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Project Examples

Examples of REU Research Themes and Projects

2023

Recently, many clinical trials have challenged the efficacy of current therapeutics for neurodegenerative diseases such as neuropathic pain after trauma due to their life-threatening side-effects including addictions. Gene Therapy utilizing lentiviral vectors enables sustained and localized expression of genes of interest leading to functional restorations. We aim to deliver specific gene-encoding lentiviral vectors into the injury to reprogram and/or knockdown downstream signaling pathways for the functional regeneration after trauma. Currently, we focus on attenuating the neuropathic pain after SCI by inflammatory responses, employing biomaterials, RNA interference (RNAi), and gene delivery strategies.

New tools to modulate specific immune cell populations could be a more effective strategy to minimize detrimental immune responses and facilitate novel therapeutic strategies for regenerative medicine. Here, delivered synthetic nanoparticles reprogram certain immune cell populations based on their physicochemical properties and not by an active pharmaceutical ingredient. Nanoparticles will provide a platform that limits acute inflammation and tissue destruction, at a favorable risk-benefit ratio, leading to a pro-regenerative microenvironment that supports regeneration and functional recovery. This platform may have applications to not only trauma but potentially other inflammatory diseases.

During a spinal cord injury (SCI), an initial trauma, such as a direct cut or blow to the spine, is followed by secondary injury, which is initiated by mitochondrial oxidative stress, an increase in reactive oxygen species, decrease in ATP production, and eventually further nerve death. It is hypothesized that if fresh mitochondria are delivered cytosolically to cells, it would be possible to rescue the tissue from this exacerbated injury.  To achieve this specific delivery, a thermo-gelling polymeric hydrogel containing curcumin-loaded nanogels has been proposed to deliver live mitochondria to the site of SCI. Curcumin, due to its antioxidant properties, has been incorporated into poly (beta-amino ester) (PBAE) nanogels to maintain mitochondrial homeostasis and thus prolong mitochondrial viability in an extracellular environment. 

Iron oxide nanoparticles have been widely studied for biomedical and environmental applications. Iron oxide nanoparticles (IONPs) can produce reactive oxygen species (ROS) through Fenton reaction [52] and previous research from our lab demonstrated that the formation of ROS can be further enhanced by the application of an alternating magnetic field (AMF) [53]. One application of interest is in the enhanced degradation of bisphenol A (BPA) using IONPs and AMF exposure.  BPA is one of the endocrine disrupting compounds which has been widely used as raw material for the manufacture of polycarbonate, flame retardants, epoxy resins, etc. and is commonly found in plastic bottles, cans, food containers, adhesives and dental fillings [54-56].  It is known that BPA has an estrogenic activity which can lead to animal female precocious and hyperplasia of prostate, and it has been also been reported to increase the occurrence of several diseases including leukemia, ovarian cancer, and embryonic malformation [54]. While biodegradation of BPA by microorganism requires long times, the Fenton reaction with the formation of ROS has been shown to increase the degradation rate of BPA into carbon dioxide, water, or biodegradable by-products [56].  In this project, the REU student will learn to synthesize IONPs and to characterize their physicochemical properties. The REU students will study the kinetics of BPA degradation via the Fenton process induced by functionalized IONPs under various exposure to AMF and investigate the impact of IONP surface functionalization, as well as other factors such as pH, initial concentration of H2O2 and nanoparticle concentration.

This project is motivated by the high demand for affordable high-performance therapeutic proteins. Among the therapeutic proteins, interferons (IFNs) are particularly important.1. They are critical in our fight against various infectious diseases, including COVID-192-5 and hepatitis6, 7. IFN-β-1b expressed by Escherichia coli is more attractive to be developed into an affordable high-performance form if we could address their low solubility and aggregation during the production and storage and enhance their blood stability and circulation half-life without sacrificing the bioactivity. One used technologies is to conjugate IFN-β-1b with synthetic hydrophilic polymers such as polyethylene glycol (PEG).8-11 However, the attached PEG chains decrease the bioactivity of IFNs and trigger an immune response.12-15 Zwitterionic materials emerge as a new technology improve the protein stability without sacrificing activity.16, 17 However, little is understood about the related mechanisms. We propose to computationally investigate the interactions between zwitterionic peptides and proteins and design zwitterionic peptides that can enhance protein stability without sacrificing their activities. The REU student will predict the structure of zwitterionic peptides and protein-peptide conjugates using computational tools such as Rosetta and AlphaFold and investigate the conformation, flexibility and solvation of the zwitterionic peptide and protein-peptide conjugates using molecular dynamics simulations.

  1. https://www.businesswire.com/news/home/20191114005524/en/Global-Interferons-Market-2019-2023-Evolving-Opportunities-Bayer.
  2. Lee, J. S.; Park, S.; Jeong, H. W.; Ahn, J. Y.; Choi, S. J.; Lee, H.; Choi, B.; Nam, S. K.; Sa, M.; Kwon, J.-S.; Jeong, S. J.; Lee, H. K.; Park, S. H.; Park, S.-H.; Choi, J. Y.; Kim, S.-H.; Jung, I.; Shin, E.-C., Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Science Immunology 2020, 5 (49), eabd1554.
  3. Hung, I. F.-N.; Lung, K.-C.; Tso, E. Y.-K.; Liu, R.; Chung, T. W.-H.; Chu, M.-Y.; Ng, Y.-Y.; Lo, J.; Chan, J.; Tam, A. R.; Shum, H.-P.; Chan, V.; Wu, A. K.-L.; Sin, K.-M.; Leung, W.-S.; Law, W.-L.; Lung, D. C.; Sin, S.; Yeung, P.; Yip, C. C.-Y.; Zhang, R. R.; Fung, A. Y.-F.; Yan, E. Y.-W.; Leung, K.-H.; Ip, J. D.; Chu, A. W.-H.; Chan, W.-M.; Ng, A. C.-K.; Lee, R.; Fung, K.; Yeung, A.; Wu, T.-C.; Chan, J. W.-M.; Yan, W.-W.; Chan, W.-M.; Chan, J. F.-W.; Lie, A. K.-W.; Tsang, O. T.-Y.; Cheng, V. C.-C.; Que, T.-L.; Lau, C.-S.; Chan, K.-H.; To, K. K.-W.; Yuen, K.-Y., Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet 2020, 395 (10238), 1695-1704.
  4. Zhang, Q.; Bastard, P.; Liu, Z.; Le Pen, J.; Moncada-Velez, M.; Chen, J.; Ogishi, M.; Sabli, I. K. D.; Hodeib, S.; Korol, C.; Rosain, J.; Bilguvar, K.; Ye, J.; Bolze, A.; Bigio, B.; Yang, R.; Arias, A. A.; Zhou, Q.; Zhang, Y.; Onodi, F.; Korniotis, S.; Karpf, L.; Philippot, Q.; Chbihi, M.; Bonnet-Madin, L.; Dorgham, K.; Smith, N.; Schneider, W. M.; Razooky, B. S.; Hoffmann, H.-H.; Michailidis, E.; Moens, L.; Han, J. E.; Lorenzo, L.; Bizien, L.; Meade, P.; Neehus, A.-L.; Ugurbil, A. C.; Corneau, A.; Kerner, G.; Zhang, P.; Rapaport, F.; Seeleuthner, Y.; Manry, J.; Masson, C.; Schmitt, Y.; Schlüter, A.; Le Voyer, T.; Khan, T.; Li, J.; Fellay, J.; Roussel, L.; Shahrooei, M.; Alosaimi, M. F.; Mansouri, D.; Al-Saud, H.; Al-Mulla, F.; Almourfi, F.; Al-Muhsen, S. Z.; Alsohime, F.; Al Turki, S.; Hasanato, R.; van de Beek, D.; Biondi, A.; Bettini, L. R.; D’Angio, M.; Bonfanti, P.; Imberti, L.; Sottini, A.; Paghera, S.; Quiros-Roldan, E.; Rossi, C.; Oler, A. J.; Tompkins, M. F.; Alba, C.; Vandernoot, I.; Goffard, J.-C.; Smits, G.; Migeotte, I.; Haerynck, F.; Soler-Palacin, P.; Martin-Nalda, A.; Colobran, R.; Morange, P.-E.; Keles, S.; Çölkesen, F.; Ozcelik, T.; Yasar, K. K.; Senoglu, S.; Karabela, Ş. N.; Gallego, C. R.; Novelli, G.; Hraiech, S.; Tandjaoui-Lambiotte, Y.; Duval, X.; Laouénan, C.; Snow, A. L.; Dalgard, C. L.; Milner, J.; Vinh, D. C.; Mogensen, T. H.; Marr, N.; Spaan, A. N.; Boisson, B.; Boisson-Dupuis, S.; Bustamante, J.; Puel, A.; Ciancanelli, M.; Meyts, I.; Maniatis, T.; Soumelis, V.; Amara, A.; Nussenzweig, M.; García-Sastre, A.; Krammer, F.; Pujol, A.; Duffy, D.; Lifton, R.; Zhang, S.-Y.; Gorochov, G.; Béziat, V.; Jouanguy, E.; Sancho-Shimizu, V.; Rice, C. M.; Abel, L.; Notarangelo, L. D.; Cobat, A.; Su, H. C.; Casanova, J.-L., Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020, eabd4570.
  5. Sallard, E.; Lescure, F.-X.; Yazdanpanah, Y.; Mentre, F.; Peiffer-Smadja, N., Type 1 interferons as a potential treatment against COVID-19. Antiviral Research 2020, 178, 104791.
  6. Davis, G. L.; Balart, L. A.; Schiff, E. R.; Lindsay, K.; Bodenheimer, H. C.; Perrillo, R. P.; Carey, W.; Jacobson, I. M.; Payne, J.; Dienstag, J. L.; VanThiel, D. H.; Tamburro, C.; Lefkowitch, J.; Albrecht, J.; Meschievitz, C.; Ortego, T. J.; Gibas, A., Treatment of Chronic Hepatitis C with Recombinant Interferon Alfa. New England Journal of Medicine 1989, 321 (22), 1501-1506.
  7. Konerman, M. A.; Lok, A. S., Interferon treatment for hepatitis B. Clinics in liver disease 2016, 20 (4), 645-665.
  8. Immordino, M. L.; Dosio, F.; Cattel, L., Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomed 2006, 1 (3), 297-315.
  9. Jevševar, S.; Kunstelj, M.; Porekar, V. G., PEGylation of therapeutic proteins. Biotechnology Journal 2010, 5 (1), 113-128.
  10. Larson, N.; Ghandehari, H., Polymeric Conjugates for Drug Delivery. Chemistry of Materials 2012, 24 (5), 840-853.
  11. Herzberger, J.; Niederer, K.; Pohlit, H.; Seiwert, J.; Worm, M.; Wurm, F. R.; Frey, H., Polymerization of Ethylene Oxide, Propylene Oxide, and Other Alkylene Oxides: Synthesis, Novel Polymer Architectures, and Bioconjugation. Chemical Reviews 2016, 116 (4), 2170-2243.
  12. Wang, X. Y.; Ishida, T.; Kiwada, H., Anti-PEG IgM elicited by injection of liposomes is involved in the enhanced blood clearance of a subsequent dose of PEGylated liposomes. J Control Release 2007, 119 (2), 236-244.
  13. Hsieh, Y. C.; Wang, H. E.; Lin, W. W.; Roffler, S. R.; Cheng, T. C.; Su, Y. C.; Li, J. J.; Chen, C. C.; Huang, C. H.; Chen, B. M.; Wang, J. Y.; Cheng, T. L.; Chen, F. M., Pre-existing anti-polyethylene glycol antibody reduces the therapeutic efficacy and pharmacokinetics of PEGylated liposomes. Theranostics 2018, 8 (11), 3164-3175.
  14. Ganson, N. J.; Povsic, T. J.; Sullenger, B. A.; Alexander, J. H.; Zelenkofske, S. L.; Sailstad, J. M.; Rusconi, C. P.; Hershfield, M. S., Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer. J Allergy Clin Immunol 2016, 137 (5), 1610-1613 e7.
  15. Zhang, P.; Sun, F.; Liu, S.; Jiang, S., Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation. J Control Release 2016, 244, 184-193.
  16. White, A. D.; Nowinski, A. K.; Huang, W.; Keefe, A. J.; Sun, F.; Jiang, S., Decoding nonspecific interactions from nature. Chemical Science 2012, 3 (12), 3488-3494.
  17. White, Andrew D.; Huang, W.; Jiang, S., Role of Nonspecific Interactions in Molecular Chaperones through Model-Based Bioinformatics. Biophysical Journal 2012, 103 (12), 2484-2491

