Employing pFUS for Treatment of Peripheral Arterial Disease via Homing of Infused Bone Marrow Stromal Cells

URI / Handle

Peripheral artery disease (PAD) manifests from vascular blockage or trauma to a region causing restricted flow of oxygen-rich blood to tissues and organs Treatment options for PAD include lifestyle modification, pharmacotherapy, and revascularization, but they often fail. Clinical data shows that administration of bone marrow stromal cells (BMSC) can provide therapeutic benefits to!promote regeneration of damaged tissue, treat inflammation, and induce angiogenesis. However <<3% of IV-infused cells arrive at the target site. Pulsed focused ultrasound (pFUS) has been used as a noninvasive and nondestructive modality to enhance tissue permeability and retention in drug delivery through physical alterations in tissue. The goal of the proposed research is to employ pFUS exposures to elicit local molecular responses for enhancing homing and retention of BMSC in PAD tissues to improve vascularization and reestablish perfusion blood flow. Hamstrings of healthy mice were treated with pFUS and harvested at various time points to characterize the biological response of tissue. The results demonstrated significant elevations in chemoattractants (homing factor) as early as 10min and subsided by 60hrs post-pFUS. From this data, an optimal time window for maximal BMSC homing to pFUS treated site was suggested. Maximum homing of IV-infused BMSC occurred pre-pFUS and up to 16 post-pFUS demonstrating enhance homing of cells by pFUS. After creation and validation of the PAD model using laser Doppler perfusion imaging, the ischemic limb was treated and harvested at various days after ischemic induction to demonstrate the feasibility of generating a transient inflammatory response outside innate inflammatory response of the disease. Fourteen days after the induction of PAD, the innate inflammatory response had subsided and pFUS was used to stimulate an inflammatory response and enhance cell homing to pFUS treated site. When therapeutic efficacy was tested for 7 weeks in aged (≥12 months) mice with PAD and treatment,(BMSC+pFUS), given 14days after ischemic induction, perfusion blood flow was significantly enhanced in the treatment group versus control. The results demonstrated the therapeutic benefits of combining pFUS and cells that can be translated in other vascular disease models. The implications of this research have the potential to enhance regenerative medicine.
Details
Title

Employing pFUS for Treatment of Peripheral Arterial Disease via Homing of Infused Bone Marrow Stromal Cells

Contributors

Frenkel, Victor (Advisor); Tebebi, Pamela Agwa (Author); Wilson, Otto (Other); Tuma, Pamela L (Other); Frank, Joseph A (Other); Portugal, Frank (Other); Namazi, Nader (Other)

Degree Information

Degree awarded: Ph.D. Biomedical Engineering. The Catholic University of America

Extent

151 p.

URI / Handle

http://hdl.handle.net/1961/cuislandora:28261

Advisor

Frenkel, Victor

URI / Handle

http://hdl.handle.net/1961/cuislandora:28261

Other

Wilson, Otto; Tuma, Pamela L; Frank, Joseph A; Portugal, Frank; Namazi, Nader

Subject

Biomedical engineering; Immunology; Cellular biology; Bone marrow stromal cells; cell homing; cytokines; ischemia; Peripheral arterial disease; pulsed focused ultrasound

Created

2015-01-01T00:00:00Z

Abstract

Peripheral artery disease (PAD) manifests from vascular blockage or trauma to a region causing restricted flow of oxygen-rich blood to tissues and organs Treatment options for PAD include lifestyle modification, pharmacotherapy, and revascularization, but they often fail. Clinical data shows that administration of bone marrow stromal cells (BMSC) can provide therapeutic benefits to!promote regeneration of damaged tissue, treat inflammation, and induce angiogenesis. However <<3% of IV-infused cells arrive at the target site. Pulsed focused ultrasound (pFUS) has been used as a noninvasive and nondestructive modality to enhance tissue permeability and retention in drug delivery through physical alterations in tissue. The goal of the proposed research is to employ pFUS exposures to elicit local molecular responses for enhancing homing and retention of BMSC in PAD tissues to improve vascularization and reestablish perfusion blood flow. Hamstrings of healthy mice were treated with pFUS and harvested at various time points to characterize the biological response of tissue. The results demonstrated significant elevations in chemoattractants (homing factor) as early as 10min and subsided by 60hrs post-pFUS. From this data, an optimal time window for maximal BMSC homing to pFUS treated site was suggested. Maximum homing of IV-infused BMSC occurred pre-pFUS and up to 16 post-pFUS demonstrating enhance homing of cells by pFUS. After creation and validation of the PAD model using laser Doppler perfusion imaging, the ischemic limb was treated and harvested at various days after ischemic induction to demonstrate the feasibility of generating a transient inflammatory response outside innate inflammatory response of the disease. Fourteen days after the induction of PAD, the innate inflammatory response had subsided and pFUS was used to stimulate an inflammatory response and enhance cell homing to pFUS treated site. When therapeutic efficacy was tested for 7 weeks in aged (≥12 months) mice with PAD and treatment,(BMSC+pFUS), given 14days after ischemic induction, perfusion blood flow was significantly enhanced in the treatment group versus control. The results demonstrated the therapeutic benefits of combining pFUS and cells that can be translated in other vascular disease models. The implications of this research have the potential to enhance regenerative medicine.

Type

Text; Dissertation

Local

Tebebi_cua_0043A_10555

Publisher

The Catholic University of America

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