Model-Based Visualization for Intervention Planning

Computer support for intervention planning is often a two-stage process: In a first stage, the relevant segmentation target structures are identified and delineated. In a second stage, image analysis results are employed for the actual planning process. In the first stage, model-based segmentation techniques are often used to reduce the interaction effort and increase the reproducibility. There is a similar argument to employ model-based techniques for the visualization as well. With increasingly more visualization options, users have many parameters to adjust in order to generate expressive visualizations. Surface models may be smoothed with a variety of techniques and parameters. Surface visualization and illustrative rendering techniques are controlled by a large set of additional parameters. Although interactive 3d visualizations should be flexible and support individual planning tasks, appropriate selection of visualization techniques and presets for their parameters is needed. In this chapter, we discuss this kind of visualization support. We refer to model-based visualization to denote the selection and parameterization of visualization techniques based on \u27a priori knowledge concerning visual perception, shapes of anatomical objects and intervention planning tasks

Biomechanical simulations of the scoliotic deformation process in the pinealectomized chicken: a preliminary study

<p>Abstract</p> <p>Background</p> <p>The basic mechanisms whereby mechanical factors modulate the metabolism of the growing spine remain poorly understood, especially the role of growth adaptation in spinal disorders like in adolescent idiopathic scoliosis (AIS). This paper presents a finite element model (FEM) that was developed to simulate early stages of scoliotic deformities progression using a pinealectomized chicken as animal model.</p> <p>Methods</p> <p>The FEM includes basic growth and growth modulation created by the muscle force imbalance. The experimental data were used to adapt a FEM previously developed to simulate the scoliosis deformation process in human. The simulations of the spine deformation process are compared with the results of an experimental study including a group of pinealectomized chickens.</p> <p>Results</p> <p>The comparison of the simulation results of the spine deformation process (Cobb angle of 37°) is in agreement with experimental scoliotic deformities of two representative cases (Cobb angle of 41° and 30°). For the vertebral wedging, a good agreement is also observed between the calculated (28°) and the observed (25° – 30°) values.</p> <p>Conclusion</p> <p>The proposed biomechanical model presents a novel approach to realistically simulate the scoliotic deformation process in pinealectomized chickens and investigate different parameters influencing the progression of scoliosis.</p

Microcarriers with Complex Architectures Manufactured by Two-Photon Lithography for Mechanobiological Manipulation and Expansion of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are a powerful tool in regenerative medicine owing to their innate capacity to differentiate into a range of cell lineages and this behaviour has been utilised as a means of tissue repair and regeneration. The prevalent issue in many treatments is the vast number of cells required for therapeutic effect, but this can be addressed through expansion of cell populations in vitro to suitable levels. Microcarriers are designed to provide a high level of cell growth surface within a small volume and have become one of the most promising expansion tools to date. However, transition to approaches that integrate biomechanical cues to modulate cell responses can lead to far greater outcomes than those that can be achieved through surface area alone. Such biophysical properties that can be integrated include geometry, roughness, topography, stiffness, and porosity which can promote specific biological responses through mechanotransduction pathways. This thesis focuses on employing this approach to microcarrier technology and examining the effects of such structures on cell control and enhancement of expansion yield to facilitate MSC production for therapeutic uses. Two-photon lithography was employed to produce microcarriers with highly complex geometry at sub-micron feature size and optimisations allowed fabrication speed to be increased by up to 423-fold at the cost of structure resolution. Biocompatibility testing identified several suitable acrylate polymers with varying characteristics but highlighted the need for further materials exploration due to suboptimal adherence in most candidates. Novel fabrication techniques allowed cell culture isolation to structures without complication by anchoring substrates which addressed a continuing issue with two-photon derived samples that has been presented in the literature. A variety of produced designs exhibited significant increase in cell proliferation and consistent interaction with structure features with observable cellular preference for certain feature types and sizes. From these selected designs further morphological analysis of cells and DNA quantification determined microcarrier designs that lead to a significant increase in expansion yield in comparison to a conventional microcarrier design. Best expansion yields were seen in Buckminsterfullerene styled structures with hollow interiors and porous outer shells and identified that expansion yield was not necessarily based on the amount of surface area alone. Analysis of stem cell phenotype changes across expansion periods indicated mixed results in the maintenance of phenotypes and requires further exploration. This thesis demonstrated biomechanical based enhancement of expansion proficiency as well as novel techniques relating to two-photon lithography. However, for scale up of work and translation to clinical applications a significant increase in microcarrier production is necessary. Microcarriers that intelligently shape cellular proliferation and differentiation present an opportunity to act both in vitro and in vivo evolving beyond their primary function of expansion and acting as multifunctional tissue modulators

