Doctor of Philosophy, Harvard University (2012)
Bachelor of Science, Massachusetts Institute of Technology (2006)
Radiation effects on tumor cell migration.
A principal challenge in wound healing is a lack of cell recruitment, cell infiltration, and vascularization, which occurs in the absence of temporal and spatial cues. We hypothesized that a scaffold that expands due to local changes in pH may alter oxygen and nutrient transport and the local cell density, leading to enhanced cell deposition and survival. In this study, we present a pH-responsive scaffold that increases oxygen transport, as confirmed by our finite element model analysis, and cell proliferation relative to a non-responsive scaffold. In vivo, responsive scaffolds induce a pro-healing gene expression profile indicative of enhanced angiogenesis, granulation tissue formation, and tissue remodeling. Scaffolds that stretch in response to their environment may be a hallmark for tissue regeneration.
View details for DOI 10.1016/j.biomaterials.2015.04.011
View details for PubMedID 25956194
Although X-ray computed tomography (CT) and magnetic resonance imaging (MRI) are the primary imaging modalities used in the clinic to monitor tumor response to radiation therapy, multi-modal molecular imaging may facilitate improved early and specific evaluation of this process. Fast and accurate imaging that can provide both quantitative and biological information is necessary to monitor treatment and ultimately to develop individualized treatment options for patients. A combination of molecular and anatomic information will allow for deeper insight into the mechanisms of tumor response, which will lead to more effective radiation treatments as well as improved anti-cancer drugs. Much progress has been made in nuclear medicine imaging probes and MRI techniques to achieve increased accuracy and the evaluation of relevant biomarkers of radiation response. This review will emphasize promising molecular imaging techniques that monitor various biological processes following radiotherapy, including metabolism, hypoxia, cell proliferation, and angiogenesis.
View details for PubMedID 26269771
Using [(18) F]PBR06 positron emission tomography (PET) to characterize the time course of stroke-associated neuroinflammation (SAN) in mice, to evaluate whether brain microglia influences motor function after stroke, and to demonstrate the use of [(18) F]PBR06 PET as a therapeutic assessment tool.Stroke was induced by transient middle cerebral artery occlusion (MCAO) in Balb/c mice (control, stroke, and stroke with poststroke minocycline treatment). [18 F]PBR06 PET/CT imaging, rotarod tests, and immunohistochemistry (IHC) were performed 3, 11, and 22 days poststroke induction (PSI).The stroke group exhibited significantly increased microglial activation, and impaired motor function. Peak microglial activation was 11 days PSI. There was a strong association between microglial activation, motor function, and microglial protein expression on IHC. Minocycline significantly reduced microglial activation and improved motor function by day 22 PSI.[18 F]PBR06 PET imaging noninvasively characterizes the time course of SAN, and shows increased microglial activation is associated with decreased motor function.
View details for DOI 10.1007/s11307-014-0745-0
View details for PubMedID 24865401
Radiotherapy (RT) is a localized therapy that is highly effective in killing primary tumor cells located within the field of the radiation beam. We present evidence that irradiation of breast tumors can attract migrating breast cancer cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) produced by tumor cells in response to radiation stimulates the recruitment of migrating tumor cells to irradiated tumors, suggesting a mechanism of tumor recurrence after radiation facilitated by transit of unirradiated, viable circulating tumor cells to irradiated tumors. Data supporting this hypothesis are presented through in vitro invasion assays and in vivo orthotopic models of breast cancer. Our work provides a mechanism for tumor recurrence in which RT attracts cells outside the radiation field to migrate to the site of treatment.
View details for DOI 10.1016/j.celrep.2014.06.011
View details for PubMedID 25017065
Materials that adhere to the endothelial cell (EC) lining of blood vessels may be useful for treating vascular injury. Cell adhesion molecules (CAMs), such as endothelial leukocyte adhesion molecule-1 (E-selectin) and vascular cell adhesion molecule-1 (VCAM1), modulate EC-leukocyte interactions. In this study, we mimicked cell-cell interactions by seeding cells on alginate hydrogels modified with antibodies against E-selectin and VCAM1, which are upregulated during inflammation. ECs were activated with interleukin-1? to increase CAM expression and subsequently seeded onto hydrogels. The strength of cell adhesion onto gels was assessed via a centrifugation assay. Strong, cooperative EC adhesion was observed on hydrogels presenting a 1:1 ratio of anti-VCAM1:anti-E-selectin. Cell adhesion was stronger on dual functionalized gels than on gels modified with anti-VCAM1, anti-E-selectin or the arginine-glycine-aspartic acid (RGD) peptide alone. Anti-VCAM1:anti-E-selectin-modified hydrogels may be engineered to adhere the endothelium cooperatively.
