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Events Calendar

The School invites anyone interested to join our weekly seminar series. Please see link below for a list of future BIOMED seminars. Recent seminar and thesis events are also available to browse.

BIOMED Seminar and Thesis Events

University Calendar


  • Developing Ultrasound Contrast Agents To Deliver siRNA to Spinal Cord Injury

    Tuesday, July 16, 2024

    10:00 AM-12:00 PM

    LeBow College of Business, Gerri C. LeBow Hall (GHALL), Room 368, located at 3220 Market Street. Also on Zoom.

    • Undergraduate Students
    • Graduate Students
    • Faculty
    • Staff

    BIOMED PhD Thesis Defense

    Title:
    Developing Ultrasound Contrast Agents To Deliver siRNA to Spinal Cord Injury

    Speaker:
    Brian E. Oeffinger, PhD Candidate
    School of Biomedical Engineering, Science and Health Systems
    Drexel University

    Advisor:
    Margaret A. Wheatley, PhD
    John M. Reid Professor
    School of Biomedical Engineering, Science and Health Systems
    Drexel University

    Details:
    Spinal cord injury (SCI) initiates a complex biological response and leads to the disruption of motor and sensory signals between the brain and the peripheral body at and below the level of damage. SCI can lead to a host of morbidities such as respiratory infections, and result in a reduced quality of life. There are no established regeneration methods to heal spinal cord damage, and treatment is limited to attempting to minimize secondary damage to the spinal cord. SCI repair is impeded by both the poor regenerative capacity of adult spinal cord and the formation of inhibitory scar tissue around a large cystic lesion. A successful healing strategy must simultaneously overcome the negative cues from the scar while providing positive cues to allow axons to grow across the lesion to connect with their targets.

    Our long-term goal is to develop a multi-component biocompatible platform that will enable a diversity of synergistic healing strategies at the site of SCI. This strategy includes a novel ultrasound-based system for targeted delivery of small interfering RNA (siRNA). Inhibiting the upregulation of neuronal proteins such as RhoA using siRNA could help mitigate the negative effects of the glial scar. However, the usefulness of naked siRNA is limited by its extreme instability in vivo and inability to penetrate the cell with ease. Both drawbacks can be addressed with the use of ultrasound and contrast agents. Ultrasound contrast agents (UCAs) are injectable, stabilized gas microbubbles that increase tissue image contrast, and can be loaded with therapeutics for use in directed delivery to desired sites, including SCI. The overall goal of this thesis was the development of UCAs loaded with RhoA siRNA for future delivery to SCI to initiate the downregulation of overexpressed RhoA protein that inhibits neuronal growth.

    A novel poly (lactic acid) (PLA) UCA, developed previously in our lab, was first investigated. It was hypothesized that these PLA microbubbles, when subjected to ultrasound, would burst using a frequency and pressure appropriate for use in the ultrasound-sensitive spinal cord, and fragmentation would facilitate delivery of siRNA. It was determined that the PLA microbubble burst best using an insonating frequency of 2.25 MHz, close to its resonance frequency, which was above the 1 MHz typically used to facilitate delivery. Bursting thresholds of approximately 0.3 MPa peak negative pressure (PNP) were found, lower than the pressure reported in the literature to be damaging. No evidence was found of the PLA UCA fragmenting or creating particles less than 0.5 µm due to ultrasound destruction, in contrast with previous results. A model siRNA was successfully combined with the PLA microbubbles. This was aided with the addition of the cationic polymer polyethyleneimine (PEI), which allowed for a loading up to 9.73 ± 0.30 µg /mg UCA, better than the calculated target of 7.5 µg/mg PLA UCA. The addition of PEI, however, was also found to prevent the release of the model siRNA during ultrasound induced microbubble bursting, rendering this solution ineffective.

