Steven R Little

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (87)391.49 Total impact

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    ABSTRACT: Introduction: The pathogenesis of periapical lesions is determined by the balance between host proinflammatory immune response and counteracting anti-inflammatory and reparative responses, which include regulatory T cells (Tregs) as potential immunoregulatory agents. In this study, we investigated (in a cause-and-effect manner) the involvement of CCL22-CCR4 axis in Treg migration to the periapical area and the role of Tregs in the determination of outcomes in periapical lesions. Methods: Periapical lesions were induced in C57Bl/6 (wild-type) and CCR4KO mice (pulp exposure and bacterial inoculation) and treated with anti-glucocorticoid-induced TNF receptor family regulated gene to inhibit Treg function or alternatively with CCL22-releasing, polylactic-glycolic acid particles to induce site-specific migration of Tregs. After treatment, lesions were analyzed for Treg influx and phenotype, overall periapical bone loss, and inflammatory/immunologic and wound healing marker expression (analyzed by real-time polymerase chain reaction array). Results: Treg inhibition by anti-glucocorticoid-induced TNF receptor family regulated gene or CCR4 depletion results in a significant increase in periapical lesion severity, associated with upregulation of proinflammatory, T-helper 1, T-helper 17, and tissue destruction markers in parallel with decreased Treg and healing marker expression. The local release of CCL22 in the root canal system resulted in the promotion of Treg migration in a CCR4-dependent manner, leading to the arrest of periapical lesion progression, associated with downregulation of proinflammatory, T-helper 1, T-helper 17, and tissue destruction markers in parallel with increased Treg and healing marker expression. Conclusions: Because the natural and CCL22-induced Treg migration switches active lesion into inactivity phenotype, Treg chemoattractant may be a promising strategy for the clinical management of periapical lesions.
    No preview · Article · Nov 2015 · Journal of endodontics
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    ABSTRACT: Single-walled carbon nanotubes (SWNTs) can be labelled with functional moieties that endow them with a number of unique characteristics, which can be applicable to biomedical applications such as imaging. Herein we describe a facile, one-step esterification process to functionalize SWNT with fluorescein.
    No preview · Article · Oct 2015 · Chemical Communications
  • Abhinav P. Acharya · Steven R. Little
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    ABSTRACT: Divalent cations, the most prevalent minerals in the body, are responsible for a wide variety of cellular functions including signaling, proliferation, differentiation and cell death, and therefore their transmembrane transportation is tightly regulated. Despite the importance of divalent cations in cell activity, there are currently no intracellular delivery methods for divalent cations or modulation of intracellular levels of minerals. Here, we describe endosome disrupting alginate nanoparticles termed Alginoketals, which can deliver divalent cations to the cytosol of the cells. Alginoketals are generated by crosslinking alginic acid with endosome disrupting ketals, and using divalent cations as the stapling or binding agent. We show that Alginoketals were able to deliver copper (II) in the cytosol of the cancer cells thereby disrupting copper homeostasis and inducing cell death via accumulation of hydrogen peroxide. Alginoketal-copper (II)-based particles act as superoxide dismutase mimics and are the first class of divalent cation delivery vehicles, with potential application in cancer therapy, regenerative medicine and drug delivery.
