CAD-Based Porous Scaffold Design of Intervertebral Discs in Tissue Engineering

With the development and maturity of three-dimensional (3D) printing technology over the past decade, 3D printing has been widely investigated and applied in the field of tissue engineering to repair damaged tissues or organs, such as muscles, skin, and bones, Although a number of automated fabrication methods have been developed to create superior bio-scaffolds with specific surface properties and porosity, the major challenges still focus on how to fabricate 3D natural biodegradable scaffolds that have tailor properties such as intricate architecture, porosity, and interconnectivity in order to provide the needed structural integrity, strength, transport, and ideal microenvironment for cell- and tissue-growth. In this dissertation, a robust pipeline of fabricating bio-functional porous scaffolds of intervertebral discs based on different innovative porous design methodologies is illustrated. Firstly, a triply periodic minimal surface (TPMS) based parameterization method, which has overcome the integrity problem of traditional TPMS method, is presented in Chapter 3. Then, an implicit surface modeling (ISM) approach using tetrahedral implicit surface (TIS) is demonstrated and compared with the TPMS method in Chapter 4. In Chapter 5, we present an advanced porous design method with higher flexibility using anisotropic radial basis function (ARBF) and volumetric meshes. Based on all these advanced porous design methods, the 3D model of a bio-functional porous intervertebral disc scaffold can be easily designed and its physical model can also be manufactured through 3D printing. However, due to the unique shape of each intervertebral disc and the intricate topological relationship between the intervertebral discs and the spine, the accurate localization and segmentation of dysfunctional discs are regarded as another obstacle to fabricating porous 3D disc models. To that end, we discuss in Chapter 6 a segmentation technique of intervertebral discs from CT-scanned medical images by using deep convolutional neural networks. Additionally, some examples of applying different porous designs on the segmented intervertebral disc models are demonstrated in Chapter 6

Non-Rigid Liver Registration for Laparoscopy using Data-Driven Biomechanical Models

