Organizational Unit:
Wallace H. Coulter Department of Biomedical Engineering

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Now showing 1 - 10 of 19
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    Influence of static and dynamic topography on osteoblast proliferation and maturation
    (Georgia Institute of Technology, 2016-11-15) Lee, Erin Marie
    Osseointegration remains a primary concern for implanted devices in patients with risk factors such as diabetes, smoking, age, arthritis, and osteoporosis. Current use of titanium alloys, while successful, comes at a high cost. Cheaper alternatives may exist with polymers for some non-load bearing applications. Advancements in polymer chemistry have yielded a class of smart materials called shape-memory polymers (SMPs), which can change their shape via changes in temperature or mechanical stress. This study follows the creation of one such temperature-sensitive SMP, benzyl acrylate-benzyl methacrylate-1,12-dodecanediol dimethacrylate, which can be compressed to remove all surface topography and at 37˚C shows nearly complete recovery within 8 hours. The examination of pre-osteoblast MG63 cell behavior on these SMPs (with and without compression) by DNA and ELISAs indicates MG63 cells can be 'clued' to proliferate and then to rapidly mature. Similar topography was created on polymers of varied stiffness to determine if there is correlation between substrate stiffness and topography on osteoblast maturation. Overall, this thesis gives insight into potential benefits of SMP use in biomedical applications. In addition, it demonstrates the potential issues concerning the use of polymers to achieve a desires cell response.
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    Multi-scale structural design of titanium implants for improved osseointegration
    (Georgia Institute of Technology, 2016-11-07) Cheng, Alice
    Osseointegration success of bone-interfacing implants is reduced for many compromised patients, necessitating improved implant design. Though material and mechanical properties of titanium make it attractive for load-bearing dental and orthopaedic implants, limited advancements have been made to increase success and survival after placement in the body. Novel surface modifications inducing combined micro- and nano-roughness on Ti and Ti-6Al-4V substrates contribute to increased wettability and can be tailored to affect cell response. Additive manufacturing can produce three dimensional constructs with natural, trabeculae-inspired porosity. Osteoblasts and mesenchymal stem cells are responsive to the porosity and detail of these constructs, and exhibit increased production of osteoblastic differentiation and maturation factors on porous constructs compared to solid substrates. Implants with trabecular porosity lead to vertical bone growth on rat calvaria, and osseointegrate in the rabbit femur. These results indicate that structural micro- and nano-modification at the surface, combined with macro-scale porosity, can enhance osteoblastic differentiation and maturation in vitro, and osseointegration in vivo. These implants are now being evaluated in clinical studies.
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    Cellular Response to Surface Wettability Gradient on Microtextured Surfaces
    (Georgia Institute of Technology, 2013-12-16) Plaisance, Marc Charles
    Objective: Topography, chemistry, and energy of titanium (Ti) implants alter cell response through variations in protein adsorption, integrin expression, and downstream cell signaling. However, the contribution of surface energy on cell response is difficult to isolate because altered hydrophilicity can result from changes in surface chemistry or microstructure. Our aim was to examine a unique system of wettability gradients created on microstructured Ti on osteoblast maturation and phenotype. Method: A surface energy gradient was created on sand-blasted/acid-etched (SLA) Ti surfaces. Surfaces were treated with oxygen plasma for 2 minutes, and then allowed to age for 1, 12, 80, or 116 hours to generate a wettability gradient. Surfaces were characterized by contact angle and SEM. MG63 cells were cultured on SLA or experimental SLA surfaces to confluence on TCPS. Osteoblast differentiation (IBSP, RUNX2, ALP, OCN, OPG) and integrin subunits (ITG2, ITGA5, ITGAV, ITGB1) measured by real-time PCR (n=6 surfaces per variable analyzed by ANOVA/Bonferroni’s modified Student’s t-test). Result: After plasma treatment, SLA surface topography was retained. A gradient of wettability was obtained, with contact angles of 32.0° (SLA116), 23.3° (SLA80), 12.5° (SLA12), 7.9° (SLA1). All surfaces were significantly more hydrophilic than the original SLA surface (126.8°). Integrin expression was affected by wettability. ITGA2 was higher on wettable surfaces than on SLA, but was highest on SLA1. ITGAV and ITGB1 were decreased on hydrophilic surfaces, but ITGA5 was not affected. IBSP, RUNX2, and ALP increased and OPG decreased with increasing wettability. OCN decreased with increasing wettability, but levels on the most wettable surface were similar to SLA. Conclusion: Here we elucidated the role of surface energy on cell response using surfaces with the same topography and chemistry. The results show that osteoblastic maturation was regulated in a wettability-dependent manner and suggest that the effects are mediated by integrins.