Skin is a natural barrier protecting our bodies from the environment but can be damaged by burns or cuts. In many cases, the bodies’ response is sufficient to heal the wound but if the tissue damage is severe enough additional treatment might be necessary. Wound dressings have been found to provide significant benefits in protecting the wound from mechanical trauma and infection. One way to improve on existing designs is to design tougher biocompatible materials.  Polycarbonates have been used in biological applications due to their biocompatibility and biodegradability. Upon hydrolytic degradation, polycarbonates produce small molecular alcohols and carbon dioxides, which are non-toxic and can be rapidly secreted. In this work, the REU student will work on synthesizing new polycarbonate polymers and create gels using established methods. The REU student will test swelling in water, water transport rate through the material, and the mechanical properties of the gels to assess their performance as a wound dressing.

Hydrogels are used in a variety of uses from tissue engineering to wearable electronics applications.  The key to these materials being capable of working in many applications, is the versatility mechanical properties and chemical identity. To meet the challenges of developing tough hydrogels for a broad range of applications, we propose to design and test new polycarbonate structures. Polycarbonates have been known to have the necessary biocompatibility and biodegradability, by degrading into alcohols and carbon dioxide. This type of material system is beneficial because it is a single polymer system approach, rather than common double and interpenetrating networks. In this work, the REU student will synthesize polycarbonates with varying chemical properties and validate the polymers’ structure. The REU student will then create crosslinked networks and test both swollen and unswollen samples for their toughness and mechanical properties.

Mentors: Givens and Chaplin

A protein corona forms immediately when nanoparticles are placed in biological environments.1, 2 These coronae can mask the external surface of the nanoparticle, thus impacting how we translate results for pharmacokinetic studies.3 One way we can improve this translation, is by generating an artificial corona, similar to what we would expect to see in vivo for characterization and cell culture investigations. The student will explore the protein corona on drug delivery polymeric nanoparticles assuming they are injected intravenously. The student will quantify protein adhered to the particle surface, and will evaluate if the corona alters properties of the nanoparticle. The student will compare the release rate of the drug within the particle in the presence and absence of a corona. The REU student will also compare the uptake of fluorescently-labeled particles with and without coronae in tumor models.

  1. Zhang, Y.; Wu, J. L. Y.; Lazarovits, J.; Chan, W. C. W., An Analysis of the Binding Function and Structural Organization of the Protein Corona. J Am Chem Soc 2020, 142 (19), 8827-8836.
  2. Berrecoso, G.; Crecente-Campo, J.; Alonso, M. J., Unveiling the pitfalls of the protein corona of polymeric drug nanocarriers. Drug Deliv Transl Res 2020, 10 (3), 730-750.
  3. Alberg, I.; Kramer, S.; Schinnerer, M.; Hu, Q.; Seidl, C.; Leps, C.; Drude, N.; Mockel, D.; Rijcken, C.; Lammers, T.; Diken, M.; Maskos, M.; Morsbach, S.; Landfester, K.; Tenzer, S.; Barz, M.; Zentel, R., Polymeric Nanoparticles with Neglectable Protein Corona. Small 2020, 16 (18), e1907574

Primary Advisor: Dr. Martha E. Grady – College of Engineering – Mechanical Engineering

Implant devices account for approximately one-fourth of hospital-acquired infections. In spite of aggressive antibiotic use, the eradication of established implant-associated infections remains difficult because of the adhesion of a population of robust, viable, and continuously expanding bacteria in biofilms. The goal of this project is to provide physical insight into biofilm infections and their treatments through stiffness and mesh size measurements. Diffusion and power law behavior of infiltrating substances in biofilms is likely dependent on a multitude of factors, including mesh size, biofilm density, probe size, biofilm depth, biofilm composition, biofilm maturity, and other environmental conditions. This work has important implications for designing biofilm penetrating particles and drugs, as a current limiting factor in antimicrobial agent efficacy is their restricted diffusion that results in sub-lethal drug exposure.

Inflammation plays a vital role in conditions that affect bone formation, resorption, and fracture healing. A growing body of evidence supports the indispensable role of macrophages in bone regeneration and fracture healing. Macrophages assume discrete functional phenotypes that promote the various characteristics of the healing process, including osteogenesis and angiogenesis. It has been hypothesized that trauma-induced immune dysregulation is the primary cause of chronic nonunion and delayed union of bone fracture. This project aims to develop matrices with customizable viscoelastic mechanics to regulate macrophage phenotype and function towards bone regeneration. Macrophages respond to the changes in ECM mechanics through actin-cytoskeletal reorganization and nuclear deformation. The scientific premise is that the substrate mechanics can be tuned to manipulate the cytoskeletal of macrophages to alter gene expression profiles and differentiation programs. This is an interdisciplinary research project that includes aspects of material science, mechanobiology, and medicine. The REU student will learn to design and synthesize various carbohydrate and protein-based biopolymer matrices and characterize their physical and biological properties using murine macrophages. The student will have the opportunity to learn mechanical testing modalities, light and electron microscopy, mammalian cell culture techniques, quantitative spectroscopy, gene and protein expression assays, and an array of biochemical assays as part of the training.

