Ferenc Horkay

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Maryland, United States

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Publications (197)550.92 Total impact

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    ABSTRACT: Mannobiose-modified polyethylenimines (PEI) are used in gene therapy to generate nanoparticles of DNA that can be targeted to the antigen-presenting cells of the immune system. We report that the sugar modification alters the DNA organization within the nanoparticles from homogenous to shell-like packing. The depth-dependent packing of DNA within the nanoparticles was probed using AFM nano-indentation. Unmodified PEI-DNA nanoparticles display linear elastic properties and depth-independent mechanics, characteristic of homogenous materials. Mannobiose-modified nanoparticles, however, showed distinct force regimes that were dependent on indentation depth, with 'buckling'-like response that is reproducible and not due to particle failure. By comparison with theoretical studies of spherical shell mechanics, the structure of mannobiosylated particles was deduced to be a thin shell with wall thickness in the order of few nanometers, and a fluid-filled core. The shell-core structure is also consistent with observations of nanoparticle denting in altered solution conditions, with measurements of nanoparticle water content from AFM images, and with images of DNA distribution in Transmission Electron Microscopy.
    Soft Matter 08/2014; · 4.15 Impact Factor
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    ABSTRACT: There is no clinically available cancer immunotherapy that exploits Langerhans cells (LCs), the epidermal precursors of dendritic cells (DCs) that are the natural agent of antigen delivery. We developed a DNA formulation with a polymer and obtained synthetic 'pathogen-like' nanoparticles that preferentially targeted LCs in epidermal cultures. These nanoparticles applied topically under a patch-elicited robust immune responses in human subjects. To demonstrate the mechanism of action of this novel vaccination strategy in live animals, we assembled a high-resolution two-photon laser scanning-microscope. Nanoparticles applied on the native skin poorly penetrated and poorly induced LC motility. The combination of nanoparticle administration and skin treatment was essential both for efficient loading the vaccine into the epidermis and for potent activation of the LCs to migrate into the lymph nodes. LCs in the epidermis picked up nanoparticles and accumulated them in the nuclear region demonstrating an effective nuclear DNA delivery in vivo. Tissue distribution studies revealed that the majority of the DNA was targeted to the lymph nodes. Preclinical toxicity of the LC-targeting DNA vaccine was limited to mild and transient local erythema caused by the skin treatment. This novel, clinically proven LC-targeting DNA vaccine platform technology broadens the options on DC-targeting vaccines to generate therapeutic immunity against cancer.Gene Therapy advance online publication, 3 April 2014; doi:10.1038/gt.2014.29.
    Gene therapy 04/2014; · 4.75 Impact Factor
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    ABSTRACT: Water self-diffusion coefficients and longitudinal relaxation rates in sodium polyacrylate solutions and gels were measured by NMR, as a function of polymer content and structure in a physiological concentration range of monovalent and divalent cations, Ca2+ and Na+. Several physical models describing the self-diffusion of the solvent were applied and compared. A free-volume model was found to be in good agreement with the experimental results over a wide range of polymer concentrations. The longitudinal relaxation rate exhibited linear dependence on polymer concentration below a critical concentration and showed non-linear behavior at higher concentrations. Both the water self-diffusion and relaxation were less influenced by the polymer in the gel state than in the uncrosslinked polymer solutions. The effect of Na+ on the mobility of water molecules was practically undetectable. In contrast, addition of Ca2+ strongly increased the longitudinal relaxation rate while its effect on the self-diffusion coefficient was much less pronounced. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014, 131, 40001.
    Journal of Applied Polymer Science 03/2014; 131(6). · 1.40 Impact Factor
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    ABSTRACT: Cartilage is a complex biological tissue that exhibits gel-like behavior. Its primary biological function is providing compressive resistance to external loading and nearly frictionless lubrication of joints. In this study, we model cartilage extracellular matrix using a biomimetic system. We demonstrate that poly(vinyl) alcohol (PVA) hydrogels are robust biomaterials exhibiting mechanical and swelling properties similar to that of cartilage extracellular matrix. A comparison is made between the macroscopic behavior of PVA gels and literature data reported for cartilage.
    MRS Online Proceeding Library 01/2014; 1622.
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    ABSTRACT: It is biologically and clinically important to understand and explain the functional properties of cartilage, such as its load bearing and lubricating ability, in terms of the structure, organization, components and their interactions. Our approach tries to explain functional material properties of these tissues as arising from polymeric interactions between and among the different molecular constituents within the tissues at different hierarchical lengthscales. We treat the tissue effectively as a complex molecular composite containing highly charged polysaccharide microgels trapped within a fine collagen meshwork. We have been developing a multi-scale experimental and theoretical framework to explain key material properties of cartilage by studying those of its constituents and the interactions among them at a variety of length and time scales. We use this approach to address important biological questions. One novel application we highlight here is the use of non-invasive magnetic resonance imaging (MRI) methods to characterize different components and compartments within cartilage and the different water environments associated with each one, in an attempt to provide a comprehensive picture of the mechanical/chemical state of cartilage.
