Current models to understand the onset and progression of scoliotic deformities in adolescent idiopathic scoliosis: a systematic review.

PURPOSE: To create an updated and comprehensive overview of the modeling studies that have been done to understand the mechanics underlying deformities of adolescent idiopathic scoliosis (AIS), to predict the risk of curve progression and thereby substantiate etiopathogenetic theories. METHODS: In this systematic review, an online search in Scopus and PubMed together with an analysis in secondary references was done, which yielded 86 studies. The modeling types were extracted and the studies were categorized accordingly. RESULTS: Animal modeling, together with machine learning modeling, forms the category of black box models. This category is perceived as the most clinically relevant. While animal models provide a tangible idea of the biomechanical effects in scoliotic deformities, machine learning modeling was found to be the best curve-progression predictor. The second category, that of artificial models, has, just as animal modeling, a tangible model as a result, but focusses more on the biomechanical process of the scoliotic deformity. The third category is formed by computational models, which are very popular in etiopathogenetic parameter-based studies. They are also the best in calculating stresses and strains on vertebrae, intervertebral discs, and other surrounding tissues. CONCLUSION: This study presents a comprehensive overview of the current modeling techniques to understand the mechanics of the scoliotic deformities, predict the risk of curve progression in AIS and thereby substantiate etiopathogenetic theories. Although AIS remains to be seen as a complex and multifactorial problem, the progression of its deformity can be predicted with good accuracy. Modeling of AIS develops rapidly and may lead to the identification of risk factors and mitigation strategies in the near future. The overview presented provides a basis to follow this development.

Feasibility of Narrow-Band Imaging, Intraductal Biopsy, and Laser Ablation During Mammary Ductoscopy: Protocol for an Interventional Study.

Introduction: Ductoscopy is a minimally invasive micro-endoscopic approach for direct visualization of intraductal lesions of the breast. Challenges of ductoscopy are low sensitivity for detecting malignancy, the lack of a proper intraductal biopsy device, and adequate treatment of intraductal lesions. This study will analyze three new approaches to enhance the effectiveness of interventional ductoscopy in patients with (premalignant) intraductal lesions: narrow-band imaging (NBI), new intraductal biopsy tools, and intraductal laser ablation. The main aims of the present study are to improve diagnostic accuracy and therapeutic efficacy of interventional ductoscopy in patients with pathological nipple discharge (PND) and to explore the feasibility of the new approaches in diagnosing and removing intraductal precursor lesions. Methods and analysis: This prospective, single-center, diagnostic feasibility study will include two patient groups. Group A: women with PND with no radiological suspicion for malignancy. Group B: women undergoing mastectomy (preventive or therapeutic). The primary endpoints for both groups are the technical feasibility of NBI ductoscopy, intraductal biopsy, and laser ablation, and as secondary endpoint the number of diagnosed and successfully treated intraductal lesions. Discussion: Enhanced ductoscopy with NBI, intraductal biopsy, and laser ablation could prevent unnecessary surgery in patients with PND. Ethics and dissemination: This study was approved by the Medical Research Ethics Committee UMC Utrecht in The Netherlands (METC protocol number 21-688/H-D). The results of this study will be published in peer-reviewed journals and presented at national and international conferences. Highlights: - Pathological nipple discharge (PND) is a common breast-related complaint in women.- Ductoscopy, a minimally invasive technique, is used in the treatment of PND.- This study will analyze three new approaches to enhance interventional ductoscopy of the breast: narrow-band imaging, new intraductal biopsy tools, and intraductal laser ablation in patients with (premalignant) intraductal lesions.

The MemoFlex II, a non-robotic approach to follow-the-leader motion of a snake-like instrument for surgery using four predetermined physical tracks.

