Comparative Tumor Models: Use for Assessing Novel Drug Strategies   |   View Presentation

Dr. Timothy Fan, Associate Professor of Veterinary Clinical Medicine

Thursday, November 29, 2011
1000 MNTL, 12:00 - 1:00 PM

Abstract: Basic science in nanomedicine has rapidly advanced over the past decade, and has generated fundamentally important discoveries.  However, clinical translation of nanomedicine remains in its infancy, and the development of nanotechnology platforms as novel drug delivery strategies for the treatment of cancer in people has not been fully explored.  Comparative oncology is the study of shared commonalities in tumor biology among different species.  In addition to human beings, the only other large mammal that develops spontaneous cancers with any frequency is the dog.  Through the use of pet dogs with spontaneously-arising cancers, it is feasible to evaluate the safety and anticancer activities of nanoparticle drug delivery strategies.  This seminar will highlight the use of canine tumor xenograft models, as well as, dogs with spontaneously-arising tumors for the testing and validation of targeted nanoparticle drug delivery strategies.  Based upon these preclinical and clinical investigations, scientific findings provide foundational support to advance the use of targeted nanoconjugates for the management of common tumors in people.

 

Pluripotency and Directed Differentiation of Human Pluripotent Stem Cells   |   View Presentation

Dr. Fei Wang, Assistant Professor of Cell and Developmental Biology

Thursday, November 17, 2011
1000 MNTL, 12:00 - 1:00 PM

Abstract: Our long-term goal is to define new conditions and molecular programs that govern fate decisions of human pluripotent stem cells such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). The knowledge is essential if we are ultimately to use these cells for therapy. To dissect the mechanism underlying hESC/hiPSC fate determination, we screened a collection of pharmacological inhibitors (~50) against kinases and other signaling molecules, enabling us to identify mTOR as a critical pluripotency-maintaining molecule in hESCs and uncover an mTOR-dependent signaling mechanism that suppresses mesoderm and endoderm differentiation. The screening efforts led us to also identify an E-cadherin-based highly integrated biochemical and mechanical signaling network essential for intercellular adhesion, stability of the transcriptional circuitry for pluripotency and long-term survival of hESCs/hiPSCs. In addition, we discovered compound C, a kinase inhibitor, as a potent regulator of hESC/hiPSC fate. Compound C suppresses mesoderm, endoderm and trophoectoderm differentiation and induces rapid and high-efficiency neural conversion in both hESCs and hiPSCs (up to 90%). Compound C targets at least seven TGF-beta superfamily receptors and thereby blocks both the Activin and BMP signaling pathways, which accounts for compound C's ability to induce high-efficiency neural conversion. This small-scale screening provided proof-of-concept for applying large-scale library screening to the study of hESCs/hiPSCs. Accordingly, we conducted large-scale screening of small molecules and shRNAs and identified a number of novel regulator components of hESC/hiPSC pluripotency and directed differentiation. In the next few years we will extend these findings to provide new mechanistic insights into pluripotency and early lineage specifications in hESCs/hiPSCs. The results of these studies will markedly improve our knowledge of the molecular mechanisms underlying fate determination and may contribute to effective strategies for tissue repair and regeneration.

 

Bio-inspired Microenvironments Regulate Cell Fate   |   View Presentation

Dr. Adam J. Engler, Department of Bioengineering, University of California, San Diego

Tuesday, November 1, 2011
1000 MNTL, 12:00 - 1:00 PM

Abstract: Epigenetic regulation of stem cell fate by intrinsic properties of the surrounding extracellular matrix (ECM), e.g. stiffness, organization, composition, etc., appears to be an important yet underappreciated contributor in development, disease, and aging. I will describe our efforts to develop biomimetic environments that mimic key intrinsic ECM properties to assess their contribution to regulating cell fate. For example, pre-cardiac mesodermal cells mature in to adult cardiomyocytes when their matrix mimics the 10-fold increase in stiffness that occurs naturally during development. Adult mesenchymal stem cells (MSCs) are particularly sensitive to small spatial stiffness gradients which can be found naturally in vivo; these gradients induce cell migration prior to differentiation and may in part explain MSC accumulation in stiffer regions of tissue interfaces. However, disease often inhibits these natural processes by creating an ischemic, fibrotic, and/or rigid environment. When matrix stiffness resembles the rigid fibrotic scar, micropatterning cells into specific morphologies can reset the cell to the appropriate contractility level required for myogenesis. Using these finding as design principles, we are engineering nano-patterned diblock copolymer foams to better guide cell differentiation in diseased microenvironments in vivo, but taken together these data at least imply that matrix properties, when displayed at the right time and place, are important regulators of cell fate.

