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Intracerebral Implantation of ECM Hydrogel for the Treatment of Stroke

GHUMAN, HARMANVIR (2019) Intracerebral Implantation of ECM Hydrogel for the Treatment of Stroke. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Stroke is the leading cause of serious, long-term disability affecting nearly 15 million people worldwide each year. After stroke, the hypoxic death of cells results in liquefactive necrosis of the damaged tissue. One of the key challenges in treating chronic stroke is the dramatic loss of brain tissue, and the formation of a cavity filled with extracellular fluid (ECF). Physical therapy and intracerebral implantation of cells has shown limited success in improving motor dysfunction, however there is no replacement of the lost tissue and hence a large tissue cavity remains in the brains of stroke survivors. Extracellular matrix (ECM), which fills the space between the cells, makes up 20% of the whole brain tissue volume and contains proteins such as laminin, fibronectin, myelin and growth factors. The objectives of this work were to determine if hydrogels composed of decellularized mammalian ECM implanted in a stroke cavity promotes cellular infiltration and constructive tissue remodeling, as well as optimization of 19F MR imaging to visualize the peripheral macrophages invading the lesion cavity.
At ECM concentrations that have similar rheological properties as brain tissue, the ECM exists in fluid phase at room temperature, while forming hydrogels at body temperature. However, large volumes of hydrogel injection into the lesion cavity will increase the intracerebral pressure and further damage brain tissue. Using non-invasive magnetic resonance imaging (MRI)-guidance, the hydrogel can be reliably delivered to the lesion cavity, while draining the ECF through another cannula. We evaluated histologically 0, 3, 4 and 8 mg/mL of porcine-derived urinary bladder matrix (UBM)-ECM hydrogel concentrations implanted in a 14-day old stroke cavity. Less concentrated hydrogels (3 and 4 mg/mL) were efficiently degraded with a 95% decrease in volume by 90 days, whereas only 32% of the more concentrated and stiffer hydrogel (8 mg/mL) was resorbed. The less concentrated hydrogels showed a robust invasion of endothelial cells that supported neovascularization. No neovascularization occurred with the stiffer hydrogel. Invasion of neural cells increased with time in all hydrogel concentrations. Differentiation of neural progenitors into mature neurons with axonal projections was evident, as well as a robust invasion of oligodendrocytes. Macrophage infiltration and density within the bioscaffold affected the hydrogel biodegradation and progressively increased in the less concentrated hydrogels and decreased in the 8 mg/mL hydrogels.
Optimization of 19F imaging parameters revealed fast imaging with steady state precession (FISP) sequence being the most efficient for the detection of perfluorocarbons (PFCs). In vivo 19F MRI shows robust visualization of peripheral macrophages invading the lesion cavity implanted with 4 mg/mL ECM hydrogel. Intravenous administration of PFCs results in accumulation of 19F labeled cells within the ECM hydrogel and in the peri-infarct tissue. Histological analysis at 1 day post-injection revealed all infiltrating Iba1+ cells to also be 19F labeled, indicating that these are peripheral macrophages rather than brain derived microglia. This body of work demonstrates that implantation of an ECM hydrogel induced neural tissue regeneration, but a more complete understanding is required to evaluate its potential therapeutic application.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairModo,
Committee MemberBrown,
Committee MemberCui,
Committee MemberRichardson,
Committee MemberWang,
Date: 23 January 2019
Date Type: Publication
Defense Date: 10 September 2018
Approval Date: 23 January 2019
Submission Date: 27 November 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 235
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Stroke, Biomaterials, Inflammation, Hydrogels, ECM
Date Deposited: 23 Jan 2019 18:29
Last Modified: 23 Jan 2020 06:15

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