    A surfactant based UCA developed ion our lab, SE61, was also investigated as it was believed that it could be modified to include a cationic species to facilitate loading anionic therapeutics. A new fabrication method that better allows for cationic additions was developed and was determined to create microbubbles with equivalent properties to prior methods. The cationic surfactant CTAB and the lipids DSTAP and DMTAP were found suitable for inclusion into SE61 without disruption to the microbubble properties. Inclusion of these cationic species increased the zeta potential of unmodified SE61 from -31.6 ± 5.5 mV to above +30 mV, onto which anionic therapeutics such as DNA and rose Bengal were loaded. SE61 microbubble ultrasound mediated destruction and fragmentation was found to be best with 1 MHz, which is optimal for potential siRNA delivery. Thes ultrasound parameters were utilized for SE61-DMTAP mediated siRNA transfection in HeLa cells, which was found to be as effective and less toxic than the gold standard Lipofectamine 2000 when using a reverse transfection protocol. Transfection using SE61-DMTAP loaded with RhoA siRNA and burst with ultrasound resulted in a successful 63.5% knockdown in RhoA protein in HeLa cells.

    Developing new therapeutic approaches to overcome the inability of the spinal cord to repair after injury remains an important goal. These findings indicate that the developed SE61-DMTAP microbubbles have significant potential to safely improve RhoA siRNA delivery to SCI using targeted ultrasound bursting. Overall, this work has shown the potential of utilizing ultrasound-induced destruction of contrast agents for the delivery of therapeutics to SCI.

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  • Controlling Inflammation To Promote Tissue Regeneration

    Thursday, July 25, 2024

    10:00 AM-12:00 PM

    Pearlstein Business Learning Center, Room 102, located at 3230 Market Street. Also on Zoom.

    • Undergraduate Students
    • Graduate Students
    • Faculty
    • Staff

    BIOMED PhD Thesis Defense

    Title:
    Controlling Inflammation To Promote Tissue Regeneration

    Speaker:
    Erin O’Brien, PhD Candidate
    School of Biomedical Engineering, Science and Health Systems
    Drexel University

    Advisor:
    Kara Spiller, PhD
    URBN Professor of Biomedical Innovation
    School of Biomedical Engineering, Science and Health Systems
    Drexel University
     
    Details:
    Dysfunctional tissue repair manifests in a number of conditions, including aging, diabetes, and catastrophic injuries. As key directors of the immune response, macrophages are responsible for sustaining a pro-regenerative environment within injuries, partly via modulation of other immune cells and progenitor cells. Normally, pro-inflammatory (M1) macrophages dominate the site of injury early on, and are subsequently replaced by reparative (M2) macrophages. M2 macrophages, typically activated with IL-4, may derive from circulating monocytes or M1 macrophages that have switched phenotypes. However, it is unknown whether these populations are different in terms of reparative function. Furthermore, in injuries where regeneration is stalled, M1 macrophages are dysfunctional and fail to switch to the M2 phenotype, resulting in chronic inflammation.

    This thesis sought to first understand the mechanisms underlying the “M1-to-M2” switch, then leverage it in a macrophage cell therapy to promote tissue regeneration. First, the responses of unactivated (M0) and M1 macrophages to IL-4 were compared in terms of gene, protein, and functional expression. Next, the crosstalk between macrophages and T helper cells was investigated using direct co-culture of human cells in vitro and a cutaneous wound model in mice. Finally, these findings informed the design of a macrophage cell therapy in which mRNA-loaded lipid nanoparticles intracellularly maintained a reparative macrophage phenotype in a murine model of volumetric muscle loss. Altogether, this thesis demonstrates the need to control the macrophage M1-to-M2 switch to promote healing, and offers a potential strategy to do so.