When functioning correctly, the immune system is a powerful force actively preventing disease and neoplastic development through immunosurveillance. Cancer cells evade the immune system through immunoediting, and begin recruiting anti-inflammatory macrophages, referred to as tumor-associated macrophages (TAM). TAM infiltration in tumors is an established biomarker of tumor aggressiveness and tumor resistance to therapy. Magnetic resonance imaging (MRI) based cell tracking techniques have proven successful in monitoring immune cell migration to the foci of inflammation in different pathologies, including cancer. This project will consist  in developing MRI cell tracking methods for ex vivo and in situ labeling of cells with iron oxide or fluorine imaging reagents. We will to develop non-invasive MRI imaging methods that could serve as a prognostic biomarker of therapy efficacy or tumor recurrence.  We will deliver iron oxide (Ferumoxytol) nanoparticles intravenously to immunocompromised mice bearing subcutaneous human head and neck tumors. As a result, systemic monocytes, macrophages and TAM will be labeled, and we will quantify longitudinal MR signal changes following radiation therapy or programmed cell death protein-1 (PD-1) immunotherapy. The REU student will learn cell culture and labeling techniques for subsequent MR imaging of infused cells. The student will also learn about animal models and experimentation, specifically mouse handling and tumor injection. The REU student will receive training in MRI safety and accompany the PI during the MRI experiments.

Lignin, which is the second most abundant natural polymer, is a significant byproduct of agricultural/forestry processing and biomass conversion.  While most lignin byproduct is currently combusted as fuel, lignin is a valuable potential resource for the sustainable production of bulk aromatic compounds traditionally derived from petroleum, as well as specialized therapeutics and advanced materials.  The inability to selectively recover lignin small molecules when lignin is chemically deconstructed limits its commercial potential.  The formation of host-guest complexes of lignin monomers and dimers with cyclodextrins (CDs) has the potential to address these limitations through the selective capture of lignin small molecules using CD-functionalized materials.  Some lignin-derived small molecules form host-guest inclusion complexes with CDs, residing in its hydrophobic core.  Our team has developed to functionalize porous silica particles with accessible CDs which capture lignin-like small molecules.  The REU student will synthesize CD-functionalized nanoporous silica particles using techniques established in our lab and measure uptake and selectivity of lignin monomers and dimers.  Techniques to alter the size of the nanopores will be used to optimize the amount and accessibility of CD attached, as measured using fluorescent probe molecules and tested in model lignin deconstruction mixtures.

Microcystin-LR (MC-LR) is among the most problematic algal toxins in America [1], with several outbreaks and appearances in fresh water supplies in recent years. Microcystins are cyclic peptides with seven amino acids, and the congener with leucine (L) at position 2 and Arginine (R) at position 4 is known as MC-LR [2], which makes common methods for management of MC-LR to have significant drawbacks or limited effectiveness [3]. Enzymatic remediation allows an engineered catalysis system to potentially destroy these toxins. To investigate enzymatic degradation of algal toxins, a fusion enzyme with active sites is proposed for multiple substrates. The REU students will test the enzyme-mediated catalysis to target microcystin degradation and removal from water. The focus will be on an enzyme trio, microcystin leucine arginine (MlrA, MlrB, and MlrC), and MC-LR as exemplary microcystin remediation [4-8]. The proposed biocatalytic degradation is shown in Figure 1. Preliminary results demonstrate that bacterium lysate with overexpressed MlrA will linearize MC-LR, which is a key step in MC-LR degradation. The overall goal of this research project is to work toward membrane-mediated biocatalysis, an innovative approach where membranes provide structural support and physical separation of the toxins, while enzymes enable their catalytic degradation.

  1. Fang, Y., Y. Zhang, W. Ma, D.M. Johnson, and Y.-p. Huang, Degradation of microcystin-lr in water: Hydrolysis of peptide bonds catalyzed by maghemite under visible light. Applied Catalysis B: Environmental, 2014. 160-161: p. 597-605.
  2. Miao, H.-F., F. Qin, G.-J. Tao, W.-Y. Tao, and W.-Q. Ruan, Detoxification and degradation of microcystin-lr and -rr by ozonation. Chemosphere, 2010. 79(4): p. 355-361.
  3. Eke, J., P. Wagh, and I.C. Escobar, Ozonation, biofiltration and the role of membrane surface charge and hydrophobicity in removal and destruction of algal toxins at basic ph values. Separation and Purification Technology, 2017.
  4. Brinkman, D.B., David, Microcystinase in Handbook of proteolytic enzymes2013.
  5. Dziga, D., G. Zielinska, B. Wladyka, O. Bochenska, A. Maksylewicz, W. Strzalka, and J. Meriluoto, Characterization of enzymatic activity of mlrb and mlrc proteins involved in bacterial degradation of cyanotoxins microcystins. Toxins (Basel), 2016. 8(3).
  6. Idroos, F.S., Manage, Pahmalal, Bioremediation of microcystins by two native bacteria: Bacillus cereus and rahnella aquatilis. Asian Jr of Microbiol. Bioech. Env. Sc. 20(3): p. 24-32.
  7. Zhang, J., Q. Lu, Q. Ding, L. Yin, and Y. Pu, A novel and native microcystin-degrading bacterium of sphingopyxis sp. Isolated from lake taihu. Int J Environ Res Public Health, 2017. 14(10).
  8. Somdee, T., M. Thunders, J. Ruck, I. Lys, M. Allison, and R. Page, Degradation of [dha7]mc-lr by a microcystin degrading bacterium isolated from lake rotoiti, new zealand. ISRN Microbiology, 2013. 2013: p. 1-8

Gene delivery polymers must be designed to perform numerous functions [1]. In particular, the materials must bind and condense DNA to protect it from extra- and intracellular nucleases and to facilitate cellular internalization. Yet, such materials must release their DNA cargo to allow transcription [2]. Numerous relatively efficient gene delivery materials are being investigated, but the mechanisms by which they perform the necessary functions are unknown [3]. Design of more efficient materials requires understanding of polymer-DNA interactions, the formation of polymer/DNA complexes (polyplexes) [4, 5], and how their structures relate to intracellular trafficking and gene delivery efficiency [6-8]. In this project, the REU student will investigate a series of zwitterionic polyethylenimine derivatives (zPEI) in which primary amines on the polymer are modified with negatively charged succinate moieties. We have demonstrated that zPEIs are remarkably efficient at transfecting a number of cell lines in the presence of serum.[9, 10] The REU student will investigate the applications of these polymers for delivery of nucleic acids, including CRISPR/Cas9 and mRNA, to a number of difficult-to-transfect cell lines and primary mesenchymal stem cells. Furthermore, because the mechanism by which succinylation leads to efficient in-serum transfection remains unclear, students will examine explanatory hypotheses such as decreased binding of serum proteins by and enhanced intracellular decomplexation of zPEI-containing polyplexes

  1. Pack, D.W., et al., Design and development of polymers for gene delivery. Nature Reviews Drug Discovery, 2005. 4: p. 581-593.
  2. Gabrielson, N.P. and D.W. Pack, Acetylation of polyethylenimine enhances gene delivery via weakened polymer/DNA interactions. Biomacromolecules, 2006. 7(8): p. 2427-2435.
  3. Lachelt, U. and E. Wagner, Nucleic Acid Therapeutics Using Polyplexes: a Journey of 50 Years (and Beyond). Chemical Reviews, 2015. 115: p. 11043-11078.
  4. An, M., et al., Role of pH on the Compaction Energies and Phase Behavior of Low Generation PAMAM-DNA Complexes. Macromolecules, 2014. 47(24): p. 8768-8776.
  5. An, M., S.R. Parkin, and J.E. DeRouchey, Intermolecular forces between low generation PAMAM dendrimer condensed DNA helices: role of cation architecture. Soft Matter, 2014. 10(4): p. 590-599.
  6. Gabrielson, N.P. and D.W. Pack, Efficient polyethylenimine-mediated gene delivery proceeds via a caveolar pathway in HeLa cells. Journal of Controlled Release, 2009. 136(1): p. 54-61.
  7. Lazebnik, M., R.K. Keswani, and D.W. Pack, Endocytic Transport of Polyplex and Lipoplex siRNA Vectors in HeLa Cells. Pharmaceutical Research, 2016. 33(12): p. 2999-3011.
  8. Lazebnik, M. and D.W. Pack, Rapid and facile quantitation of polyplex endocytic trafficking. Journal of Controlled Release, 2017. 247: p. 19-27.
  9. Uddin, N., et al., Enhanced Gene Delivery and CRISPR/Cas9 Homology-Directed Repair in Serum by Minimally Succinylated Polyethylenimine. Molecular Pharmaceutics, 2021.
  10. Warriner, L.W., et al., Succinylated Polyethylenimine Derivatives Greatly Enhance Polyplex Serum Stability and Gene Delivery In Vitro. Biomacromolecules, 2018. 19(11): p. 4348-4357.

Of the classes of compounds found in biorefinery wastewater, melanoidins have severe environmental  impacts due to visible light absorption (brown color), slow biodegradation, and acidity.1  They are complex mixtures formed by the reaction of proteins and carbohydrates that resist traditional wastewater treatment methods such as anaerobic digestion.  This project will utilize surfactant-templated metal oxide materials with tunable mesopores2-4 and functionalized surfaces for selective biomolecule adsorption5-13 to address melanoidin contaminants.  Specifically, TiO2 is hypothesized serve as a site for binding melanoidins through chelation,14-16 and additional functional groups can be introduced to the surface of mesoporous TiO2 to aid selective binding.  After adsorption, we will measure the photocatalytic partial oxidation of melanoidins under environmentally friendly (aqueous, near-ambient temperature) conditions to produce low molecular weight products.  This project will allow us to remove a common fermentation process byproduct, while also moving towards value-added products from biorefinery waste streams.