During laparoscopic liver resection, the limited access to the organ, the small field of view and lack of palpation can obstruct a surgeon’s workflow. Automatic navigation systems could use the images from preoperative volumetric organ scans to help the surgeons find their target (tumors) and risk-structures (vessels) more efficiently. This requires the preoperative data to be fused (or registered) with the intraoperative scene in order to display information at the correct intraoperative position. One key challenge in this setting is the automatic estimation of the organ’s current intra-operative deformation, which is required in order to predict the position of internal structures. Parameterizing the many patient-specific unknowns (tissue properties, boundary conditions, interactions with other tissues, direction of gravity) is very difficult. Instead, this work explores how to employ deep neural networks to solve the registration problem in a data-driven manner. To this end, convolutional neural networks are trained on synthetic data to estimate an organ’s intraoperative displacement field and thus its current deformation. To drive this estimation, visible surface cues from the intraoperative camera view must be supplied to the networks. Since reliable surface features are very difficult to find, the networks are adapted to also find correspondences between the pre- and intraoperative liver geometry automatically. This combines the search for correspondences with the biomechanical behavior estimation and allows the networks to tackle the full non-rigid registration problem in one single step. The result is a model which can quickly predict the volume deformation of a liver, given only sparse surface information. The model combines the advantages of a physically accurate biomechanical simulation with the speed and powerful feature extraction capabilities of deep neural networks. To test the method intraoperatively, a registration pipeline is developed which constructs a map of the liver and its surroundings from the laparoscopic video and then uses the neural networks to fuse the preoperative volume data into this map. The deformed organ volume can then be rendered as an overlay directly onto the laparoscopic video stream. The focus of this pipeline is to be applicable to real surgery, where everything should be quick and non-intrusive. To meet these requirements, a SLAM system is used to localize the laparoscopic camera (avoiding setup of an external tracking system), various neural networks are used to quickly interpret the scene and semi-automatic tools let the surgeons guide the system. Beyond the concrete advantages of the data-driven approach for intraoperative registration, this work also demonstrates general benefits of training a registration system preoperatively on synthetic data. The method lets the engineer decide which values need to be known explicitly and which should be estimated implicitly by the networks, which opens the door to many new possibilities.:1 Introduction 1.1 Motivation 1.1.1 Navigated Liver Surgery 1.1.2 Laparoscopic Liver Registration 1.2 Challenges in Laparoscopic Liver Registration 1.2.1 Preoperative Model 1.2.2 Intraoperative Data 1.2.3 Fusion/Registration 1.2.4 Data 1.3 Scope and Goals of this Work 1.3.1 Data-Driven, Biomechanical Model 1.3.2 Data-Driven Non-Rigid Registration 1.3.3 Building a Working Prototype 2 State of the Art 2.1 Rigid Registration 2.2 Non-Rigid Liver Registration 2.3 Neural Networks for Simulation and Registration 3 Theoretical Background 3.1 Liver 3.2 Laparoscopic Liver Resection 3.2.1 Staging Procedure 3.3 Biomechanical Simulation 3.3.1 Physical Balance Principles 3.3.2 Material Models 3.3.3 Numerical Solver: The Finite Element Method (FEM) 3.3.4 The Lagrangian Specification 3.4 Variables and Data in Liver Registration 3.4.1 Observable 3.4.2 Unknowns 4 Generating Simulations of Deforming Organs 4.1 Organ Volume 4.2 Forces and Boundary Conditions 4.2.1 Surface Forces 4.2.2 Zero-Displacement Boundary Conditions 4.2.3 Surrounding Tissues and Ligaments 4.2.4 Gravity 4.2.5 Pressure 4.3 Simulation 4.3.1 Static Simulation 4.3.2 Dynamic Simulation 4.4 Surface Extraction 4.4.1 Partial Surface Extraction 4.4.2 Surface Noise 4.4.3 Partial Surface Displacement 4.5 Voxelization 4.5.1 Voxelizing the Liver Geometry 4.5.2 Voxelizing the Displacement Field 4.5.3 Voxelizing Boundary Conditions 4.6 Pruning Dataset - Removing Unwanted Results 4.7 Data Augmentation 5 Deep Neural Networks for Biomechanical Simulation 5.1 Training Data 5.2 Network Architecture 5.3 Loss Functions and Training 6 Deep Neural Networks for Non-Rigid Registration 6.1 Training Data 6.2 Architecture 6.3 Loss 6.4 Training 6.5 Mesh Deformation 6.6 Example Application 7 Intraoperative Prototype 7.1 Image Acquisition 7.2 Stereo Calibration 7.3 Image Rectification, Disparity- and Depth- estimation 7.4 Liver Segmentation 7.4.1 Synthetic Image Generation 7.4.2 Automatic Segmentation 7.4.3 Manual Segmentation Modifier 7.5 SLAM 7.6 Dense Reconstruction 7.7 Rigid Registration 7.8 Non-Rigid Registration 7.9 Rendering 7.10 Robotic Operating System 8 Evaluation 8.1 Evaluation Datasets 8.1.1 In-Silico 8.1.2 Phantom Torso and Liver 8.1.3 In-Vivo, Human, Breathing Motion 8.1.4 In-Vivo, Human, Laparoscopy 8.2 Metrics 8.2.1 Mean Displacement Error 8.2.2 Target Registration Error (TRE) 8.2.3 Champfer Distance 8.2.4 Volumetric Change 8.3 Evaluation of the Synthetic Training Data 8.4 Data-Driven Biomechanical Model (DDBM) 8.4.1 Amount of Intraoperative Surface 8.4.2 Dynamic Simulation 8.5 Volume to Surface Registration Network (V2S-Net) 8.5.1 Amount of Intraoperative Surface 8.5.2 Dependency on Initial Rigid Alignment 8.5.3 Registration Accuracy in Comparison to Surface Noise 8.5.4 Registration Accuracy in Comparison to Material Stiffness 8.5.5 Champfer-Distance vs. Mean Displacement Error 8.5.6 In-vivo, Human Breathing Motion 8.6 Full Intraoperative Pipeline 8.6.1 Intraoperative Reconstruction: SLAM and Intraoperative Map 8.6.2 Full Pipeline on Laparoscopic Human Data 8.7 Timing 9 Discussion 9.1 Intraoperative Model 9.2 Physical Accuracy 9.3 Limitations in Training Data 9.4 Limitations Caused by Difference in Pre- and Intraoperative Modalities 9.5 Ambiguity 9.6 Intraoperative Prototype 10 Conclusion 11 List of Publications List of Figures Bibliograph