The fields of Minimally Invasive Surgery (MIS) and Natural Orifices Transluminal Endoscopic Surgery (NOTES) strive to reduce the level of invasiveness by entering the body through smaller incisions and natural orifices. Hyper-redundant snake-like instruments can help in this pursuit of reducing invasiveness. Such instruments can pass along multi-curved pathways through the body without any support or guidance from its anatomical environment. In this way, the width of the surgical pathway and thus the invasiveness of the procedure can be reduced significantly. This is referred to as Follow-the-Leader (FTL) motion. Generally, surgical instruments intended for FTL-motion are robotic systems that require medical grade actuators, sensors, and controllers, driving up costs and increasing their footprint in the operation room. Our goal was to discard the need for these elements and develop a non-robotic instrument capable of FTL-motion along pre-determined paths. A proof of concept prototype called MemoFlex II was developed, consisting of a cable-driven hyper-redundant shaft that is controlled via four physical tracks. The MemoFlex II was able to perform 3D FTL-motion along pre-determined paths. Among other things, this study reports on a Ø8 mm shaft containing seven segments and 14 degrees of freedom (DOFs) following several multi-curved paths with an average maximal footprint between 11.0 and 17.1 mm.

Experimental evaluation of a self-propelling bio-inspired needle in single- and multi-layered phantoms.

In percutaneous interventions, reaching targets located deep inside the body with minimal tissue damage and patient pain requires the use of long and thin needles. However, when pushed through a solid substrate, a structure with a high aspect ratio is prone to buckle. We developed a series of multi-element needles with a diameter smaller than 1 mm and a length larger than 200 mm, and we experimentally evaluated the performance of a bio-inspired insertion mechanism that prevents needle buckling of such slender structures. The needles consisted of Nitinol wires and advance into a substrate by pushing the wires forward one after the other, followed by pulling all the wires simultaneously backward. The resulting net push force is low, allowing the needles to self-propel through the substrate. We investigated the effect of the needle design parameters (number of wires and their diameter) and substrate characteristics (stiffness and number of layers) on the needle motion. Three needle prototypes (consisting of six 0.25-mm wires, six 0.125-mm wires, and three 0.25-mm wires, respectively) were inserted into single- and multi-layered tissue-mimicking phantoms. The prototypes were able to move forward in all phantoms without buckling. The amount of needle slip with respect to the phantom was used to assess the performance of the prototypes. The six-wire 0.25-mm prototype exhibited the least slip among the three prototypes. Summarizing, we showed that a bio-inspired motion mechanism prevents buckling in very thin (diameter <1 mm), long (length >200 mm) needles, allowing deep insertion into tissue-mimicking phantoms.

A gesture-based design tool: Assessing 2DOF vs. 4DOF steerable instrument control.

Iterative prototyping is costly and time-consuming. Particularly when designing medical instruments, human factors related design choices significantly impact performance and safety. A tool is presented that allows for the evaluation of steerable instrument controls before the onset of the prototyping stage. The design tool couples gestural input to virtually simulated instrument motions using hand motion tracking. We performed a human-subject evaluation of two manual control strategies that differed in their degrees of freedom (DOF). 2DOF thumb control was compared to 4DOF thumb-index finger control. Results identified regions within the instrument workspace that are difficult to reach and showed participants to favor using the thumb for gross and fine-tuning motions at both control strategies. Index finger ab/adduction was found to be least functional. A strong learning effect was observed at 4DOF control. Based on the results, gesture-based instrument design is a viable design tool.

Ovipositor-inspired steerable needle: design and preliminary experimental evaluation.

Flexible steerable needles have the potential to allow surgeons to reach deep targets inside the human body with higher accuracy than rigid needles do. Furthermore, by maneuvering around critical anatomical structures, steerable needles could limit the risk of tissue damage. However, the design of a thin needle (e.g. diameter under 2 mm) with a multi-direction steering mechanism is challenging. The goal of this paper is to outline the design and experimental evaluation of a biologically inspired needle with a diameter under 2 mm that advances through straight and curved trajectories in a soft substrate without being pushed, without buckling, and without the need of axial rotation. The needle design, inspired by the ovipositor of parasitoid wasps, consisted of seven nickel titanium wires and had a total diameter of 1.2 mm. The motion of the needle was tested in gelatin phantoms. Forward motion of the needle was evaluated based on the lag between the actual and the desired insertion depth of the needle. Steering was evaluated based on the radius of curvature of a circle fitted to the needle centerline and on the ratio of the needle deflection from the straight path to the insertion depth. The needle moved forward inside the gelatin with a lag of 0.21 (single wire actuation) and 0.34 (double wire actuation) and achieved a maximum curvature of 0.0184 cm-1and a deflection-to-insertion ratio of 0.0778. The proposed biologically inspired needle design is a relevant step towards the development of thin needles for percutaneous interventions.