    No preview · Article · Sep 2015 · Journal of Drug Targeting
  • E.A. Bayer · R Gottardi · M.V. Fedorchak · S.R. Little
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    ABSTRACT: Bone regeneration is a complex process, that in vivo, requires the highly coordinated presentation of biochemical cues to promote the various stages of angiogenesis and osteogenesis. Taking inspiration from the natural healing process, a wide variety of growth factors are currently being released within next generation tissue engineered scaffolds (in a variety of ways) in order to heal non-union fractures and bone defects. This review will focus on the delivery of multiple growth factors to the bone regeneration niche, specifically 1) dual growth factor delivery signaling and crosstalk, 2) the importance of growth factor timing and temporal separation, and 3) the engineering of delivery systems that allow for temporal control over presentation of soluble growth factors. Alternative methods for growth factor presentation, including the use of gene therapy and platelet-rich plasma scaffolds, are also discussed. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Aug 2015 · Journal of Controlled Release
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    ABSTRACT: The influence of electrostatic interactions and/or acylation on release of charged (“sticky”) agents from biodegradable polymer matrices was systematically characterized. We hypothesized that release of peptides with positive charge would be hindered from negatively charged poly(lactic-co-glycolic acid) (PLGA) microparticles. Thus, we investigated release of peptides with different degrees of positive charge from several PLGA microparticle formulations, with different molecular weights and/or end groups (acid- or ester-terminated). Indeed, release studies revealed distinct inverse correlations between the amount of positive charge on peptides and their release rates from each PLGA microparticle formulation. Furthermore, we examined the case of peptides with net charge that changes from negative to positive within the pH range observed in degrading microparticles. These charge changing peptides displayed counterintuitive release kinetics, initially releasing faster from slower degrading (less acidic) microparticles, and releasing slower from the faster degrading (more acidic) microparticles. Importantly, trends between agent charge and release rates for model peptides also translated to larger, therapeutically relevant proteins and oligonucleotides. The results of these studies may improve future design of controlled release systems for numerous therapeutic biomolecules exhibiting positive charge, ultimately reducing time-consuming and costly trial and error iterations of such formulations.
    No preview · Article · May 2015
  • Timothy D Knab · Steven R Little · Robert S Parker
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    ABSTRACT: Mathematical models of controlled release that span the in vitro to in vivo transition are needed to speed the development and translation of clinically-relevant controlled release drug delivery systems. Fully mechanistic approaches are often challenged due to the use of highly-parameterized mathematically complex structures to capture the release mechanism. The simultaneous scarcity of in vivo data to inform these models and parameters leads to a situation where overfitting to capture observed phenomena is common. A data-driven approach to model development for controlled drug release from polymeric microspheres is taken herein, where physiological mechanisms impacting controlled release are incorporated to capture observed changes between in vitro release profiles and in vivo device dynamics. The model is generalizable, using non-specific binding to capture drug-polymer interactions via charge and molecular structure, and it has the ability to describe both inhibited (slowed) and accelerated release resulting from electrostatic or steric interactions. Reactive oxygen species (ROS)-induced degradation of biodegradable polymers was incorporated via a reaction-diffusion formalism, and this suggests that ROS may be the primary effector of the oft-observed accelerated in vivo release of polymeric drug delivery systems. Model performance is assessed through comparisons between model predictions and controlled release of several drugs from various-sized microparticles in vitro and in vivo. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · May 2015 · Journal of Controlled Release
  • James D. Fisher · Abhinav P. Acharya · Steven R. Little
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    ABSTRACT: Despite decades of advances in transplant immunology, tissue damage caused by acute allograft rejection remains the primary cause of morbidity and mortality in the transplant recipient. Moreover, the long-term sequelae of lifelong immunosuppression leaves patients at risk for developing a host of other deleterious conditions. Controlled drug delivery using micro- and nanoparticles (MNPs) is an effective way to deliver higher local doses of a given drug to specific tissues and cells while mitigating systemic effects. Herein, we review several descriptions of MNP immunotherapies aimed at prolonging allograft survival. We also discuss developments in the field of biomimetic drug delivery that use MNP constructs to induce and recruit our bodies' own suppressive immune cells. Finally, we comment on the regulatory pathway associated with these drug delivery systems. Collectively, it is our hope the studies described in this review will help to usher in a new era of immunotherapy in organ transplantation. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · May 2015 · Clinical Immunology
