Benjamin Keselowsky | University of Florida (original) (raw)

Papers by Benjamin Keselowsky

Proceedings of the First Joint BMES/EMBS Conference. 1999 IEEE Engineering in Medicine and Biology 21st Annual Conference and the 1999 Annual Fall Meeting of the Biomedical Engineering Society (Cat. No.99CH37015), 1999

Adsorption of fibronectin onto untreated and tissue culture grade polystyrenes and collagen type ... more Adsorption of fibronectin onto untreated and tissue culture grade polystyrenes and collagen type I resulted in changes in the conformation of the adsorbed molecule. These changes in conformation altered the binding of specific integrins (α3β1) to fibronectin. This modulation in integrin binding controlled osteoblast-specific gene expression in human SaOs-2 osteoblast-like cells. The principle of controlling cell function by conformational changes

Proceedings of the Second Joint 24th Annual Conference and the Annual Fall Meeting of the Biomedical Engineering Society] [Engineering in Medicine and Biology, 2002

... [2]lohnsar, Kamin. I., H mq Sage, Gina B"scoe, and Harold P. Erickson. &... more ... [2]lohnsar, Kamin. I., H mq Sage, Gina B"scoe, and Harold P. Erickson. "The Compact Confamtion of Fibconeclin Is Determined by Innarnolecvlar Ionic Interactions." J Bid Chem. 274 15473-79(1999). [3]Keselowsky, Benjamin G.. David M. Collard, and hdr& 1. Garcia. ...

Proceedings of the Second Joint 24th Annual Conference and the Annual Fall Meeting of the Biomedical Engineering Society] [Engineering in Medicine and Biology, 2002

Integrin-mediated adhesion to the extracellular matrix protein fibronectin (FN) triggers signals ... more Integrin-mediated adhesion to the extracellular matrix protein fibronectin (FN) triggers signals that control proliferation, gene expression and matrix mineralization in osteoblasts. We have engineered model surfaces presenting well-defined chemistries that modulate FN adsorption/conformation, integrin binding and focal adhesion assembly. These changes in adhesive interactions modulate osteoblast-specific gene expression and matrix mineralization.

Scientific reports, 2015

Targeted delivery of self-antigens to the immune system in a mode that stimulates a tolerance-ind... more Targeted delivery of self-antigens to the immune system in a mode that stimulates a tolerance-inducing pathway has proven difficult. To address this hurdle, we developed a vaccine based-approach comprised of two synthetic controlled-release biomaterials, poly(lactide-co-glycolide; PLGA) microparticles (MPs) encapsulating denatured insulin (key self-antigen in type 1 diabetes; T1D), and PuraMatrix(TM) peptide hydrogel containing granulocyte macrophage colony-stimulating factor (GM-CSF) and CpG ODN1826 (CpG), which were included as vaccine adjuvants to recruit and activate immune cells. Although CpG is normally considered pro-inflammatory, it also has anti-inflammatory effects, including enhancing IL-10 production. Three subcutaneous administrations of this hydrogel (GM-CSF/CpG)/insulin-MP vaccine protected 40% of NOD mice from T1D. In contrast, all control mice became diabetic. In vitro studies indicate CpG stimulation increased IL-10 production, as a potential mechanism. Multiple su...

Proceedings of the National Academy of Sciences of the United States of America, Jan 29, 2015

A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneo... more A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneous phenotypes within a tumor. The cancer stem cell hypothesis postulates that a minute fraction of cells within a tumor, termed cancer stem cells (CSCs), have a tumor-initiating capacity that propels tumor growth. An application of this discovery is to target this critical cell population using chemotherapy; however, the process of isolating these cells is arduous, and the rarity of CSCs makes it difficult to test potential drug candidates in a robust fashion, particularly for individual patients. To address the challenge of screening drug libraries on patient-derived populations of rare cells, such as CSCs, we have developed a drug-eluting microarray, a miniaturized platform onto which a minimal quantity of cells can adhere and be exposed to unique treatment conditions. Hundreds of drug-loaded polymer islands acting as drug depots colocalized with adherent cells are surrounded by a nonf...

The ability to control the behavior of cells interacting with materials is desirable for the succ... more The ability to control the behavior of cells interacting with materials is desirable for the success of implanted devices such as biosensors or drug delivery devices. In this study, we investigated the use of ZnO nanorods for modulating the adhesion and viability of NIH 3T3 fibroblasts, umbilical vein endothelial cells and capillary endothelial cells. Cells adhered far less to ZnO nanorods than the ZnO flat substrate. The few cells that adhered on the nanorods were not viable and rounded. Cells were unable to assemble focal adhesions and stress fibers on nanorods. Time-lapse imaging revealed that cells that initially adhered to nanorods were unable to spread. This suggests that it is the lack of initial spreading, rather than the long-term exposure to ZnO that causes cell death. We conclude that ZnO nanorods are potentially useful as an adhesion-resistant biomaterial capable of reducing viability in anchorage-dependent cells.