Microcarriers with Complex Architectures Manufactured by Two-Photon Lithography for Mechanobiological Manipulation and Expansion of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are a powerful tool in regenerative medicine owing to their innate capacity to differentiate into a range of cell lineages and this behaviour has been utilised as a means of tissue repair and regeneration. The prevalent issue in many treatments is the vast number of cells required for therapeutic effect, but this can be addressed through expansion of cell populations in vitro to suitable levels. Microcarriers are designed to provide a high level of cell growth surface within a small volume and have become one of the most promising expansion tools to date. However, transition to approaches that integrate biomechanical cues to modulate cell responses can lead to far greater outcomes than those that can be achieved through surface area alone. Such biophysical properties that can be integrated include geometry, roughness, topography, stiffness, and porosity which can promote specific biological responses through mechanotransduction pathways. This thesis focuses on employing this approach to microcarrier technology and examining the effects of such structures on cell control and enhancement of expansion yield to facilitate MSC production for therapeutic uses. Two-photon lithography was employed to produce microcarriers with highly complex geometry at sub-micron feature size and optimisations allowed fabrication speed to be increased by up to 423-fold at the cost of structure resolution. Biocompatibility testing identified several suitable acrylate polymers with varying characteristics but highlighted the need for further materials exploration due to suboptimal adherence in most candidates. Novel fabrication techniques allowed cell culture isolation to structures without complication by anchoring substrates which addressed a continuing issue with two-photon derived samples that has been presented in the literature. A variety of produced designs exhibited significant increase in cell proliferation and consistent interaction with structure features with observable cellular preference for certain feature types and sizes. From these selected designs further morphological analysis of cells and DNA quantification determined microcarrier designs that lead to a significant increase in expansion yield in comparison to a conventional microcarrier design. Best expansion yields were seen in Buckminsterfullerene styled structures with hollow interiors and porous outer shells and identified that expansion yield was not necessarily based on the amount of surface area alone. Analysis of stem cell phenotype changes across expansion periods indicated mixed results in the maintenance of phenotypes and requires further exploration. This thesis demonstrated biomechanical based enhancement of expansion proficiency as well as novel techniques relating to two-photon lithography. However, for scale up of work and translation to clinical applications a significant increase in microcarrier production is necessary. Microcarriers that intelligently shape cellular proliferation and differentiation present an opportunity to act both in vitro and in vivo evolving beyond their primary function of expansion and acting as multifunctional tissue modulators

Building 3D architectures for cardiomyocytes

Pharmaceutical companies currently rely on animal models for drug screening. This is a very expensive, time-consuming process and in some cases has been shown to be a poor predictor of human cardiac toxicity. Animal cells and tissue are not identical to their human counterparts. Therefore, it is not until human clinical trials at the later stages of drug screening that unexpected reactions to the drug are identified (Burridge et al., 2014). It would be greatly beneficial if this process could be shortened by identifying the risks of a drug earlier in the screening stages-chip based screening using mature human cardiomyocytes (CMs) is a route to achieve this. Substrates used to support CM growth have been identified including high-throughput chip-based screening strategies (Hook et al., 2013) (Celiz et al., 2014b) but so far stem cell derived CMs on these substrates do not adequately recapitulate the adult human CMs in terms of maturity (Denning et al., 2016). Many factors can affect how a cell matures from the soluble extracellular signals around it to the chemistry, topography, architecture/shape and mechanics of the substrate on which it is supported (Nikkhah et al., 2012). Mature cardiomyocytes have been successfully grown on 3 polymers synthesised by UV polymerisation-it has been confirmed that polymers like these can be successfully processed by 2-photon lithography. Photo initiator concentration has been optimised to create a complete structure. Glycerol propoxylate triacrylate and Tricyclodecane dimethanol diacrylate were shown to provide a wide operating window. Many relevant structures for CM growth were chosen and designed on AutoCAD to demonstrate the potential application of this material in CM culture. The 3D design freedom of the lithography approach will be used to explore the relationship between architecture and cell maturity. This will then enable a platform to be created using various architectures on a chip which will be utilised to assess cardiomyocyte maturity. This enables structure fabrication with more accuracy compared to previous methods due to the sub-micron scale of 2-photon lithography (Maruo et al., 1997). Greater resolution means improved results as cells interact on the sub-micron scale (~1µm) (Guck et al., 2010)Various architectures used for cardiomyocyte culture can show which ones are the most suitable to guide cardiomyocytes to a mature adult form

