Biomimetics

The lack of physiologically relevant human esophageal cancer models has as a result that many esophageal cancer studies are encountering major bottleneck challenges in achieving breakthrough progress. To address the issue, here a 3D esophageal tumor tissue model was engineered using a biomimetic decellularized esophageal matrix in a customized bioreactor. To obtain a biomimetic esophageal matrix, a detergent-free, rapid decellularization method was developed to decellularize porcine esophagus. The decellularized esophageal matrix (DEM) was characterized and the DEM was utilized for the growth of esophageal cancer cell KYSE30 in well plates and the bioreactor. Then the expression of cancerrelated markers of KYSE30 cells was analyzed and compared with formalin-fixed, paraffin-embedded (FFPE) esophageal squamous cell carcinoma (ESCC) tissue biospecimens. Results show that the detergent-free decellularization method preserved the esophageal matrix components and effectively removed cell nucleus. KYSE30 cancer cells proliferated well on and inside the DEM. KYSE30 cells cultured on the DEM in the dynamic bioreactor show different cancer marker expressions than those in the static well plate, and also share some similarities to the FFPE-ESCC biospecimens.

Navigation of unmanned underwater vehicles in coastal zones, tight spaces and close to structures such as ports, ship hulls and pipelines remains a difficult challenge. Currently Autonomous Underwater Vehicles (AUVs) use a variety of techniques for motion control, including single thrusters with diving planes or hydrofoils, robotic wrists, or a moving mass. However, these techniques provide limited maneuverability. The objective of this work was to understand the mechanics of elongated fin propulsion for swimming and motion control of underwater vehicles. This bio-inspired propulsion is used by several fishes that swim by undulating a thin and elongated median fin that allow them to perform forward and directional maneuvers. In the first chapter we present the literature review as well as the mathematical formulation using thrust vectoring approach to achieve forward and turning maneuvers. In the second chapter, we used a robotic vessel with elongated fin propulsion to determine the thrust scaling and efficiency. Using precise force and swimming kinematics measurements with the robotic vessel, the thrust generated by the undulating fin was found to scale with the square of the relative velocity between the free streaming flow and the wave speed. In addition, a hydrodynamic efficiency is presented based on propulsive force measurements and a model on the power required to oscillate the fin laterally.

Throughout history, natural products have produced a plethora of biologically active compounds that have established applications in medicine, biology, and pharmacy. The exploration for improved cytotoxic agents has continued to be a crucial path in natural products drug discovery. The focal point of this thesis sheds light on the biosynthetic relationship between the two distinct classes of briarane diterpenoids, the γ-lactone briarane and the briareolate esters. Additionally, this study elaborates on the discovery and elucidation of structurally unique secondary metabolites from the gorgonian coral Briareum asbestinum.
The first chapter of this thesis provides a review of the development and discovery of diverse
secondary metabolites. In addition, this chapter describes the role of natural products in drug discovery and summarizes the research progress in marine natural product chemistry in conjunction with a detailed overview of the current marine-derived pharmaceuticals.

Human esophageal squamous cell carcinoma (hESCC) is a very aggressive form of cancer due to its ability to easily metastasize into proximal lymph nodes and adjacent organs. The role of the extracellular matrix (ECM) and its stromal cells in metastasis remains unclear. To better understand the effect of the ECM and fibroblast cells on esophagus cancer cell migration and invasion, we propose a biomimetic human esophagus model cultured with hESCC and human primary fibroblast cells (fibroblast). To mimic the extracellular matrix of human esophagus we use decellularized porcine esophagus matrix (DEM) to culture with hESCC and fibroblasts in static conditions. This DEM can recapitulate the human esophagus tumor microenvironment with relevant cues. This model will provide valuable information regarding esophagus cancer cell migration with respect to the heterogeneous extracellular matrix and stromal fibroblast cells. We expect to discover the mechanisms by which extracellular matrix and stromal cells affect cancer migration and invasion in vitro. Characterizing this process will provide vital insight towards the effects of fibroblasts cells on facilitating migration and invasion of esophageal cancer cells. This esophagus cancer model also provides promising potential to study drug screening and develop new strategies against esophagus metastasis.

Natural products play a historical role in the discovery of medicine but present unique challenges for chemical isolation, identification and production. In this work we describe the identification of twenty novel diterpenoids. These were isolated by use of chromatography, and the structures determined by spectroscopic methods, primarily 1D and 2D NMR. Six of these possess unprecedented diterpenoid skeletons and two of them show significant growth inhibitory effects on cancer cell lines in vitro (GI50 < 10 μM). The biomimetic semisynthesis of diterpendoids and analogues is also presented.
Access to the bielschowskyane carbon skeleton by dearomatization of a furanocembranoid precursor is described. Highlights include a stereoselective alkene epoxidation, a novel kinetic furan dearomatization method, and an efficient [2+2] photochemical cycloaddition. The role of conformational steering was studied spectroscopically using VT 1H-NMR and NOESY as well as quantum chemical calculations at the DFT level of theory. We also disclose a biomimetic synthesis of providencin using a photochemical Norrish-Yang cyclization. This provided the absolute configuration by chemical correlation with the precursor bipinnatin E, the latter determined by x-ray diffraction. An unexpected, regioisomeric byproduct was observed and a possible mechanism is proposed. A biomimetic synthesis of the diterpene alkaloid aceropterine is also described, using an epoxidation-rearrangement cascade. This work led to a revised structure of aceropterine, formulated by spectroscopic methods. Finally, the isolation and structure elucidation of a novel, cyclic lipopeptide from Pseudomonas sp. is described. The compound was obtained using a unique antibiotic crowd sourcing approach and the structure determined by spectroscopic methods and advanced Marfey’s analysis.

In this work a bio-inspired flapping actuator based on varied magnetic fields is
developed, controlled and characterized. The actuator is sought to contribute to the
toolbox of options for bio-mimetics research. The design is that of a neodymium bar
magnet on one end of an armature which is moved by two air core electromagnetic coils
in the same manner as agonist and antagonist muscle pairs function in biological systems.
The other end of the armature is fitted to a rigid fin extending beyond the streamline
enclosure body to produce propulsion. A series of tests in still water were performed to
measure the kinematics and propulsive force for different control schemes including the
effect of adding antagonistic resistance to the control schemes. Control methods based on
armature position and based on setpoint error were tested and antagonist force was found
to increase consistency of control of the systems in certain cases.