Clinical immunology (Orlando, Fla.), 2015

We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing con... more We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing concurrent delivery of multiple encapsulated immuno-suppressive factors and antigen, for in vivo conditioning of dendritic cells (DCs) toward a tolerance promoting pathway. Subcutaneous administration prevents onset of type 1 diabetes (T1D) in NOD mice. Two MP sizes were made: phagocytosable MPs were fabricated encapsulating vitamin D3 or insulin B(9-23) peptide, while unphagocytosable MPs were fabricated encapsulating TGF-β1 or GM-CSF. The combination of Vit D3/TGF-β1 MPs confers an immature and LPS activation-resistant phenotype to DCs, and MP-delivered antigen is efficiently and functionally presented. Notably, two subcutaneous injections into 4week old NOD mice using the combination of MPs encapsulating Vit D3, Ins B, TGF-β1 and GM-CSF protected 40% of mice from T1D development, significant in comparison to the control. This work represents one of the first applications of a biomaterial...

Biointerfacial Strategies, Tissue Engineering And Targeted Drug Delivery, 2002

Engineering of Integrin-Specific Biomimetic Surfaces to Control Cell Adhesion and Function Andres... more Engineering of Integrin-Specific Biomimetic Surfaces to Control Cell Adhesion and Function Andres J. Garcia, David M. Collard, Benjamin G. Keselowsky, Sarah M. Cutler, Nathan D. Gallant, Benjamin A. Byers, and Sean N. Stephansson Georgia Institute of Technology, Atlanta ...

Smart Biomedical and Physiological Sensor Technology VI, 2009

Imaging of immune system and tissue response to immunogenic agents can be important to the develo... more Imaging of immune system and tissue response to immunogenic agents can be important to the development of new biomaterials. Additionally, quantitative functional imaging can be useful for testing and evaluation of methods to alter or control the immune system response to implanted materials. In this preliminary study, we employ spectral imaging and fluorescence imaging to measure immune system and tissue

Bio-inspired Materials for Biomedical Engineering, 2014

ABSTRACT Biomedical engineers have taken aim at modulating host immune responses, including the f... more ABSTRACT Biomedical engineers have taken aim at modulating host immune responses, including the foreign body reaction, to desired outcomes for improved diagnostic and therapeutic applications. This marriage of materials engineering and immunobiology has led to new immunomodulatory materials. This chapter highlights development and application of a number of immunomodulatory materials, categorized by the following general approaches: (a) surface motifs targeting cell surface receptors to direct immune cell responses; (b) morphogenic factor-related materials that release growth, differentiation, chemotactic, and immune-modulating factors; (c) stimuli-responsive materials that influence immune cell responses based on environmental conditions; and (d) self-assembly motifs, that when assembled, influence immune responses.

Angiogenesis, 2014

Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are direct... more Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are directly connected through a complex, tangled web of abnormal AV fistulae without a normal capillary network. Hereditary hemorrhagic telangiectasia (HHT) types 1 and 2 arise from heterozygous mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively. HHT patients possess AVMs in various organs, and telangiectases (small AVMs) along the mucocutaneous surface. Understanding why and how AVMs develop is crucial for developing therapies to inhibit the formation, growth, or maintenance of AVMs in HHT patients. Previously, we have shown that secondary factors such as wounding are required for Alk1-deficient vessels to develop skin AVMs. Here, we present evidences that AVMs establish from nascent arteries and veins rather than from remodeling of a preexistent capillary network in the wound-induced skin AVM model. We also show that VEGF can mimic the wound effect on skin AVM formation, and VEGF-neutralizing antibody can prevent skin AVM formation and ameliorate internal bleeding in Alk1-deficient adult mice. With topical applications at different stages of AVM development, we demonstrate that the VEGF blockade can prevent the formation of AVM and cease the progression of AVM development. Taken together, the presented experimental model is an invaluable system for precise molecular mechanism of action of VEGF blockades as well as for preclinical screening of drug candidates for epistaxis and gastrointestinal bleedings.

Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy, 2011

Tribology Letters, 2010

Living human corneal epithelial cells have been probed in vitro via atomic force microscopy, reve... more Living human corneal epithelial cells have been probed in vitro via atomic force microscopy, revealing the frictional characteristics of single cells. Under cell media, measured shear stresses of 0.40 kPa demonstrate the high lubricity of epithelial cell surfaces in contact with a microsphere probe. The mechanical properties of individual epithelial cells have been further probed through nanometer scale indentation measurements. A simple elastic foundation model, based on experimentally verifiable parameters, is used to fit the indentation data, producing an effective elastic modulus of 16.5 kPa and highlighting the highly compliant nature of the cell surface. The elastic foundation model is found to more accurately fit the experimental data, to avoid unverifiable assumptions, and to produce a modulus significantly higher than that of the widely used Hertz-Sneddon model.