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  • Predicting Failure of Non-Invasive Ventilation in Children with a Risk Stratification Model

    Monday, July 29, 2024

    11:00 AM-1:00 PM

    Remote

    • Undergraduate Students
    • Graduate Students
    • Faculty
    • Staff

    BIOMED PhD Thesis Defense

    Title:
    Predicting Failure of Non-Invasive Ventilation in Children with a Risk Stratification Model

    Speaker:
    Natalie Napolitano, PhD Candidate
    School of Biomedical Engineering, Science and Health Systems
    Drexel University

    Advisor:
    Amy Throckmorton, PhD
    Professor
    School of Biomedical Engineering, Science and Health Systems
    Drexel University

    Details:
    Respiratory distress and the need for assistance with breathing is one of the most frequent reasons a child is admitted into the pediatric intensive care unit (PICU). Mechanical assistance with breathing is performed non-invasively or invasively and the determination of which level of support is required and when to transition from one level to another is unknown.   Although non-invasive ventilation (NIV) has been shown to improve outcomes of care and shorten time in the hospital when successful, the failure of NIV has been reported to cause an increase time on advanced respiratory support, time in the intensive care unit, and time in the hospital. Therefore, it is theorized that if we can predict which patients will not be successfully treated with NIV and at what time-point we should make this decision, we can improve the long-term outcomes of patients and support their faster recovery. The historical definition of NIV failure is flawed and not in line with the traditional framework of therapy failure determination. There is little evidence to support how best to manage NIV, including best approach for success and the appropriate timing of transition to a higher level of care.

    Motivated by the need strive for more evidence-based approach to the delivery of respiratory support in the PICU. here we redefined NIV failure in children using the incidence of unfavorable long-term outcomes, provide a landscape of NIV use in a large, busy, tertiary care, referral children’s hospital, and developed a failure prediction model to assist with determination of when to change from NIV to invasive ventilation (IV) to optimize favorable long-term outcome. A new compound outcome definition of NIV failure was designed, and a patient cohort was defined and separated into success and failure groups for comparison. Statistical comparisons were made between groups utilizing Wilcoxon Rank Sum test for non-normally distributed continuous variables and Chi-squared test for categorial variables with our large sample size. A p-value of 0.5 indicates a significant difference between groups.

    A retrospective observational study was performed with patient data from the PICU at the Children’s Hospital of Philadelphia from January 1, 2015 – December 31, 2019. The first case of NIV before tracheal intubation (TI) during the first PICU stay was used for data analysis. Complex NIV failure was defined by the incidence of any of the following criteria occurring during the PICU admission: (1) PICU mortality, (2) new tracheostomy, (3) IV for 7 or more days, (4) relevant tracheal intubation associated events during TI (cardiac arrest, hypotension requiring intervention, dysrhythmia, emesis with aspiration, or pneumothorax/ pneumomediastinum), or (5) severe desaturation during TI (SpO2 greater than 90% after preoxygenation and lowest SpO2 during intubation of less than 70%). During the study period, 3,273 patients had 3,844 courses of NIV, during 3,967 PICU admissions that met criteria for inclusion. Of these, 231 (6%) courses met criteria for failure. These cases had a significantly higher rate of TI (72% vs 0.6%, P=<0.001), demonstrated longer time on respiratory support (342.35 days vs 26.68 days, P<0.001), and more time in the PICU (23.31 days vs 2.43 days, P<0.001).

    Per these data sets and detailed analysis, nine physiologic metrics or features were identified as important to predicting the worsening of the clinical condition and thus to be important to predicting failure of NIV. These features were isolated for each hour for the first 24-hours of therapy and used in a logistic regression prediction model. This failure prediction model benchmarked and accurately predicted complex NIV failure at 6-hours of therapy (AUPRC = 0.32 and AUROC = 0.803).

    Known gaps in the clinical management of NIV failure of definition, physiologic metrics, and timing of  NIV failure have been addressed in the development of (1) a new prediction model with metrics of NIV therapy failure and (2) a new clinical tool that will be used to better inform clinical teams who are treating children with respiratory distress and who require the proper data and trends for clinical decision making.

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  • Save the Date: Immune Modulation and Engineering Symposium 2024

    November 13, 2024 through November 15, 2024

    9:00 AM-7:00 PM

    Drexel University

    • Everyone
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