A. James Clark School of Engineering

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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.

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    Effect of Protein Folding State and Conformational Fluctuations on Hydrogel Formation and Protein Aggregation
    (2022) Nikfarjam, Shakiba; Woehl, Taylor J; Anisimov, Mikhail; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    In this thesis we investigate the role of protein unfolding on protein aggregation and hydrogel formation in two different systems. In the context of designing protein-based hydrogels as biomaterials, we investigate how protein unfolding affects the formation dynamics of hydrogels in response to temperature changes, denaturation, and chemical reactions. In a second context we establish how microsecond to millisecond fluctuations in an amyloid forming protein, beta-2-microglobulin, correlate to the amyloid forming propensity of the protein, with an emphasis on understanding how conformational changes in the native folded state provide thermodynamic driving forces for amyloid nucleation.The work on protein hydrogel yielded two key results. First, we observed that the lifetime of dissipative hydrogels decreased and their mechanical stiffness increased with increasing denaturant concentration and constant fuel concentration. At a higher denaturant concentration, the concentration of solvent-accessible cysteines increases the stiffness of the hydrogel at the cost of a faster consumption of H_2 O_2, which is the cause of the shorter gel lifetime. This work utilizing biological macromolecules in kinetically controlled dissipative structures opens the door to future applications of such systems in which the biomolecules' structures can control the reaction kinetics. Another substantial outcome of our work is to uncover mechanisms underlying the initiation of nucleation in the initial stages of amyloid aggregate formation. The study of conformational fluctuations in the structure of the amyloid-forming protein beta 2-microglobulin (β_2 M) yielded three key results. First, β_2 M variants' aggregation propensity correlates with their conformational fluctuations rate. A longer-lived misfolded subpopulation increases the chance of aggregation initiation by increasing the collision chance of the protein's sticky regions. Second, the observed millisecond interconversions agree with the timescales required for the interconversion of a protein's structure between its subpopulations. Third, the fluctuations themselves could be a driving force for the nucleation of aggregates by decreasing the lag-time of nucleus formation by a sudden large fluctuation.
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    Mechanical, Structural and Biological Properties of Biopolymer-Based Hydrogels
    (2012) Hyland, Laura; Yu, Yihua B.; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The aim of this dissertation was to begin to understand how biopolymer interactions affect mechanical and structural properties of biomaterials, and how those properties affect stem cell behavior. Polysaccharide, oligopeptide and oligopeptide-polysaccharide composite materials were made and then characterized using a range of techniques. It was found that chondroitin addition to chitosan-alginate networks improved both tensile and compressive strength. Increasing polysaccharide concentration also improved mechanical properties. Also, polysaccharide incorporation into peptide hydrogels increased biomaterial resistance to strain break. Structural analysis supported mechanical data, showing that incorporation of the peptides dramatically changed the morphology of the polysaccharide networks. Biopolymer chirality was also explored in this work. By incorporating polysaccharides and oligosaccharides into both L- and D-forms of peptide hydrogels, we observed differences in mechanical properties not seen in L- and D-oligopeptide hydrogels alone. Greater interactions between L-oligopeptides and D-saccharides lead to stronger materials with distinctively different structural characteristics from hydrogels made from D-oligopeptides and D-saccharides. This phenomenon, known as chiral selectivity, has previously only been seen at the molecular level. Here, we showed that chiral selectivity is another unique property of biopolymers that can be exploited to tune mechanical and structural properties of materials. Chiral selectivity was also observed in terms of stem cell behavior in this work. However another property, hydrogel charge, was used to diminish the effects of chiral selectivity in order to enhance the biocompatibility of D-oligopeptide hydrogels. It was found that negative charges significantly improved human mesenchymal stem cell attachment and proliferation in D-oligopeptide gels but had little effect on their interactions with L-oligopeptide gels. These results suggest that it is possible to use charge and other properties of biopolymers to engineer biomaterials whose chirality is distinct from that of natural biomaterials but whose performance is close to that of natural biomaterials. These oligopeptide-based biomaterials also offer new tools to investigate biohomochirality, an important and unresolved question in biology.
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    ORBITAL FLOOR REGENERATION USING CYCLIC ACETAL HYDROGELS THROUGH ENHANCED OSTEOGENIC CELL SIGNALING OF MESENCHYMAL STEM CELLS
    (2009) Betz, Martha Wheaton; Fisher, John P; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Orbital floor fractures are a serious consequence of craniofacial trauma and account for approximately 60-70% of all orbital fractures. Unfortunately, the body's natural response to orbital floor defects generally does not restore proper function and facial aesthetics which is complicated by the thin bone and adjacent sinuses. We propose using a tissue engineering strategy to regenerate orbital floor bone. To this end, a functional biomaterial was investigated to enhance orbital floor regeneration. First, a bone marrow stromal cell population was isolated and differentiation assessed via coculture with chondrocytes and osteogenic media supplements. A cyclic acetal biomaterial composed of the cyclic acetal monomer 5-ethyl-5-(hydroxymethyl)-β,β-dimethyl-1,3-dioxane-2-ethanol diacrylate (EHD) and poly(ethylene glycol) diacrylate (PEGDA) was then developed for cell encapsulation. The previously investigated bone marrow stromal cells were then used to determine the effects of the ammonium persulfate/N,N,N',N'-tetramethylethylenediamine initiator system used to crosslink the EH-PEG hydrogels on cell viability, metabolic activity, and osteogenic differentiation. Next, EH-PEG hydrogels were implanted into orbital floor defects with bone morphogenetic protein-2, where tissue response and surrounding bone growth was analyzed. To improve surrounding tissue interaction and cell infiltration, macroporous EH-PEG hydrogels were created using porogen-leaching. These hydrogels were characterized using optical coherence tomography for pore size, porosity, and cell viability. In addition, these macroporous hydrogels were created with varying architecture to analyze the effects on osteogenic signaling and differentiation. This work outlines the potential application of EH-PEG hydrogels for use in orbital floor repair.