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ENGINEERING OF CLINICAL-SCALE, IN VITRO VASCULARIZED BONE TISSUE FOR IMPLANTATION
Title
ENGINEERING OF CLINICAL-SCALE, IN VITRO VASCULARIZED BONE TISSUE FOR IMPLANTATION
Creator
Gandhi, Jarel K.
Date
2016, 2016-05
Description
Tissue engineering has been a rapidly expanding field dedicated to regeneration of tissue. The field has focused on application through...
Show moreTissue engineering has been a rapidly expanding field dedicated to regeneration of tissue. The field has focused on application through combinations of 3 key components: cells, signals, and scaffolds. One ambitious combination of all three is the desire to engineer functional tissues in vitro to meet the clinical-demand of organ replacement. While major advances have been made, a critical obstacle that has yet to be overcome is the need to grow large volumes of complex 3D tissue. In this proposal, this issue is addresed in two ways: the use of a perfusion bioreactor system to culture 3D scaffolds to enhance mass transport, and engineering of a vascular network withing the scaffold for rapid perfusion once implanted in vivo. This thesis aims to address both aspects for bone tissue engineering by engineering pre-vascularized, mineralizing scaffolds that can be scaled up to clinically-relevant volumes by using a tubular perfusion bioreactor system (TPS). To address this, 3 aims were addressed. First, 3D culture of endothelial colony forming cells (ECFCs), a clinically-relevant cell population, was demonstrated utilizing fibrin gels within the TPS. The TPS allowed for viable culture of ECFCs within fibrin bead scaffold up to 1 week without a reduction in cell amount or genomic quality of the cells. Second, a co-culture model of angiogenesis utilizing ECFCs and mesenchymal stem cells (MSCs) was demonstrated to reproducibly form pre-formed vessel networks within a mineralizing fibrin scaffold. Data shows that MSC suspension concentration and fibrinogen concentration modulate the angiogenic response. Mineralization is demonstrated without the use of osteogenic media utilizing shear stress within the TPS. Finally, functionality of the pre-formed vessels is demonstrated following implantation to a SCID mouse model. Engineered human vessels showed anastasmosis to the host vasculature, with evidence of interconnected host and human vessel networks as well as formation of hybrid vessels. Additionally, evidence of mineralization within the scaffolds is maintained in TPS-cultured samples. In demonstrating these aims, future work should focus on fortifying the scaffold material to enable addressing implantation and persistence of clinically-relevant tissue volumes. In conclusion, pre-vascularization within bioreactor-cultured scaffolds represents a promising solution for future tissue engineering application.
Ph.D. in Biomedical Engineering, May 2016
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BIOMATERIAL SYSTEMS WITH PERSISTENT GROWTH FACTOR GRADIENTS IN VIVO FOR TISSUE ENGINEERING APPLICATIONS
Title
BIOMATERIAL SYSTEMS WITH PERSISTENT GROWTH FACTOR GRADIENTS IN VIVO FOR TISSUE ENGINEERING APPLICATIONS
Creator
Akar, Banu
Date
2016, 2016-12
Description
Tissue engineering aims to develop strategies for the replacement of damaged, injured or missing tissues with biologically compatible...