The synthesis and applications of responsive, multifunctional materials and membranes for environmental and bio-related use requires a high level of control of both the characteristics of the base polymeric or inorganic support layer, as well as, its corresponding surface properties. The special features for membrane processes that make them attractive for industrial applications are their compactness, ease of fabrication, operation, and modular design. Although membrane processes such as, Reverse Osmosis, Nanofiltration, Ultrafiltration, and Microfiltration have provided many successful applications ranging from high quality water production to material recovery, but incorporation of nanostructured aspects with tunable properties (learning from life sciences, such as enzymes, and porins)) in membranes has added immense value in the area of separations, reactions, water applications, and green synthesis. The use of macromolecules, such as, poly-acrylic acid (PAA), poly-glutamic acid (PLGA) provide pH responsive behavior through helix-coil transitions, whereas poly-N-isopropylacrylamide (pNIPAAm) provides temperature responsive behavior. Further, one can synthesize catalytic metal nanoparticles in the functionalized membrane for water decontamination applications.

2019

Primary Advisor: Dr. Brad Berron – College of Engineering – Chemical and Material Engineering 

Lab Mentor:  Kara Davis – College of Engineering – Chemical and Material Engineering

Ischemic heart disease, often caused by acute myocardial infarction (AMI), is the leading cause of morbidity and mortality in the developed world. Despite significant advances in revascularization techniques, millions of patients with AMI progress to suffer ischemic cardiomyopathy and heart failure. The use of therapeutic stem cells for cardiac regeneration has gained traction in animal research and translational human studies, however, low cell engraftment and retention after transplantation has limited cardiac recovery. To address the issue of cell retention, our lab has developed adhesive and biodegradable gelatin-based cellular coatings. Our recent in vivo study showed the gelatin-based cell coating enhances therapeutic cell retention in the ischemic myocardium without significantly impacting cell viability or metabolism. However, the adhesive properties of the gelatin coating to the ischemic myocardium is not fully understood.

Our goal is to determine the adhesion mechanism and strength of the gelatin coated therapeutic stem cells to the heart tissue. We plan to determine if the GelMA coatings are adhering through collagen specific integrins or heart extracellular matrix (ECM) to improve cell retention. Custom microarrays of cell integrins and heart ECM will be created on epoxy coated slides using our established printing protocols. Both gelatin coated and uncoated therapeutic cells will be allowed to settle onto the arrays and a microfluidic device connected to a syringe pump will shear the cells at varying rates, and the number of retained cells will be determined by optical microscopy. Ability of coated cells to adhere to the microarray spots when subject to shear will allow us to determine where the gelatin coating is adhering most strongly to and the ability of the adhesion to withstand blood flow in the heart.

Primary Advisor: Prof. D. Bhattacharyya, Chemical and Materials Engineering

Co-Advisor: Prof. D.Y. Kim, Chemistry

Graduate student mentors: Ashish Aher 

Membranes are finding broad applications in water treatment and many other areas. These range from removal of dissolved inorganics/organics from water to selective separations. Graphene-based membranes with imbedded polyelectrolytes bring advanced approaches in selective separations from water and other solvents. This project will allow synthesis and evaluation of new types of synthetic membranes and establishment of membrane transport parameters through flux-pressure correlations.  The REU student will work on: (1) synthesis of GO (graphene oxide) membranes, (2) synthesis of GO-polyelectrolyte composite membranes, and quantify membrane surface charge and contact angle information, (3) quantify flux and separation behavior with salts and model organics.  Advanced characterization will include use of zeta potential and contact angle analyzer, SEM/TEM to look at membrane structures.  Ashish Aher, a senior PhD student, will be the graduate student mentor for membrane synthesis and experimental aspects.

Primary Advisor: Dr. Jason DeRouchey – College of Arts & Sciences - Chemistry 

Lab Mentor:  Kanthi Nuti – College of Arts & Sciences - Chemistry

Alzheimer’s disease (AD) is estimated to affect one in ten elderly individuals in the United States. Currently 5.8 million Americans are living with Alzheimer’s and it is projected by 2050 this number will rise to nearly 14 million. AD is characterized by deposition of plaques and neurofibrillary tangles in effected brain tissue, resulting in cognitive decline and ultimately death. Plaques result from aggregation of the Aβ peptide, and tangles from aggregation of hyperphosphorylated forms of the microtubule-binding protein tau. Tau is one of many proteins involved in neurodegenerative diseases that have been observed recently to mingle in liquid droplets. In vivo, the process of liquid-liquid phase separation (LLPS) leads to membraneless organelles. Currently, very little is known as to the function of these membraneless organelles in vivo. They have been proposed to lead to formation of toxic aggregates or disrupt essential cellular functions by recruitment of specific molecules within the organelles. The goal of LeeLee Sands research is to both study the formation of the tau droplets under a variety of conditions as well as characterize the concentration and transport behavior of different probe molecules in the droplets using fluorescence correlation spectroscopy (FCS).  Although most experimental methods do not allow for the direct measurement of diffusion coefficients in turbid media, it has been shown that FCS effectively measures the dynamic processes of small molecules in polymeric systems, hydrogels, and tissues. Tau droplet formation will be explored under various conditions including salt, pH and protein truncations for their effect on particle recruitment as well as particle transport properties within the droplets.

Primary Advisor:  Dr. Tom Dziubla – College of Engineering – Chemical & Materials Engineering

Co-Advisor:  Dr. Patrick Marsac – College of Pharmacy

Lab Mentor:  Kelley Wiegman – College of Engineering – Chemical & Materials Engineering

The current approach to pharmaceutical manufacturing is filled with legacy-based approaches that, while individually relatively easy to implement, require extensive development for each newly proposed API. Indeed, given the variability and complexity of these processes, extensive trial and error is still employed to create an appropriately scalable approach that meets the specific formulation and drug delivery needs.  While there has been recent strides in continuous manufacturing for tablets, predicting and managing the flow of solids remains a challenging problem.  The film-based formulation approach side steps the piecemeal process train of traditional pharmaceutical approaches and combines upfront modeling and controls to streamline new formulation development.  The technology will permit advanced solutions to tuning drug release rates, drug stabilization, and dose flexibility, while allowing for extemporaneous preparation of such products in the clinic with line-of-sight to robust continuous manufacturing.   In this work, students will apply Fused Deposition tablet Printing as a means of generating fundamental parameters to work toward establishing a holistic predictive model for pharmaceutical manufacturing. This film-based approach permits strong dimensional control in the thickness length scales relevant in solid dosage form organization. By regulating all transport and phase behavior to a one-dimensional layer, predictive modeling and behavior is greatly simplified, streamlining the manufacturing and scaling process and enabling adaptive clinical design while avoiding costly scale-up paradigms.

Primary Advisor: Dr. Martha E. Grady – College of Engineering – Mechanical Engineering

Lab Mentor: J. D. Boyd – College of Engineering – Mechanical Engineering

Implant devices account for approximately one-fourth of hospital-acquired infections. In spite of aggressive antibiotic use, the eradication of established implant-associated infections remains difficult because of the adhesion of a population of robust, viable, and continuously expanding bacteria in biofilms. For this reason, measuring the propensity for biofilm adhesion to a device surface is crucial in evaluating the safety of medical devices. Current methods to explore biological adhesion mechanisms rely solely on single interactions of a bacterium with a substrate surface. Biofilm attachment strength, however, is a macroscale phenomenon, highlighting the need for effective approaches to evaluate larger interfacial areas. We seek develop a macroscale approach to measure adhesion strength of biofilms on medical device surfaces. Our goal is to determine what factors including surface roughness, surface functionalization, membrane tension, or nutrient access, contribute most to strong biofilm adhesion on these device surfaces. We aim to decrease propensity for biofilm-forming infections by developing protocols for rational selection of device surfaces based on our results.

Eric Grulke, Chemical & Materials Engineering

Bob Yokel, Pharmaceutical Sciences

Background

Cerium dioxide, a metal oxide with antioxidant capabilities, is being considered for treating a variety of conditions, including cancer. Our research team has measured the biodistribution of injected nanoceria in the body, and once in situ, is stoichiometrically retained for as much as 90 days. We have measured pro- and anti-oxidant responses over long periods of time but want to develop a method that can provide rapid response screening for nanoceria effects on cancer cells.

Our approach 

Macrophages are one of the body’s defenses, surrounding foreign objects such as nanoparticles, and trying to render them inert. Caco-2 cells are well-known models for cancer studies and can be stimulated to pro- or anti-inflammatory states. In pro-inflammatory states, they are polarized into phenotype states that release reactive species and inflammatory agents to fight pathogens. In anti-inflammatory states (alternatively activated), the phenotypes lead to cellular processes that facilitate tissue repair. Our basic approach is to produce three phenotypes of Caco-2 cells, a control that is untreated (M0), a pro-inflammatory activated phenotype (M1), and an anti-inflammatory activated phenotype (M2). These will be challenged by direct contact nanoceria in in vitro studies. Prior research studies have found qualitative differences in cell and nuclei morphologies for such studies, but there have been no quantitative studies on morphologies that could lead to metrics for direct linkages between macrophage morphology in contact with nanoparticles.