Tribology Letters, 2007

Arterial stent deployment by balloon or selfexpandable structure introduces shear forces and radi... more Arterial stent deployment by balloon or selfexpandable structure introduces shear forces and radial forces that can damage or remove the endothelial cell layer. These factors can subsequently cause failure by restenosis or endothelial leaks. These conditions can be exacerbated by pulsatile blood flow and arterial asymmetry, which can cause migration or displacement. In mechanical or finiteelement models which attempt to explain this motion, friction between the stent materials and endothelial cells is eclipsed by pressure, or assumptions that cells are moved along with the stent. During device deployment or migration, some relative motion between stent materials and endothelial cells occurs. This study aims to quantify friction between a polished glass pin and a single layer of arterial endothelial cells, and include observations of cell damage in an attempt to better understand the biological response to tribological stresses. Measured friction coefficient values were on the order of l = 0.03-0.06.

Proceedings of the National Academy of Sciences, 2005

Biomaterial surface chemistry has profound consequences on cellular and host responses, but the u... more Biomaterial surface chemistry has profound consequences on cellular and host responses, but the underlying molecular mechanisms remain poorly understood. Using self-assembled monolayers as model biomaterial surfaces presenting well defined chemistries, we demonstrate that surface chemistry modulates osteoblastic differentiation and matrix mineralization independently from alterations in cell proliferation. Surfaces were precoated with equal densities of fibronectin (FN), and surface chemistry modulated FN structure to alter integrin adhesion receptor binding. OH- and NH(2)-terminated surfaces up-regulated osteoblast-specific gene expression, alkaline phosphatase enzymatic activity, and matrix mineralization compared with surfaces presenting COOH and CH(3) groups. These surface chemistry-dependent differences in cell differentiation were controlled by binding of specific integrins to adsorbed FN. Function-perturbing antibodies against the central cell binding domain of FN completely inhibited matrix mineralization. Furthermore, blocking antibodies against beta(1) integrin inhibited matrix mineralization on the OH and NH(2) surfaces, whereas function-perturbing antibodies specific for beta(3) integrin increased mineralization on the COOH substrate. These results establish surface-dependent differences in integrin binding as a mechanism regulating differential cellular responses to biomaterial surfaces. This mechanism could be exploited to engineer materials that control integrin binding specificity to elicit desired cellular activities to enhance the integration of biomaterials and improve the performance of biotechnological culture supports.

Molecular and Cellular Neuroscience, 2004

Early inductive signals within the embryonic mammalian forebrain establish two major germinal reg... more Early inductive signals within the embryonic mammalian forebrain establish two major germinal regions along the dorsal-ventral axis. The dorsal germinal zone eventually forms the cerebral cortex while the ventral ganglionic eminence primarily forms the striatum and globus pallidus. The mechanisms leading to patterning of specific forebrain structures from these distinct germinal regions are not fully understood but may involve the adhesive and migratory properties of regionally specified cells and their interactions with the extracellular environments in which they reside. In the present study, we isolated ganglionic eminence neural progenitor cells (geNPC), precursors of the adult striatum, from the ventral forebrain germinal zone and analyzed adhesion, migration, and differentiation of geNPC on various extracellular matrix (ECM) substrates in vitro. Specifically, we evaluated the role of beta1 integrins, a family of cell surface receptors important in neural development, in mediating geNPC behavior on ECM molecules expressed in embryonic brain tissue. Adhesion and migration of geNPC were significantly enhanced on laminin (LN) and fibronectin (FN) relative to other ECM substrates. Antibody perturbation experiments revealed that although geNPC express several beta1 integrins (alpha1beta1, alpha2beta1, alpha3beta1, alpha5beta1, alpha6beta1, alphavbeta1), adhesion and migration on LN and FN were primarily mediated by alpha6beta1 and alpha5beta1, respectively, and these interactions were confirmed by biochemical cross-link/extraction procedures. Finally, neuronal differentiation of geNPC was enhanced on LN, indicating a role for LN in geNPC differentiation. beta1 integrin-ECM interactions may contribute to basic mechanisms of striatal development and may explain the potent migratory capacity of geNPC transplanted into the adult brain.