    MRS Online Proceeding Library 01/2014; 1622.
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    ABSTRACT: Self-assembly of small molecules, as a more common phenomenon than one previously thought, can be either beneficial or detrimental to cells. Despite its profound biological implications, how the self-assembly of small molecules behave in cellular environment is largely unknown and barely explored. This work studies four fluorescent molecules that consist of the same peptidic backbone (e.g., Phe-Phe-Lys) and enzyme trigger (e.g., a phosphotyrosine residue), but bear different fluorophores on the side chain of the lysine residue of the peptidic motif. These molecules, however, exhibit different ability of self-assembly before and after enzymatic transformation (e.g., dephosphorylation). Fluorescent imaging reveals that self-assembly directly affects the distribution of these small molecules in cellular environment. Moreover, cell viability tests suggest that the states and the location of the molecular assemblies in the cellular environment control the phenotypes of the cells. For example, the molecular nanofibers of one of the small molecules apparently stabilize actin filaments and alleviate the insult of an F-actin toxin (e.g., latrunculin A). Combining fluorescent imaging and enzyme-instructed self-assembly of small peptidic molecules, this work, for the first time, not only demonstrates that self-assembly as a key factor for dictating the spatial distribution of small molecules in cellular environment, but also illustrates a useful approach, based on enzyme-instructed self-assembly of small molecules, to modulate spatiotemporal profiles of small molecules in cellular environment for using the emergent properties of small molecules to control the fate of cells.
    Langmuir 11/2013; · 4.38 Impact Factor
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    ABSTRACT: The Hungarian adult heart transplant program, which started in 1992, has changed gradually in the past 20 years. After the early enthusiasm of the first cases it changed significantly and it became an organized programme. However, low donation activity and moderate referral numbers to the national transplant waiting list slowed down the process therefore, heart transplant numbers did not fulfill expectations in the early years. After a moderate increase in 2007 transplant numbers have dropped again until recently when Hungary partially joined Eurotransplant network. Excess fundamental resources allocated to cardiac transplantation by health care professionals and reorganizing transplant coordination as well as logistics forced dramatic changes in clinical management. In 2011 and 2012 major structural changes had been made at Semmelweis University. The newly established transplant intensive care unit and the initiation of mechanical circulatory support and assist device programme increased transplant numbers by 131% compared to previous years, as well as it resulted an 86.63% 30-day survival rate, hence last year was the most successful year of cardiac transplantation ever. Orv. Hetil., 2013, 154, 863-867.
    Orvosi Hetilap 06/2013; 154(22):863-867.
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    ABSTRACT: Knowledge of microstructural features of nerve fascicles, such as their axon diameter, is crucial for understanding normal function in the central and peripheral nervous systems as well as assessing changes due to pathologies. In this study double-pulsed field gradient (d-PFG) filtered MRI was used to map the average axon diameter (AAD) in porcine spinal cord, which was then compared to AADs measured with optical microscopy of the same specimen, as a way to further validate this new MRI method. A novel 3D d-PFG acquisition scheme was used to obtain AADs in each voxel of a coronal slice of rat brain corpus callosum. AAD measurements were also acquired using optical microscopy performed on histological sections and validated using a glass capillary array phantom.
    NeuroImage 04/2013; · 6.13 Impact Factor
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    ABSTRACT: Storage protocols of vascular grafts need further improvement against ischemia/reperfusion (IR)-injury. Hypoxia elicits a variety of complex cellular responses by altering the activity of many signalling pathways, such as the oxygen-dependent prolyl-hyroxylase-domain containing enzyme (PHD). Reduction of PHD-activity during hypoxia leads to stabilisation and accumulation of hypoxia inducible factor (HIF) 1α. We examined the effects of PHD-inhibiton by dimethyloxalylglycine on the vasomotor responses of isolated rat aorta and aortic vascular smooth muscle cells (VSMC) in a model of cold ischemia/warm reperfusion. Aortic segments underwent 24h cold ischemic preservation in saline or DMOG-supplemented saline solution. We investigated endothelium-dependent and -independent vasorelaxations. To simulate IR-injury hypochlorite (NaOCl) was added during warm reperfusion. VSMCs were incubated in NaCl or DMOG solution at 4°C for 24h after the medium was changed for a supplied standard medium at 37°C for 6h. Apoptosis was assessed by the TUNEL-method. Gene expression analysis was performed by quantitative real-time PCR. Cold ischemic preservation + NaOCl induced severe endothelial dysfunction, which was significantly improved by DMOG supplementation (maximal relaxation of aortic segments to acetylcholine: control 95±1 vs. NaOCl 44±4 vs. DMOG 68±5%). Number of TUNEL-positive cell nuclei was significantly higher in the NaOCl-group and DMOG-treatment significantly decreased apoptosis. Inducible heme-oxygenase 1 mRNA expressions were significantly higher in the DMOG group. Pharmacological modulation of oxygen sensing system by DMOG in an in vitro model of vascular IR effectively preserved endothelial function. Inhibition of PHDs could be therefore a new therapeutic avenue for protecting endothelium and vascular muscle cells against IR-injury.