Our working hypothesis

In related work, we have developed methods for quantitative comparisons between particle size and shape descriptor distributions using several statistical methods. Electron microscope images or confocal microscope images are captured using open-source image analysis programs (ImageJ, NIH) and descriptor distributions are analyzed further by statistical methods. The image capture, descriptors, and statistics tools are described in a document likely to become an ISO International Standard, developed by the ISO/TC229 Nanotechnologies committee. 

Our working hypothesis: there are direct linkages between differentiated size and shape descriptor distributions of the three Caco-2 cell phenotypes of two cell features, the cell boundary and the cell nucleus, at two different growth times, 6 and 12 hours after activation, directly linking these differences to the mode of action of nanoceria in each case. Note: for each descriptor, there are nine possible combinations: 3 phenotypes, 2 cell features, and 2 times. If successful, the work should lead to a rapid, early detection method for the quantitative effects on metal oxide nanoparticles on macrophase size and shape distributions, which correspond to pro- or anti-oxidant behavior of macrophages.

 

Primary Advisor: Dr. J. Zach Hilt – College of Engineering - Chemical and Materials Engineering

Co-Advisor: Dr. Thomas D. Dziubla – College of Engineering - Chemical and Materials Engineering

Lab Mentor:  Molly Frazar – College of Engineering - Chemical & Materials Engineering

Stimuli-responsive polymers can undergo rapid physical transitions in response to small environmental changes, such as temperature or pH. Thermoresponsive polymers can exhibit a reversible transition around their lower critical solution temperature (LCST) in which the polymer becomes hydrophilic below the LCST and hydrophobic above the LCST, and this unique response has led to these materials being applied in numerous biomedical and environmental remediation applications.  For example, a dissolved thermoresponsive polymer could easily be made to “collapse” into a precipitated state by inducing a small temperature change, and this process can be used as a smart flocculation technique, and it can potentially be employed for the removal of dissolved and non-dissolved contaminated species in aqueous medium (e.g., ground water, blood, etc.). This work will focus on synthesis of temperature responsive linear polymers that incorporate different functionalities such as fluorinated and/or cationic moieties. Their ability to bind various contaminants such as inorganic nanoparticles and per- and polyfluoroalkyl substances (PFAS) through temperature controlled flocculation studies will be investigated. Characterization of synthesized materials will be conducted in order to determine shifts in LCST and confirm successful incorporation of functional monomers (e.g, Fourier transform infrared spectroscopy).

Li, S., Liao, Y., Li, G., Li, Z., & Cao, Y. (2017). Flocculating and dewatering performance of

hydrophobic and hydrophilic solids using a thermal-sensitive copolymer. Water Science and Technology, 76(3), 694–704.

Zhang, D., Thundat, T., & Narain, R. (2017). Flocculation and dewatering of mature fine tailings using temperature-responsive cationic polymers. Langmuir, 33(23), 5900–5909.

Primary Advisor:  Dr. J. Zach hilt – College of Engineering – Chemical & Materials Engineering

Co-Advisor:  Dr. Tom Dziubla – College of Engineering – Chemical & Materials Engineering 

Lab Mentor:  Angela Gutierrez – College of Engineering – Chemical & Materials Engineering 

As human activity has increased around the globe, the Earth has been contaminated with a large number of toxic pollutants from multiple sources. Environmental contamination continues to burden human health through their accumulation in the human body and the numerous health issues they can cause. Over the past decade, engineered nanomaterials have found new applications as food additives to enhance texture, color, flavor, nutrient stability and packaging safety.  One possible new application of these materials is their use as an in vivo remediation strategy to reduce the burden of toxic contaminants in the human body, specifically the gastrointestinal (GI) tract.

The proposed project consists on the development of polymeric nanocomposites with high affinity for environmental contaminants that can bind and remove the presence of these pollutants in the GI tract. Magnetic nanocomposite microparticles (MNMs) will be developed to target persistent organic pollutants commonly present in humans. The capacity of the MNMs for binding contaminants along the GI tract will be evaluated as well as their stability throughout this process. Some of the variables to study include pH, temperature, and presence of other chemicals.

Primary Advisor: Dr. J. Zach Hilt – College of Engineering - Chemical and Materials Engineering

Co-Advisor: Dr. Thomas D. Dziubla – College of Engineering - Chemical and Materials Engineering 

Lab Mentor:  Molly Frazar – College of Engineering - Chemical & Materials Engineering 

The potential applications for magnetic nanoparticles (MNPs) in environmental and biomedical treatments is vast. The interaction of MNPs with magnetic fields offer an array of unique properties that can be exploited: (1) the MNPs can be controlled spatially with the use of magnets (2) alternating magnetic fields can be used to heat the particles (3) magnetic properties can also influence magnetic fields for use as contrast agents in magnetic resonance imaging (MRI).1 Modification of the surface chemistry of MNPs can mitigate some of the issues that can limit their use (e.g., dissolution, surface reactivity, etc.), and the introduction of a gold-shell coating is an attractive solution, as the gold coating can provide protection of the magnetic core to reduce corrosion, oxidation and aggregation.2 There are two routes that can be taken to obtain a gold shell: direct or indirect formation onto the magnetic core. The direct route can achieve a gold coating using MNPs that are in aqueous phase whereas the indirect route obtains gold coated MNPs by first attaching a “glue layer” to the magnetic core and subsequently forming the outer gold shell on top of the glue.1 This work seeks to investigate an array of methods for obtaining uniformly distributed MNPs that can be fully coated with a gold-shell layer of uniform thickness and roughness. Surface modification of the synthesized gold-shell magnetic nanoparticles (Au-MNPs) will be investigated through functionalization with polymer coatings and/or thiol groups. Additionally, characterization of the Au-MNPs will be performed via various techniques such as transmission and scanning electron microscopy, thermogravimetric analysis, and Fourier transform infrared spectroscopy. 

1 Moraes Silva, S., Tavallaie, R., Sandiford, L., Tilley, R. D., & Gooding, J. J. (2016). Gold coated magnetic nanoparticles: From preparation to surface modification for analytical and biomedical applications. Chemical Communications, 52(48), 7528–7540.

2 Goon, Ian Y., Leo M. H. Lai, May Lim, Paul Munroe, J. Justin Gooding, and Rose Amal. Fabrication

and Dispersion of Gold-Shell-Protected Magnetite Nanoparticles: Systematic Control Using Polyethyleneimine. Chemistry of Materials 21.4 (2009): 673-81.

Primary Advisor: Dr. Folami Ladipo – Chemistry Department

Co-Advisor: Dr. Barbara Knutson – College of Engineering - Chemical and Materials Engineering

Co-Advisor: Dr. Steve Rankin – College of Engineering - Chemical and Materials Engineering

Lab Mentor:  Folami Ladipo – Department of Chemistry

To reach the full potential of lignocellulosic biomass as a renewable resource for fuels and chemicals production, efficient processes must be developed to convert lignin and cellulosic biomass into small molecules that can be upgraded into fuel and/or chemicals streams. Glucose is the most abundant monosaccharide in cellulosic biomass hence the development of efficient catalytic processes for its conversion into chemicals and biofuels is highly desired. Glucose dehydration is a promising method for the synthesis of 5-hydroxymethylfurfural (HMF), an emerging bio-derived platform chemical that potentially could be used to produce a wide variety of high-value chemicals. We have found that aluminum complexes that contain easily modified bidentate (aminomethyl)phenolate ligands are very promising catalysts in ionic liquid (IL) solvents for glucose conversion into HMF (G2H reaction). However, both the HMF selectivity and yield need improvement . This project will investigate the reactivity of aluminum (aminomethyl)phenolate complexes with cocatalysts in imidazolinum-based ILs with glucose as well as sugar model compounds such as methylglyoxal and glycoaldehyde. These studies will help to elucidate the nature of the active catalyst in G2H reaction and reaction conditions best suited for creating a highly active and selective catalytic process.

Primary Advisor: Dr. Daniel Pack – Colleges of Pharmacy and Engineering – Pharmaceutical Sciences and Chemical and Materials Engineering 

Co-Advisor: Dr. Jason DeRouchey – College of Arts and Sciences - Chemistry

Lab Mentor:  Logan Warriner – College of Engineering - Chemical & Materials Engineering

We have recently demonstrated engineering of human cells to express a cluster of plant-derived enzymes that catalyze the biosynthesis of curcuminoids from tyrosine. Curcuminoids are potent antioxidants and are being investigated as treatments for a range of disease states including inflammation, ischemia, atherosclerosis, and neurodegenerative diseases. In addition, curcumin is a potent inhibitor of nuclear factor-kB (NF-kB) and enhances expression of p53, making curcuminoids potential chemotherapeutics. The effectiveness of curcuminoids as drugs is limited, however, by their poor oral bioavailability, low aqueous solubility, limited stability in physiological media, and rapid clearance from the blood. In-vivo biosynthesis of curcuminoids could overcome these limitations and provide for long-term curcuminoid therapy with a single treatment. In our work to date, the curcuminoid-producing enzymes were introduced into human cell lines by the transient transfection of plasmid cocktails. The goal of this project will be to generate cell lines stably expressing the enzymes at optimal levels using CRISPR/Cas9 to integrate the appropriate genes into the genome. We will quantify curcuminoid concentrations within the cells and in the growth medium by HPLC, investigate the antioxidant activity using a mitochondrial stress assay, and demonstrate the potential of curcuminoid biosynthesis to inhibit proliferation and migration of breast cancer cell lines in vitro.