Design of an endovascular morcellator for the surgical treatment of equine Cushing's disease.

BACKGROUND: A new paradigm of surgical treatment of equine Cushing's disease has been developed using the vascular system combined with a flexible morcellation instrument to reach the pituitary gland. OBJECTIVE: The goal was twofold: (1) to design, prototype, and test an instrument that can reach the pituitary gland using the vascular system unique to equids and (2) to test the feasibility of the endovascular approach. ANIMALS AND METHODS: The morcellator consists of a radial rotating cutting blade for tissue resection, a flexible shaft incorporating a cable drive for flexible actuation, and central morcellated tissue transportation lumen. The morcellator prototype was tested on a horse's cadaver head for the validation of the cutting blade design, actuator design, and feasibility of the endovascular approach. RESULTS: The overall assembled length of the morcellator tip was 13.9 mm, allowing for non-traumatic steering through the vascular system from the proximal end. The radially rotating cutting blade (barrel of Ø 4 and 4.4 mm width) incorporated multiple cutting edges to deliver the action force during resection and provides the necessary grasping force to draw the tissue towards the second cutting edge of the morcellator incorporated inside the blunted cuboidal static tip element (5 mm square and wall-thickness of 0.3 mm). In the tests, the morcellator was successfully guided towards the pituitary and managed to sample pituitary tissue. CONCLUSION AND CLINICAL IMPORTANCE: Continued development of the prototype and the endovascular approach may in time improve the outcome and quality of life of horses suffering from Cushing's disease.

Comparison of endoscopic closure modalities for standardized colonic perforations in a porcine colon model.

BACKGROUND AND STUDY AIM: Colonic perforation is a serious complication of colonoscopy, with surgical repair usually indicated. The aim was to compare acute strength of various endoscopic colonic closure techniques by assessing air leak pressures in a previously described ex vivo experimental apparatus. METHODS: Standardized colonic perforations were created using fresh porcine colon and subsequently closed on a bench. Six techniques included surgical suture (gold standard), QuickClips, T-tags, over-the-scope-clip (OTSC) system, and two types of flexible stapler (Covidien). After closure, each specimen was fixed in the apparatus and pressure was gradually increased until air bubbles were seen. Leak pressure was the primary outcome parameter. Closure using the gold standard (first 15 experiments) resulted in a mean leak pressure of 86.9 mmHg (SD 7). Using a noninferiority design a sample size of 12 specimens for each closure technique was determined. RESULTS: Mean colotomy leak pressures in millimeters of mercury (mmHg) and difference (with 95% confidence intervals [CI]) between each technique and the gold standard were: QuickClips 85.1 (difference -1.8; 95% CI -7.0 to 3.9); T-tags 53.9 (difference -33.0; -39.0 to -27.0); OTSC 90.3 mmHg (difference 3.4; -6.1 to 12.9); 15-mm shaft stapler 98.5 mmHg (difference 9.7; 0.8 to 18.5) and 8-mm shaft stapler 96.6 mmHg (difference 11.6; 1.5 to 21.7). CONCLUSIONS: OTSCs, QuickClips, and both flexible staplers produced results comparable to hand-sewn colotomy closure in this ex vivo porcine colonic model. These devices seem to be prime candidates for further evaluation in survival animal studies.

Mechanisms of temporary adhesion in benthic animals.