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    ABSTRACT: Colloidal crystals are interesting materials owing to their customizable photonic properties, high surface area, and analogy to chemical structures. The flexibility of these materials has been greatly enhanced through mixing particles with varying sizes, compositions, and surface charges. In this way, distinctive patterns or analogies to chemical stoichiometries are produced; however, to date, this body of research is limited to particles with nanoscale dimensions. A simple method is now presented for bottom-up assembly of non-Brownian particle mixtures to create a new class of hierarchically-ordered materials that mimic those found in nature (both in pore distribution as well as stoichiometry). Additionally, these crystals serve as a template to create particle-based inverted crystalline structures with customizable properties. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Full-text · Article · Apr 2015 · Angewandte Chemie International Edition
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    ABSTRACT: Inflammatory bone resorption is a hallmark of periodontitis, being Treg and Th2 cells independently associated with disease progression attenuation. In this study, we employed an infection-triggered inflammatory osteolysis model to investigate the mechanisms underlying Treg and Th2 cell migration and impact on disease outcome. A. actinomycetemcomitans-infected C57Bl/6 (WT) mice develop an intense inflammatory reaction and alveolar bone resorption, being Tregs of Th2 cells migration temporally associated with disease progression attenuation. Tregs extracted from the lesions preferentially express CCR4 and CCR8, while Th2 cells express CCR3, CCR4 and CCR8. The absence of CCR5 and CCR8 did not impact Th2 and Tregs migration or disease outcome in a significant manner. CCR4KO mice presented a minor reduction in Th2 in parallel with major impairment of Tregs migration, associated with increased inflammatory bone loss and higher pro-inflammatory and osteoclastogenic cytokines levels. The blockade of the CCR4 ligand CCL22 in WT mice resulted in increased inflammatory bone loss phenotype similarly to CCR4KO strain. Adoptive transfer of CCR4+Tregs to CCR4KO strain revert the increased disease phenotype to WT mice-like levels, being the production of CCL22 in the lesions mandatory for Tregs migration and the consequent bone loss arrest. The local release of exogenous CCL22 provided by PLGA-microparticles promote Tregs migration and disease arrest in the absence of endogenous CCL22 IL-4KO strain, characterized by the lack of endogenous CCL22 production, defective Tregs migration and exacerbated bone loss. In summary, our results demonstrate that the involvement of IL-4/CCL22/CCR4 axis in the migration of Tregs to osteolytic lesions sites, and attenuates development of lesions by inhibiting inflammatory migration and the production of pro-inflammatory and osteoclastogenic mediators. © 2014 American Society for Bone and Mineral Research
    Full-text · Article · Mar 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • Melissa H. Lash · Morgan Fedorchak · Steven R. Little
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    ABSTRACT: Particle-based crystals have been explored as a basis for creating ordered porous materials for applications in molecular electronics, photonics, sensors, and drug delivery. However, much of the research on these crystals has been focused on particles of nano and sub-micron dimensions (so-called colloidal crystals) with limited attention directed towards building blocks with dimensions ranging from tens to hundreds of microns. Larger (particle) components, however, offer many practical benefits ranging from a mass transfer as well as mechanical strength perspective and often involve easier synthesis of materials, easier yet potentially more sophisticated surface functionality, simpler measurements of the assembly process, and greater control of the interaction strength and selectivity. Despite these advantages, self-assembly at larger scales remains in its infancy. Components on the meso- and macro-scales are generally influenced by forces within the system in a different manner than their nano-scale counterparts; the underlying thermal effects in these larger systems typically cannot naturally overcome kinetic barriers generally leading to the components becoming kinetically arrested in non-equilibrium states. In this work, we introduce ultrasonic agitation into a system of large particles (or mixtures of particles) and explore the impact that external agitation at varying input energies has on the packing behavior of both monodispersed microparticle populations as well as mixtures of microparticles. Additionally, we will examine the implications of this work on the resulting mechanical properties of “large particle”-based crystals (both monodisperse and mixed-size). The implications of this work will hopefully lead to a better understanding of the assembly behavior and resulting mechanical properties of “large particle”-based crystals.