Primary Advisor: Dr. Yinan Wei – College of Arts and Sciences – Chemistry

Lab Mentor:  Ankit Pandeya– College of Arts and Sciences – Chemistry

The fast-growing population of pathogenic bacteria that are resistant to multiple antimicrobials, coupled with the dwindling of the drug development efforts to establish new antimicrobials, made infection an increasingly lethal disease. No new class of antimicrobials has been brought to market in the past two decades, illustrated the intrinsic difficulty of discovering new compounds that can be developed into suitable antimicrobials. Much of current drug development effort has been focused on the modification of existing drugs and evading bacterial resistance. β-lactams are among the first class of compounds used in the treatment of infection, and thus resistance to β-lactams is wild spread. One mechanism conferring resistance to β-lactams is efflux by multidrug transporters such as the RND family efflux pump AcrAB-TolC. We hypothesize that modification of the β-lactam structure to avoid efflux will be a useful strategy to overcome efflux. Toward this end, we chose several β-lactams and modified a functionally non-essential amino group through biotinylation. The effect of biotinylation on the antimicrobial activity of these compounds will be tested both in a normal wild type strain and an efflux deficient strain. The change of the minimum inhibitory concentration will reveal the effect of modification in evading efflux. If proven successful, we will expand the idea to test the effect of biotinylation on other classes of compounds.

Primary Advisor: Dr. Guigen Zhang – College of Engineering – Biomedical Engineering

Co-Advisor/Lab Mentor: Dr. Yu Zhao – College of Engineering – Biomedical Engineering

Microfluidic technology has been intensively exploited in the past two decades for developing lab-on-chip devices. The device allows incorporation of different functionalities on a single chip for biological applications including in vitro diagnosis and drug screening, among others. What’s more, desired functionalities can be realized via selecting tools from an arsenal of techniques based on physical, chemical and biological processes. Among these techniques, magnetophoresis has attracted more attention recently because of the increasing research efforts in the development of novel magnetic nanoparticles for biomedical applications. To fully realize its potential in manipulating particles/cells, an integrative approach including both theoretical and experimental studies is needed.

Magnetophoresis is conventionally used for separation of particles based on the difference in magnetic properties between particle and medium. By constructing non-uniform magnetic field with proper setup of magnets, particles in medium can be pushed towards either weak magnetic field region when the permeability of particle is smaller than the medium (which is called negative magnetophoresis) or strong magnetic field region when the permeability of particle larger than the medium (which is called positive magnetiphoresis). Our modeling results based on numerical calculation of the magnetophoretic force on a particle have shown an unreported phenomenon in which the existence of permeability gradient will oppose the movement of particles towards weak field region under negative magnetophoresis. To test this idea, we plan to take advantage of the laminar flow characteristics in microfluidic channels. Y shaped channels can be used to create an interface by injection of two media with different permeability into separate inlets. Under the effect of diffusion, a field gradient will form at the interface and its magnitude depends on the flow rate as well as the permeability difference between two media. We expect that this REU experience will allow the student to perform experiments and investigate the influence of these factors on particle movement in a parametric manner. The obtained results will help validate the prediction from our modeling results.

2018

Primary Advisor: – Dr. Barbara Knutson- College of Engineering - Chemical & Materials Engineering

Co-Advisor: Dr. Stephen Rankin – College of Engineering - Chemical & Materials Engineering

Lab Mentor:  Mahsa Moradipour – College of Engineering - Chemical & Materials Engineering

 

Plants have a broad range of defenses to ensure their survival, including the production of antimicrobial compounds to protect them from microorganisms. Plant-based antimicrobials have the potential to serve as supplements (in livestock production, for instance) and as functional precursors for antifouling and antimicrobial coatings.  A common mechanism of antimicrobial action is their interaction with the lipid bilayer in the cell membranes of microorganisms, altering the transport of ions and small molecules across the cell membrane.  This project will focus on the synthesis of surfaces (nanoparticles and thin films) with covalently-bound plant-derived antimicrobial compounds, focusing on derivatives recently developed from monomers and dimers of lignin.  The interaction of functionalized nanoparticles with synthetic lipid bilayer will be investigated using a quartz crystal microbalance (QCM).  Lipid bilayers will first be assembled on the QCM sensors and then the QCM will be used to detect uptake of particles by the layer and subsequent bilayer disruption.  The effect of particle functionalization and concentration on bilayer uptake and disruption will be investigated and compared to the corresponding effect of the antimicrobial in solution.  These uptake studies will be coupled with investigations of ion binding and antimicrobial activity for the design of structures which insert into lipid bilayers and effect membrane transport.  Success of this research will result in strategies to design antimicrobial surfaces using the same principles as nature.

Primary Advisor: Dr. Brad Berron – College of Engineering – Chemical and Material Engineering

Lab Mentor:  Cong Li– College of Engineering – Chemical and Material Engineering

 

Heart disease is the number one cause of death worldwide. For end-stage heart failure, the only solution would be heart transplantation, however there is extremely limited the number of donors available for transplantation, and the recipients require long-term immune suppressants to prevent organ rejection. Our lab is trying to develop bioartificial organs suitable for transplantation. Building a heart requires a scaffold that can support cardiac function. Decellularized scaffolds made from alpha-galactose deficient hearts are stripped of all immunogenic materials. One of the critical challenges of converting decellularized scaffolds into viable therapeutic option is the reseeding of cells. The positioning and density of cells within the matrix are potentially the greatest challenges to recellularize hearts. The beating heart is composed of dozens of specialized cell types that need to be accurately positioned for proper function. Recellularizing by vascular perfusion or intramyocardial injection only offers approximate control over position but lacks cell precision, orientation, and density We seek to pattern the cells in the position they are needed, to create artificial hearts with better function. We will first focus on cell patterning on a glass slides. The slide will be patterned with a cell-binding chemical with UV light. Our goal is to develop patterning conditions that support cells sticking only in targeted parts of the slide. From there, we will work with a team in cardiology to apply the patterning method to heart tissues.

Primary Advisor:  Dr. Martha Grady – College of Engineering – Mechanical Engineering

Co-Advisor:  Dr. Brad Berron – College of Engineering – Chemical & Materials Engineering

Lab Mentor:  Dr. Martha Grady – College of Engineering – Mechanical Engineering

 

Cell therapies have been developed to assist in the repair of damaged tissues [1-4]. For example, stem cells have been injected into the heart after damage due to myocardial infarction or heart failure [1-2]. One critical challenge is that the vast majority of cells injected into the heart tissue disappear within a week [5]. One way to improve cell retention is by increasing adhesion to target sites with a cell coating, but a novel method is needed to quantify any advances in adhesion due to coatings. REU students will work on the development of the laser spallation technique [6-8] to apply and quantify stresses at critical cell-substrate interfaces. The student will explore adhesion of Jurkat cells to a multi-layer system terminating in a layer of streptavidin designed to mimic an idealized biological surface. The student will learn to navigate an optical setup, pulsed and continuous wave lasers, as well as a high-rate oscilloscope. In addition, characterization of the loaded and unloaded regions will require the aid of fluorescence staining and microscopy, SEM, and image analysis software such as Image.

 

[1.]         Diaz-Herraez, P.; Saludas, L.; Pascual-Gil, S.; Simon-Yarza, T.; Abizanda, G.; Prosper, F.; Garbayo, E.; Blanco-Prieto, M. J., Transplantation of adipose-derived stem cells combined with neuregulin-microparticles promotes efficient cardiac repair in a rat myocardial infarction model. J Control Release 2017, 249, 23-31.

[2.]         Sanganalmath, S. K.; Bolli, R., Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 2013, 113 (6), 810-34.

[3.]         Freyman, T.; Polin, G.; Osman, H.; Crary, J.; Lu, M.; Cheng, L.; Palasis, M.; Wilensky, R. L., A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. Eur Heart J 2006, 27 (9), 1114-22.

[4.]         Houtgraaf, J. H.; den Dekker, W. K.; van Dalen, B. M.; Springeling, T.; de Jong, R.; van Geuns, R. J.; Geleijnse, M. L.; Fernandez-Aviles, F.; Zijlsta, F.; Serruys, P. W.; Duckers, H. J., First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2012, 59 (5), 539-40.