 

Investigating Dendritic Filopodial Dynamics in Highly Controlled Microenvironments

Anika Jain, Department of Cell and Developmental Biology

Tuesday, October 18, 2011
1000 MNTL, 12:30 - 1:00 PM

Abstract: The establishment of the intricate wiring of the nervous system relies on filopodial navigation to form complex interconnections between neurons. Until recently, cellular level investigations into filopodial dynamics had focused primarily on axonal growth cone filopodia. Here we focus on their oft ignored cousins—dendritic filopodia, and the cues that guide their development. While being implicated in crucial developmental processes of dendritic morphogenesis, spinogenesis and synaptogenesis, these filopodia have received only limited attention. Our long-term goal is to advance our understanding of the processes that define and modulate the connectivity of neurons in the mammalian brain, with our overall objective being the elucidation of the underlying filopodial dynamics as governed by chemical guidance cues.

 

Deconvolving Stiffness in MEMS Pedestal Cell Mass Measurements

Elise Corbin, Department of Mechanical Science and Engineering

Tuesday, October 18, 2011
1000 MNTL, 12:00 - 12:30 PM

Abstract: The complex relationships between a cell's behavior and the physical properties of both itself and its environment have long been of interest. Specifically, the understanding the mechanisms through which a cell's physical properties influence cell growth, cell differentiation, cell cycle progression, and apoptosis. The accuracy and versatility of measurement techniques play an integral part in investigating how a cell's physical properties influence its behavior. We developed an improved MEMS resonator sensor that can be used to directly measure the biophysical properties, mass, and growth rate of single adherent cells. However, our measurement technique offers a combination of complex elastic and viscoelastic dynamic properties of cells. Decoupling the relationship between the cell's dynamics and the apparent mass reported by the sensor is of utmost importance. Understanding this relationship will further empower the measurement technique, enabling even more prudent investigations that will benefit efforts in cancer diagnosis and treatment, biological accurate design, cell-to-cell interfacing, and tissue engineering, among others.

 

Mechanotransduction at Cell-Cell Contact   |   View Presentation

Hamid Tabdili, Department of Chemical and Biomolecular Engineering

Tuesday, October 4, 2011
1000 MNTL, 12:40 - 1:00 PM

Abstract: Differential adhesion between cadherin subtypes expressed on cell surfaces is postulated to direct cell segregation during tissue morphogenesis. The studies described here used magnetic twisting cytometry and traction force microscopy to test the impact of cadherin binding selectivity on mechanotransduction and substrate rigidity sensing at cadherin-based adhesions. Micropipette measurements in turn quantified the binding affinities of different cadherin subtypes. Here we present evidence that the ability to transduce mechanical information across cadherin junctions depends on the identity of the ligand, such that only homophilic bonds between identical cadherins support force-activated junction remodeling. Mechanical stimulation with dissimilar cadherins or with anti-cadherin antibodies failed to elicit any response to force. Surprisingly, this behavior does not correlate with protein binding affinities, suggesting that mechanical differences may supercede protein-binding affinities in controlling intercellular organization during development.

 

Directed Blood Vessel Growth Using an Angiogenic Microfiber/Microparticle Composite Patch   |   View Presentation

Ross DeVolder, Department of Chemical and Biomolecular Engineering

Tuesday, October 4, 2011
1000 MNTL, 12:20 - 12:40 PM

Abstract: Therapeutic angiogenesis has emerged as a promising strategy to treat various acute and chronic vascular diseases, and to enhance tissue repair and regeneration. Common revascularization therapies include the administration of angiogenic factors, such as vascular endothelial growth factor (VEGF). The success of these therapies greatly relies on the ability to control the spatial organization of mature and functional neovessels at physiologically relevant micrometer scales; however, there is a lack of biomedical devices that control the directional growth and spacing of blood vessels. The objective of this study was to develop an angiogenic patch that releases angiogenic growth factors and ultimately regulates the directional growth of mature and functional blood vessels.

 

Multi-Modal and Multi-Functional Magnetic Particles for Cancer Imaging   |   View Presentation

Adeel Ahmad, Department of Electrical and Computer Engineering

Tuesday, October 4, 2011
1000 MNTL, 12:00 - 12:20 PM

Abstract: Iron oxide magnetic nanoparticles (MNP's), due to their small size, unique magnetic properties and the ability to manipulate these remotely, are promising materials for diagnostic, imaging, and therapeutics in biomedical applications. In this presentation, we describe the fabrication, characterization and some applications of protein-shell microspheres embedded with MNP's in their cores. These magnetic microspheres have been functionalized to target the αvb3 integrin receptors that are known to be overexpressed in tumors and atherosclerotic lesions. An external magnetic field can be used to perturb these particles and the resultant displacements can be optically measured with nano-scale accuracy using magnet-motive optical coherence tomography (MM-OCT) to provide not only dynamic contrast in imaging but to also assess the biomechanical properties of the microenvironment. Preliminary results demonstrate tracking in vivo dynamics of these functionalized microspheres by using fluorescence imaging followed by ex vivo MM-OCT. Ongoing research includes studying the targeting and binding efficiency of these particles under flow conditions.