Adhesive systems are ubiquitous in benthic animals and play a key role in diverse functions such as locomotion, food capture, mating, burrow building, and defence. For benthic animals that release adhesives, surface and material properties and external morphology have received little attention compared to the biochemical content of the adhesives. We address temporary adhesion of benthic animals from the following three structural levels: (a) the biochemical content of the adhesive secretions, (b) the micro- and mesoscopic surface geometry and material properties of the adhesive organs, and (c) the macroscopic external morphology of the adhesive organs. We show that temporary adhesion of benthic animals is affected by three structural levels: the adhesive secretions provide binding to the substratum at a molecular scale, whereas surface geometry and external morphology increase the contact area with the irregular and unpredictable profile of the substratum from micro- to macroscales. The biochemical content of the adhesive secretions differs between abiotic and biotic substrata. The biochemistry of the adhesives suitable for biotic substrata differentiates further according to whether adhesion must be activated quickly (e.g. as a defensive mechanism) or more slowly (e.g. during adhesion of parasites). De-adhesion is controlled by additional secretions, enzymes, or mechanically. Due to deformability, the adhesive organs achieve intimate contact by adapting their surface profile to the roughness of the substratum. Surface projections, namely cilia, cuticular villi, papillae, and papulae increase the contact area or penetrate through the secreted adhesive to provide direct contact with the substratum. We expect that the same three structural levels investigated here will also affect the performance of artificial adhesive systems.

Micro-scale thermal tissue gripper.

During eye surgery translocating a graft of retinal tissue without damaging the vulnerable top layer is highly problematic using the currently available instruments. This study presents indirect Heat Induced Attachment and Detachment (HIAD) as a new concept for single side attachment of tissue to, and detachment from a heated metal wire. A small-scale prototype was built, having a 50 mum molybdenum wire that could be heated via an electric current. Tests (n = 60) were performed on submerged chicken meat to study the attachment and detachment properties of the prototype at different electric signal lengths. A 9V signal was applied to the prototype, with amplifier input signal lengths varying from 0.6-1.5 ms. Voltages and currents were sampled at 250 kHz to obtain energies. Both attachment and detachment occurred with 98% and 90% certainty, respectively, supplying 41 and 110 mJ of energy to the prototype in 0.7 and 1.5 ms. The attachment strength was estimated at 0.2 mN. Visible damage appeared to be approximately 0.005 mm(2). The concept of indirect heating of the instrument-tissue interface proved to be effective as the prototype could induce attachment and detachment of tissue. Indirect HIAD may be applicable in many different surgical applications.

In vitro comparison and evaluation of seven gastric closure modalities for natural orifice transluminal endoscopic surgery (NOTES).

BACKGROUND AND STUDY AIMS: Secure transluminal closure is the most fundamental prerequisite for the safe introduction of natural orifice transluminal endoscopic surgery (NOTES). The aim was to compare acute strength of various gastrotomy closure techniques in an in vitro porcine stomach model by assessing leak pressures. METHODS: Standardized gastrotomies were closed manually, without the use of an endoscope, by one of seven NOTES closure devices: (i) T tags, (ii) purse string modified T tags, (iii) Eagle Claw VIII, (iv) Resolution clips, (v) flexible stapler; (vi) purse string suturing device, and (vii) flexible Endostitch. After closure, each specimen was fixed on the experimental apparatus and the pressure was gradually increased. By linking the pressure gauge and two cameras, the leak location and pressure could be determined in detail. We began by collecting gold standard reference values, by testing 15 gastrotomies closed with interrupted surgical sutures; these were associated with a mean leak pressure of 206 mmHg (SD 59). Using a noninferiority design, a sample size of 11 specimens for each NOTES closure technique was determined. RESULTS: The Resolution clips ( P = 0.0285), Eagle Claw VIII ( P = 0.0325), flexible stapler ( P < 0.001) and flexible Endostitch ( P = 0.002) produced noninferior closures in comparison with the predetermined gold standard; T tags ( P > 0.6775), purse string modified T tags ( P > 0.999), and the purse string suturing device ( P = 0.9875) resulted in inferior closures. CONCLUSIONS: The Eagle Claw VIII, Resolution clips, flexible stapler and flexible Endostitch produced noninferior closures in comparison with surgical closure in this model. These techniques seem to be the prime candidates for further testing in animal experiments before human trials can be initiated.

Decreased plasma glutamate in early phases of septic shock with acute liver dysfunction is an independent predictor of survival.