    No preview · Conference Paper · Nov 2014
  • Melissa H. Lash · Morgan Fedorchak · Steven R. Little
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    ABSTRACT: Hierarchically ordered porous materials hold promise for enhanced performance in a variety of fields. Specifically, in terms of a hierarchical pore structure (ranging from the nano-micron size regimes) many practical advantages can be derived from having a high surface area and pore volume, as well as providing size selectivity for molecule/particle diffusion and substantial interfacial area. An exceptionally promising technique for the formation of ordered porous materials is the use of colloidal crystal templating, with much attention paid to nano-scale self-assembly. Larger (micron-scale particle) components, however, offer benefits from a mass transfer as well as mechanical strength perspective and often involve easier synthesis of materials, easier yet potentially more sophisticated surface functionality, simpler measurements of the assembly process, and greater control of the interaction strength and selectivity. Despite these advantages, self-assembly at larger scales remains in its infancy. Larger components become more readily arrested in a non-equilibrium configuration (compared to nano-scale counterparts) as these larger systems are less influenced by the underlying thermal effects. This tendency for kinetic arrest limits the translation of nano-scale assembly techniques up to larger component scales. In this work, ultrasonic agitation is explored as a means of allowing large microparticles (18-750m) to overcome kinetic barriers to packing in the creation of close-packed, highly ordered, crystalline structures. Specifically, the relationship between particle packing behavior and energy input is being characterized in terms of crystallinity. Additionally, we have extended this technique for crystal fabrication to create multi-component crystals made from two or more particle sizes. When we combine these "large-particle" assembly techniques with traditional nano-scale colloidal crystallization an exciting opportunity arises to tailor the mechanical and surface properties as well as the pore size of the resulting hierarchically structured materials.
    No preview · Conference Paper · Nov 2014
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    ABSTRACT: Disease and injury perturb the balance of processes associated with inflammation and tissue remodeling, resulting in positive feedback loops, exacerbation of disease and compromised tissue repair. Conversely, under homeostatic healthy conditions, these processes are tightly regulated through the expansion and/or recruitment of specific cell populations, promoting a balanced steady-state. Better understanding of these regulatory processes and recent advances in biomaterials and biotechnology have prompted strategies to utilize cells for the treatment and prevention of disease through regulation of inflammation and promotion of tissue repair. Herein, we describe how cells that regulate these processes can be increased in prevalence at a site of disease or injury. We review several relevant cell therapy approaches as well as new strategies for directing endogenous regulatory cells capable of promoting environmental homeostasis and even the establishment of a pro-regenerative micro-environment. Collectively, these examples may provide a blueprint for next-generation "medicine" that spurs the body's own cells to action and replaces conventional drugs.
    Full-text · Article · Sep 2014 · Annals of Biomedical Engineering
  • S. N. Rothstein · C. Donahue · Jr. L. D. Falo · S. R. Little
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    ABSTRACT: The ability to deliver but hide immunogenic payloads and then reveal them at predetermined times could lead to autonomously boosting vaccine formulations or improved antigen–adjuvant vaccine designs. We used in silico modeling to determine the appropriate formulation and material properties for poly(lactic-co-glycolic) acid (PLGA) microparticles such that they would delay the in vitro “unmasking” of an ovalbumin-alum payload for precise and predetermined intervals. A preferred formulation was then tested in vivo. In vivo T cell proliferation data confirmed the presentation of antigen released through the programmed delayed burst while antibody subclass data demonstrated immunogenicity comparable to that observed with established multiple injection prime-boost regimens.
