자료유형  

 학위논문

Control Number  

0017164818

International Standard Book Number  

9798346389729

Dewey Decimal Classification Number  

600

Main Entry-Personal Name  

Saouaf, Olivia Michelle.

Publication, Distribution, etc. (Imprint  

[S.l.] : Stanford University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

214 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-05, Section: A.

General Note  

Advisor: Appel, Eric.

Dissertation Note  

Thesis (Ph.D.)--Stanford University, 2024.

Summary, Etc.  

요약As pharmaceutical makers increasingly look to control the release kinetics of their products, physically crosslinked hydrogels are emerging as a promising drug carrier due to their injectability and depot-forming abilities. In this thesis, we examine the physical properties of Polymer-Nanoparticle (PNP) hydrogels, materials that are shear-thinning, rapidly self-assembling, and biocompatible, and which have been shown to be effective in many therapeutic and prophylactic applications. Herein, we investigate the microscale structure of the PNP hydrogel, its mechanical properties, and the diffusivity of components within its network. Informed by these findings, we have engineered the PNP platform to deliver physicochemically distinct cargos of adjuvanted influenza vaccines, resulting in greatly improved humoral responses. Our tuning of PNP hydrogel formulation and physical properties has allowed us to utilize the benefits of extended release to add potency and breadth to our current vaccination technologies with an easily injectable platform.We first describe the use of sustained delivery technologies to improve immune responses. We detail how modulating the immune system via strategies such as vaccines and cancer treatments has allowed humankind to fight against infection and disease but show the great need for improvements to address diseases outside the reach of our current technology. We describe how exposing the immune system to immunomodulatory signals for weeks rather than hours can provoke stronger and more effective cellular responses and depict the biomaterial technologies that have been v developed over recent years to leverage this finding. Subsequently, we probe the physical properties of the PNP hydrogel and investigate how its structure enables the retention and sustained release of physicochemically distinct cargos.We next show the ability of the PNP hydrogel to enhance humoral immune response to subunit single-antigen influenza vaccines. We use our drug delivery platform to administer influenza hemagglutinin protein antigens alongside an immune stimulatory small molecule adjuvant and find a marked improvement in antibody titer over liquidadministered controls. We further display the importance of co-delivery of antigen and adjuvant in the improvement of the nanoparticle-tethered small molecule adjuvant over its soluble counterpart. We then investigate the effect of hydrogel formulation and mechanical properties on vaccine efficacy. While we find that all PNP formulations perform significantly better than a standard liquid control, we also see that the stronger, less diffusive formulations outperform our weakest and most quickly dissipating hydrogel, signifying that prolonged exposure time of vaccine components to the immune system has further benefits as time increases, within a demonstrable threshold.In the final chapter of this thesis, we expand the use of the PNP hydrogel to advance multivalent influenza vaccines, improving on current clinical flu vaccine formulations which incorporate three or four distinct strains. We note that the current efficacy of our annual multivalent influenza vaccines is often very low, leaving populations unprotected against some of the strains included in the vaccine as well as future strains of the rapidly mutating virus. Administration of both trivalent subunit and quadrivalent clinical subunit Fluzone vaccines in the adjuvanted PNP hydrogel results in complete seroconversion against all included strains as well as increased protection against heterologous, never-before-encountered influenza viruses.

Subject Added Entry-Topical Term  

Infections.

Subject Added Entry-Topical Term  

Polymers.

Subject Added Entry-Topical Term  

Cells.

Subject Added Entry-Topical Term  

Pathogens.

Subject Added Entry-Topical Term  

Human immunodeficiency virus--HIV.

Subject Added Entry-Topical Term  

Immunity (Disease).

Subject Added Entry-Topical Term  

Antibodies.

Subject Added Entry-Topical Term  

Immunotherapy.

Subject Added Entry-Topical Term  

Adjuvants.

Subject Added Entry-Topical Term  

Rheology.

Subject Added Entry-Topical Term  

Nanoparticles.

Subject Added Entry-Topical Term  

Cytotoxicity.

Subject Added Entry-Topical Term  

Lymphatic system.

Subject Added Entry-Topical Term  

Immune system.

Subject Added Entry-Topical Term  

Lymphocytes.

Subject Added Entry-Topical Term  

Influenza.

Subject Added Entry-Topical Term  

Aluminum.

Subject Added Entry-Topical Term  

Smallpox.

Subject Added Entry-Topical Term  

Biomedical materials.

Subject Added Entry-Topical Term  

Antigens.

Subject Added Entry-Topical Term  

Hydrogels.

Subject Added Entry-Topical Term  

Cancer vaccines.

Subject Added Entry-Topical Term  

Biomedical engineering.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Immunology.

Subject Added Entry-Topical Term  

Materials science.

Subject Added Entry-Topical Term  

Morphology.

Subject Added Entry-Topical Term  

Nanotechnology.

Subject Added Entry-Topical Term  

Polymer chemistry.

Subject Added Entry-Topical Term  

Therapy.

Subject Added Entry-Topical Term  

Physics.

Added Entry-Corporate Name  

Stanford University.

Host Item Entry  

Dissertations Abstracts International. 86-05A.

Electronic Location and Access  

로그인을 한후 보실 수 있는 자료입니다.

Control Number  

joongbu:656018