[5.]         Hong, K. U.; Li, Q. H.; Guo, Y.; Patton, N. S.; Moktar, A.; Bhatnagar, A.; Bolli, R., A highly sensitive and accurate method to quantify absolute numbers of c-kit+ cardiac stem cells following transplantation in mice. Basic Res Cardiol 2013, 108 (3), 346.

[6.]         Hagerman, E.; Shim, J.; Gupta, V.; Wu, B., Evaluation of laser spallation as a technique for measurement of cell adhesion strength. J Biomed Mater Res A 2007, 82A (4), 852-860.

[7.]         Shim, J.; Hagerman, E.; Wu, B.; Gupta, V., Measurement of the tensile strength of cell-biomaterial interface using the laser spallation technique. Acta Biomater 2008, 4 (6), 1657-1668.

[8.]         Hu, L. L.; Zhang, X.; Miller, P.; Ozkan, M.; Ozkan, C.; Wang, J. L., Cell adhesion measurement by laser-induced stress waves. J. Appl. Phys. 2006, 100 (8).

Primary Advisor:  Dr. Guigen Zhang – College of Engineering - Biomedical Engineering

Co-Advisor:  Dr. Yu Zhao – College of Engineering – Biomedical Engineering

Lab Mentor:  Dr. Yu Zhao – College of Engineering – Biomedical Engineering

 

This summer research experience will provide the student(s) basic exposure to biomedical engineering research in one to two areas (if time permits): 1) basic science exploration by taking advantage of thermodynamics-driven computational modeling, and 2) hands-on development.

  1. On the modeling side, we will investigate drug release behavior of periodontal treatment drugs.

Understanding drug release kinetics and the underlying transport/reaction mechanisms is crucial for the design of efficient microfluidic devices. Combination of different types of drugs as well as carriers leads to different representative drug release profiles. In this part of the learning experience, the student(s) will learn how to develop computational models which incorporate multiple possible release mechanisms by starting from previously developed models on diffusion of drugs encapsulated in porous carrier. This part of learning will entail

  • Collect review/original papers on modeling of drug release process and identify existing gaps between mathematical/physical models and real behavior of drug release.
  • Learn how to use COMSOL, especially modules relevant to transport and chemical engineering. Get familiar with how to set up COMSOL model to study problems of interest.
  • Expand the capability of existing models, try to gain new knowledge and obtain new insight into the drug release process by incorporating as many relevant physics as possible.
  1. On the hands-on development side, we will take advantage of 3D printing technique to develop repeatable means to slice bone tissues into test specimens with desired dimensions.  

We will first use 3D scanning method to build a 3D virtual model of a sesamoid bone and then invert it into a CAD file for a hollow mold with hexahedral exterior. This CAD file of this virtual hexahedral mold will then be fed to a 3D printer to generate physical molds on demand. The 3D printed molds are then used for obtaining repeatable bone specimens (in terms of size and orientation) for use in future mechanical evaluation of bones.

Primary Advisor: Dr. Yinan Wei – College of Arts and Sciences – Chemistry

Co-Advisor: Dr. Dabakar Bhattacharyya – College of Engineering - Chemical and Materials Engineering

Lab Mentor:  Prasangi Rajapaksha – College of Arts and Sciences – Chemistry

 

Cell membranes define the boundary of cells and prevent the cellular contents from diffusing away, while protecting the cell from environmental stresses and toxins. To enable selective permeability to allow material exchange while fend off harmful toxins, cell membrane is composed of a highly impermeable lipid bilayer containing protein channels and transporters to allow exchange of nutrients and waste. To mimic nature and create smart membranes, this project will use E. coli outer membrane transporter FhuA as the template to create protein channels with tailor made pore size and polarity. FhuA is involved in iron uptake in bacteria. The structure of FhuA is composed of 22 transmembrane beta-strands that form a barrel, with the N-terminal domain fold into a plug in the middle of the barrel to block leakage. We will delete the N-terminal plug domain and modify the amino acid residues lining up the inner side of the protein channel to create selective filters with tailor-made properties. Performance of the designed channels will be tested after incorporation into membrane support.

Primary Advisor: Dr. Zach Hilt – College of Engineering - Chemical & Materials Engineering

Secondary Advisor: Dr. Tom Dziubla – College of Engineering - Chemical & Materials Engineering

Lab Mentor:  Trang Mai – College of Engineering – Chemical & Materials Engineering

 

Bisphenol A (BPA) is one of the endocrine disrupting compounds which has been widely used as raw material for the manufacture of polycarbonate, flame retardants, epoxy resins, etc. It can be found in plastic bottle, cans, food containers, adhesives and dental fillings 1-3.  It has been known that BPA has an estrogenic activity which can leads to animal female precocious and hyperplasia of prostate. BPA has been also reported that it can increase the occurrence of several diseases including leukemia, ovarian cancer, and embryonic malformation 1. The biodegradation of BPA by microorganism requires long times to remove BPA. The Fenton reaction with the formation of reactive oxygen species (ROS), such as hydroxyl radicals (˙OH), has been shown to be promising for the degradation of BPA. These highly reactive species will degrade BPA into carbon dioxide, water, or biodegradable by-products 3. It has been shown that iron oxide nanoparticles can produce ROS through Fenton reaction as below 4

Fe2++ H2O2 → Fe3+ + OH- + OH∙

Fe3++ O2∙ - → Fe2++ O2

Previous research from our lab demonstrated that the formation of ROS can be further enhanced by the application of an alternating magnetic field (AMF) 5. This project will focus on kinetic study of BPA degradation via Fenton process induced by functionalized iron oxide nanoparticles under exposure to AMF. Other factors such as pH, initial concentration of H2O2 and particles will be also investigated.

 

1.            W. Chen, C. Zou, Y. Liu and X. Li, Journal of Industrial and Engineering Chemistry, 2017, 56, 428-434.

2.            H. Katsumata, S. Kawabe, S. Kaneco, T. Suzuki and K. Ohta, Journal of Photochemistry and Photobiology A: Chemistry, 2004, 162, 297-305.

3.            M. J. Rivero, E. Alonso, S. Dominguez, P. Ribao, R. Ibañez, I. Ortiz and A. Irabien, Journal of Chemical Technology & Biotechnology, 2014, 89, 1228-1234.

4.            A. M. Hauser, M. I. Mitov, E. F. Daley, R. C. McGarry, K. W. Anderson and J. Z. Hilt, Biomaterials, 2016, 105, 127-135.

5.            R. J. Wydra, C. E. Oliver, K. W. Anderson, T. D. Dziubla and J. Z. Hilt, Royal Society of Chemistry Advances, 2015, 5, 18888-18893.

Primary Advisor: Dr. J. Zach Hilt – College of Engineering - Chemical and Materials Engineering

Co-Advisor: Dr. Thomas D. Dziubla – College of Engineering - Chemical and Materials Engineering

Lab Mentor:  Rishabh Shah – College of Engineering - Chemical & Materials Engineering

Lab Co-Mentor: Shuo Tang – College of Engineering - Chemical & Materials Engineering

 

Polymeric materials have unique properties depending on the type of monomers incorporated and how they interact. The tuning of these interactions provides the potential to form polymers with a wide variety of chemical and physical properties. Temperature responsive polymers are polymers that exhibit a change in their physical properties when the temperature changes. With the inclusion of a crosslinking moiety that can be covalent or non-covalent in nature, polymers can be designed to swell in different solvents rather than dissolve. This project will investigate the swelling of non-covalently crosslinked polymer networks with N-isopropylacrylamide (NIPAAm) as the monomer backbone. NIPAAm has a unique temperature responsive property of it being hydrophilic below its lower critical solution temperature (LCST: 32ᵒC) and hydrophobic above its LCST. The different comonomers used along with NIPAAm will have a biphenyl functional group which will be utilized to form a non-covalent crosslinked network due to the pi-pi stacking interactions present between the biphenyl groups. This project will include synthesis, characterization of the polymers, swelling them in water, and characterizing their swelling properties as a function of polymer composition as well as temperature. These novel responsive materials are expected to have application in biomedical and environmental fields.

Primary Advisor: Dr. Folami Ladipo – Chemistry Department

Co-Advisor: Dr. Barbara Knutson – College of Engineering - Chemical and Materials Engineering

Co-Advisor: Dr. Steve Rankin – College of Engineering - Chemical and Materials Engineering

Lab Mentor:  Daudi Saang’onyo – Department of Chemistry

 

To reach the full potential of lignocellulosic biomass as a renewable resource for fuels and chemicals production, efficient processes must be developed to convert lignin and cellulosic biomass into small molecules that can be upgraded into fuel and/or chemicals streams. Glucose is the most abundant monosaccharide in cellulosic biomass hence the development of efficient catalytic processes for its conversion into chemicals and biofuels is highly desired. Glucose dehydration is a promising method for the synthesis of 5-hydroxymethylfurfural (HMF), an emerging bio-derived platform chemical that potentially could be used to produce a wide variety of high-value chemicals. We have found that aluminum complexes that contain easily modified bidentate (aminomethyl)phenolate ligands are very promising catalysts in ionic liquid (IL) solvents for glucose conversion into HMF (G2H reaction). However, the use of ILs as bulk solvents has some significant drawbacks, including challenges with recovery of nonvolatile, polar solutes (such as our Al catalysts), reuse of some ILs, and their high cost. Thus, this project will investigate the reactivity of aluminum (aminomethyl)phenolate and related complexes in imidazolinum-based ILs with glucose as well as sugar model compounds such as methylglyoxal and glycoaldehyde. These studies will help to elucidate the nature of the active catalyst in G2H reaction and ligand properties best suited for creating a highly active and selective catalyst.

