Defense Date

5-31-2023

Graduation Date

Summer 8-5-2023

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Pharmaceutics

School

School of Pharmacy

Committee Chair

Jelena M. Janjic

Committee Member

James K. Drennen III

Committee Member

Peter Wildfong

Committee Member

Kevin Tidgewell

Committee Member

Vijay S. Gorantla

Keywords

nanoemulsions, formulation development, perfluorocarbons, quality by design, ischemia-reperfusion, process validation, artificial oxygen carriers, resveratrol, microfluidization

Abstract

According to a 2022 report, organs destined for transplantation are discarded 15% of the time for various reasons (Israni et al. 2022). This highlights a critical need in transplant practices. Transplant donor tissues are in need of essential nutrients, including molecular oxygen, to maintain integrity during preservation. A current trend in preservation is to perfuse the ex vivo tissue graft with nutrient-rich aqueous perfusate on a closed circuit. This practice, known as machine perfusion (MP) is limited by the absence of an oxygen-carrying component in the perfusate. Additionally, injuries to the recipient are sustained on reperfusion of the transplanted graft. Reactive oxygen species (ROS) are produced during ischemia-reperfusion (IR) events such as transplantation and contribute to secondary oxidative damage. Perfluorocarbon (PFC) materials, which are characteristically good oxygen carriers, can be utilized to fulfill the role of oxygen carrier. PFCs are hydrophobic and must therefore be formulated as a liquid dispersion (e.g., PFC-in-water nanoemulsion (NE)) in order to be considered as a biomedical-grade product. Stability difficulties is one reason why PFC-NEs have not acquired commercial success. We believe that utilization of systematic Quality by Design (QbD) principles may hold the key to overcoming poor stability and generating a stable, proficient oxygen carrier. The central hypothesis of this work is that QbD-centered development can yield colloidally stable antioxidant- and molecular-oxygen-co-loaded PFC-NEs for action against oxidative stress and hypoxia in ex vivo machine perfusion preservation. We test this hypothesis by adapting QbD concepts to the development of PFC-NEs. We used quality risk management and multivariate statistical modeling to deepen the understanding of the process and composition of PFC-NEs. We proposed an optimal formulation and demonstrated its process robustness. Finally, we illustrate its impact in scavenging radical species and delivering oxygen intracellularly in macrophages.

Language

English

Additional Citations

(1) Lambert, E.; Gorantla, V. S.; Janjic, J. M. Pharmaceutical design and development of perfluorocarbon nanocolloids for oxygen delivery in regenerative medicine. Nanomedicine (Lond) 2019, 14 (20), 2697-2712. DOI: 10.2217/nnm-2019-0260.

(2) Lambert, E.; Janjic, J. M. Multiple linear regression applied to predicting droplet size of complex perfluorocarbon nanoemulsions for biomedical applications. Pharm Dev Technol 2019, 24 (6), 1-11. DOI: 10.1080/10837450.2019.1578372.

(3) Lambert, E.; Janjic, J. M. Quality by design approach identifies critical parameters driving oxygen delivery performance in vitro for perfluorocarbon based artificial oxygen carriers. Scientific Reports 2021, 11 (1), 5569. DOI: 10.1038/s41598-021-84076-1.

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