Enabling technology for non-rigid registration during image-guided neurosurgery

In the context of image processing, non-rigid registration is an operation that attempts to align two or more images using spatially varying transformations. Non-rigid registration finds application in medical image processing to account for the deformations in the soft tissues of the imaged organs. During image-guided neurosurgery, non-rigid registration has the potential to assist in locating critical brain structures and improve identification of the tumor boundary. Robust non-rigid registration methods combine estimation of tissue displacement based on image intensities with the spatial regularization using biomechanical models of brain deformation. In practice, the use of such registration methods during neurosurgery is complicated by a number of issues: construction of the biomechanical model used in the registration from the image data, high computational demands of the application, and difficulties in assessing the registration results. In this dissertation we develop methods and tools that address some of these challenges, and provide components essential for the intra-operative application of a previously validated physics-based non-rigid registration method.;First, we study the problem of image-to-mesh conversion, which is required for constructing biomechanical model of the brain used during registration. We develop and analyze a number of methods suitable for solving this problem, and evaluate them using application-specific quantitative metrics. Second, we develop a high-performance implementation of the non-rigid registration algorithm and study the use of geographically distributed Grid resources for speculative registration computations. Using the high-performance implementation running on the remote computing resources we are able to deliver the results of registration within the time constraints of the neurosurgery. Finally, we present a method that estimates local alignment error between the two images of the same subject. We assess the utility of this method using multiple sources of ground truth to evaluate its potential to support speculative computations of non-rigid registration

A Coupled Finite Element-Boundary Element Method for Modeling Diffusion Equation in 3d Multi-Modality Optical Imaging

Three dimensional image reconstruction for multi-modality optical spectroscopy systems needs computationally efficient forward solvers with minimum meshing complexity, while allowing the flexibility to apply spatial constraints. Existing models based on the finite element method (FEM) require full 3D volume meshing to incorporate constraints related to anatomical structure via techniques such as regularization. Alternate approaches such as the boundary element method (BEM) require only surface discretization but assume homogeneous or piece-wise constant domains that can be limiting. Here, a coupled finite element-boundary element method (coupled FE-BEM) approach is demonstrated for modeling light diffusion in 3D, which uses surfaces to model exterior tissues with BEM and a small number of volume nodes to model interior tissues with FEM. Such a coupled FE-BEM technique combines strengths of FEM and BEM by assuming homogeneous outer tissue regions and heterogeneous inner tissue regions. Results with FE-BEM show agreement with existing numerical models, having RMS differences of less than 0.5 for the logarithm of intensity and 2.5 degrees for phase of frequency domain boundary data. The coupled FE-BEM approach can model heterogeneity using a fraction of the volume nodes (4-22%) required by conventional FEM techniques. Comparisons of computational times showed that the coupled FE-BEM was faster than stand-alone FEM when the ratio of the number of surface to volume nodes in the mesh (Ns/Nv) was less than 20% and was comparable to stand-alone BEM ( ± 10%)

A multiscale model for collagen alignment in wound healing

It is thought that collagen alignment plays a significant part in scar tissue formation during dermal wound healing. We present a multiscale model for collagen deposition and alignment during this process. We consider fibroblasts as discrete units moving within an extracellular matrix of collagen and fibrin modelled as continua. Our model includes flux induced alignment of collagen by fibroblasts, and contact guidance of fibroblasts by collagen fibres. We can use the model to predict the effects of certain manipulations, such as varying fibroblast speed, or placing an aligned piece of tissue in the wound. We also simulate experiments which alter the TGF-β concentrations in a healing dermal wound and use the model to offer an explanation of the observed influence of this growth factor on scarring