    No preview · Article · Aug 2014
  • G P Garlet · C S Sfeir · S R Little
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    ABSTRACT: The disruption of host-microbe homeostasis at the site of periodontal disease is considered a key factor for disease initiation and progress. While the downstream mechanisms responsible for the tissue damage per se are relatively well-known (involving various patterns of immune response operating toward periodontal tissue destruction), we are only beginning to understand the complexity of host-microbe interactions in the periodontal environment. Unfortunately, most of the research has been focused on the disruption of host-microbe homeostasis instead of focusing on the factors responsible for maintaining homeostasis. In this context, regulatory T-cells (Tregs) comprise a CD4+FOXp3 +T-cell subset with a unique ability to regulate other leukocyte functions to avoid excessive immune activation and its pathological consequences. Tregs act as critical determinants of host-microbe homeostasis, as well as determinants of a balanced host response after the disruption of host-microbe homeostasis by pathogens. In periodontitis, Tregs play a protective role, with their natural recruitment being responsible for conversion of active into inactive lesions. With controlled-release technology, it is now possible to achieve a selective chemoattraction of Tregs to periodontal tissues, attenuating experimental periodontitis evolution due to the local control of inflammatory immune response and the generation of a pro-reparative environment.
    No preview · Article · Jul 2014 · Journal of Dental Research
  • Hui-Li Fu · Yi Hong · Steven R Little · William R Wagner
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    ABSTRACT: As a means to stimulate wound healing, a hollow fiber membrane system might be placed within a wound bed to provide local and externally regulated controlled delivery of regenerative factors. After sufficient healing, it would be desirable to triggerably degrade these fibers as opposed to pulling them out. Accordingly, a series of enzymatically degradable thermoplastic elastomers was developed as potential hollow fiber base material. Polyurethane ureas (PUUs) were synthesized based on 1, 4-diisocyanatobutane, polycaprolactone (PCL) diol and polyethylene glycol (PEG) at different molar fractions as soft segments, and collagenase-sensitive peptide GGGLGPAGGK-NH2 as a chain extender (defined as PUU-CLxEGy-peptide, where x and y are the respective molar percents). In these polymers, PEG in the polymer backbone decreased tensile strengths and initial moduli of solvent-cast films in the wet state, while increasing water absorption. Collagenase degradation was observed at 75% relative PEG content in the soft segment. Control PUUs with putrescine or nonsense peptide chain extenders did not degrade acutely in collagenase. Conduits electrospun from PUU-CL25EG75-peptide and PUU-CL50EG50-peptide exhibited appropriate mechanical strength and sustained release of a model protein from the tube lumen for 7 d. Collapse of PUU-CL25EG75-peptide tubes occurred after collagenase degradation for 3 d. In conclusion, through molecular design, synthesis and characterization, a collagenase-labile PUU-CL25EG75-peptide polymer was identified that exhibited the desired traits of triggerable lability, processability, and the capacity to act as a membrane to facilitate controlled protein release.
    No preview · Article · Jul 2014 · Biomacromolecules
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    ABSTRACT: Colloidal crystals have been explored in the literature for applications in molecular electronics, photonics, sensors, and drug delivery. However, much of the research on colloidal crystals has been focused on nano-sized particles with limited attention directed towards building blocks with dimensions ranging from tens to hundreds of microns. This can be attributed, in part, to the fact that particles with greater than sub-micron dimensions do not naturally assemble in an organized fashion due to the relatively miniscule influence of thermalizing forces. Nevertheless, ordered arrays of large, micron-scale particles are of interest as a basis for the production of hierarchically structured materials with customizable pore sizes. In this work, ultrasonic agitation is being explored as a means of allowing large, non-Brownian microparticles (18-750µm) to overcome kinetic barriers to packing in the creation of close packed, highly ordered, crystalline structures. In addition we study how the energy input affects bulk particle behavior and describe several new ways to characterize colloidal crystals made from microparticles.