    Journal of Pharmacology and Experimental Therapeutics 02/2013; · 3.89 Impact Factor
  • Biophysical Journal 01/2013; 104(2):349-. · 3.83 Impact Factor
  • Ferenc Horkay
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    ABSTRACT: Articular cartilage is a low-friction, load-bearing tissue located at joint surfaces. The extracellular matrix (ECM) of cartilage consists of a fibrous collagen network, which is pre-stressed by the osmotic swelling pressure exerted by negatively charged proteoglycan aggregates embedded in the collagen network. The major proteoglycan is the bottlebrush shaped aggrecan, which forms complexes with linear hyaluronic acid chains. We quantify microscopic and macroscopic changes resulting from self-assembly between aggrecan and hyaluronic acid using a complementary set of physical measurements to determine structure and interactions by combining scattering techniques, including small-angle X-ray scattering, small-angle neutron scattering, and dynamic light scattering with macroscopic osmotic pressure measurements. It is demonstrated that the osmotic pressure that defines the load bearing ability of cartilage is primarily governed by the main macromolecular components (aggrecan and collagen) of the ECM. Knowledge of the interactions between the macromolecular components of cartilage ECM is essential to understand biological function and to develop successful tissue engineering strategies for cartilage repair.
    Journal of Polymer Science Part B Polymer Physics 12/2012; 50(24):1699-1705. · 2.55 Impact Factor
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    ABSTRACT: In earlier studies severe ventricular arrhythmias developed during intrapericardial (i.p.) endothelin-1 (ET-1) infusion. Monophasic action potential duration (MAPD90) increase and significant ST segment elevation preceded the onset of arrhythmias. The aim of this study was to test the antiarrhythmic and antiischemic efficacy of the mixed endothelin-A- and -B- (ETA/B) receptor antagonist bosentan (BOS) on ET-1-induced arrhythmias on six mongrel dogs. Ten minutes after an intravenous bolus dose of BOS (10 mg/kg), ET-1 (33 pmol/kg/min) was given into the pericardial space for 30 min (BOS group). Six control dogs received only ET-1 infusion (control group). Mean arterial blood pressure (MAP), cardiac output, electrocardiograph (ECG), right and left ventricular endo- and epicardial (RVEND, RVEP, LVEND, LVEP) MAPD90s were recorded. MAP and cardiac output did not change significantly in the BOS group. Significant MAPD90 prolongation was found in all investigated regions of the control group (ET start vs ET 20 min: LVEP, 174 +/- 3 vs 208 +/- 10*; RVEND, 206 +/- 9 vs 241 +/- 12* ms, *p < 0.05), while significant MAPD90 alterations were not observed in the BOS group (basic vs ET 20 min: RVEP, 189 +/- 5 vs 196 +/- 5; LVEP, 199 +/- 5 vs 199 +/- 4; RVEND, 194 +/- 5 vs 195 +/- 6; LVEND, 209 +/- 3 vs 213 +/- 5 ms). Early afterdepolarizations (EADs) were observed in three control dogs. Severe ventricular arrhythmias [incessant nonsustained ventricular tachycardias (nsVTs) in all cases, sustained VTs (sVTs) in four, ventricular fibrillation (VF) in two instances] were present in the control group, whereas nsVTs were observed only in two dogs in the BOS group. ST segment elevation was more pronounced in the control group than in the BOS group (1.01 +/- 0.2 vs 0.41 +/- 0.07 mV, p < 0.05). In summary, bosentan effectively inhibits intrapericardial ET-1-induced ventricular arrhythmias, moreover it may have a protective effect against epimyocardial ischemia. (C) 2000 Lippincott Williams & Wilkins, Inc.