Show moreTissue engineering aims to develop strategies for the replacement of damaged, injured or missing tissues with biologically compatible substitutes such as bioengineered tissues. However, generating tissues of su cient volume for clinical application requires the formation of stable and extensive vasculature within the tissue constructs. The overall goal of this work is to enhance vascularization using a gradient biomaterial system and apply this research to engineering vascularized bone of clinical size. First, a method was developed to create persistent growth factor gradients with an adjustable gradient magnitude in vivo. This method generated persistent gradients of platelet-derived growth factor (PDGF-BB) within brin/poly (ethylene glycol) (PEG) sca olds. The presence of a growth factor gradient within the system was veri ed in vivo using near-infrared imaging. Also, a computational model was developed to investigate gradient characteristics within the system. Gradient properties can be controlled by varying the degradation rate of the gradient layer components or dose of PDGF-BB delivered. The angiogenic potential of gradient sca olds was tested in rodents using a subcutaneous implantation model. The depth of tissue invasion and density of blood vessels formed in response to the biomaterial increased with dose of the growth factor. The gradient biomaterial system allows formation of persistent gradients that can be in uenced by biomaterial characteristics, and enhances vascularization. Therefore, this biomaterial system can be used for tissue engineering applications. Second, the brin/PEG-based sca olds were modi ed to be degradable via hydrolysis and to include bioactive ceramic particles (hydroxyapatite and -tri-calcium phosphate). Characteristics of the hydrogel ceramic composites were investigated in vitro and in vivo. The presence of ceramic particles extended degradation time of thehydrogels in vitro and in vivo. Hydrogel ceramic composites were tested in a rodent cranial defect model and enhanced bone tissue regeneration. Third, strategies developed from the previous studies were combined to prepare ceramic supplemented gradient sca olds for bone tissue engineering applications. A gradient layer was applied to the hydrogel-ceramic composites and bone tissue response was evaluated in a periosteum guided large animal model. Ceramic supplemented gradient sca olds augmented vascularization and bone regeneration in vivo. In conclusion, a biomaterial system with persistent growth factor gradients was developed and enhanced vascularization and bone regeneration in vivo. This system holds a great potential for tissue engineering applications.
Ph.D. in Biomedical Engineering, December 2016
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MULTI-AGENT MODELING OF TISSUE GROWTH AND ANGIOGENESIS WITH HIGH PERFORMANCE COMPUTING
Title
MULTI-AGENT MODELING OF TISSUE GROWTH AND ANGIOGENESIS WITH HIGH PERFORMANCE COMPUTING
Creator
Bayrak, Elif Seyma
Date
2015, 2015-07
Description
Tissue engineering emerged as a result of the high demand of transplant organ and tissues in spite of low number of donors. Rapid and stable...
Show moreTissue engineering emerged as a result of the high demand of transplant organ and tissues in spite of low number of donors. Rapid and stable vascularization still presents the major challenge for three-dimensional functional tissues. Bone is a highly vascularized tissue. Regeneration of vascularized bone tissue from osteogenic cells in biodegradable scaffolds is strongly affected by the interplay between scaffold properties, chemical cues and precursor cells. The number of variables that contribute to the formation of engineered tissues present a challenging optimization problem that cannot be addressed with the experimentation alone. Complex system such as vascularized tissue growth can benefit from properly developed computational models. Computational models can help us understand interactions between the various parts of the complex systems, imagine all possible outcomes of a specific event, explain reasons and causes and forecast future trajectories. Agent-based modeling (ABM) is a powerful modeling and simulation technique that builds a structure from bottom-up to model and understand systems comprised of autonomous, interacting entities. ABM is a natural choice to model biological system that is comprised of many interacting cells. ABM possesses great advantages including simulating of each individuals behavior, holding their history, allowing them to adapt to dynamic conditions and learn through simple to complex algorithms. One main concern of the modelers is the computational heaviness of ABMs that limits the use of this technique in real time optimization, monitoring and control applications. Discovering the full potential of ABM in biological system with huge population size depend on the computational power available.A multi layer agent based model to simulate vascular bone regeneration in degradable porous hydrogels is developed both for personal computer (PC) environment and high performance computing (HPC) platforms. The personal computer (PC) version of this model is built upon the angiogenesis model that was previously developed by Arsun Artel and Hamidreza Mehdizadeh. This work is focused on development of bone tissue growth layer while considering the interactions and improving the existing layers and uses the parallel processing paradigm for running tissue growth more efficiently and more quickly. This model aims to help investigating and understanding the interactions between soluble factors, scaffolds and cells, and finding the optimal biomaterial structure and soluble cues to maximize vascularization and differentiation to bone tissue.
