Department
of Materials Science and Engineering
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Materials Science
RESEARCH DESCRIPTION: Functional biomaterials for tissue engineering RESEARCH PROJECTS:
Characterization of osteoblast-material adhesion strength by laser-generated stress waves Student: Cell adhesion is crucial in numerous physiological processes such as embryogenesis, growth and development, wound healing, tumor migration, immune response, pathogenic biofilm formation, and tissue remodeling adjacent to foreign implants. The ability to design synthetic biomaterials which promote cell function and differentiation requires further understanding of the dependence between cell-material adhesion and cell function. The ability to directly and accurately quantify cell adhesion provides a powerful tool to complement molecular techniques, and facilitates the determination of the fundamental relationship between cell adhesion and function. Cell adhesion is presently measured using radial flow chamber, micro-cantilever, and jet impingement based techniques, in which the cell interface is subjected to a multi-axial stress-state. Although these techniques provide a valuable measure of relative adhesion, they do not provide direct measurement of this stress-state at cell detachment point. Instead, the local stress-state is modeled from experimentally-measurable far-field flow parameters (in jet impingement and radial flow chamber-based techniques) or force/deflection characteristics (in microcantilever-based technique) as an input. It is noteworthy that the material deformation in these experiments is complex and any reasonable model may involve largely unknown deformation properties of the intervening medium. The laser spallation technique differs from existing techniques by providing a localized one-dimensional strain pulse at the cell interface, which in turn, is calculable through direct recording of surface displacement, albeit requiring sophisticated optics. We are currently investigating of two methods for quantification of cell adhesion strength, laser spallation and jet impingement, and determining the mechanism for cell detachment associated with each method. (Funded by AO Foundation grants)
Substrate-mediated hypertrophy and differentiation of neonatal rat cardiomyocytes Student: Differentiation of neonatal cardiomyocytes to the adult phenotype accompanies a change in contractile function through reorganization and turnover of myofibril proteins, which determine both the energetic and mechanical characteristics of the heart. Additionally and often concurrently, neonatal cardiomyocytes exhibit a hypertrophic response to a wide range of stimulants with an increase in cellular protein, RNA, surface area, and volume in addition to a pronounced upregulation of fetal myosin isoforms and non-contractile genes such as atrial natriuretic factor (ANF), among others. Though the clinical relevance of these phenotypic changes cannot be concluded per se, the eventual construction of cardiac grafts will likely rely heavily on controlling and monitoring cardiomyocyte hypertrophy due to its intrinsic relation with heart function. Current investigations into substrate-mediated cardiomyocyte behavior address in detail the relationship between substrate composition and cell spreading, protein content, ANF expression, and other genetic markers of hypertrophy and differentiation in 2-D and 3-D systems in efforts to elucidate biological design rules for scaffold material selection and design. (Funded by UCLA Stein Oppenheim Grant)
Formation mechanism and structure-property properties of biomimetic apatites Students: Collaborators: We recently developed a basic mechanistic understanding of a rapid mineralization process that allows us to uniformly template sub-micron (~100 nm) apatite structures with micron level periodicity in three dimensional tissue engineering scaffolds. These apatite structures can support attachment and proliferation of a wide range of cell types in vitro, and stimulate the expression of mature osteoblastic markers from marrow-derived cells in vitro. We further showed that the cationic surfaces of the apatite can be exploited to bind biomolecules. By selecting the appropriate molecules, the resultant biomolecular apatite structures offer a simple method to confer uniform templating of biomolecules within complex 3D porous structures at sub-micron resolution and micron level periodicity. Current projects aim to further develop our mechanistic understanding of apatite formation, investigate structure-property relation of biomolecular apatites, and characterize the osteogenic properties of apatites and biomolecular apatites. (Funded by NIH)
Fibrin structure function effects on osteoblast function Student: The utilization of natural biopolymers such as fibrin is appealing for tissue engineers, particularly since fibrin plays a prominent role during natural wound healing. Hybrid scaffolds containing interpenetrating networks of fibrin and synthetic degradable polymers couple the flexibility in mechanical property and degradation time of synthetic polymers with the biological activity of fibrin. Cell function can be further stimulated by delivering cells/proteins/growth factors/drugs/DNA locally. We recently identified selected thrombin-fibrinogen formulations which preferentially promote human marrow stromal cell activities. We are currently investigating the process-structure-function-property relations of various formulations, and determine their effects on adhesion receptor expression, cell morphology, cell proliferation, gene expression, and protein synthesis. Fibrin's ability to maintain cultured bone marrow stromal cell growth and differentiation as well as induce the development of the appropriate tissue infrastructure will be assessed by examining cellular responses to structural variations within selected formulations of fibrin sealant. Ultimately, in vitro and in vivo studies investigating the behavior of bone marrow stromal cells inside fibrin clots will help define the parameters crucial to engineering a formulation of fibrin sealant that can serve as a biomimetic scaffold capable of bone regeneration.
Resident: Short bowel syndrome occurs in children with an inadequate length of intestine to maintain normal digestion and absorption. These children are dependent on intravenous nutrition to sustain normal growth, however, this is associated with significant cost ($100,000 per patient per year) and morbidity, including infection and liver cirrhosis. Although intestinal transplantation for these patients is possible, outcomes are marginal and there are significant side effects associated with life-long immunosuppression. The long-term objective of this project is to engineer functional intestinal tissue that can be used to treat patients with short-bowel syndrome. Specifically, this project will focus on developing a genetically modified intestinal cell that can be grown on a bio-engineered scaffolding and ultimately, implanted into an animal model. The project can be broken down into three specific goals: 1. Developing a genetically-modified intestinal stem cell line. 2. Examining the effect of engineered scaffolds on the functions of these intestinal cells. 3. Following the fate of these intestinal cells after they have been implanted in an animal model. (Funded by UCLA Chancellor’s Border Crossing Initiative)
Bioactive-Absorbable Coil for Brain Aneurysm Therapy Collaborators: Guglielmi detachable coils (GDCs) are the gold standard for endovascular treatment of brain aneurysms. However, GDCs appear less effective when treating wide-necked aneurysms (>4mm). We are developing biologically active coils aimed at accelerating aneurysmal healing by controlling inflammatory reaction inside the aneurysms. We are also investigating the in vitro and in vivo degradation properties, respectively, of potential candidate materials which are being considered for use in 100% bio-absorbable endovascular embolic coils. (Funded by NIH)
Microsphere delivery of bioactive and immunoactive agents for neuronal regeneration Student: Neuronal regeneration after injury is crucially dependent on its intrinsic capacity for initiating a cellular program for regeneration. This regenerative capacity is in general enhanced by neurotrophicagents, and inhibited by growth inhibitors. Factors that contribute to lack of spontaneous regeneration include the absence of positive cues, such as the lack of expression of growth associated proteins and axon-promoting cues such as neurotrophic factors; and the presence of inhibitory cues, such as myelin-associated growth protein (MAG), chondroitin sulfate proteoglycan (CSPG), arretin, Nogo proteins, etc. The long-term goal of this project is to improve axon regeneration and recovery of function by providing a biopolymer tissue matrix that provides the necessary structural support and release the appropriate positive cues, and inhibitors of negative cues. (Funded by California Roman Reed Grants)
Mechanical stimulation for ACL tissue engineering Student: This project aims to determine the role of strain amplitude and frequency on cell reorganization and matrix deposition during ACL tissue engineering. (Funded by Musculoskeletal Transplant Foundation)
Other NON tissue engineering projects UCLA Collaborative Oral Fluid Diagnostic Research Center (Funded by NIH) Reconfigurable Fabric (Funded by NSF) |