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    Ceramic materials mimicking normal bone surface microstructure and chemistry modulate osteoblast response
    (Georgia Institute of Technology, 2013-09-20) Adams, Brandy Rogers
    Bone consists of collagen/hydroxyapatite (HA) composites in which poorly crystalline carbonated calcium phosphate is intercalated within the fibrillar structure. Normal bone mineral is a carbonated-apatite, but there are limited data on the effect of mineral containing carbonate on cell response. Although the exact biological role of silicate in bone formation is unclear, silicate has been identified at trace levels in immature bone and is believed to play a metabolic role in new bone formation. To mimic the inorganic and organic composition of bone we have developed a variety of bone graft substitutes. In the present body of research, we characterized the surface composition of human cortical and trabecular bone. When then characterized the surface compositions of the following potential bone substitutes: carbonated hydroxyapatite (CO₃²-HA), silicated hydroxyapatite (Si-HA), and collagen sponges mineralized with calcium phosphate using the polymer-induced liquid-precursor (PILP) process. In the latter substitutes, the PILP process leads to type I collagen fibrils infiltrated with an amorphous mineral precursor upon which crystallization leads to intrafibrillar HA closely mimicking physiological bone mineral. We then determined the osteoblast-like cell response to each bone substitute to characterize the substrate’s effect on osteoblast differentiation. The observations collectively indicate that cells are sensitive to the formatting of the mineral phase of a bone substitute and that this format can be altered to modulate cell behavior.
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    The controlled release of rat adipose-derived stem cells from alginate microbeads for bone regeneration
    (Georgia Institute of Technology, 2013-05-13) Leslie, Shirae
    Cell-based therapies have potential for tissue regeneration but poor delivery methods lead to low viability or dispersal of cells from target sites, limiting clinical utility. Here, we developed a degradable and injectable hydrogel to deliver stem cells for bone regeneration. Alginate microbeads <200µm are injectable, persist at implantation sites and contain viable cells, but do not readily degrade in-vivo. We hypothesized that controlled release of rat adipose-derived stem cells (ASCs) from alginate microbeads can be achieved by incorporating alginate-lyase in the hydrogel. Microbeads were formed using high electrostatic potential. Controlled degradation was achieved through direct combination of alginate-lyase and alginate at 4°C. Results showed that microbead degradation and cell release depended on the alginate-lyase to alginate ratio. Viability of released cells ranged from 87% on day 2 to 71% on day 12. Monolayer cultures of released ASCs grown in osteogenic medium produced higher levels of osteocalcin and similar levels of other soluble factors as ASCs that were neither previously encapsulated nor exposed to alginate-lyase. Bmp2, Fgf2, and Vegfa mRNA in released cells were also increased. Thus, this delivery system allows for controlled release of viable cells and can modulate their downstream osteogenic factor production.