Building 3D architectures for cardiomyocytes

Pharmaceutical companies currently rely on animal models for drug screening. This is a very expensive, time-consuming process and in some cases has been shown to be a poor predictor of human cardiac toxicity. Animal cells and tissue are not identical to their human counterparts. Therefore, it is not until human clinical trials at the later stages of drug screening that unexpected reactions to the drug are identified (Burridge et al., 2014). It would be greatly beneficial if this process could be shortened by identifying the risks of a drug earlier in the screening stages-chip based screening using mature human cardiomyocytes (CMs) is a route to achieve this. Substrates used to support CM growth have been identified including high-throughput chip-based screening strategies (Hook et al., 2013) (Celiz et al., 2014b) but so far stem cell derived CMs on these substrates do not adequately recapitulate the adult human CMs in terms of maturity (Denning et al., 2016). Many factors can affect how a cell matures from the soluble extracellular signals around it to the chemistry, topography, architecture/shape and mechanics of the substrate on which it is supported (Nikkhah et al., 2012). Mature cardiomyocytes have been successfully grown on 3 polymers synthesised by UV polymerisation-it has been confirmed that polymers like these can be successfully processed by 2-photon lithography. Photo initiator concentration has been optimised to create a complete structure. Glycerol propoxylate triacrylate and Tricyclodecane dimethanol diacrylate were shown to provide a wide operating window. Many relevant structures for CM growth were chosen and designed on AutoCAD to demonstrate the potential application of this material in CM culture. The 3D design freedom of the lithography approach will be used to explore the relationship between architecture and cell maturity. This will then enable a platform to be created using various architectures on a chip which will be utilised to assess cardiomyocyte maturity. This enables structure fabrication with more accuracy compared to previous methods due to the sub-micron scale of 2-photon lithography (Maruo et al., 1997). Greater resolution means improved results as cells interact on the sub-micron scale (~1µm) (Guck et al., 2010)Various architectures used for cardiomyocyte culture can show which ones are the most suitable to guide cardiomyocytes to a mature adult form

Improving Outcomes in NF1 Spine Fusion

NF1 (neurofibromatosis type 1) is a relatively common genetic disease which may be characterized by the presence of scoliosis and altered bone metabolism, amongst its many orthopaedic manifestations. Traditionally, spine fusion procedures have been used to correct and limit the progression of this deformity. NF1 bone healing at the tibia and spine feature impaired bone anabolism, excessive catabolism, and fibrosis. Fibrotic tissue in the tibia and between the vertebrae can lead to pseudarthrosis, which can require substantive clinical intervention. In particular, complications associated with the spine can represent a significant source of morbidity in this population, often presenting with persistent deformity, pain, and hardware failure. Revision procedures, themselves a source of morbidity, are often required when a primary procedure has failed. This thesis explores systematic approaches to modelling deficient NF1 spine healing and treatment to improve outcomes in this patient population. A murine model of posterolateral fusion using rhBMP-2 (bone morphogenetic protein-2) was developed to test a range of pharmacological interventions. This model was first applied to Nf1 heterozygous mice and was reproducible and reliable. Nf1+/- mice exhibited a mild orthopaedic phenotype with increased osteoclasts on histology. Treatment with the bisphosphonate Zoledronic acid (ZA) increased the bone volume of the fusion masses in both control and Nf1+/- mice, though the improvement was larger in controls. Several studies have shown that tibial pseudarthroses can be associated with a localized double inactivation of the Nf1 gene, and we speculated that this could underlie local lesions in the spine. To recapitulate this, we utilized a model where a Cre-expressing adenovirus induced local double inactivation in Nf1flox/flox mice. This was then applied to the established spine fusion model. Consistent with the clinical presentation of spinal pseudarthrosis, a limited amount of rhBMP-2 bone was formed and substantive fibrous tissue was present. Targeted treatments with pharmaceutical agents were next trialled in this model. The MEK inhibitor PD0325901 increased bone volume in all groups while ZA increased bone density. In summary, this model represents a robust platform upon which to test targeted interventions to reduce the fibroproliferative phenotype of NF1. A second goal of this research project was to investigate the cellular contributors to spine fusion in general, which could be used to design new treatments both for NF1 and non-NF1 spine fusion. To accomplish this, a murine genetic model of lineage tracking was employed. This featured Tie2- -creERT2:Col2.3- GFP:Ai9 reporter mice. Spine fusion operations were performed in these mice, and the distribution of lineage-labelled cells were traced using fluorescence. Notably, Tie2 lineage cells co-labelled with TRAP positive cells, suggesting a primary contribution to the osteoclasts but not osteoblasts of the fusion mass. Conversely, lineage cells co-labelled with Col2.3-GFP expressing osteoblasts, suggesting new bone primarily arises from mesenchymal cells with negligible input from endothelial cells undergoing transdifferentiation. In conclusion, treatment of scoliosis remains a challenge in individuals with NF1. The development of a fibroproliferative model of spine fusion in an Nf1 deficient mouse represents a robust platform upon which to test targeted interventions to improve outcomes in NF1. Additionally, advancements in genetic modeling of human disease in animals may provide new models in which to investigate this process

