Date of Award

Summer 8-2016

Embargo Period

1-24-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Mechanical Engineering

Advisor(s)

Burak Ozdoganlar

Abstract

Transdermal delivery of biologically active molecules offers many attractive advantages over prevailing oral and parenteral drug delivery approaches toward addressing the low bioavailability of oral drugs and the inconvenience of hypodermic needle injections. However, transdermal delivery is hampered by the inability of the vast majority of drugs to penetrate through skin due to the physical barrier imposed by the skin’s outer layer, stratum corneum (SC), which allows only very small molecules (< 500 Da) to pass through. This places significant limits on the types of vaccines and therapeutics that can be directly delivered through skin. To mitigate these limitations while retaining the advantages of transdermal delivery, microneedle arrays (MNAs) have been developed to mechanically penetrate the SC for enabling the delivery of bioactive micro- and macromolecules through skin. In addition to transdermal applications of MNA technology that deliver drugs systemically through the skin’s microvasculature and lymphatic flow, MNAs have been used for intradermal applications to deliver drugs locally to the targeted skin microenvironments. Specifically, dissolvable MNAs that incorporate drug (and dissolve when inserted into skin) provide an effective and minimally-invasive means to deliver vaccines and therapeutics to and through skin. Despite recent advancements in MNA technology, there still remain considerable challenges in design and manufacturing, which hinders rapid and low cost fabrication of dissolvable MNAs with clinically-relevant materials and geometries, thereby limiting optimal skin-targeting immunization and treatment strategies.

In this Ph.D. research, to address the issues with the current MNA fabrication technologies, which impose strict limitations on manufacturable MNA designs, a novel micro- manufacturing technique based on mechanical diamond micromilling and micromolding is proposed. The overarching objective of this Ph.D. thesis research is to design and evaluate a new and comprehensive manufacturing strategy for successful creation of dissolvable MNA-based trans/intradermal delivery platforms that enable efficient, precise, and reproducible delivery of bioactive molecules to and through skin toward effective vacci- nation strategies and skin-targeted therapies. The specific objectives include: (1) to devise a novel micromilling/elastomer molding/spin-casting based fabrication approach for accurate and reproducible manufacturing of dissolvable MNAs with diverse and unique geometries, and from a myriad of biodissolvable and biodegradable materials, (2) to investigate the intradermal delivery characteristics of the created dissolvable MNAs through ex vivo and in vivo studies in mouse and human skin, and (3) to evaluate the use of the fabricated dissolvable MNAs for effective intradermal delivery of a number of vaccines (e.g., antigens and adjuvants), therapeutics (e.g., anti-cytokine biologics), and genetic materials (e.g., recombinant DNA and RNA) relevant to a broad range of novel cutaneous applications, including enhanced intradermal immunization strategies and skin-targeted therapies.

Available for download on Monday, January 24, 2022

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