Advancement of Biomaterials Characterization and Tissue Engineering to Model Human Immunity 137 views

Amidst surging drug costs and high clinical trial failure rates, the successful development of new therapeutics demands drug testing platforms having high accuracy to human physiology. Changes in regulatory oversight, such as the FDA Modernization Act 2.0, echo the desperate need for better models. The fields of tissue engineering and bioanalytical chemistry have innovated for decades toward meeting this need, resulting in organ-on-chip technology. As immunomodulating agents are among the most expensive and failure prone areas of medicine, models of the human adaptive immune response and the lymph node are desperately needed. Despite major advances in this space, the human immune system poses inherent challenges for advanced models. While organ-on-chip technology has enabled effective modeling of tissue-properties, a major gap in the field is a lack of established immune models in the context of organ-on-chip models. In particular few models exist for modeling the complex processes that lead to the response to infection or vaccine. Chapter 2 of this thesis describes effective modeling of T-cell-dependent B cell activation in an organ-on-chip platform. This adaptive immune process was exploited by enabling TCR/BCR independent and dependent cross-talk. Cell-cell interactions were then inhibited with a clinically available JAK inhibitor. Chapter 3 describes efforts to construct this immune modeling platform from materials suitable for manufacturing at scale. Chapters 4 and 5 focus on more fundamental advancements in tissue engineering and analytical chemistry. First, technological advancements regarding mimicking tissue at the microscale is discussed. Next, analytical developments for characterizing photopolymerizable biomaterials are described. Lastly, a novel method for assessing crosslinking density within light-curing materials is described, and then demonstrated for predicting the stability of biomaterials in physiological settings. In summary, the advancements described herein have met the need for more human relevant models of adaptive immunity, and improved analytical methods for characterizing complex biomaterials. Future applications of this work will enable more accurate models of the vaccine response. In addition, applications toward modeling complex immune signaling environments such as neuroimmunity and autoimmunity are discussed. Finally, an application of the novel crosslinking density measurement is described.

PHD (Doctor of Philosophy)

Bioanalytical Chemistry; Biomaterials; Immunoengineering; Lymph-node-on-a-chip

English

2024-04-30