Tissue-engineered in vitro models for studying lymphatic morphogenesis, pathogenesis, and drug delivery

The lymphatic system is a network consisting of lymphatic vessels and lymphoid organs such as lymph nodes (LNs), which drain excess interstitial fluid and eventually return it to the blood circulatory system via the thoracic duct and subclavian veins. It plays a key role in interstitial fluid homeostasis, adaptive immune response, biomolecular uptake (dietary lipid, albumin, amyloid beta, etc.), and tumor metastasis. Dysfunction of the lymphatic system thus can lead to various diseases, including lymphedema, lipedema, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, cancer, and glaucoma. Despite the significant roles of lymphatics, its morphogenesis, pathogenesis, and drug delivery strategies are still not completely understood. Organ-on-chip systems combine microfabrication technology with biology, which enables in vitro models to recapitulate key aspects of human physiology and disease. In this dissertation, I discuss organ-on-chip models for studying different compartments of lymphatic vessels (initial lymphatics and collecting lymphatics) and organ-specific ocular lymphatics under physiological and pathological conditions. Specifically, I first describe the aqueous humor outflow model that incorporates trabecular meshwork and Schlemm’s canal, and TGF-β1/ALK5/VEGFC signaling axis in steroid-induced glaucoma. Then, I discuss the double-casting sacrificial 3D printing method to study lymphatic valve morphogenesis and inflammation-induced lymphatic valve dysfunction. Finally, I discuss the use of initial lymphatic vessel-on-chip devices to study nanoparticle delivery to lymphatic systems, revealing previously unappreciated size-dependent intracellular accumulation of nanoparticles in lymphatic endothelial cells.

Name thesis:degree_name

Ph. D., Biomedical Engineering

Level thesis:degree_level

Doctor of Philosophy

Discipline thesis:degree_discipline

Biomedical Engineering

Grantor

Cornell University

Year dc:date.issued

2024

Author dc:creator

• Lu, Renhao

Committee members dc:contributor.committeemember

• Ma, Minglin
• Kurpios, Natasza

• 3D bioprinting
• Drug delivery
• Glaucoma
• Lymphatics
• Nanoparticle
• Tissue engineering

Statement dc:rights

• Attribution 4.0 International

Licence dc:rights.uri

• https://creativecommons.org/licenses/by/4.0/

Language dc:language.iso

en

DOI

https://doi.org/10.7298/nj8j-5913

Dc Identifier Other

ProQuest Submission ID: 14223
ProQuest Publication ID: 31239443

OAI identifier oai:identifier

oai:ecommons.cornell.edu:1813/115956