BACKGROUND & AIMS: Liver organ dysfunction is an important determinant for clinical deterioration and outcome in patients with sepsis. Although glutamate plays a central role in the metabolism of the liver, liver cellular injury during sepsis is clinically determined by plasma values of the enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The aim of this study was to determine the predictive value of measuring the amino acids glutamate and glutamine concentrations in the early phases of septic shock. METHODS: In a prospective observational study the amino acids glutamate and glutamine were compared to the standard parameters of liver dysfunction used as predictors of outcome in patients with acute liver dysfunction as part of the development of multiple organ failure. RESULTS: Glutamate concentrations were consistently and significantly lower in non-survivors (p=0.03) compared to surviving septic patients. Plasma Glu/Gln ratio was consistently lower in non-survivors compared to survivors (p=0.002). Both parameters were good predictors of outcome (area under the ROC curve) 0.75 (95% CI 0.65-0.85) and 0.82 (95% CI 0.74-0.91) respectively, p<0.0001. Glutamate concentration was an independent and better risk factor for mortality compared to the liver enzyme plasma values. CONCLUSIONS: Patients who die of septic shock with acute liver dysfunction can be predicted by significantly lowered plasma glutamate concentrations and lowered glutamate/glutamine ratios already in the first 24 h of septic shock.

Mucoadhesive films inside the colonic tube: performance in a three-dimensional world.

A self-propelling colonoscopic device moving inside the colonic tube should be able to periodically grip safely to the colonic wall as well as to manipulate the generated friction. The feasibility of achieving high grip and friction manipulation by covering the device with mucoadhesive films is experimentally tested. More precisely, the frictional behaviour of mucoadhesive films inside the colonic tube is tested in vitro in porcine colon. It appears that mucoadhesive films generate significantly higher friction than conventional materials (ANOVA p=0, 95% CIs=-3.04, -2.14). The geometry of the film plays a role as well. When holes are, for instance, present in the film geometry and are large enough so that the colonic tissue can wrap their borders, friction can be significantly increased (ANOVA p=0, 95% CIs=-2.53, -1.26). By altering the contact area or the film geometry, friction manipulation can be achieved. Moreover, a simple theoretical model is developed and experimentally verified (R=0.92). The model can be used to estimate the level of the friction generated by three-dimensional configurations of mucoadhesive films as a function of their geometric characteristics and the material properties of the colon.

The anatomy of the thoracic spinal canal investigated with magnetic resonance imaging (MRI).

BACKGROUND AND OBJECTIVES: Anesthesiologists are reluctant to consider higher levels for spinal anesthesia, largely due to direct threats to the spinal cord. The goal of this study is to investigate, with magnetic resonance imaging (MRI), the distances between the relevant structures of the spinal canal (spinal cord, thecal tissue, etc.) to determine modal anatomical positions for neuraxial anesthesia. METHOD: A group of 19 patients were imaged with an MRI scanner in supine position. Medial sagittal slices of the thoracic and lumbar spine were measured for the relative distances between anatomical structures, including epidural space, dura, and spinal cord. RESULTS: The posterior dura - spinal cord distance is significantly greater in the middle thoracic region than at upper and lower thoracic levels (e.g. T6 9.5 +/- 1.8 mm, T12 3.7 +/- 1.2 mm, p < 0.001, T1 4.7 +/- 1.7 mm, p < 0.001). There is variation in modal distances between the structures important for neuraxial anesthesia, at different levels of the spinal canal. CONCLUSIONS: The spinal cord tends to follow the straightest line through the imposed geometry of the spine. Considering the necessary angle of entry of the needle at mid-thoracic levels, there is relatively (more than at upper thoracic and lumbar levels) substantial separation of cord and surrounding thecal tissue. Anesthesiologists perform spinal blockades up to the L2-L3 interspace, but avoid higher levels for fear of neurological damage. The information that there is substantially more space in the dorsal subarachnoid space at thoracic level, might lead to potential applications in regional anesthesia. In contrast, the cauda equina sits more dorsally in the lumbar region.