    Journal of Cardiovascular Pharmacology 08/2012; 36. · 2.11 Impact Factor
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    ABSTRACT: Chondroitin sulphate (CS) is a linear sulfated polysaccharide found in cartilage and other tissues in the body. Small angle neutron scattering (SANS) and dynamic light scattering (DLS) measurements are made on semi-dilute CS solutions to determine ion induced changes in the local order of the CS chains and in their dynamic properties. In salt-free CS solutions SANS detects the correlation peak due to local ordering between adjacent chains in which the characteristic interchain distance is d ≈ 57 Å. In both monovalent and divalent salts (NaCl and CaCl2) aligned linear regions are distinguishable corresponding to distance scales ranging from the length of the monomer unit (8 Å) to about 1000 Å. With increasing calcium ion concentration, the scattering intensity increases. Even in the presence of 200 mM CaCl2, however, neither phase separation nor cross-linking occurs. DLS in the CS solutions reveals two characteristic relaxation modes, the fast mode corresponding to the thermal concentration fluctuations. The collective diffusion coefficient D decreases with increasing calcium ion concentration and exhibits a power law function of the single variable c/J, where c is the CS concentration and J is the ionic strength of the salt in the solution. This result implies that the effect of the sodium and calcium ions on the dynamic properties of CS solutions is fully accounted for by the ionic strength.
    Macromolecules 03/2012; 45(6):2882-2890. · 5.93 Impact Factor
  • Biophysical Journal 01/2012; 102(3):719-. · 3.83 Impact Factor
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    ABSTRACT: Because the boronic acid moiety reversibly binds to sugar molecules and has low cytotoxicity, boronic acid-containing hydrogels are being used in a variety of implantable glucose sensors under development, including sensors based on optical, fluorescence, and swelling pressure measurements. However, some method of glucose selectivity enhancement is often necessary, because isolated boronic acid molecules have a binding constant with glucose that is some forty times smaller than their binding constant with fructose, the second most abundant sugar in the human body. In many cases, glucose selectivity enhancement is obtained by incorporating pendant tertiary amines into the hydrogel network, thereby giving rise to a hydrogel that is zwitterionic at physiological pH. However, the mechanism by which incorporation of tertiary amines confers selectivity enhancement is poorly understood. In order to clarify this mechanism, we use the osmotic deswelling technique to compare the thermodynamic interactions of glucose and fructose with a zwitterionic smart hydrogel containing boronic acid moieties. We also investigate the change in the structure of the hydrogel that occurs when it binds to glucose or to fructose using the technique of small angle neutron scattering.
    Sensors and Actuators B Chemical 12/2011; 160(1):1363-1371. · 3.84 Impact Factor
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    ABSTRACT: Measurement of diffusion in porous materials and biological tissues with the pulsed field gradient (PFG) MR techniques has proven useful in characterizing the microstructure of such specimens noninvasively. A natural extension of the traditional PFG technique comprises multiple pairs of diffusion gradients. This approach has been shown to provide the ability to characterize anisotropy at different length scales without the need to employ very strong gradients. In this work, the double-PFG imaging technique was used on a specimen involving a series of glass capillary arrays with different diameters. The experiments on the phantom demonstrated the ability to create a quantitative and accurate map of pore sizes. The same technique was subsequently employed to image a celery stalk. A diffusion tensor image (DTI) of the same specimen was instrumental in accurately delineating the regions of vascular tissue and determining the local orientation of cells. This orientation information was incorporated into a theoretical double-PFG framework and the technique was employed to estimate the cell size in the vascular bundles of the celery stalk. The findings suggest that the double-PFG MRI framework could provide important new information regarding the microstructure of many plants and other food products.
    Magnetic Resonance in Chemistry 12/2011; 49 Suppl 1:S79-84. · 1.56 Impact Factor
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    ABSTRACT: The hierarchical organization of cartilage proteoglycans is investigated on different length and time scales using osmotic pressure measurements, small angle neutron scattering (SANS), small angle X-ray scattering (SAXS), static and dynamic light scattering and neutron spin echo techniques. Osmotic pressure measurements reveal association of aggrecan bottlebrushes into microgel-like assemblies. SAXS, SANS and light scattering results indicate weak interpenetration between neighboring aggrecan molecules. As opposed to DNA and many synthetic polyelectrolytes, which display great sensitivity to ion valence, aggrecan exhibits exceptional insensitivity to calcium ions in the physiological ion concentration range and beyond. This property allows aggrecan to play a role of ion reservoir that can mediate calcium metabolism in cartilage and bone.
    Macromolecular Symposia 09/2011; 306-307(1):11-17.
