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BOSTON UNIVERSITY’S TEJAL DESAI ENGINEERS INNOVATIVE SYSTEM FOR ORAL DRUG DELIVERY
Desai has designed an oral drug delivery system that is so tiny, so efficient, so carefully engineered that administration promises to be a snap and on-target delivery of a fully active drug seems virtually guaranteed. Her breakthrough effort, reported in the March 7, 2003, issue of the Journal of Controlled Release, is a microdelivery vehicle that boasts a host of sought-after qualities. It “sticks” to the membranes of cells lining the human gut, ensuring direct drug delivery to target sites. It carries reservoirs engineered to hold picoliter (pL) volumes of drugs that can be dispensed at a pace that maintains drug concentration. And it has a thin, flat profile that maximizes the vehicle’s contact with the cell membrane and minimizes the drug’s contact with denaturing enzymes found in intestinal fluids. Desai engineered all this into a tiny square wafer measuring twice the width of a human hair. Desai planned the new delivery system with an eye toward using microelectromechanical systems techniques developed for the integrated circuit industry. These techniques, used to achieve the exacting specifications of this industry’s micron-sized, silicon-based sensors, switches, and gears, include the iterative use of manufacturing processes such as oxidation, photolithography, etching, diffusion, and epitaxy. Desai used these microfabrication techniques to craft a device from poly(methyl methacrylate) or PMMA, a polymer that is biocompatible, has a track record as a photolithographic resist for MEMS devices, and includes a modifiable methyl ester that would allow her to customize the device’s surface. Using a silicon wafer as a removable construction platform, Desai layered, baked, and etched the bioMEMS device, producing different versions that were evaluated for their thickness, size and number of reservoirs, and pL capacity. The version that ultimately became her prototype was constructed using a double layer of PMMA, measured a mere 150 ìm x 150 ìm x 5 ìm, and featured an 80 ìm x 80 ìm reservoir with a carrying capacity of 19.2 pL. With the device designed, Desai turned her efforts to making the reservoir-containing surface “sticky” so that it could adhere tightly to cellular membranes. To work in this system, Desai needed to use a bioadhesive agent that was nontoxic, would not be targeted by the body’s immune system, and was capable of specifically binding to structures on the surfaces of epithelial cells. Plant lectins fit the bill. This class of carbohydrate-binding proteins resists enzymatic degradation, tolerates the low pH of gastrointestinal fluids, is nonimmunogenic, and binds extremely well to surfaces lining the human gut. To moor the lectin to the vehicle’s surface, Desai choreographed a series of chemical reactions that began with the fixing of the egg-white protein avidin to the PMMA and concluded with the formation of an avidin–biotin–lectin linkage. Desai tested the bioMEMS devices for bioadhesiveness and attachment stability by incubating them with Caco-2 cells, a line of human colorectal carcinoma cells used in studies of intestinal epithelial permeability and function. In comparison tests of unmodified microdevices, microdevices carrying peanut lectin, and microdevices carrying tomato lectin, Desai found the microdevices with lectins, particularly those with tomato lectin, to be sticky and stable. Rates of bioadhesion for devices with tomato lectin increased logarithmically with time, from more than 50 percent after 15 minutes of incubation to approximately 92 percent after 2-hours incubation. In stability tests, Desai found that nearly 70 percent of devices with tomato lectins remained attached to the Caco-2 cells after repeated washings. “This work has shown that bioMEMS devices with bioadhesive surfaces can be constructed using microfabrication techniques,” says Desai. “I am excited by the potential this holds for the development of platforms serving a number of new drug delivery applications.” The Biomedical Engineering Department, established in 1966 in Boston University’s College of Engineering, applies engineering, computational, and analytical techniques to biological systems from the nanoscale level of DNA to the macroscopic level of organ systems.
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