Ph.D. in Chemical Engineering, July 2015
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MULTI-LAYER AGENT-BASED MODELING FOR BONE TISSUE ENGINEERING
Title
MULTI-LAYER AGENT-BASED MODELING FOR BONE TISSUE ENGINEERING
Creator
Lu, Chenlin
Date
2018, 2018-05
Description
Bone tissue engineering (BTE) has emerged over the past few decades as a potential alternative to the field of conventional bone regenerative...
Show moreBone tissue engineering (BTE) has emerged over the past few decades as a potential alternative to the field of conventional bone regenerative medicine due to the exceedingly high demand of adequate bone grafts. Regeneration of bone tissue in BTE requires synergistic combination of biomaterial scaffolds, growth factors, and osteogenic cells. Scaffolds with well-designed architectures and degradation characteristics, provided with appropriate angiogenic and osteogenic factors are essential for bone tissue regeneration. Taking into account these factors that contribute to bone tissue regeneration process simultaneously and optimizing their characteristics presents a highly difficult task and cannot be addressed with experimentation alone. Computational models combined with experimental methods provide better understanding of the underlying mechanisms of the complex process. The agent-based modeling (ABM) approach is used to develop three-dimensional models of vascularization and bone growth. ABM is a powerful modeling and simulation technique and is naturally suitable for complex biological system as it simulates actions and interactions of individual agents in an attempt to re-create and predict the appearance of complex phenomena. In this work, a multi-layered, agent-based computational model has been proposed to simulate the vascularization and bone tissue regeneration in a porous, biodegradable biomaterial scaffold. This model aims to investigate the interactions between osteogenic cells, signaling molecules, and biomaterial scaffolds in order to enhance scaffold vascularization and bone tissue formation. Our previous works have already investigated the interactions between endothelial cells (ECs) and biodegradable scaffolds, and provided us significant insights into the combined effect of scaffold geometrical properties and degradation dynamics on scaffold vascularization. Furthermore, the controlled release of angiogenic growth factors has been studied tothis work, a multi-layered, agent-based computational model has been proposed to simulate the vascularization and bone tissue regeneration in a porous, biodegradable biomaterial scaffold. This model aims to investigate the interactions between osteogenic cells, signaling molecules, and biomaterial scaffolds in order to enhance scaffold vascularization and bone tissue formation. Our previous works have already investigated the interactions between endothelial cells (ECs) and biodegradable scaffolds, and provided us significant insights into the combined effect of scaffold geometrical properties and degradation dynamics on scaffold vascularization. Furthermore, the controlled release of angiogenic growth factors has been studied to investigate their effects on vascularization process. This work will mainly focus on three aspects: 1) the improvement of scaffold degradation model. 2) the development of vascularized bone regeneration agent-based model in Repast High Performance Computing (Repast HPC). 3) the investigation of in vitro prevascularization strategy to enhance angiogenesis and overall bone regeneration in BTE applications. The developed model integrates all these factors and simulates the regeneration of bone tissue in biodegradable scaffolds over time. Simulation results can be used in combination with experimental data to design optimal scaffold constructs for bone tissue engineering. A multi-layer scaffold model is implemented in the degradation ABM. Scaffold vascularization is enhanced by the multi-layer scaffold strategy without losing the necessary mechanical support of biomaterial scaffolds. A integrated vascularized bone tissue regeneration ABM was developed using Repast HPC platform. The model successfully simulated the scaffold vascularization and coupled osteogenic differentiation in a 3D porous scaffold. The study demonstrated that scaffolds with higher porosity and combined angiogenic and osteogenic GF factor resulted in optimal vascularized bone formation. A diffusion ABM is developed to simulate the growth factor release in the scaffold. Simulation results indicated a good agreement between the diffusion ABM and mathematical model.The prevascularization high performance ABM is developed to simulate the integrated process of in vitro prevascularization followed by in vivo vascularized bone formation and evaluate the potential of prevascularization strategy to enhance overall scaffold vascularization and bone formation. The results demonstrated that prevascularized scaffold increases overall defect vascularization and bone formation upon implantation.
Ph.D. in Chemical and Biological Engineering, May 2018
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