A Novel Sensor for Tissue Mechanical Property Detection During Robotic Surgery.

Haptic feedback relays important tissue mechanical properties to surgeons during open surgery. However, this information is lost during Robot-assisted Minimally Invasive Surgery (RMIS). Here we present a proof-of-concept for a novel instrument-integrated sensor that uses fiber Bragg grating (FBG) arrays to identify tissues based on mechanical properties. Subjects were tasked with sorting tissue phantoms based on hardness. When using a conventional surgical robot, the average error for novices (N=5) and the expert user was 22.5% and 12.5% respectively. This reduced to 2.5% and 0% when sorting with direct palpation by hand. In contrast, the senorized instrument with automated analysis was able to perform the task without any error across all trials. Clinical Relevance - The proposed sensor has the potential of identifying different tissues based on mechanical properties and thus characterize tumors and other relevant structures. It is envisaged that this will improve decision making process during RMIS and also provide useful sensory information for autonomous surgery.

Reducing retraction forces with tactile feedback during robotic total mesorectal excision in a porcine model.

Excessive tissue-instrument interaction forces during robotic surgery have the potential for causing iatrogenic tissue damages. The current in vivo study seeks to assess whether tactile feedback could reduce intraoperative tissue-instrument interaction forces during robotic-assisted total mesorectal excision. Five subjects, including three experts and two novices, used the da Vinci robot to perform total mesorectum excision in four pigs. The grip force in the left arm, used for retraction, and the pushing force in the right arm, used for blunt pelvic dissection around the rectum, were recorded. Tissue-instrument interaction forces were compared between trials done with and without tactile feedback. The mean force exerted on the tissue was consistently higher in the retracting arm than the dissecting arm (3.72 ± 1.19 vs 0.32 ± 0.36 N, p < 0.01). Tactile feedback brought about significant reductions in average retraction forces (3.69 ± 1.08 N vs 4.16 ± 1.12 N, p = 0.02), but dissection forces appeared unaffected (0.43 ± 0.42 vs 0.37 ± 0.28 N, p = 0.71). No significant differences were found between retraction and dissection forces exerted by novice and expert robotic surgeons. This in vivo animal study demonstrated the efficacy of tactile feedback in reducing retraction forces during total mesorectal excision. Further research is required to quantify the clinical impact of such force reduction.

Bio-Inspired Haptic Feedback for Artificial Palpation in Robotic Surgery.

Adding haptic feedback has been reported to improve the outcome of minimally invasive robotic surgery. In this study, we seek to determine whether an algorithm based on simulating responses of a cutaneous afferent population can be implemented to improve the performance of presenting haptic feedback for robot-assisted surgery. We propose a bio-inspired controlling model to present vibration and force feedback to help surgeons localize underlying structures in phantom tissue. A single pair of actuators was controlled by outputs of a model of a population of cutaneous afferents based on the pressure signal from a single sensor embedded in surgical forceps. We recruited 25 subjects including 10 expert surgeons to evaluate the performance of the bio-inspired controlling model in an artificial palpation task using the da Vinci surgical robot. Among the control methods tested, the bio-inspired system was unique in allowing both novices and experts to easily identify the locations of all classes of tumors and did so with reduced contact force and tumor contact time. This work demonstrates the utility of our bio-inspired multi-modal feedback system, which resulted in superior performance for both novice and professional users, in comparison to a traditional linear and the existing piecewise discrete algorithms of haptic feedback.

Extracellular Matrix Proteins Confer Cell Adhesion-Mediated Drug Resistance Through Integrin α v in Glioblastoma Cells.

Chemotherapy resistance to glioblastoma (GBM) remains an obstacle that is difficult to overcome, leading to poor prognosis of GBM patients. Many previous studies have focused on resistance mechanisms intrinsic to cancer cells; the microenvironment surrounding tumor cells has been found more recently to have significant impacts on the response to chemotherapeutic agents. Extracellular matrix (ECM) proteins may confer cell adhesion-mediated drug resistance (CAMDR). Here, expression of the ECM proteins laminin, vitronectin, and fibronectin was assessed in clinical GBM tumors using immunohistochemistry. Then, patient-derived GBM cells grown in monolayers on precoated laminin, vitronectin, or fibronectin substrates were treated with cilengitide, an integrin inhibitor, and/or carmustine, an alkylating chemotherapy. Cell adhesion and viability were quantified. Transcription factor (TF) activities were assessed over time using a bioluminescent assay in which GBM cells were transduced with lentiviruses containing consensus binding sites for specific TFs linked to expression a firefly luciferase reporter. Apoptosis, mediated by p53, was analyzed by Western blotting and immunocytofluorescence. Integrin α v activation of the FAK/paxillin/AKT signaling pathway and effects on expression of the proliferative marker Ki67 were investigated. To assess effects of integrin α v activation of AKT and ERK pathways, which are typically deregulated in GBM, and expression of epidermal growth factor receptor (EGFR), which is amplified and/or mutated in many GBM tumors, shRNA knockdown was used. Laminin, vitronectin, and fibronectin were abundant in clinical GBM tumors and promoted CAMDR in GBM cells cultured on precoated substrates. Cilengitide treatment induced cell detachment, which was most pronounced for cells cultured on vitronectin. Cilengitide treatment increased cytotoxicity of carmustine, reversing CAMDR. ECM adhesion increased activity of NFκB and decreased that of p53, leading to suppression of p53-mediated apoptosis and upregulation of multidrug resistance gene 1 (MDR1; also known as ABCB1 or P-glycoprotein). Expression of Ki67 was correlative with activation of the integrin α v -mediated FAK/paxillin/AKT signaling pathway. EGFR expression increased with integrin α v knockdown GBM cells and may represent a compensatory survival mechanism. These results indicate that ECM proteins confer CAMDR through integrin α v in GBM cells.

Brain-Mimetic 3D Culture Platforms Allow Investigation of Cooperative Effects of Extracellular Matrix Features on Therapeutic Resistance in Glioblastoma.

Glioblastoma (GBM) tumors exhibit potentially actionable genetic alterations against which targeted therapies have been effective in treatment of other cancers. However, these therapies have largely failed in GBM patients. A notable example is kinase inhibitors of EGFR, which display poor clinical efficacy despite overexpression and/or mutation of EGFR in >50% of GBM. In addressing this issue, preclinical models may be limited by the inability to accurately replicate pathophysiologic interactions of GBM cells with unique aspects of the brain extracellular matrix (ECM), which is relatively enriched in hyaluronic acid (HA) and flexible. In this study, we present a brain-mimetic biomaterial ECM platform for 3D culturing of patient-derived GBM cells, with improved pathophysiologic properties as an experimental model. Compared with orthotopic xenograft assays, the novel biomaterial cultures we developed better preserved the physiology and kinetics of acquired resistance to the EGFR inhibition than gliomasphere cultures. Orthogonal modulation of both HA content and mechanical properties of biomaterial scaffolds was required to achieve this result. Overall, our findings show how specific interactions between GBM cell receptors and scaffold components contribute significantly to resistance to the cytotoxic effects of EGFR inhibition.Significance: Three-dimensional culture scaffolds of glioblastoma provide a better physiological representation over current methods of patient-derived cell culture and xenograft models. Cancer Res; 78(5); 1358-70. ©2017 AACR.