Thursday, November 8, 2018
4:00 pm

Special Medical Engineering Seminar

Presentations by Medical Engineering Ph.D. Students: Colin Cook, David Mittelstein, Luizetta Navrazhnykh

Colin Cook-Tai Research Lab. 

"Stakeholder-driven design of therapies for hypoxic retinal diseases"

This talk will outline how early and frequent feedback from patients, physicians, public health officials, and investors motivated a research pivot and led to the development of non-invasive, preventive phototherapy solutions for patients suffering from leading causes of blindness like diabetic retinopathy. Technical details of the device and preliminary in vivo data will be presented along with a discussion of strategies to improve patient compliance with preventative therapies. https://www.mems.caltech.edu

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David Mittelstein-Gharib Lab

"Ultrasound Oncotripsy: Targeting Cancer Cells Selectively Via Resonant Harmonic Excitation"

Therapeutic ultrasound (US) is a promising non-invasive tumor ablation method as it is able to disrupt cells, enhance drug uptake, and stimulate anti-neoplastic immune response. However, high intensity focused US uses non-specific heating or cavitation and safe use requires precise tumor targeting to prevent off-target ablation. Low intensity focused US (LIFU) may allow for more selective US therapy. Pulsed US at <5 W/cm2 has been shown to cause bioeffects, although its mechanisms are not well understood. We propose a new paradigm in which LIFU induces resonant cell membrane oscillation. "Oncotripsy" involves applying waveforms that exploit this resonance vulnerability to selectively lyse cancer cells (Fig 1a). We developed an in vitro testbed with mylar-bottom sample plates suspended over a water bath containing a focused US transducer. Pulsed US at 10% duty cycle 0.7 MPa PNP is applied for 1 min. We apply US at various frequencies and pulse durations, while maintaining constant acoustic energy (Fig 1b). We assess cell death of myeloid cancer (K562), lymphoid cancer (U937) and healthy T cells using LIVE/DEAD fluorescence. We perturb cell's mechanical properties using viscous isotonic sucrose instead of saline, 1 hr pretreatment with actin depolymerizing cytochalasin D, or 16 hr pretreatment with microtubule depolymerizing paclitaxel. We confirmed that long pulse duration (PD) LIFU (>10 ms) lead to irreversible cell death in cancer models. We observed that this cyto-disruption was frequency and cell-type dependent (Fig 1c). All trials used the same US intensity, but cancer selective targeting was achieved with 500 kHz 20 ms PD US (p<.001). Finally, perturbing mechanical properties altered the LIFU response. In vivo, we observed PD dependent necrosis in xenografted tumors after 670 kHz 1 MPa LIFU. LIFU's PD-dependent response that is sensitive to frequency, cell type, and mechanical properties supports the theory that growing resonant oscillations passing a lethal threshold may cause cell death. We are currently investigating alternate cavitation mechanisms. Our data suggest that adjusting US parameters can achieve cell-selective targeting without contrast agents. Furthering the reach of therapeutic US could provide clinicians access to the benefits of US ablation in regimes where it was previously unsafe. https://www.gharib.caltech.edu

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Luizetta Navrazhnykh-Greer Lab

"Changing the shape of microscale architectures in response to the environment: two photon lithography with shape memory polymers"

3D polymer structures of virtually any geometry with features on the submicron scale can currently be fabricated with two photon lithography. Their mechanical properties are influenced by architecture, greatly expanding the range of mechanical responses that can be achieved by a particular material. We aim to develop a polymer system compatible with two photon lithography that would enable changes in shape, and therefore mechanical properties, to occur in response to an environmental stimulus. Specifically, we are synthesizing architected microscale shape memory polymer networks which can undergo temporary deformations but return to their original shape in response to heat. This talk will explore the synthesis, dynamic mechanical analysis and shape memory programming of these structures. Future applications in the design of implantable brain electrodes, where a change in stiffness in response to the brain environment is necessary, will also be discussed.
 www.jrgreer.caltech.edu

Contact Christine Garske ccgarske@caltech.edu
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