MRS Bulletin, 2014

ABSTRACT Recently, biomaterial scientists have married materials engineering and immunobiology to... more ABSTRACT Recently, biomaterial scientists have married materials engineering and immunobiology to conceptualize new immunomodulatory materials. This special class of biomaterials can modulate and harness the innate properties of immune functionality for enhanced therapeutic efficacy. Generally, two fundamental strategies are followed in the design of immunomodulatory biomaterials: (1) immuno-evasive (immuno-mimetic, immuno-suppressing, or immuno-inert) biomaterials and (2) immuno-activating or immuno-enhancing biomaterials. This article highlights the development and application of a number of immunomodulatory materials, categorized by these two general approaches.

Langmuir, 2003

Protein adsorption onto synthetic materials influences cell adhesion and signaling events that di... more Protein adsorption onto synthetic materials influences cell adhesion and signaling events that direct cell function in numerous biomedical applications. Adsorption of fibronectin (FN) to different surfaces alters protein structure and modulates R5 1 integrin binding, cell adhesion, cell spreading, and cell migration. In the present study, self-assembled monolayers of alkanethiols on Au were used to analyze the effects of surface chemistry (CH 3, OH, NH2, and COOH) on the adsorption of a recombinant fragment of FN, FNIII7-10, that incorporates both the synergy and RGD cell binding motifs. Surface chemistry potentiated differential FNIII7-10 adsorption kinetics and adsorbed structure as determined by surface plasmon resonance spectroscopy and antibody binding assays. FNIII7-10 functional activity, determined by cell adhesion strength, was modulated in a fashion consistent with these structural changes (OH ) NH2 > COOH > CH3). However, these changes in protein parameters did not correlate simply to differences in surface hydrophobicity, indicating that additional surface parameters influence protein adsorption. These results demonstrate that surface chemistry modulates adsorbed protein structure and activity and establish a relationship between surface-dependent changes in structural domains of FNIII 7-10 and functional activity.

JOM, 2011

…describe the overall signifi cance of this paper? The development of biodegradable implant mater... more …describe the overall signifi cance of this paper? The development of biodegradable implant materials is a complex and interdisciplinary problem. This paper enumerates a design approach that utilizes experimental research coupled with modeling and simulation to reduce the cost and time associated with the development of new materials. …describe this work to a materials science and engineering professional with no experience in your technical specialty? There has been signifi cant interest in the development of biodegradable magnesium alloys for implant applications. This paper illustrates the design strategy which combines experimental research with computational thermodynamics and mechanistic modeling. It also explains in detail the important factors that need to be considered while designing for properties like strength, biocompatibility, and corrosion resistance. …describe this work to a layperson? Biodegradable implants are an important tool in repairing and healing damaged body parts. In the past few years, there has been signifi cant interest in developing magnesium alloys for biodegradable implant applications. This paper describes a systematic approach for designing new materials and illustrates the possible use of this approach in developing biodegradable and biocompatible magnesium alloys. The integration of biodegradable and bioabsorbable magnesium implants into the human body is a complex undertaking that faces major challenges. Candidate biomaterials must meet both engineering and physiological requirements to ensure the desired properties. Historically, efforts have been focused on the behavior of commercial magnesium alloys in biological environments and their resultant effect on cell-mediated processes. Developing causal relationships between alloy chemistry and microstructure, and effects as a cellular behavior can be a diffi cult and time-intensive process. A systems design approach has the power to provide signifi cant contributions in the development of the next generation of magnesium alloy implants with controlled degradability, biocompatibility, and optimized mechanical properties, at reduced time and cost. This approach couples experimental research with theory and mechanistic modeling for the accelerated development of materials. The aim of this article is to enumerate this strategy, design considerations, and hurdles for developing new cast magnesium alloys for use as biodegradable implant materials. Harpreet S. Brar and Michele V.

Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2012

Magnesium has recently received an increased amount of interest due to its potential use in biode... more Magnesium has recently received an increased amount of interest due to its potential use in biodegradable implant applications. The rapid degradation of conventional Mg is, however, a major limitation that needs to be addressed in the design of these materials, along with consideration of toxicity in selection of alloying elements. In this study, five alloys in the Mg-xCa-ySr system (x ¼ 0.5-7.0 wt %; y ¼ 0.5-3.5 wt %) were prepared and characterized for their suitability as degradable orthopedic implant materials. The alloys were characterized using optical microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, degradation measurements in Hanks' solution at 37 C, compression testing, and in vitro cytotoxicity testing with a mouse osteoblastic cell line. The results indicate that the Mg-1.0Ca-0.5Sr alloy is the most promising alloy for orthopedic implant applications since it showed the lowest degradation rate in Hanks' solution (0.01 mL cm À2 h À1 ) along with no significant toxicity to MC3T3-E1 osteoblasts and a compressive strength of 274 6 4 MPa. V C 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 100B: 1524-1534, 2012.