Three-dimensional printing as a cutting-edge, versatile and personalizable vascular stent manufacturing procedure:Toward tailor-made medical devices

Vascular stents (VS) have revolutionized the treatment of cardiovascular diseases, as evidenced by the fact that the implantation of VS in coronary artery disease (CAD) patients has become a routine, easily approachable surgical intervention for the treatment of stenosed blood vessels. Despite the evolution of VS throughout the years, more efficient approaches are still required to address the medical and scientific challenges, especially when it comes to peripheral artery disease (PAD). In this regard, three-dimensional (3D) printing is envisaged as a promising alternative to upgrade VS by optimizing the shape, dimensions and stent backbone (crucial for optimal mechanical properties), making them customizable for each patient and each stenosed lesion. Moreover, the combination of 3D printing with other methods could also upgrade the final device. This review focuses on the most recent studies using 3D printing techniques to produce VS, both by itself and in combination with other techniques. The final aim is to provide an overview of the possibilities and limitations of 3D printing in the manufacturing of VS. Furthermore, the current situation of CAD and PAD pathologies is also addressed, thus highlighting the main weaknesses of the already existing VS and identifying research gaps, possible market niches and future directions.This work was funded by the Basque Country Government/Eusko Jaurlaritza (Department of Education, University and Research, Consolidated Groups IT448- 22) . Sandra Ruiz-Alonso and Fouad Al -Hakim thank the Basque Country Government for the granted fellowships PRE_2021_2_0153 and PRE_2021_2_0181, respectively. Denis Scaini gratefully acknowledges support from IKERBASQUE, the Basque Foundation of Science

A Novel Flexible and Steerable Probe for Minimally Invasive Soft Tissue Intervention

Current trends in surgical intervention favour a minimally invasive (MI) approach, in which complex procedures are performed through increasingly small incisions. Specifically, in neurosurgery, there is a need for minimally invasive keyhole access, which conflicts with the lack of maneuverability of conventional rigid instruments. In an attempt to address this fundamental shortcoming, this thesis describes the concept design, implementation and experimental validation of a novel flexible and steerable probe, named “STING” (Soft Tissue Intervention and Neurosurgical Guide), which is able to steer along curvilinear trajectories within a compliant medium. The underlying mechanism of motion of the flexible probe, based on the reciprocal movement of interlocked probe segments, is biologically inspired and was designed around the unique features of the ovipositor of certain parasitic wasps. Such insects are able to lay eggs by penetrating different kinds of “host” (e.g. wood, larva) with a very thin and flexible multi-part channel, thanks to a micro-toothed surface topography, coupled with a reciprocating “push and pull” motion of each segment. This thesis starts by exploring these foundations, where the “microtexturing” of the surface of a rigid probe prototype is shown to facilitate probe insertion into soft tissue (porcine brain), while gaining tissue purchase when the probe is tensioned outwards. Based on these findings, forward motion into soft tissue via a reciprocating mechanism is then demonstrated through a focused set of experimental trials in gelatine and agar gel. A flexible probe prototype (10 mm diameter), composed of four interconnected segments, is then presented and shown to be able to steer in a brain-like material along multiple curvilinear trajectories on a plane. The geometry and certain key features of the probe are optimised through finite element models, and a suitable actuation strategy is proposed, where the approach vector of the tip is found to be a function of the offset between interlocked segments. This concept of a “programmable bevel”, which enables the steering angle to be chosen with virtually infinite resolution, represents a world-first in percutaneous soft tissue surgery. The thesis concludes with a description of the integration and validation of a fully functional prototype within a larger neurosurgical robotic suite (EU FP7 ROBOCAST), which is followed by a summary of the corresponding implications for future work