Modulation of oral drug bioavailability: from preclinical mechanism to therapeutic application.

Currently, more than one fourth of all anticancer drugs are developed as oral formulations, and it is expected that this number will increase substantially in the near future. To enable oral drug therapy, adequate oral bioavailability must be achieved. Factors that have proved to be important in limiting the oral bioavailability are the presence of ATP-binding cassette drug transporters (ABC transporters) and the cytochrome P450 enzymes. We discuss the tissues distribution and physiological function of the ABC transporters in the human body, their expression in tumors, currently known polymorphisms and drugs that are able to inhibit their function as transporter. Furthermore, the role of the ABC transporters and drug-metabolizing enzymes as mechanisms to modulate the pharmacokinetics of anticancer agents, will be reviewed. Finally, some clinical examples of oral drug modulation are discussed. Among these examples are the coadministration of paclitaxel with CsA, a CYP3A4 substrate with P-glycoprotein (P-gp) modulating activity, and topotecan combined with the BCRP/P-gp transport inhibitor elacridar. Both are good examples of improvement of oral drug bioavailability by temporary inhibition of drug transporters in the gut epithelium.

A clearly visible endoscopic instrument shaft on the monitor facilitates hand-eye coordination.

BACKGROUND: Passing an instrument through a small incision alters the kinematics of the instrument, thus hampering hand-eye coordination. Nevertheless, the incision provides a stable, nearly invariant, point of rotation for instrument movements. Therefore, we set out to evaluate the effects of the altered kinematics on hand-eye coordination. In addition, we assessed the hypothesis that the hand-eye coordination of laparoscopic surgeons incorporates the incision as a point of reference. METHODS: Eight surgeons with experience in laparoscopy repeatedly performed a positioning task on a two-dimensional endoscopic manipulation simulator. Task time was measured. In the first experiment, normal endoscopic manipulation was compared to a condition in which the kinematic effects of the incision were compensated for. In the second experiment, the instrument shaft on the monitor was not visible during half of the trials, so that all visual information about the location of the incision was obscured. RESULTS: Task performance improved significantly when the kinematic effects of the incision were compensated for (p = 0.001). Task performance improved when the instrument shaft was clearly visible on the monitor (p <0.05). CONCLUSIONS: Compensating for the kinematic effects introduced by the incision improves hand-eye coordination. The results of this study indicate that the incision provides a point of reference for hand-eye coordination during endoscopic manipulation.

Observation in laparoscopic surgery: overview of impeding effects and supporting aids.

Within a Dutch research program on minimally invasive surgery, a large literature survey has been carried out. This article describes the state of the art in research on observation in laparoscopy. It gives an overview of factors impeding the surgeon and technical developments designed to overcome these problems. A large number of journals, proceedings, patents, and books starting from the year 1991 have been consulted. The survey was completed with a thorough MEDLINE search. The survey showed that many authors have an incomplete background in the fundamentals of visual perception. This leads to a lack of understanding and to the design of supporting aids that often are not very useful. The new aspect of this study is that it gives a complete and structured overview of laparoscopic observation problems and current solutions. The observation problems are structured according to visual perception theory. The solutions are critically considered, and their benefits and drawbacks are identified. The study shows that the benefits of stereo-endoscopes and motorized endoscope positioners are questionable. The addition of shadows and movement parallax is still a very important research topic.

Manipulation in laparoscopic surgery: overview of impeding effects and supporting aids.

Within a Dutch research program on minimally invasive surgery, a large literature survey has been carried out. This article describes the state of the art in research on manipulation in laparoscopy. It gives an overview of factors impeding the surgeon and technical developments designed to overcome these problems. Starting from the year 1991, a large number of journals, proceedings, patents, and books have been consulted. The survey was completed with a thorough MEDLINE search. The impeding effects have been subdivided into two groups: transformation of spatial and grasping movements of the hand. The article gives an overview of these effects and of supporting aids that have been developed. The studies show that many aids are based on a technology-driven rather than a clinically-driven approach. The development of simple instruments that can be used for a large range of tasks instead of only one is still a very important topic of research.