorientation. Furthermore, retroflexion, missing fixed anatomical references, and limited field-of-view are key factors contributing to disorientation in NOTES.A hybrid approach of integrated orientation sensing and real-time vision processing is proposed to restore orientation cues for improved surgical navigation. The distal tip of an articulated robotic endoscope is equipped with an inertial measurement unit (IMU) enabling video images to be reoriented and stabilized with respect to the horizon. This is performed by measuring the direction of gravity in relation to the cameras. Dynamic view expansion is used to increase the field-of-view of the endoscope. The method registers past video images to the current image and creates an enlarged visualization of the anatomy through simultaneous localization and mapping (SLAM).The clinical potential of the system is demonstrated on a NOTES appendectomy procedure performed on the NOSsE phantom. This involves an articulated robotic endoscope navigating to visualize the appendix while retroflexed. The horizon stabilization is additionally evaluated quantitatively against known ground truth.The combination of horizon stabilization and dynamic view expansion presents a realistic approach for reintroducing orientation and navigation cues during NOTES. The platform allows real-time implementation, which is an important prerequisite for further clinical evaluation.

This paper introduces two techniques for controlling an articulated mechatronic laparoscope through the eyes of the surgeon during minimally invasive surgery. The system consists of a 2D eye tracking unit interfaced with a mechatronic laparoscope that has five controllable degrees-of-freedom (DoF) located at the distal end of a rigid shaft. Through the use of image feedback from a tip mounted camera, a closed-loop gaze contingent framework featuring two separate control techniques (“Individual Joint Selection” and “Automatic Joint Selection”) was developed. Under this framework, the location of a surgeon's 2D fixation point is converted into commands that servo the laparoscope. Experimental results illustrate the ability of both techniques to perform real-time gaze contingent laparoscope control. A key advantage of the proposed system is the ability to provide the operator with sufficient distal dexterity to achieve stable off-axis visualisation in an intuitive, hands-free manner, thus allowing other handheld instruments to be controlled simultaneously. Potential applications include Single Incision Laparoscopic Surgery (SILS) or Natural Orifice Trans-Endoluminal Surgery (NOTES), where the use of multiple instruments passing through a single incision presents both visualization and ergonomic challenges.

Recent developments in optical spectroscopic techniques have permitted in vivo, in situ cellular and molecular sensing and imaging to allow for real-time tissue characterization, functional assessment, and intraoperative guidance. The small area sensed by these probes, however, presents unique challenges when attempting to obtain useful tissue information in-vivo due to the need to maintain constant distance or contact with the target, and tissue deformation. In practice, the effective area can be increased by translating the tip of the probe over the tissue surface and generating functional maps of the underlying tissue response. However, achieving such controlled motions under manual guidance is very difficult, particularly since the probe is typically passed down the instrument channel of a flexible endoscope. This paper describes a force adaptive multi-spectral imaging system integrated with an articulated robotic endoscope that allows a constant contact force to be maintained between the probe and the tissue as the robot tip is actuated across complex tissue profiles. Detailed phantom and ex-vivo tissue validation is provided.

We describe a novel approach for the localization of tissue abnormalities during minimally invasive surgery using a force-sensitive wheeled probe. The concept is to fuse the kinaesthetic information from the wheel-tissue rolling interaction into a pseudocolor rolling mechanical image (RMI) to visualize the spatial variation of stiffness within the internal tissue structure. Since tissue abnormalities are often firmer than the surrounding organ or parenchyma, a surgeon then can localize abnormalities by analyzing the image. Initially, a testing facility for validating the concept in an ex vivo setting was developed and used to investigate rolling ?wheel-tissue? interaction. A silicone soft-tissue phantom with embedded hard nodules was constructed to allow for experimental comparison between an RMI and a known soft-tissue structure. Tests have also been performed on excised porcine organs to show the efficacy of the method when applied to biological soft tissues. Results indicate that the RMI technique is particularly suited to identifying the stiffness distribution within a tissue sample, as the continuous force measurement along a given rolling trajectory provides repeatable information regarding relative variations in the normal tissue response. When compared to multiple discrete uniaxial indentations, the continuous measurement approach of RMI is shown to be more sensitive and facilitates coverage of a large area in a short period of time. Furthermore, if parametric classification of tissue properties based on a uniaxial tissue indentation model is desirable, the rolling indentation probe can be easily employed as a uniaxial indenter.

