Person:

Graham, Adam

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites—subcutaneous, intraperitoneal and intramuscular. In particular incorporation of GW2580, a Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor, into a range of devices including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.

Two-beam systems (focused ion beam (FIB) integrated with a scanning electron microscope (SEM)) have enabled site-specific analysis at the nano-scale through in situ "mill and view" capability at high resolution. In addition, a FIB-SEM can be used to cut away a lamella from a bulk sample and thin it for transmission electron microscopy (TEM) imaging. We studied the temperature dependence of FIB milling on compound semiconductors and thin films such as copper that are used in integrated circuits. These materials (GaAs, GaN, InN, etc) react chemically and physically with the gallium in the FIB and change chemical composition and may also change morphology. Copper metallization of IC's has been difficult to mill without undesirable side effects. FIB milling for analysis of these materials becomes difficult if not impossible. Since temperature can be a big factor in chemical and physical reactions we investigated this and report here the effect of cooling the sample to cryogenic temperatures while milling. In addition, we report on the development of a process to prepare TEM lamellae with FIB entirely in a cryogenic environment.