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    Preethi L Chandran, Ferenc Horkay
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    ABSTRACT: Aggrecan is a high-molecular-weight, bottlebrush-shaped, negatively charged biopolymer that forms supermolecular complexes with hyaluronic acid. In the extracellular matrix of cartilage, aggrecan-hyaluronic acid complexes are interspersed in a collagen meshwork and provide the osmotic properties required to resist deswelling under compressive load. In this review we compile aggrecan solution behavior from different experimental techniques, and discuss them in the context of concentration regimes that were identified in osmotic pressure experiments. At low concentrations, aggrecan exhibits microgel-like behavior. With increasing concentration, the bottlebrushes self-assemble into large complexes. In the physiological concentration range (2<c(aggrecan)<8% w/w), the physical properties of the solution are dominated by repulsive electrostatic interactions between aggrecan complexes. We discuss the consequences of the bottlebrush architecture on the polyelectrolyte characteristics of the aggrecan molecule, and its implications for cartilage properties and function.
    Acta biomaterialia 08/2011; 8(1):3-12. · 5.68 Impact Factor
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    ABSTRACT: Here we characterize the structure, stability and intracellular mode of action of DermaVir nanomedicine that is under clinical development for the treatment of HIV/AIDS. This nanomedicine comprises pathogen-like pDNA/PEIm nanoparticles (NPs) having the structure and function resembling spherical viruses that naturally evolved to deliver nucleic acids to the cells. Atomic force microscopy demonstrated spherical 100 - 200 nm NPs with a smooth polymer surface protecting the pDNA in the core. Optical absorption determined both the NP structural stability and biological activity relevant to their ability to escape from the endosome and release the pDNA at the nucleus. Salt, pH and temperature influence nanomedicine shelf-life and intracellular stability. This approach facilitates the development of diverse polyplex nanomedicines where the delivered pDNA-expressed antigens induce immune responses to kill infected cells. FROM THE CLINICAL EDITOR: The authors investigated DermaVir nanomedicine comprised of pathogen-like pDNA/PEIm nanoparticles with structure and function resembling spherical viruses. DermaVir delivery of pDNA expresses antigens that induce immune responses to kill HIV infected cells.
    Nanomedicine: nanotechnology, biology, and medicine 08/2011; 8(4):497-506. · 6.93 Impact Factor
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    ABSTRACT: For swollen polymer networks there is no generally accepted relation between the macroscopic osmotic properties and the scattering behaviour. Detailed information on the relationship between these properties can, however, be deduced from complementary measurements of osmotic and elastic behaviour, small angle neutron and X-ray scattering (SANS and SAXS) and quasi-elastic light scattering. We describe such an investigation in two types of networks, differing in the mechanism of cross-linking.The SANS spectra yield information on the structure, which is generated both by the dynamics of the system and by long range static constraints. The former, arising from thermodynamic concentration fluctuations, governs the macroscopic osmotic and elastic moduli of the swollen network.The static superstructure in the gel reflects local variations in the cross-link density. The resulting concentration polydispersity, <δφ2>/φ2, is determined by the details of the cross-linking procedure. Its concentration dependence as a function of gel swelling can be expressed in terms of the same macroscopic osmotic and elastic variables as those that govern the thermodynamic properties of the gel.
    Macromolecular Symposia 03/2011; 93(1):35 - 42.

Publication Stats

2k Citations
550.92 Total Impact Points


  • 2009–2014
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Maryland, United States
  • 2000–2014
    • National Institutes of Health
      • Section on Tissue Biophysics and Biomimetics
      Maryland, United States
  • 1995–2012
    • Semmelweis University
      • • Department of Cardiac Surgery
      • • First Department of Internal Medicine
      • • Department of Vascular Surgery
      Budapest, Budapest fovaros, Hungary
  • 2011
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 1989–2011
    • Eötvös Loránd University
      Budapeŝto, Budapest, Hungary
  • 2002–2008
    • National Institute of Child Health and Human Development
      Maryland, United States
    • Washington University in St. Louis
      • Department of Ophthalmology and Visual Sciences
      Saint Louis, MO, United States
  • 1989–2008
    • University Joseph Fourier - Grenoble 1
      • Laboratoire Interdisciplinaire de Physique
      Grenoble, Rhône-Alpes, France
  • 1980–2003
    • The National Institute of Child Health, Budapest
      Budapeŝto, Budapest, Hungary
  • 1994–1995
    • National Institute of Standards and Technology
      • Polymers Division
      Gaithersburg, MD, United States
  • 1990
    • University of Grenoble
      Grenoble, Rhône-Alpes, France
  • 1986
    • Hungarian Academy of Sciences
      Budapeŝto, Budapest, Hungary