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Improving Stem Cell Survival and Differentiation in Ischemic and Inflammatory Tissues

Li, Xiaofei
http://orcid.org/0000-0002-5793-7836
http://rave.ohiolink.edu/etdc/view?acc_num=osu1469174124

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Materials Science and Engineering.
Ischemia disease, mainly including heart ischemia, brain ischemia, and limb ischemia, are severe vascular diseases. Millions of people worldwide are suffered from these diseases and the death rate has remained high. Ischemia is induced when blood supply to the tissue is not enough due to the blockage of blood vessel. Cells die and tissues are damaged because of the ischemic environment. To regenerate the damaged tissue and restore lost tissue function, stem cell therapy is regarded as a promising approach. Stem cells are multipotent cells which can renew themselves and also may differentiate into many cell types in the host tissue. However, efficacy of the therapy is extremely low when the stem cells are implanted directly into the target tissue area. Dramatic cell death is caused by three major factors: no proper stem cell carrier exists as an ECM and delivery vehicle, harsh ischemic conditions (low oxygen and low nutrient), and immunorejection and inflammation. In this thesis, the above issues were addressed accordingly in order to improve the implanted cell survival. A series of polyNIPAAm based biodegradable thermosensitive hydrogels were synthesized to serve as proper carriers of stem cell, biomolecules (like growth factors), and oxygen releasing microspheres. In Chapter 2, growth factor bFGF was encapsulated in hydrogel together with the cells. The bFGF could sustain release from the hydrogel for 28 days and remain bioactive. The released bFGF was able to enhance stem cell survival under ischemic conditions in vitro and in vivo. This system also promoted angiogenesis to restore blood perfusion in vivo. To overcome the low oxygen environment, a novel oxygen releasing microspheres were fabricated by electrospray technique. The core shell structured microspheres were based on PLGA for the shell and H2O2/PVP complex for the core. The complex is released when PLGA is degraded, and generated oxygen via catalase. The complex-stabilized H2O2 and the slow degradation of PLGA guaranteed a sustained release for a relatively long period of time. The oxygen release system could enhance stem cell survival and proliferation in vitro and in vivo. To make the oxygen releasing microspheres more functional and could perform environment responsive releasing behavior, several upgrade version of microspheres were developed as described in Chapter 3, Chapter 4, and Chapter 5. Catalase was conjugated on the surface of the microspheres to make the oxygen releasing system more accessible. By introducing fluorescent agent hepericin into the complex, imagable oxygen releasing microspheres were fabricated and could be fluorescently detected both in vitro and in vivo. In addition, hypoxia–sensitive degradable polymer was synthesized as shell material. The releasing kinetics of the oxygen releasing microspheres were shown to be environmentally responsive to the oxygen level. All the above mentioned advanced oxygen releasing system could promote stem cell survival under ischemic conditions. Necrosis of the damaged tissue under ischemic conditions recruit large immune cells and protein which secrete pro-inflammatory cytokines. The small cytokines, mainly TNF-α and IL-1β, could penetrate into the hydrogel and stimulate cell apoptosis. Peptides which showed binding affinity to specific cytokines were used to modify the hydrogel surface via biotin-avidin interaction. The newly developed hydrogels were able to block the cytokines and eliminate inflammation. The survival and differentiation of the encapsulated stem cells were significantly enhanced and promoted in vitro and in vivo. The developed strategies and approaches to improve stem cells survival under ischemic and inflammatory conditions should offer therapeutic options for tissue regeneration.
Jianjun Guan (Advisor)
John Lannutti (Committee Member)
Heather Powell (Committee Member)
340 p.
Materials Science
Ischemic disease; tissue regeneration; stem cell therapy; cell survival and differentiation; biomaterials; thermosensitive hydrogel; oxygen release; imaging; hypoxia-sensitive; anti-inflammation

Recommended Citations

Citations

  • Li, X. (2016). Improving Stem Cell Survival and Differentiation in Ischemic and Inflammatory Tissues [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1469174124

    APA Style (7th edition)

  • Li, Xiaofei. Improving Stem Cell Survival and Differentiation in Ischemic and Inflammatory Tissues. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1469174124.

    MLA Style (8th edition)

  • Li, Xiaofei. "Improving Stem Cell Survival and Differentiation in Ischemic and Inflammatory Tissues." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1469174124

    Chicago Manual of Style (17th edition)

osu1469174124
318
© 2016, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.