Proceedings of the First Joint BMES/EMBS Conference. 1999 IEEE Engineering in Medicine and Biology 21st Annual Conference and the 1999 Annual Fall Meeting of the Biomedical Engineering Society (Cat. No.99CH37015), 1999

Adsorption of fibronectin onto untreated and tissue culture grade polystyrenes and collagen type ... more Adsorption of fibronectin onto untreated and tissue culture grade polystyrenes and collagen type I resulted in changes in the conformation of the adsorbed molecule. These changes in conformation altered the binding of specific integrins (α3β1) to fibronectin. This modulation in integrin binding controlled osteoblast-specific gene expression in human SaOs-2 osteoblast-like cells. The principle of controlling cell function by conformational changes

Proceedings of the Second Joint 24th Annual Conference and the Annual Fall Meeting of the Biomedical Engineering Society] [Engineering in Medicine and Biology, 2002

... [2]lohnsar, Kamin. I., H mq Sage, Gina B"scoe, and Harold P. Erickson. &... more ... [2]lohnsar, Kamin. I., H mq Sage, Gina B"scoe, and Harold P. Erickson. "The Compact Confamtion of Fibconeclin Is Determined by Innarnolecvlar Ionic Interactions." J Bid Chem. 274 15473-79(1999). [3]Keselowsky, Benjamin G.. David M. Collard, and hdr& 1. Garcia. ...

Proceedings of the Second Joint 24th Annual Conference and the Annual Fall Meeting of the Biomedical Engineering Society] [Engineering in Medicine and Biology, 2002

Integrin-mediated adhesion to the extracellular matrix protein fibronectin (FN) triggers signals ... more Integrin-mediated adhesion to the extracellular matrix protein fibronectin (FN) triggers signals that control proliferation, gene expression and matrix mineralization in osteoblasts. We have engineered model surfaces presenting well-defined chemistries that modulate FN adsorption/conformation, integrin binding and focal adhesion assembly. These changes in adhesive interactions modulate osteoblast-specific gene expression and matrix mineralization.

Scientific reports, 2015

Targeted delivery of self-antigens to the immune system in a mode that stimulates a tolerance-ind... more Targeted delivery of self-antigens to the immune system in a mode that stimulates a tolerance-inducing pathway has proven difficult. To address this hurdle, we developed a vaccine based-approach comprised of two synthetic controlled-release biomaterials, poly(lactide-co-glycolide; PLGA) microparticles (MPs) encapsulating denatured insulin (key self-antigen in type 1 diabetes; T1D), and PuraMatrix(TM) peptide hydrogel containing granulocyte macrophage colony-stimulating factor (GM-CSF) and CpG ODN1826 (CpG), which were included as vaccine adjuvants to recruit and activate immune cells. Although CpG is normally considered pro-inflammatory, it also has anti-inflammatory effects, including enhancing IL-10 production. Three subcutaneous administrations of this hydrogel (GM-CSF/CpG)/insulin-MP vaccine protected 40% of NOD mice from T1D. In contrast, all control mice became diabetic. In vitro studies indicate CpG stimulation increased IL-10 production, as a potential mechanism. Multiple su...

Proceedings of the National Academy of Sciences of the United States of America, Jan 29, 2015

A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneo... more A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneous phenotypes within a tumor. The cancer stem cell hypothesis postulates that a minute fraction of cells within a tumor, termed cancer stem cells (CSCs), have a tumor-initiating capacity that propels tumor growth. An application of this discovery is to target this critical cell population using chemotherapy; however, the process of isolating these cells is arduous, and the rarity of CSCs makes it difficult to test potential drug candidates in a robust fashion, particularly for individual patients. To address the challenge of screening drug libraries on patient-derived populations of rare cells, such as CSCs, we have developed a drug-eluting microarray, a miniaturized platform onto which a minimal quantity of cells can adhere and be exposed to unique treatment conditions. Hundreds of drug-loaded polymer islands acting as drug depots colocalized with adherent cells are surrounded by a nonf...

The ability to control the behavior of cells interacting with materials is desirable for the succ... more The ability to control the behavior of cells interacting with materials is desirable for the success of implanted devices such as biosensors or drug delivery devices. In this study, we investigated the use of ZnO nanorods for modulating the adhesion and viability of NIH 3T3 fibroblasts, umbilical vein endothelial cells and capillary endothelial cells. Cells adhered far less to ZnO nanorods than the ZnO flat substrate. The few cells that adhered on the nanorods were not viable and rounded. Cells were unable to assemble focal adhesions and stress fibers on nanorods. Time-lapse imaging revealed that cells that initially adhered to nanorods were unable to spread. This suggests that it is the lack of initial spreading, rather than the long-term exposure to ZnO that causes cell death. We conclude that ZnO nanorods are potentially useful as an adhesion-resistant biomaterial capable of reducing viability in anchorage-dependent cells.