This paper introduces a stereoscopic fibroscope imaging system for Minimally Invasive Surgery (MIS) and examines the feasibility of utilizing images transmitted from the distal fibroscope tip to a proximally mounted CCD camera to recover both camera motion and 3D scene information. Fibre image guides facilitate instrument miniaturization and have the advantage of being more easily integrated with articulated robotic instruments. In this paper, twin 10,000 pixel coherent fibre bundles (590µm diameter) have been integrated into a bespoke laparoscopic imaging instrument. Images captured by the system have been used to build a 3D map of the environment and reconstruct the laparoscope's 3D pose and motion using a SLAM algorithm. Detailed phantom validation of the system demonstrates its practical value and potential for flexible MIS instrument integration due to the small footprint and flexible nature of the fibre image guides.

In this paper, we introduce an inexpensive, realistic, and robust simulator model for training and requirement assessment of natural orifice transluminal endoscopic surgery (NOTES). A laparoscopic box trainer is converted into an effective NOTES environment, in which many of the challenges facing this new approach can be explored firsthand in a laboratory setting. Using this simulator, experiments researching this new surgical field can be refined before moving into in vivo trials, such that the number of animals required for acquiring basic skills and validating new surgical protocols can be reduced. Additionally, the simulator has the potential to be utilized as an effective platform for education and training in NOTES, although formal validation is required before this can truly be appreciated.

This paper presents an articulated robotic-controlled device to facilitate large-area in vivo tissue imaging and characterization through the integration of miniaturized reflected white light and fluorescence intensity imaging for minimally invasive surgery (MIS). The device is composed of a long, rigid shaft with a robotically controlled distal tip featuring three degrees of in-plane articulation and one degree of rotational freedom. The constraints imposed by the articulated section, coupled with the small footprint available in MIS devices, require a novel optical configuration to ensure effective target illumination and image acquisition. A tunable coherent supercontinuum laser source is used to provide sequential white light and fluorescence illumination through a multimode fiber (200 microm diameter), and the reflected images are transmitted to an image acquisition system using a 10,000 pixel flexible fiber image guide (590 microm diameter). By using controlled joint actuation to trace overlapping trajectories, the device allows effective imaging of a larger field of view than a traditional dual-mode laparoscope. A first-generation prototype of the device and its initial phantom and ex vivo tissue characterization results are described. The results demonstrate the potential of the device to be used as a new platform for in vivo tissue characterization and navigation for MIS.

This paper proposes a novel approach for the identification of the internal structure and mechanical properties of biological soft tissue using a force sensitive wheeled probe to generate a 'mechanical image' by rolling across the surface of a solid organ. Initially, a testing facility for validating the concept ex-vivo was developed. Preliminary validation tests were carried out on a silicone phantom with embedded abnormalities with the aim to link the derived 'mechanical image' with the known internal structure. Ex-vivo validation tests were also conducted on excised porcine livers. The data were analyzed in four parts: 1) the dynamic analysis of wheel-tissue interaction to validate that the measured parameters are representative of underlying tissue stiffness; 2) the development of a 'mechanical image' from the rolling data; 3) a comparison of standard 1-DOF indentation testing with 2-DOF rolling and 4) the characterization of the relationship between force and tissue deflection from the data contained within the mechanical image. The results show that the 'rolling mechanical image' is capable of capturing information relating to the underlying tissue stiffness distribution and characterizing the force-tissue deflection profile for a tissue sample. Examples of scenarios, where this information could potentially be used, include providing a surgeon with the ability to probe solid organs in-vivo during robot-assisted MIS or providing prior information for the modeling of tool-tissue interactions, such as steerable needles.

Recent developments in bio-photonics have called for the need of bringing cellular and molecular imaging modalities to an in vivo --- in situ setting to allow for real-time tissue characterization and functional assessment. Before such techniques can be used effectively in routine clinical environments, it is necessary to address the visualization requirement for linking point based optical biopsy to large area tissue visualization. This paper presents a novel approach for fibered endoscopic video mosaicing that permits wide region tissue visualization. A feature-based registration method is used to register the frames of the endoscopic video sequence by taking into account the characteristics of fibroscopic imaging such as non-linear lens distortion and high-frequency fiber optic facet pattern. The registration is combined with an efficient optimization scheme in order to align all input frames in a globally consistent way. An evaluation on phantom and ex vivotissue images allowing free-hand camera motion is presented.