View details for DOI 10.1016/j.actbio.2012.04.010
View details for Web of Science ID 000306442400028
View details for PubMedID 22504076
Cell adhesion molecules govern leukocyte-endothelial cell (EC) interactions that are essential in regulating leukocyte recruitment, adhesion, and transmigration in areas of inflammation. In this paper, we synthesized hydrogel matrices modified with antibodies against vascular cell adhesion molecule-1 (VCAM1) and endothelial leukocyte adhesion molecule-1 (E-Selectin) to mimic leukocyte-EC interactions. Adhesion of human umbilical vein ECs to polyvinyl alcohol (PVA) hydrogels was examined as a function of the relative antibody ratio (anti-VCAM1:anti-E-Selectin) and substrate elasticity. Variation of PVA backbone methacrylation was used to affect hydrogel matrix stiffness, ranging from 130 to 720 kPa. Greater EC adhesion was observed on hydrogels presenting 1:1 anti-VCAM1:anti-E-Selectin than on gels presenting either arginine-glycine-asparagine (RGD) peptide, anti-VCAM1, or anti-E-Selectin alone. Engineered cell adhesion - based on complementing the EC surface presentation - may be used to increase the strength of EC-matrix interactions. Hydrogels with tunable and synergistic adhesion may be useful in vascular remodeling.
View details for DOI 10.1016/j.biomaterials.2012.02.017
View details for Web of Science ID 000303273200011
View details for PubMedID 22364701
Inspired by morphogenesis in biology, we present a strategy for developing functional 3D materials with the capacity to morph based on environmental cues. We utilized local mechanical stresses to cause global shape changes in colloidosomes. Colloidosomes were assembled from pH-sensitive calcium alginate particles (CAPs) with high and low swelling ratios. Colloidosomes were subsequently cross-linked via diamine compounds with varying carbon chain lengths. New colloidosome isoforms were generated from heterogeneous mixtures of CAPs, which resulted in nonuniform stresses. Our study demonstrated that coordinated networks of heterogeneous subunits may be used to design programmable materials.
View details for DOI 10.1021/la202430m
View details for Web of Science ID 000294790500003
View details for PubMedID 21823661
Scaffolds that couple electrical and elastic properties may be valuable for cardiac cell function. However, existing conductive materials do not mimic physiological properties. We prepared and characterized a tunable, hybrid hydrogel scaffold based on Au nanoparticles homogeneously synthesized throughout a polymer templated gel. Conductive gels had Young's moduli more similar to myocardium relative to polyaniline and polypyrrole, by 1-4 orders of magnitude. Neonatal rat cardiomyocytes exhibited increased expression of connexin 43 on hybrid scaffolds relative to HEMA with or without electrical stimulation.
View details for DOI 10.1021/nl201514a
View details for Web of Science ID 000294790200023
View details for PubMedID 21800912
Fluidic devices are often made by irreversibly bonding a polydimethylsiloxane (PDMS) mold to itself or a glass substrate by plasma treatment. This method limits the range of materials for fluidic device fabrication and utility for subsequent processing. Here, we present a simple and inexpensive method to fabricate fluidic devices using magnets to reversibly adhere PDMS and other polymer matrices to glass or gel substrates. This approach enables fluidic devices to be fabricated from a variety of materials other than PDMS and glass. Moreover, this method can be used to fabricate composite devices, three-dimensional scaffolds and hydrogel-based fluidic devices.
View details for DOI 10.1039/b907957b
View details for Web of Science ID 000270285600024
View details for PubMedID 19789760
Micellization and solution properties of the aglycon triterpenoids asiatic acid (AA) and madecassic acid (MA) were examined experimentally and in computational simulations. AA and MA belong to the large class of bioactive aglycon triterpenoids, for which limited physicochemical data are available. In this study, solubility, partition coefficient, critical micelle concentrations (CMC), and surface tensions of AA and MA were measured. Reverse phase HPLC data, supported by dye probe experiments and drop shape analysis, showed the CMC in phosphate buffered saline (PBS) to be 15+/-2 microM, and 86+/-9 microM for AA and MA, respectively. The surface tensions of AA and MA in PBS were 64.1 and 64.4 mN/m, respectively. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry indicated the aggregation numbers of AA and MA to be 5 to 7. Molecular dynamics simulations confirmed that molecular association could occur between 5 and 7 molecules in solution. The IC(50) of AA and MA on human small cell carcinoma and human glioblastoma cell lines was 25+/-5 microM and 66+/-13 microM, respectively. The IC(50) is within the range of calculated CMC of AA and MA in bioassay media, suggesting that the micellar aggregates may lead to their cytotoxicity.
View details for DOI 10.1016/j.jcis.2008.05.046
View details for Web of Science ID 000258553900004
View details for PubMedID 18565534