Cost-effective 3D scanning and printing technologies for outer ear reconstruction: Current status

Current 3D scanning and printing technologies offer not only state-of-the-art developments in the field of medical imaging and bio-engineering, but also cost and time effective solutions for surgical reconstruction procedures. Besides tissue engineering, where living cells are used, bio-compatible polymers or synthetic resin can be applied. The combination of 3D handheld scanning devices or volumetric imaging, (open-source) image processing packages, and 3D printers form a complete workflow chain that is capable of effective rapid prototyping of outer ear replicas. This paper reviews current possibilities and latest use cases for 3D-scanning, data processing and printing of outer ear replicas with a focus on low-cost solutions for rehabilitation engineering

lifex-ep: a robust and efficient software for cardiac electrophysiology simulations

Background: Simulating the cardiac function requires the numerical solution of multi-physics and multi-scale mathematical models. This underscores the need for streamlined, accurate, and high-performance computational tools. Despite the dedicated endeavors of various research teams, comprehensive and user-friendly software programs for cardiac simulations, capable of accurately replicating both normal and pathological conditions, are still in the process of achieving full maturity within the scientific community. Results: This work introduces lifex-ep, a publicly available software for numerical simulations of the electrophysiology activity of the cardiac muscle, under both normal and pathological conditions. lifex-ep employs the monodomain equation to model the heart's electrical activity. It incorporates both phenomenological and second-generation ionic models. These models are discretized using the Finite Element method on tetrahedral or hexahedral meshes. Additionally, lifex-ep integrates the generation of myocardial fibers based on Laplace-Dirichlet Rule-Based Methods, previously released in Africa et al., 2023, within lifex-fiber. As an alternative, users can also choose to import myofibers from a file. This paper provides a concise overview of the mathematical models and numerical methods underlying lifex-ep, along with comprehensive implementation details and instructions for users. lifex-ep features exceptional parallel speedup, scaling efficiently when using up to thousands of cores, and its implementation has been verified against an established benchmark problem for computational electrophysiology. We showcase the key features of lifex-ep through various idealized and realistic simulations conducted in both normal and pathological scenarios. Furthermore, the software offers a user-friendly and flexible interface, simplifying the setup of simulations using self-documenting parameter files. Conclusions: lifex-ep provides easy access to cardiac electrophysiology simulations for a wide user community. It offers a computational tool that integrates models and accurate methods for simulating cardiac electrophysiology within a high-performance framework, while maintaining a user-friendly interface. lifex-ep represents a valuable tool for conducting in silico patient-specific simulations