Primary Advisor:  Dr. Daniel Pack – Colleges of Pharmacy and Engineering – Pharmaceutical Sciences and Chemical and Materials Engineering

Co-Advisor:  Dr. Jason DeRouchey – College of Arts and Sciences - Chemistry

Lab Mentor:  Logan Warriner – College of Engineering - Chemical & Materials Engineering

 

The need for safe and efficient gene delivery methods remains the primary barrier to human gene therapy. Non-viral vector materials, including polymers, can be designed to be biocompatible and non-immunogenic, but lack the efficiency to be clinically relevant. Gene therapy awaits the development of new materials that are both safe and efficient. Gene delivery polymers must be designed to perform numerous functions. In particular, the materials must bind and condense DNA to protect it from extra- and intracellular nucleases and to facilitate cellular internalization. Yet, such materials must release their DNA cargo to allow transcription. Design of more efficient materials requires understanding of polymer-DNA interactions, the formation of polymer/DNA complexes (polyplexes), and how their structures relate to intracellular trafficking and gene delivery efficiency. This project will investigate a series of zwitterion-like polymers, fabricated through modification of polyethylenimine (PEI)—a model gene delivery polymer—with succinic anhydride, that allow systematic tuning of polymer-DNA interactions. We will quantify gene delivery efficiency of these polymers and investigate their internalization and intracellular trafficking mechanisms.

Primary Advisor: Dr. Stephen Rankin – College of Engineering - Chemical & Materials Engineering

Co-Advisor: Dr. Barbara Knutson – College of Engineering - Chemical & Materials Engineering

Lab Mentor: Mr. Arif Khan – College of Engineering – Chemical & Materials Engineering

 

Engineered silica nanoparticles (ESNPs) are being developed at the University of Kentucky that have multiple levels of functionality required for delivery into and excretion from plant, insect and mammalian cells.  ESNPs are used fairly widely in the scientific community as carriers for drugs, proteins and nucleic acids into cells – for instance to deliver small interfering RNA (siRNA) to silence the expression of targeted genes.  A novel approach being pursued at UK is to use similar carriers not to only to deliver cargo, but also to harvest, at a molecular level, therapeutic compounds from living cells, such as plant cell cultures.  We call this process nanoharvesting.  Plants produce a number of complex small molecules to regulate their interactions with other organisms – for instance, to attract desired pollinators, to kill pathogenic fungi, or to disrupt the nervous system of pest insects.  These natural products are a historically important and ongoing source of new leads for pharmaceuticals, and new advances in plant biotechnology has made available mutant strains selected to produce compounds known to target specific human receptors.  This project will focus on better understanding how ESNPs are taken up within cells (for both drug delivery and nanoharvesting), and also what factors control their expulsion after uptake.  Recent studies showed that a combination of transition metal and amine functionalization allows particles to be taken up in root cells and to bind active flavonoid compounds, but then to be released without causing significant harm to the plant.  Here, the goal will be to visualize and quantify particle uptake into cells in culture, so that mechanisms involved in biomolecule delivery and nanoharvesting can be better understood and controlled.

Primary Advisor: Dr. Dave Puleo – College of Engineering – Biomedical Engineering

Co-Advisor: Dr. Nikita Gupta – College of Medicine - Otolaryngology

Lab Mentor:  Alex Chen – College of Engineering - Biomedical Engineering

 

Local anesthetics are often used to block specific peripheral nerves for control of postoperative pain.  Even the longer lasting local anesthetics, such as bupivacaine, have short durations and are effective for only a few hours.  Approaches to prolong local analgesia include insertion of catheters for sustained infiltration and development of controlled release drug formulations.  More recently, a multivesicular liposome suspension has become available for injection into joints following arthroplasty. 

 

The objective of this project is to develop a sustained release bupivacaine delivery system for application in facial plastic and reconstructive surgical applications.  Two design requirements are that the system be injectable through a small gauge needle and that it provide locally effective yet not systemically toxic concentrations of bupivacaine for at least one week.  Undergraduate researcher contributions will involve formulating injectable, polymeric materials encapsulating bupivacaine, measuring drug release in vitro, and quantifying “injectability” of the system.

Primary Advisor: Dr. Eric Munson – College of Pharmacy – Pharmaceutical Sciences

Co-Advisor: Dr. Tom Dziubla – College of Engineering - Chemical and Materials Engineering

Lab Mentor:  Kanika Sarpal – College of Pharmacy – Pharmaceutical Sciences

 

Most drug candidates under development have poor solubility.  Amorphous solid dispersions are the most commonly-used approach to increase the solubility of poorly water-soluble drugs, as the solubility of the amorphous form of the drug may be up to an order of magnitude or more higher than the crystalline form of the drug.  In order to minimize the likelihood that the amorphous drug will not crystallize in the formulation, polymers are added to create an intimate mixture between the drug and the polymer in an amorphous solid dispersion.  This project will investigate how the stability of these amorphous solid dispersions can be probed using advanced analytical techniques.  In particular, the ability to discern the crystallization tendencies of amorphous solid dispersions in a differential scanning calorimeter will be compared with phase separation as determined using solid-state NMR spectroscopy.  Additional studies will take this information and show how it can be translated to functional properties such as propensity to crystallize and dissolution rate.

Primary Advisor: Prof. D. Bhattacharyya, Chemical and Materials Engineering

Co-Advisor: Prof. Yinan Wei– College of Arts and Sciences – Chemistry

Graduate student mentors: Andrew Colburn and Saiful Islam

 

Membranes are finding wide applications in the area of bio to water related separations.  The need for creating specific surface functionality for metal capture to creating antifouling surfaces is of high importance. This project will allow synthesis and evaluation of cellulosic and other polymeric membranes.  The REU student will work on: (1) membrane preparation and functionalization (2) permeability and separation studies with model compounds (3) functionalized membrane regeneration aspects.  Advanced characterization will include use of zeta potential and contact angle analyzer, SEM/TEM to look at membrane structures.  Andrew Colburn and Saiful Islam will be the graduate student mentors for membrane synthesis and experimental aspects.

Primary Advisor:  Dr. Tom Dziubla – College of Engineering – Chemical & Materials Engineering

Co-Advisor:  Dr. Zach hilt – College of Engineering – Chemical & Materials Engineering

Lab Mentor:  Kelley Wiegman – College of Engineering – Chemical & Materials Engineering

 

                Despite rapid advances in the pharmaceutical and biotechnology fields and an increase in the frequency of melanoma and other skin cancers, there have been no new sunscreen ingredients approved by the FDA in the past 20 years. Natural polyphenols, such as apigenin, quercetin and resveratrol, show high in vitro UV absorbances as well as antioxidant effects. The goal of my summer research will be to synthesize and characterize polymers of apigenin, quercetin, and resveratrol using poly (ß-amino ester).

                Polymers will be synthesized by replacing the -OH groups on the polyphenols with reactive acrylate groups via acrylation by acryloyl chloride. The acrylated polyphenols will be analyzed through high performance liquid chromatography (HPLC), Fourier-transform infrared spectroscopy (FT-IR), and nuclear magnetic resonance spectroscopy (NMR) to ensure complete reaction. After the polyphenols have been acrylated, they will be synthesized into polymer networks by reaction with an amine and an additional ‘blank’ monomer (polyethylene glycol diacrylate). Polymer networks with varying weight loadings of polyphenol will be characterized by their degradation profiles in a 7.4 pH phosphate buffer solution at standard conditions, as well as after UV-exposure to determine if UV light from the sun would impact the polymer’s effectiveness as a sunscreen ingredient. The identity of degradation byproducts will be determined through HPLC; product concentration will be analyzed through UV-visible light spectroscopy.

Primary Advisor: Jonathan Pham – College of Engineering, Chemical and Materials Engineering

Lab Mentor: Justin Glover - College of Engineering, Chemical and Materials Engineering

 

Biological systems are able to move at amazingly high rates that provide certain functions necessary for life.  For example, some seedpods explode to disperse their seeds at a rate of ~5 m/s, to a sufficiently far distance for reproduction purposes. The accelerations can be as high as ~50x that of the fastest accelerating commercially available car. Mantis shrimps are another example of fast motion, which are able to strike the shells of their prey at ~20 m/s in a fluid, allowing them to crack open shells for feeding. Although there are fantastic demonstrations in nature, engineering fast motions in synthetic systems is a challenge. This project will explore the potential to develop fast moving structures by balancing elastic deformations of soft materials and their adhesive boundaries. This will be done by preparing model materials with different elastic moduli, characterizing their deformations, and exploring different possible boundary conditions, such as capillarity or magnetism. The results may lead to unique routes for cargo delivery containers, soft actuators, or soft robotics.