Improving the function and longevity of implantable drug and cell delivery devices by overcoming the foreign body response

The success of implantable medical devices is hindered by an inevitable inflammatory response called the Foreign Body Response. The human body recognises any implanted biomaterial as a foreign object, and isolates it from the rest of the body by producing a thick, hypopermeable fibrous capsule around it. Fibrous encapsulation can eventually lead to device failure and require its replacement. Diabetes Mellitus is a group of metabolic diseases that affect approximately 9% of the population worldwide. The technologies used to infuse insulin or to protect transplanted pancreatic islets to restore normoglycaemia are hampered by the Foreign Body Response. This thesis presents research on strategies improving the function and longevity of implantable drug and cell delivery devices by leveraging soft robotic technology. Insulin is often delivered to insulin-dependent patients via continuous subcutaneous insulin infusion, in which a cannula sits under the skin for multiple days. Due to the fibrous encapsulation of the cannula as a result of the Foreign Body Response, infusion sets fail to live up to their expected performance. A soft robotic apparatus was developed to infuse insulin via convective flow rather than diffusion. The ”active cannula”, through actuation-augmented insulin delivery, has the potential to increase the longevity and functionality of infusion sets. Implantable drug delivery devices often fail due to the Foreign Body Response as therapeutic dosing cannot be maintained because of the diffusion barrier caused by their fibrous encapsulation. An implantable soft robotic drug delivery device capable of monitoring fibrosis in real-time was developed. By probing the periimplant environment via electrochemical impedance spectroscopy, and by selfadapting its pneumatic actuations, the device has the potential to maintain therapeutic dosing despite a loss in diffusion. Overall, the technologies presented in this thesis have the potential to improve the quality of life of people with Diabetes Mellitus by increasing the longevity and performance of various treatment strategies. In addition, recombinant fusion proteins were produced in Escherichia coli as part of an industrial training in synthetic biology. Lethal factor, a toxin which can facilitate the delivery of therapeutic cargos into cells, and vascular endothelial growth factor, a protein with potential to improve the success of islet transplantation strategies, were produced recombinantly. The production of those proteins is discussed in the Appendix of this thesis.2025-02-0