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    The role of Pdia3 in vitamin D signaling in osteoblasts
    (Georgia Institute of Technology, 2012-08-24) Chen, Jiaxuan
    1a,25-Dihydroxyvitamin D3 (1a,25(OH)2D3) is a major functional metabolic form of vitamin D. 1a,25(OH)2D3 has drawn increasing attention due to its functions in addition to maintaining calcium phosphate homeostasis. It directly regulates mineralization by osteoblasts, matrix production and remodeling by chondrocytes, and contraction of cardiomyocytes. 1a,25(OH)2D3 and its analogues have shown beneficial effects in treating multiple sclerosis, diabetes and various types of cancer. In order to maximize the pharmaceutical potential of 1a,25(OH)2D3, a better understanding its cell signaling pathway is necessary. 1a,25(OH)2D3 regulates osteoblasts through both classical nuclear vitamin D receptor (nVDR) mediated genomic effects and plasma membrane receptor-mediated rapid responses. The identity of the plasma membrane receptor for 1a,25(OH)2D3 is controversial. Protein disulfide isomerase associated 3 (Pdia3) has been hypothesized as one of the putative plasma membrane receptors for 1a,25(OH)2D3. The overall goal of this thesis was to understand the general role and the molecular mechanism of Pdia3 in 1a,25(OH)2D3-initiated rapid responses, and to determine the role of Pdia3 and its dependent signaling in osteoblast biology. The results show that Pdia3 is required for membrane-mediated responses of 1a,25(OH)2D3. Moreover, both Pdia3 and nVDR are critical components of the plasma membrane receptor complex for 1a,25(OH)2D3. Finally, Pdia3 and signaling via Pdia3 regulate osteoblast differentiation and mineralization. Taken together, this study demonstrates the role of Pdia3 in rapid responses to 1a,25(OH)2D3 and osteoblast biology, reveals the unexpected complexity of the 1a,25(OH)2D3 plasma receptor complex and opens the new target, Pdia3, for pharmaceutical application and tissue engineering.
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    Hydrogel therapy for re-synostosis based on the developmental and regenerative changes of murine cranial sutures
    (Georgia Institute of Technology, 2012-05-23) Hermann, Christopher Douglas
    Craniosynostosis is the premature fusion of one or more cranial sutures in the developing skull. If left untreated, craniosynostosis can result in developmental delays, blindness, deafness, and other impairments resulting from an increase in the intracranial pressure. In many cases, the treatment consists of complex calvarial vault reconstruction with the hope of restoring a normal skull appearance and volume. Re-synostosis, the premature re-closure following surgery, occurs in up to 40% children who undergo surgery. If this occurs, a second surgery is needed to remove portions of the fused skull in an attempt to correct the deformities and/or relieve an increase in intracranial pressure. These subsequent surgeries are associated with an incredibly high incidence of life threatening complications. To address this unmet clinical need we have developed strategies to delay the post-operative bone growth in a clinically relevant murine model of re-synostosis. The overall objective of this thesis was to develop a hydrogel based therapy to delay rapid bone regeneration in a murine model of re-synostosis. The overall hypothesis was that delivery of key BMP inhibitors involved in regulating normal suture development and regeneration will delay the rapid bone growth that in seen in a pediatric murine model of re-synostosis. The overall approach is to use micro-computed tomography (µCT) to determine the time course of suture fusion and to identify genes associated with key developmental time points, to develop a pediatric specific mouse model that displays rapid re-synostosis, and lastly to develop a hydrogel based therapy to delay the re-synostosis of this cranial defect.
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    Directing the paracrine actions of adipose stem cells for cartilage regeneration
    (Georgia Institute of Technology, 2012-05-04) Lee, Christopher S. D.
    Current cartilage repair methods are ineffective in restoring the mechanical and biological functions of native hyaline cartilage. Therefore, using the paracrine actions of stem cell therapies to stimulate endogenous cartilage regeneration has gained momentum. Adipose stem cells (ASCs) are an attractive option for this endeavor because of their accessibility, chondrogenic potential, and secretion of factors that promote connective tissue repair. In order to use the factors secreted by ASCs to stimulate cartilage regeneration, the signaling pathways that affect postnatal cartilage development and morphology need to be understood. Next, approaches need to be developed to tailor the secretory profile of ASCs to promote cartilage regeneration. Finally, delivery methods that localize ASCs within a defect site while facilitating paracrine factor secretion need to be optimized. The overall objective of this thesis was to develop an ASC therapy that could be effectively delivered in cartilage defects and stimulate regeneration via its paracrine actions. The general hypothesis was that the secretory profile of ASCs can be tailored to enhance cartilage regeneration and be effectively delivered to regenerate cartilage in vivo. The overall approach used the growth plate as an initial model to study changes in postnatal cartilage morphology and the molecular mechanisms that regulate it, different media treatments and microencapsulation to tailor growth factor production, and alginate microbeads to deliver ASCs in vivo to repair cartilage focal defects.