Clinical immunology (Orlando, Fla.), 2015

We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing con... more We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing concurrent delivery of multiple encapsulated immuno-suppressive factors and antigen, for in vivo conditioning of dendritic cells (DCs) toward a tolerance promoting pathway. Subcutaneous administration prevents onset of type 1 diabetes (T1D) in NOD mice. Two MP sizes were made: phagocytosable MPs were fabricated encapsulating vitamin D3 or insulin B(9-23) peptide, while unphagocytosable MPs were fabricated encapsulating TGF-β1 or GM-CSF. The combination of Vit D3/TGF-β1 MPs confers an immature and LPS activation-resistant phenotype to DCs, and MP-delivered antigen is efficiently and functionally presented. Notably, two subcutaneous injections into 4week old NOD mice using the combination of MPs encapsulating Vit D3, Ins B, TGF-β1 and GM-CSF protected 40% of mice from T1D development, significant in comparison to the control. This work represents one of the first applications of a biomaterial...

Biointerfacial Strategies, Tissue Engineering And Targeted Drug Delivery, 2002

Engineering of Integrin-Specific Biomimetic Surfaces to Control Cell Adhesion and Function Andres... more Engineering of Integrin-Specific Biomimetic Surfaces to Control Cell Adhesion and Function Andres J. Garcia, David M. Collard, Benjamin G. Keselowsky, Sarah M. Cutler, Nathan D. Gallant, Benjamin A. Byers, and Sean N. Stephansson Georgia Institute of Technology, Atlanta ...

Smart Biomedical and Physiological Sensor Technology VI, 2009

Imaging of immune system and tissue response to immunogenic agents can be important to the develo... more Imaging of immune system and tissue response to immunogenic agents can be important to the development of new biomaterials. Additionally, quantitative functional imaging can be useful for testing and evaluation of methods to alter or control the immune system response to implanted materials. In this preliminary study, we employ spectral imaging and fluorescence imaging to measure immune system and tissue

Bio-inspired Materials for Biomedical Engineering, 2014

ABSTRACT Biomedical engineers have taken aim at modulating host immune responses, including the f... more ABSTRACT Biomedical engineers have taken aim at modulating host immune responses, including the foreign body reaction, to desired outcomes for improved diagnostic and therapeutic applications. This marriage of materials engineering and immunobiology has led to new immunomodulatory materials. This chapter highlights development and application of a number of immunomodulatory materials, categorized by the following general approaches: (a) surface motifs targeting cell surface receptors to direct immune cell responses; (b) morphogenic factor-related materials that release growth, differentiation, chemotactic, and immune-modulating factors; (c) stimuli-responsive materials that influence immune cell responses based on environmental conditions; and (d) self-assembly motifs, that when assembled, influence immune responses.

Angiogenesis, 2014

Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are direct... more Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are directly connected through a complex, tangled web of abnormal AV fistulae without a normal capillary network. Hereditary hemorrhagic telangiectasia (HHT) types 1 and 2 arise from heterozygous mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively. HHT patients possess AVMs in various organs, and telangiectases (small AVMs) along the mucocutaneous surface. Understanding why and how AVMs develop is crucial for developing therapies to inhibit the formation, growth, or maintenance of AVMs in HHT patients. Previously, we have shown that secondary factors such as wounding are required for Alk1-deficient vessels to develop skin AVMs. Here, we present evidences that AVMs establish from nascent arteries and veins rather than from remodeling of a preexistent capillary network in the wound-induced skin AVM model. We also show that VEGF can mimic the wound effect on skin AVM formation, and VEGF-neutralizing antibody can prevent skin AVM formation and ameliorate internal bleeding in Alk1-deficient adult mice. With topical applications at different stages of AVM development, we demonstrate that the VEGF blockade can prevent the formation of AVM and cease the progression of AVM development. Taken together, the presented experimental model is an invaluable system for precise molecular mechanism of action of VEGF blockades as well as for preclinical screening of drug candidates for epistaxis and gastrointestinal bleedings.

Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy, 2011

Tribology Letters, 2010

Living human corneal epithelial cells have been probed in vitro via atomic force microscopy, reve... more Living human corneal epithelial cells have been probed in vitro via atomic force microscopy, revealing the frictional characteristics of single cells. Under cell media, measured shear stresses of 0.40 kPa demonstrate the high lubricity of epithelial cell surfaces in contact with a microsphere probe. The mechanical properties of individual epithelial cells have been further probed through nanometer scale indentation measurements. A simple elastic foundation model, based on experimentally verifiable parameters, is used to fit the indentation data, producing an effective elastic modulus of 16.5 kPa and highlighting the highly compliant nature of the cell surface. The elastic foundation model is found to more accurately fit the experimental data, to avoid unverifiable assumptions, and to produce a modulus significantly higher than that of the widely used Hertz-Sneddon model.

