A. James Clark School of Engineering
Permanent URI for this communityhttp://hdl.handle.net/1903/1654
The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
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Item Induced Pluripotent Stem Cell-Derived Extracellular Vesicles Promote Wound Repair in a Diabetic Mouse Model via an Anti-Inflammatory Immunomodulatory Mechanism(Wiley, 2023-06-19) Levy, Daniel; Abadchi, Sanaz Nourhammadi; Shababi, Niloufar; Ravari, Mohsen Rouhani; Pirolli, Nicholas H.; Bergeron, Cade; Obiorah, Angel; Mokhtari-Esbuie, Farzad; Gheshlaghi, Shayan; Abraham, John M.; Smith, Ian M.; Powsner, Emily H.; Solomon, Talia J.; Harmon, John W.; Jay, Steven M.Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have recently been explored in clinical trials for treatment of diseases with complex pathophysiologies. However, production of MSC EVs is currently hampered by donor-specific characteristics and limited ex vivo expansion capabilities before decreased potency, thus restricting their potential as a scalable and reproducible therapeutic. Induced pluripotent stem cells (iPSCs) represent a self-renewing source for obtaining differentiated iPSC-derived MSCs (iMSCs), circumventing both scalability and donor variability concerns for therapeutic EV production. Thus, it is initially sought to evaluate the therapeutic potential of iMSC EVs. Interestingly, while utilizing undifferentiated iPSC EVs as a control, it is found that their vascularization bioactivity is similar and their anti-inflammatory bioactivity is superior to donor-matched iMSC EVs in cell-based assays. To supplement this initial in vitro bioactivity screen, a diabetic wound healing mouse model where both the pro-vascularization and anti-inflammatory activity of these EVs would be beneficial is employed. In this in vivo model, iPSC EVs more effectively mediate inflammation resolution within the wound bed. Combined with the lack of additional differentiation steps required for iMSC generation, these results support the use of undifferentiated iPSCs as a source for therapeutic EV production with respect to both scalability and efficacy.Item Mesenchymal Stem Cell Culture within Perfusion Bioreactors Incorporating 3D-Printed Scaffolds Enables Improved Extracellular Vesicle Yield with Preserved Bioactivity(Wiley, 2023-03-17) Kronstadt, Stephanie M.; Patel, Divya B.; Born, Louis J.; Levy, Daniel; Lerman, Max J.; Mahadik, Bhushan; McLoughlin, Shannon T.; Fasuyi, Arafat; Fowlkes, Lauren; Van Heyningen, Lauren Hoorens; Aranda, Amaya; Abadchi, Sanaz Nourmohammadi; Chang, Kai-Hua; Hsu, Angela Ting Wei; Bengali, Sameer; Harmon, John W.; Fisher, John P.; Jay, Steven M.Extracellular vesicles (EVs) are implicated as promising therapeutics and drug delivery vehicles in various diseases. However, successful clinical translation will depend on the development of scalable biomanufacturing approaches, especially due to the documented low levels of intrinsic EV-associated cargo that may necessitate repeated doses to achieve clinical benefit in certain applications. Thus, here the effects of a 3D-printed scaffold-perfusion bioreactor system are assessed on the production and bioactivity of EVs secreted from bone marrow-derived mesenchymal stem cells (MSCs), a cell type widely implicated in generating EVs with therapeutic potential. The results indicate that perfusion bioreactor culture induces an ≈40-80-fold increase (depending on measurement method) in MSC EV production compared to conventional cell culture. Additionally, MSC EVs generated using the perfusion bioreactor system significantly improve wound healing in a diabetic mouse model, with increased CD31+ staining in wound bed tissue compared to animals treated with flask cell culture-generated MSC EVs. Overall, this study establishes a promising solution to a major EV translational bottleneck, with the capacity for tunability for specific applications and general improvement alongside advancements in 3D-printing technologies.Item SPRAYABLE, BIODEGRADABLE POLYMER BLENDS FOR TISSUE ADHESION(2019) Daristotle, John L; Kofinas, Peter; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Tissue adhesive materials can revolutionize surgical procedures, but they are often difficult to apply safely because of a required curing step where the viscous components of a glue solidify and become sticky. To simplify their deposition and improve their usability, this dissertation introduces tissue adhesive polymer blends that can be sprayed using a fiber production technique called solution blow spinning. The polymer blends studied here are innovative because they are non-curing: the polymer accumulates as a solid material directly on the tissue substrate of interest during spraying, quickly forming a strong bond. To achieve a rapid increase in tissue adhesion, we developed a surgical sealant composed of poly(lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) that becomes adhesive in response to warming to body temperature. We then evaluated PLGA/PEG in small and large animal models of intestinal anastomosis and partial thickness skin wounds. Additional improvements to hemostasis, flexibility, and adhesion were made by incorporating micron-sized silica particles, which produced textured fibers with suppressed crack formation. We also developed the first pressure-sensitive tissue adhesive by formulating elastomeric copolymer blends with two components of different molecular weights. An additional objective of this dissertation was to study sprayable polymers that can be used as a controlled release system for various drugs. Towards this goal, we incorporated antimicrobial silver into solution blow spun PLGA/PEG fibers. At the optimal concentration, silver ions released over 14 days at levels that were effectively antimicrobial with minimal cytotoxicity. Coating strategies for controlling the delivery of polyelectrolyte complexes were also investigated.