Cancer modelling: Getting to the heart of the problem

Paradoxically, improvements in healthcare that have enhanced the life expectancy of humans in the Western world have, indirectly, increased the prevalence of certain types of cancer such as prostate and breast. It remains unclear whether this phenomenon should be attributed to the ageing process itself or the cumulative effect of prolonged exposure to harmful environmental stimuli such as ultraviolet light, radiation and carcinogens (Franks and Teich, 1988). Equally, there is also compelling evidence that certain genetic abnormalities can predispose individuals to specific cancers (Ilyas et al., 1999). The variety of factors that have been implicated in the development of solid tumours stems, to a large extent, from the fact that ‘cancer’ is a generic term, often used to characterize a series of disorders that share common features. At this generic level of description, cancer may be viewed as a cellular disease in which controls that usually regulate growth and maintain homeostasis are disrupted. Cancer is typically initiated by genetic mutations that lead to enhanced mitosis of a cell lineage and the formation of an avascular tumour. Since it receives nutrients by diffusion from the surrounding tissue, the size of an avascular tumour is limited to several millimeters in diameter. Further growth relies on the tumour acquiring the ability to stimulate the ingrowth of a new, circulating blood supply from the host vasculature via a process termed angiogenesis (Folkman, 1974). Once vascularised, the tumour has access to a vast nutrient source and rapid growth ensues. Further, tumour fragments that break away from the primary tumour, on entering the vasculature, may be transported to other organs in which they may establish secondary tumours or metastases that further compromise the host. Invasion is another key feature of solid tumours whereby contact with the tissue stimulates the production of enzymes that digest the tissue, liberating space into which the tumour cells migrate. Thus, cancer is a complex, multiscale process. The spatial scales of interest range from the subcellular level, to the cellular and macroscopic (or tissue) levels while the timescales may vary from seconds (or less) for signal transduction pathways to months for tumour doubling times The variety of phenomena involved, the range of spatial and temporal scales over which they act and the complex way in which they are inter-related mean that the development of realistic theoretical models of solid tumour growth is extremely challenging. While there is now a large literature focused on modelling solid tumour growth (for a review, see, for example, Preziosi, 2003), existing models typically focus on a single spatial scale and, as a result, are unable to address the fundamental problem of how phenomena at different scales are coupled or to combine, in a systematic manner, data from the various scales. In this article, a theoretical framework will be presented that is capable of integrating a hierarchy of processes occurring at different scales into a detailed model of solid tumour growth (Alarcon et al., 2004). The model is formulated as a hybrid cellular automaton and contains interlinked elements that describe processes at each spatial scale: progress through the cell cycle and the production of proteins that stimulate angiogenesis are accounted for at the subcellular level; cell-cell interactions are treated at the cellular level; and, at the tissue scale, attention focuses on the vascular network whose structure adapts in response to blood flow and angiogenic factors produced at the subcellular level. Further coupling between the different spatial scales arises from the transport of blood-borne oxygen into the tissue and its uptake at the cellular level. Model simulations will be presented to illustrate the effect that spatial heterogeneity induced by blood flow through the vascular network has on the tumour’s growth dynamics and explain how the model may be used to compare the efficacy of different anti-cancer treatment protocols

Multi-Material Mesh Representation of Anatomical Structures for Deep Brain Stimulation Planning

The Dual Contouring algorithm (DC) is a grid-based process used to generate surface meshes from volumetric data. However, DC is unable to guarantee 2-manifold and watertight meshes due to the fact that it produces only one vertex for each grid cube. We present a modified Dual Contouring algorithm that is capable of overcoming this limitation. The proposed method decomposes an ambiguous grid cube into a set of tetrahedral cells and uses novel polygon generation rules that produce 2-manifold and watertight surface meshes with good-quality triangles. These meshes, being watertight and 2-manifold, are geometrically correct, and therefore can be used to initialize tetrahedral meshes. The 2-manifold DC method has been extended into the multi-material domain. Due to its multi-material nature, multi-material surface meshes will contain non-manifold elements along material interfaces or shared boundaries. The proposed multi-material DC algorithm can (1) generate multi-material surface meshes where each material sub-mesh is a 2-manifold and watertight mesh, (2) preserve the non-manifold elements along the material interfaces, and (3) ensure that the material interface or shared boundary between materials is consistent. The proposed method is used to generate multi-material surface meshes of deep brain anatomical structures from a digital atlas of the basal ganglia and thalamus. Although deep brain anatomical structures can be labeled as functionally separate, they are in fact continuous tracts of soft tissue in close proximity to each other. The multi-material meshes generated by the proposed DC algorithm can accurately represent the closely-packed deep brain structures as a single mesh consisting of multiple material sub-meshes. Each sub-mesh represents a distinct functional structure of the brain. Printed and/or digital atlases are important tools for medical research and surgical intervention. While these atlases can provide guidance in identifying anatomical structures, they do not take into account the wide variations in the shape and size of anatomical structures that occur from patient to patient. Accurate, patient-specific representations are especially important for surgical interventions like deep brain stimulation, where even small inaccuracies can result in dangerous complications. The last part of this research effort extends the discrete deformable 2-simplex mesh into the multi-material domain where geometry-based internal forces and image-based external forces are used in the deformation process. This multi-material deformable framework is used to segment anatomical structures of the deep brain region from Magnetic Resonance (MR) data