Tribology Letters, 2007

Arterial stent deployment by balloon or selfexpandable structure introduces shear forces and radi... more Arterial stent deployment by balloon or selfexpandable structure introduces shear forces and radial forces that can damage or remove the endothelial cell layer. These factors can subsequently cause failure by restenosis or endothelial leaks. These conditions can be exacerbated by pulsatile blood flow and arterial asymmetry, which can cause migration or displacement. In mechanical or finiteelement models which attempt to explain this motion, friction between the stent materials and endothelial cells is eclipsed by pressure, or assumptions that cells are moved along with the stent. During device deployment or migration, some relative motion between stent materials and endothelial cells occurs. This study aims to quantify friction between a polished glass pin and a single layer of arterial endothelial cells, and include observations of cell damage in an attempt to better understand the biological response to tribological stresses. Measured friction coefficient values were on the order of l = 0.03-0.06.

Proceedings of the National Academy of Sciences, 2005

Biomaterial surface chemistry has profound consequences on cellular and host responses, but the u... more Biomaterial surface chemistry has profound consequences on cellular and host responses, but the underlying molecular mechanisms remain poorly understood. Using self-assembled monolayers as model biomaterial surfaces presenting well defined chemistries, we demonstrate that surface chemistry modulates osteoblastic differentiation and matrix mineralization independently from alterations in cell proliferation. Surfaces were precoated with equal densities of fibronectin (FN), and surface chemistry modulated FN structure to alter integrin adhesion receptor binding. OH- and NH(2)-terminated surfaces up-regulated osteoblast-specific gene expression, alkaline phosphatase enzymatic activity, and matrix mineralization compared with surfaces presenting COOH and CH(3) groups. These surface chemistry-dependent differences in cell differentiation were controlled by binding of specific integrins to adsorbed FN. Function-perturbing antibodies against the central cell binding domain of FN completely inhibited matrix mineralization. Furthermore, blocking antibodies against beta(1) integrin inhibited matrix mineralization on the OH and NH(2) surfaces, whereas function-perturbing antibodies specific for beta(3) integrin increased mineralization on the COOH substrate. These results establish surface-dependent differences in integrin binding as a mechanism regulating differential cellular responses to biomaterial surfaces. This mechanism could be exploited to engineer materials that control integrin binding specificity to elicit desired cellular activities to enhance the integration of biomaterials and improve the performance of biotechnological culture supports.

Molecular and Cellular Neuroscience, 2004

Early inductive signals within the embryonic mammalian forebrain establish two major germinal reg... more Early inductive signals within the embryonic mammalian forebrain establish two major germinal regions along the dorsal-ventral axis. The dorsal germinal zone eventually forms the cerebral cortex while the ventral ganglionic eminence primarily forms the striatum and globus pallidus. The mechanisms leading to patterning of specific forebrain structures from these distinct germinal regions are not fully understood but may involve the adhesive and migratory properties of regionally specified cells and their interactions with the extracellular environments in which they reside. In the present study, we isolated ganglionic eminence neural progenitor cells (geNPC), precursors of the adult striatum, from the ventral forebrain germinal zone and analyzed adhesion, migration, and differentiation of geNPC on various extracellular matrix (ECM) substrates in vitro. Specifically, we evaluated the role of beta1 integrins, a family of cell surface receptors important in neural development, in mediating geNPC behavior on ECM molecules expressed in embryonic brain tissue. Adhesion and migration of geNPC were significantly enhanced on laminin (LN) and fibronectin (FN) relative to other ECM substrates. Antibody perturbation experiments revealed that although geNPC express several beta1 integrins (alpha1beta1, alpha2beta1, alpha3beta1, alpha5beta1, alpha6beta1, alphavbeta1), adhesion and migration on LN and FN were primarily mediated by alpha6beta1 and alpha5beta1, respectively, and these interactions were confirmed by biochemical cross-link/extraction procedures. Finally, neuronal differentiation of geNPC was enhanced on LN, indicating a role for LN in geNPC differentiation. beta1 integrin-ECM interactions may contribute to basic mechanisms of striatal development and may explain the potent migratory capacity of geNPC transplanted into the adult brain.