 

Magnetomotive Molecular Nanoprobe   |   View Presentation

Dr. Stephen Allan Boppart, Beckman Institute, Bioengineering, and ECE

Tuesday, September 20, 2011
1000 MNTL, 12:00 - 1:00 PM

Abstract: The diagnostic, interrogational, and therapeutic potential of molecular nanoprobes is rapidly being investigated and exploited across virtually every biomedical imaging modality. While many types of probes enhance contrast or delivery therapy by static localization to targeted sites, significant potential exists for utilizing dynamic molecular nanoprobes. Recent examples include molecular beacons, photoactivatable probes, or controlled switchable drug-releasing particles, to name a few. We have developed a novel class of dynamic molecular nanoprobes that rely on the application and control of localized external magnetic fields. These magnetomotive molecular nanoprobes can provide optical image contrast through a modulated scattering signal, can interrogate the biomechanical properties of their viscoelastic microenvironment by tracking their underdamped oscillatory step-response to applied fields, and can potentially delivery therapy through nanometer-to-micrometer mechanical displacement or local hyperthermia. This class of magnetomotive agents includes not only magnetic iron-oxide nanoparticles, but also new magnetomotive microspheres or nanostructures with embedded iron-oxide agents. In vitro three-dimensional cell assays and in vivo targeting studies in animal tumor models have demonstrated the potential for multimodal detection and imaging, using magnetic resonance imaging for whole-body localization, and magnetomotive optical coherence tomography for high-resolution localization and imaging.

 

In vitro Cancer Metastasis Driven by Elasticity of Micro-environment   |   View Presentation

Xin Tang, Department of Mechanical Science and Engineering

Tuesday, September 6, 2011
1000 MNTL, 12:00 - 12:30 PM

Abstract: Cancer deaths are primarily caused by metastases, not by the parent tumor. However, the physical-chemical mechanisms and parameters within the cellular micro-environment that initiate the onset of metastasis, are not understood. Here we show that human colon carcinoma (HCT-8) cells can exhibit a dissociative, metastasislike phenotype (MLP) in vitro when cultured on substrates with appropriate mechanical stiffness, physiologically relevant 21 kPa- 47 kPa, but not on very soft (1 kPa) and very stiff (3.6 GPa) substrates. The cell-cell adhesion molecule E-Cadherin, a metastasis hallmark, decreases 4.73 ± 1.43 times on cell membranes in concert with disassociation. Both specific and non-specific cell adhesion decrease once the cells have disassociated. After reculturing the disassociated cells on fresh substrates, they retain the disassociated phenotype regardless of substrate stiffness. Inducing E-Cadherin overexpression in MLP cells only partially reverses the MLP pheno-type in a minority population of the dissociated cells. Traction Force Microscopy reveals that after dissociation, HCT-8 cells exert weaker traction force (~100 Pa) on substrates than they do prior to dissociation (~250 Pa). Our results indicate, during culture on the appropriate mechanical microenvironment, HCT-8 cells undergo a stable cell-state transition with increased in vitro metastasis-like characteristics as compared to parent cells grown on standard, very stiff tissue culture dishes. This novel finding suggests that the onset of metastasis may, in part, be linked to the intracellular forces and the mechanical microenvironment of the tumor.

 

Precisely Size Controlled Drug-silica Nanoconjugate for Cancer Therapy   |   View Presentation

Li Tang, Department of Materials Science and Engineering

Tuesday, September 6, 2011
1000 MNTL, 12:30 - 1:00 PM

Abstract: Drug delivery nanomedicine, exemplified by micelles and nanoparticles roughly in the size range of 1-200 nm, have attracted much interest in the past 2-3 decades as alternative modalities for cancer treatment. The size of these drug delivery vehicles has been strongly correlated with their in vivo biodistribution, penetration in tumor tissue, and intracellular trafficking. It potentially has significant impact on their antitumor efficacy. However, it is challenging to make nanomedicine in large quanti-ties with controlled particle size and narrow particle size ranges, in particular for nanomedicine smaller than 50 nm. Here we report a novel drug delivery platform based on drug-silica nanoconju-gates (drug-NCs) that can be controlled fabricated at nearly any desired size between 20 and 200 nm, with extremely narrow particle size distribution, in multi-gram scale within a few hours. Several in vitro and in vivo studies demonstrated that the sizes of the drug-NCs have huge impact on cell uptake and tumor penetration; the drug-NCs with size of 20 nm outperform their counterparts with larger sizes, showing great promise in cancer therapy and diagnosis.