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    Fabrication of electrospun fibrous meshes and 3D porous titanium scaffolds for tissue engineering
    (Georgia Institute of Technology, 2012-03-06) Wang, Xiaokun
    Tissue engineering is a multidisciplinary field that is rapidly emerging as a promising approach for tissue repair and regeneration. In this approach, scaffolds which allow cells to invade the construct and guide the cells grow into specific tissue play a pivotal role. Electrospinning has gained popularity recently as a simple and versatile method to produce fibrous structures with nano- to microscale dimensions. These electrospun fibers have been extensively applied to create nanofiber scaffolds for tissue engineering applications. Specifically for bone and cartilage tissue engineering, polymeric materials have some attractive properties such as the biodegradability. Ceramic scaffolds and implant coatings, such as hydroxyapatite and silica-based bioglass have also been considered as bone graft substitutes for bone repair because of their bioactivity and, in some cases, tunable resorbability. Besides tissue engineering scaffolds, for clinical application, especially for load-bearing artificial implants, metallic materials such as titanium are the most commonly used material. Osseointegration between bone and implants is very essential for implant success. To achieve better osseointegration between bone and the implant surface, three dimensional porous structures can provide enhanced fixation with bone by allowing tissue to grow into the pores. In this study, pre-3D electrospun polymer and ceramic scaffolds with peptide conjugation and 3D titanium scaffolds with different surface morphology were fabricated to testify the osteoblast and mensechymal stem cell attachment and differentiation. The overall goal of this thesis is to determine if the peptide functionalization of polymeric scaffolds and physical parameters of ceramic and metallic scaffold can promote osteoblast maturation and mesenchymal stem cell differentiation in vitro to achieve an optimal scaffold design for greater osseointegration. The results of the studies showed with functionalization of MSC- specific peptide, polymer scaffolds behaved with higher biocompatibility and MSC affinity. For the ceramic and metallic scaffolds, microstructures and nanostructures can synergistically promote osteoblast maturation and 3D micro-environment with micro-roughness is a promising design for osteoblast maturation and MSC differentiation in vitro compared to 2D surfaces.
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    The role of biomaterial properties in peri-implant neovascularization
    (Georgia Institute of Technology, 2011-07-08) Raines, Andrew Lawrence
    An understanding of the interactions between orthopaedic and dental implant surfaces with the surrounding host tissue is critical in the design of next generation implants to improve osseointegration and clinical success rates. Critical to the process of osseointegration is the rapid establishment of a patent neovasculature in the peri-implant space to allow for the delivery of oxygen, nutrients, and progenitor cells. The central aim of this thesis is to understand how biomaterials regulate cellular and host tissue response to elicit a pro-angiogenic microenvironment at the implant/tissue interface. To address this question, the studies performed in this thesis aim to 1) determine whether biomaterial surface properties can modulate the production and secretion of pro-angiogenic growth factors by cells, 2) determine the role of integrin and VEGF-A signaling in the angiogenic response of cells to implant surface features, and 3) to determine whether neovascularization in response to an implanted biomaterial can be modulated in vivo. The results demonstrate that biomaterial surface microtopography and surface energy can increase the production of pro-angiogenic growth factors by osteoblasts and that these growth factors stimulate the differentiation of endothelial cells in a paracrine manner and the results suggest that signaling through specific integrin receptors affects the production of angiogenic growth factors by osteoblast-like cells. Further, using a novel in vivo model, the results demonstrate that a combination of a rough surface microtopography and high surface energy can improve bone-to-implant contact and neovascularization. The results of these studies also suggest that VEGF-A produced by osteoblast-like cells has both an autocrine and paracrine effect. VEGF-A silenced cells exhibited reduced production of both pro-angiogenic and osteogenic growth factors in response to surface microtopgraphy and surface energy, and conditioned media from VEGF-A silenced osteoblast-like cell cultures failed to stimulate endothelial cell differentiation in an in vitro model. Finally, the results show that by combining angiogenic and osteogenic biomaterials, new bone formation and neovascularization can be enhanced. Taken together, this research helps to provide a better understanding of the role of material properties in cell and host tissue response and will aid in the improvement of the design of new implants.