Organizational Unit:
Wallace H. Coulter Department of Biomedical Engineering

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https://ror.org/02j15s898
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Now showing 1 - 3 of 3
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    Incorporation of bio-inspired microparticles within embryonnic stem cell aggregates for directed differentiation
    (Georgia Institute of Technology, 2015-08-04) Sullivan, Denise D.
    Embryonic stem cells (ESCs) are a unique cell population that can differentiate into all three embryonic germ layers (endoderm, mesoderm, and ectoderm), rendering them an invaluable cell source for studying the molecular mechanisms of embryogenesis. Signaling molecules that direct tissue patterning during embryonic development are secreted by ESC aggregates, known as embryoid bodies (EBs). As many of these signaling proteins interact with the extracellular matrix (ECM), manipulation of the ESC extracellular environment provides a means to direct differentiation. ECM components, such as glycosaminoglycans (GAGs), play crucial roles in cell signaling and regulation of morphogen gradients during early development through binding and concentration of secreted growth factors. Thus, engineered biomaterials fabricated from highly sulfated GAGs, such as heparin, provide matrices for manipulation and efficient capture of ESC morphogens via reversible electrostatic and affinity interactions. Ultimately, biomaterials designed to efficiently capture and retain morphogenic factors offer an attractive platform to enhance the differentiation of ESCs toward defined cell types. The overall objective of this work was to examine the ability of microparticles synthesized from both synthetic and naturally-derived materials to enhance the local presentation of morphogens to direct ESC differentiation. The overall hypothesis was that microparticles that mimic the ECM can modulate ESC differentiation through sequestration of endogenous morphogens present within the EB microenvironment.
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    Delivery of prolyl hydroxylase inhibitors to MSC spheroids for enhanced angiogenic factor secretion
    (Georgia Institute of Technology, 2015-07-24) Lassahn, Katy Ann
    Mesenchymal stromal cells (MSCs) are of clinical interest due to their ability to differentiate towards musculoskeletal lineages, modulate inflammatory responses, and promote new blood vessel formation. Angiogenesis is an important aspect of both tissue engineering and wound healing because it is critical to deliver essential nutrients and oxygen in order to facilitate tissue repair and regeneration. In hypoxic environments, the pro-angiogenic effects of MSCs are enhanced through stimulation of the HIF-1α pathway. A class of small molecules termed prolyl hydroxylase inhibitors (PHDi), stabilize HIF-1α through inhibition of the enzyme that degrades HIF-1α in the presence of oxygen. Thus, a chemically induced hypoxic cell response could be engineered to enable greater control over the pro-angiogenic secretory response of transplanted cells through varying the duration and dosage of exposure to PHDi. Treatment of MSCs with PHDi has been shown to enhance cell survival, improve bone regeneration, and increase new vessel formation in vivo. In addition to treatment with PHDi, the culture format of MSC growth can affect the angiogenic properties of MSCs. The culture of MSCs as spheroids has been shown to promote secretion of angiogenic growth factors such as VEGF. Thus, delivery of PHDi to MSC spheroids may have a greater effect on the angiogenic properties of MSCs than monolayer treatment. Sustained delivery of PHDi may be achieved within spheroids via biomaterial based microparticle incorporation. The microparticle delivery of PHDi within spheroids may allow for localized delivery of PHDi in order to reduce potential off target effects if delivered in vivo. The objective of this project is to determine the effect of sustained delivery of PHDi on the angiogenic properties of MSC spheroids. It is hypothesized that sustained delivery of a PHDi in MSC spheroids via MP incorporation will enhance the angiogenic factor secretion of the MSC spheroids compared to spheroid culture alone. To address this hypothesis, three candidate PHDi were screened to determine appropriate dosage based on VEGF secretion and efficiency of encapsulation within MPs. IOX2 was chosen to be encapsulated in poly lactic-co-glycolic acid (PLGA) microparticles (MPs) as a vehicle for sustained delivery within the spheroids. The effect of PHDi delivery on pro-angiogenic factor secretion was assessed by measuring expression of HIF-1α, secretion of angiogenic growth factors such as VEGF, and HUVEC migration assays. While soluble PHDi treatment of MSC spheroids had a significant effect on pro-angiogenic factor secretion, delivery of PHDi via PLGA MPs was unsuccessful. The ability to modulate the hypoxia response of MSC spheroids through PHDi delivery may prolong and enhance the pro-angiogenic effects of hypoxic environments on MSCs, thus alternative biomaterials should be investigated in the future for efficient PHDi delivery.
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    Chondroitin sulfate microparticles modulate TGF-B1-induced chondrogenesis in human mesenchymal stem cell spheroids
    (Georgia Institute of Technology, 2014-04-28) Goude, Melissa Chou
    Due to the limited intrinsic healing ability of mature cartilage tissue, stem cell therapies offer the potential to restore cartilage lost due to trauma or arthritis. Mesenchymal stem cells (MSCs) are a promising cell source due to their ability to differentiate into various adult tissues under specific biochemical and physical cues. Current MSC chondrogenic differentiation strategies employ large pellets, however, we have previously developed a high-throughput technique to form small MSC aggregates (500-1,000 cells) that may reduce diffusion barriers while maintaining a multicellular structure that is analogous to cartilaginous condensations. The objective of this study was to examine the effects on chondrogenesis of incorporating chondroitin sulfate methacrylate (CSMA) microparticles (MPs) within these small MSC spheroids when cultured in the presence of transforming growth factor-β1 (TGF-β1) over 21 days. Spheroids +MP induced earlier increases in collagen II and aggrecan gene expression (chondrogenic markers) than spheroids -MP, although no large differences in immunostaining for these matrix molecules were observed by day 21. Collagen I and X was also detected in the ECM of all spheroids by immunostaining. Interestingly, histology revealed that CSMA MPs clustered together near the center of the MSC spheroids and induced circumferential alignment of cells and ECM around the material core. Because chondrogenesis was not hindered by the presence of CSMA MPs, this study demonstrates the utility of this culture system to further examine the effects of matrix molecules on MSC phenotype, as well as potentially direct differentiation in a more spatially controlled manner that better mimics the architecture of specific target tissues.