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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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CONTROLLED RELEASE OF VANCOMYCIN FROM A THERMORESPONSIVE HYDROGEL SYSTEM FOR THE PROPHYLACTIC TREATMENT OF POST-OPERATIVE ACUTE ENDOPHTHALMITIS
Title
CONTROLLED RELEASE OF VANCOMYCIN FROM A THERMORESPONSIVE HYDROGEL SYSTEM FOR THE PROPHYLACTIC TREATMENT OF POST-OPERATIVE ACUTE ENDOPHTHALMITIS
Creator
Dosmar, Emily
Date
2017, 2017-05
Description
Current clinical treatment for preventing the post-operative endophthalmitis include a bolus injection of the antibiotic, vancoymin (VAN),...
Show moreCurrent clinical treatment for preventing the post-operative endophthalmitis include a bolus injection of the antibiotic, vancoymin (VAN), during surgery followed by a 1-2-week period of patient administered, topically applied antibiotics. Due to poor patient compliance, drug loss due to poor drug residence time for topically applied drops, and limitations of drug injection sites, there is a clinical need for a subconjunctival, sustained release drug delivery system. While a controlled drug delivery system is beneficial by eliminating patient drug administration and improving drug delivery, the challenges of initial burst (IB), drug release kinetics, and drug distribution must be addressed in order to design an optimal system to address this need. The primary goal of this study was to develop a drug delivery system (DDS) capable of delivering VAN for 10-14 days and replacing both the bolus VAN injection and the topical eye drops. We hypothesized that controlled and extended release of VAN will perform equally or better than bolus VAN administration and eye drops. To accomplish this goal, three specific aims were performed: 1) Development of an injectable drug delivery system to release bioactive VAN for at least 10 days; 2) Validation of the efficacy of the developed DDS; and 3) Development of a compartmental model analysis model used to predict the loading dose required to achieve therapeutic drug concentration in the vitreous.
Ph.D. in Biomedical Engineering, May 2017
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Gradient Hydrogels for Neovascularization of Engineered Tissues
Title
Gradient Hydrogels for Neovascularization of Engineered Tissues
Creator
He, Yusheng Jason
Date
2020
Description
The inability to induce extensive and perfusable microvasculature within complex engineered tissues that possess spatial variations in...
Show moreThe inability to induce extensive and perfusable microvasculature within complex engineered tissues that possess spatial variations in mechanical properties, physical architecture and biochemical composition remains as a major hurdle to their clinical translation. Biomaterial strategies focused on designing scaffolds with physiologically relevant gradients provide a promising means for elucidating 3D vascular cell responses to spatial and temporal variations in matrix properties. This work developed a cell-laden hydrogel platform with tunable decoupled and combined gradients of multiple matrix properties critical for maintenance of long term-vascular cell viability, adhesion, migration and invasion outgrowth to elucidate the impact of gradient matrix cues on 3D neovascularization in culture. This was achieved through the completion of three specific aims. First, a novel ascending frontal polymerization (AFP) technique was developed to generate gradient-based PEG hydrogel scaffolds with tunable individual and combined matrix gradients. Using programmable syringe pumps to control the delivery of precursors with distinct composition during crosslinking, we were able to generate gradient scaffolds with decoupled spatial variations in the immobilized concentration of the RGD cell adhesion peptide ligand and elastic modulus. Using this approach, the slope and magnitude of the imposed RGD gradients were readily manipulated without inducing variations in elastic modulus. Vascular spheroids inserted into gradient hydrogel scaffolds supported 3D vascular sprout formation, while the immobilized RGD gradient promoted an increase in sprout length towards the imposed gradient. Next, to create cell-laden scaffolds photopolymerization conditions were optimized to enable viable cell encapsulation during scaffold fabrication. To achieve this, an experimental sensitivity analysis combined with the design of experiments (DOE) was implemented to design isotropic hydrogel scaffolds with a broad range of matrix properties (elastic modulus, immobilized RGD and proteolytic degradation) that supported vascular sprouting in 3D culture. We examined the individual and interaction effects of each matrix property and demonstrated that an optimal combination associated with increases in immobilized RGD and proteolytic degradation of mediate synergistic enhancements in 3D vascular sprouting. Based on the findings from this in vitro study with isotropic hydrogel scaffolds, we designed scaffolds with 5 types of gradient combinations in immobilized RGD, stiffness and protease-sensitivity and explored the impact of spatial variations these matrix cues on vascular sprouting within the constructs in 3D culture. Specifically, we created hydrogel scaffolds with gradients in immobilized RGD with (1) steep and (2) shallow slopes, (3) gradients in elastic modulus, (4) gradients in protease-sensitivityand and (5) opposing gradients of RGD and modulus and concurrent gradients of protease sensitivity and RGD. By encapsulating vascular spheroids in different regions of each gradient scaffold, we observed spatial variations in total sprout length within all gradient scaffolds. We also found that RGD gradient and combined gradient scaffolds induced biased vascular sprouting toward increased RGD concentration and that biased sprouting was enhanced by gradient magnitude and slopes of immobilized RGD concentration. Conversely, directional sprouting responses diminished in scaffolds possessing opposing gradients in RGD (with concurrent gradients of degradation) and modulus. The presented work is the first to demonstrate the use of a cell-laden biomaterial platform to explore the impact of gradients in RGD, proteolytic degradation, and stiffness on vascular sprouting responses in 3D culture. The presented platform and findings of this thesis work hold great potential in the fields of tissue engineering specifically for prevascularization of complex tissues that possess spatial variations in mechanical properties, degradation rate and adhesion ligand composition to facilitate their regeneration.
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