This paper proposes a novel nonlinear viscoelastic soft tissue model generated from ex vivo experimental results on ovine liver using a force sensitive probe. In order to study the biomechanics of soft tissue, static indentation tests were applied on ovine liver. An empirical constitutive equation was extracted from the examined data. A mechanical model combining linear viscoelasticity with a nonlinear function of strain-stress is proposed. The developed model has been evaluated both statically and dynamically with different strain rates - i.e. where the velocity of indentation is varied. By comparing simulation results and measured experimental data, it has been concluded that the proposed model is robust for modelling both static and dynamic indentation conditions. The effect of changing boundary conditions on the parameters in the proposed model has been studied by choosing test sites with different underlying tissue thicknesses. The results indicate that for small strain, the effect of the thickness condition is reasonable to be neglected.

This paper proposes a novel approach for the identification of tissue properties in-vivo using a force sensitive wheeled probe. The purpose of such a device is to compensate a surgeon for a portion of the loss of haptic and tactile feedback experienced during robotic-assisted minimally invasive surgery. Initially, a testing facility for validating the concept ex-vivo was developed and used to characterize two different testing modalities - static (1-DOF) tissue indentation and rolling (2-DOF) tissue indentation. As part of the static indentation experiments a mathematical model was developed to classify tissue condition based on changes in mechanical response. The purpose of the rolling indentation tests was to detect tissue abnormalities, such as tumors, which are difficult to isolate under static testing conditions. During such tests, the test-rig was capable of detecting simulated miniature buried masses at depths of 12mm. Based on these experiments a portable device capable of carrying out similar tests in-vivo was developed. The device was designed to be operated through a trocar port and its key feature is the ability to transition between static indentation and rolling indentation modalities without retracting and changing the tool.

Micro Electro Mechanical Systems have become increasingly more diversified in their applications. This trend is expected to continue and one of the main areas of focus will be biomedical applications. Condition monitoring of biological structures and intelligent implants are being researched and developed with increasing levels of complexity. Although many of these devices are in the conceptual stage, in most cases, they assume that power will be provided by a built-in battery. This limits the practical applications of such devices when they are designed to work for very long periods of time.Copyright © 2006 by ASME

Introduction Endoscopic probe-based confocal endomicroscopy (pCLE) provides 500 μm diameter en-face , cellular resolution, ‘optical biopsies’ of the gastrointestinal mucosal surface. Many burgeoning classification criteria incorporate crypt morphology analysis: hyperplastic colonic polyps display ‘star-shaped’ crypt openings; ulcerative colitis features enlarged crypt openings with increased intercryptal separation.1 We hypothesised that pCLE probe tip contact force and bowel distension may affect crypt morphology independently. Methods For the ex-vivo force study, still pCLE images were acquired of 3 × 3 cm pieces of porcine colon applied with topical 0.02% acriflavine. A rig vertically suspended the bowel against a compressible surface. A 2.5 mm diameter pCLE probe, clamped to a force-sensitive linear servo mechanism was driven perpendicularly into fresh tissue regions until a contact force of 0.005, 0.05, 0.1, or 0.5 N was achieved. 20 images were analysed for each force. For the in vivo bowel distension study, in an anaesthetised 70 kg pig using intravenous fluorescein 10%, 20 representative stills were analysed from each of 2-min endoscopic pCLE video loops with gentle probe contact against sigmoid (A) collapsed, (B) inflated to 4 cm diameter and (C) hyperinflated to 6 cm diameter using a proximal bowel clamp. Results In the ex vivo study, as the probe contact force increased, the crypts appeared to be squeezed out of the field of view, and the mean visible crypt number per image decreased: 16.8 (±3.1) at 0.005N, 9.5 (±1.4) at 0.05N, 8.3 (±1.4) at 0.1N and 5.7 (±1.4) at 0.5N. Furthermore, the mean crypt diameter increased according to contact force: 46 μm (±11) at 0.005N, 61 μm (±18) at 0.05N, 74 μm (±16) at 0.1N and 89 μm (±27) at 0.5N. In the sigmoidoscopy study, for collapsed, inflated and hyperinflated sigmoid colon respectively, the mean number of visible crypts decreased: 23.7 (±3.1), 14.0 ((±2.1) and 8.1(±0.7). Similarly, the mean crypt diameter increased: 65.4 μm (±2.2), 85 μm (±2.1) and 95.6 μm (±2.8). Conclusion Both increasing pCLE probe tip contact force and bowel distension reduce the number of visible crypts per field of view, and increase the mean crypt diameter. This may have important implications for standardising image acquisition protocol during endoscopic pCLE to ensure morphological alterations to crypts can be exclusively attributed to tissue differences.