MRS Bulletin, 2014

ABSTRACT Recently, biomaterial scientists have married materials engineering and immunobiology to... more ABSTRACT Recently, biomaterial scientists have married materials engineering and immunobiology to conceptualize new immunomodulatory materials. This special class of biomaterials can modulate and harness the innate properties of immune functionality for enhanced therapeutic efficacy. Generally, two fundamental strategies are followed in the design of immunomodulatory biomaterials: (1) immuno-evasive (immuno-mimetic, immuno-suppressing, or immuno-inert) biomaterials and (2) immuno-activating or immuno-enhancing biomaterials. This article highlights the development and application of a number of immunomodulatory materials, categorized by these two general approaches.

Langmuir, 2003

Protein adsorption onto synthetic materials influences cell adhesion and signaling events that di... more Protein adsorption onto synthetic materials influences cell adhesion and signaling events that direct cell function in numerous biomedical applications. Adsorption of fibronectin (FN) to different surfaces alters protein structure and modulates R5 1 integrin binding, cell adhesion, cell spreading, and cell migration. In the present study, self-assembled monolayers of alkanethiols on Au were used to analyze the effects of surface chemistry (CH 3, OH, NH2, and COOH) on the adsorption of a recombinant fragment of FN, FNIII7-10, that incorporates both the synergy and RGD cell binding motifs. Surface chemistry potentiated differential FNIII7-10 adsorption kinetics and adsorbed structure as determined by surface plasmon resonance spectroscopy and antibody binding assays. FNIII7-10 functional activity, determined by cell adhesion strength, was modulated in a fashion consistent with these structural changes (OH ) NH2 > COOH > CH3). However, these changes in protein parameters did not correlate simply to differences in surface hydrophobicity, indicating that additional surface parameters influence protein adsorption. These results demonstrate that surface chemistry modulates adsorbed protein structure and activity and establish a relationship between surface-dependent changes in structural domains of FNIII 7-10 and functional activity.

JOM, 2011

…describe the overall signifi cance of this paper? The development of biodegradable implant mater... more …describe the overall signifi cance of this paper? The development of biodegradable implant materials is a complex and interdisciplinary problem. This paper enumerates a design approach that utilizes experimental research coupled with modeling and simulation to reduce the cost and time associated with the development of new materials. …describe this work to a materials science and engineering professional with no experience in your technical specialty? There has been signifi cant interest in the development of biodegradable magnesium alloys for implant applications. This paper illustrates the design strategy which combines experimental research with computational thermodynamics and mechanistic modeling. It also explains in detail the important factors that need to be considered while designing for properties like strength, biocompatibility, and corrosion resistance. …describe this work to a layperson? Biodegradable implants are an important tool in repairing and healing damaged body parts. In the past few years, there has been signifi cant interest in developing magnesium alloys for biodegradable implant applications. This paper describes a systematic approach for designing new materials and illustrates the possible use of this approach in developing biodegradable and biocompatible magnesium alloys. The integration of biodegradable and bioabsorbable magnesium implants into the human body is a complex undertaking that faces major challenges. Candidate biomaterials must meet both engineering and physiological requirements to ensure the desired properties. Historically, efforts have been focused on the behavior of commercial magnesium alloys in biological environments and their resultant effect on cell-mediated processes. Developing causal relationships between alloy chemistry and microstructure, and effects as a cellular behavior can be a diffi cult and time-intensive process. A systems design approach has the power to provide signifi cant contributions in the development of the next generation of magnesium alloy implants with controlled degradability, biocompatibility, and optimized mechanical properties, at reduced time and cost. This approach couples experimental research with theory and mechanistic modeling for the accelerated development of materials. The aim of this article is to enumerate this strategy, design considerations, and hurdles for developing new cast magnesium alloys for use as biodegradable implant materials. Harpreet S. Brar and Michele V.

Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2012

Magnesium has recently received an increased amount of interest due to its potential use in biode... more Magnesium has recently received an increased amount of interest due to its potential use in biodegradable implant applications. The rapid degradation of conventional Mg is, however, a major limitation that needs to be addressed in the design of these materials, along with consideration of toxicity in selection of alloying elements. In this study, five alloys in the Mg-xCa-ySr system (x ¼ 0.5-7.0 wt %; y ¼ 0.5-3.5 wt %) were prepared and characterized for their suitability as degradable orthopedic implant materials. The alloys were characterized using optical microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, degradation measurements in Hanks' solution at 37 C, compression testing, and in vitro cytotoxicity testing with a mouse osteoblastic cell line. The results indicate that the Mg-1.0Ca-0.5Sr alloy is the most promising alloy for orthopedic implant applications since it showed the lowest degradation rate in Hanks' solution (0.01 mL cm À2 h À1 ) along with no significant toxicity to MC3T3-E1 osteoblasts and a compressive strength of 274 6 4 MPa. V C 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 100B: 1524-1534, 2012.