    No preview · Article · Jul 2014 · Langmuir
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    ABSTRACT: Treatment of glaucoma by intraocular pressure (IOP) reduction is typically accomplished through the administration of eye drops, the difficult and frequent nature of which contributes to extremely low adherence rates. Poor adherence to topical treatment regimens in glaucoma patients can lead to irreversible vision loss and increased treatment costs. Currently there are no approved treatments for glaucoma that address the inherent inefficiences in drug delivery and patient adherence. Brimonidine tartrate (BT), a common glaucoma medication, requires dosing every 8-12 hours, with up to 97% of patients not taking it as prescribed. This study provides proof-of-principle testing of a controlled release BT formulation. BT was encapsulated in poly(lactic-co-glycolic) acid microspheres and drug release was quantified using UV-Vis spectroscopy. For in vivo studies, rabbits were randomized to receive a single subconjunctival injection of blank (no drug) or BT-loaded microspheres or twice daily topical 0.2% BT drops. The microspheres released an average of 2.1±0.37 μg BT/mg microspheres/day in vitro. In vivo, the percent decrease in IOP from baseline was significantly greater in the treated eye for both topical drug and drug-loaded microspheres versus blank microspheres throughout the 4-week study, with no evidence of migration or foreign body response. IOP measurements in the contralateral, untreated eyes also suggested a highly localized effect from the experimental treatment. A treatment designed using the release systems described in this study would represent a vast improvement over the current clincial standard of 56-84 topical doses over 28 days.
    No preview · Article · Jun 2014 · Experimental Eye Research
  • Stephen C Balmert · Steven R Little
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    ABSTRACT: The field of biomimetic particle-based delivery has advanced considerably in recent years. Drawing inspiration from various ways cells in the body exchange information, researchers have developed synthetic particles with several modes of “delivery” (loosely defined here as presentation of biological signals) for diverse therapeutic applications. Particles have been rationally designed to mimic the systematic secretion of soluble factors, presentation of surface-bound ligands, and physical properties of natural cells, all of which dictate unique responses by other cells. This chapter focuses on more complex particle delivery systems that feature biomimetic compartmental, surface, and shape anisotropy, and provide greater temporospatial context for biological signals than is possible with isotropic particles. In particular, release of soluble factors from multi-compartment particles, presentation of surface-bound ligands on both patterned and fluid particle surfaces, and orientation-specific interactions between non-spherical particles and cells are examined in depth. Ultimately, the next generation of biomimetic particle delivery systems will likely integrate multiple modes of delivery (each with anisotropic context) to orchestrate more efficient and precise responses by target cells.
    No preview · Chapter · May 2014
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    ABSTRACT: The hydrolytic degradation behavior of biodegradable poly (lactic-co-glycolic acid) (PLGA) copolymers is shown to depend on monomer sequence. Although polymer properties would be expected to correlate with monomer sequence there are relatively few examples outside of biological polymers to substantiate this assertion. PLGA, one of the most widely used biodegradable polymers, was prepared with repeating sequences, e.g., (LLG)n (L = lactic unit; G = glycolic unit). All properties related to hydrolytic degradation including molecular weight, lactic acid release, mass loss, water uptake, morphology, and in vitro release of encapsulated rhodamine-B were shown to depend on sequence. In contrast with random copolymers, sequenced PLGAs were found to exhibit a steady hydrolysis profile without abrupt changes in properties release rates.
    No preview · Chapter · Jan 2014
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    ABSTRACT: Although approved by the United States Food and Drug Administration, enfuvirtide is rarely used in combination antiretroviral therapies (cART) to treat HIV-1 infection, primarily because of its intense dosing schedule that requires twice daily subcutaneous injection. Here, we describe the development of enfuvirtide-loaded, degradable poly(lactic-co-glycolic) acid microparticles that provide linear in vitro release of the drug over an 18 day period. This sustained release formulation could make enfuvirtide more attractive for use in cART.
    No preview · Article · Dec 2013 · Antimicrobial Agents and Chemotherapy

Publication Stats

2k Citations
391.49 Total Impact Points

Institutions

  • 2006-2015
    • University of Pittsburgh
      • • Chemical and Petroleum Engineering
      • • Department of Ophthalmology
      • • Department of Immunology
      Pittsburgh, Pennsylvania, United States
  • 2004-2010
    • Massachusetts Institute of Technology
      • Department of Chemical Engineering
      Cambridge, Massachusetts, United States