Tejal Desai and researchers at University of California, San Francisco describe current nano- and microfabrication techniques for creating drug delivery devices. They first review the main physiological barriers to delivering therapeutic agents. Then, they describe how novel fabrication methods can be utilized to combine many features into a single physiologically relevant device to overcome drug delivery challenges.
The barrier function of the epithelia has important implications for drug delivery. Epithelial tissues compartmentalize the body into cavities and are composed of specialized cells that are sealed together by tight junction proteins in the intercellular space. The paracellular pathway around the cells is one of the main routes for drug diffusion. However, the tight junction pores are small and are approximately 0.5–2 nm, while the hydrodynamic volumes of conventional therapeutics range from few to several hundred nanometers. Therefore, the tight junctions are a major barrier to drug delivery, particularly for large molecular weight therapeutics. In order to deliver large molecules systemically, hypodermic needle injections are administered which have several disadvantages including: low patient compliance, accidental needle-sticks, and the associated medical personnel costs.
There was a 30 slide presentation. I saw a version of this talk at the Foresight Nanotech Technical conference.
New Device Architectures:
– containing both therapeutic payloads and biophysical cues
– that can gain access to biological barriers
– combine affinity
– based + size and shape + surface properties
• Enable our ability:
– to time the release multiple drugs
– to deliver in a controlled manner
– to house engineered cellular “factories”
– To facilitate tissue integration and bioadhesion
Microfabrication enables the rational design of nano- and microparticles with different shapes and geometries in order to probe the cell membrane barrier. The shape of the particle influences a number of behaviors associated with drug delivery. For example, recent studies have reported that particles of various non-spherical geometries influence the rates of cellular internalization. In one study, HeLa cells were reported to internalize nonspherical particles made by PRINT processing that resemble rod-like bacteria with dimensions as large as 3 µm.30 However, other studies by this group showed that cubic particles with lengths of 3–5 µm were not internalized. They reported how the particles with higher aspect ratios seemed to exhibit higher internalization rates than the lower aspect ratio cubic particles. Interestingly, it appears that aspect ratios that are too high have greater difficulty being internalized by macrophages. For example, studies by Geng et al. and Sharma et al. reported that particles with aspect ratios greater than 23 exhibited reduced phagocytosis, and studies by Champion et al. also show that aspect ratios greater than 20 are not phagocytosed. The observed trends in particle aspect ratio could be explained by the thermodynamic and kinetic modeling and analyses reported by Li et al. They constructed an endocytosis phase diagram of radius versus particle aspect ratio for the rational design of drug delivery nanoparticles. In this paper, Li et al reported that the optimal nanoparticle radius for the fastest endocytosis rate is 25 nm. This minimum radius decreases as the aspect ratio increases which would explain the empirical results from the studies by Geng et al., Sharma et al., and Champion et al. Nano- and microfabrication allows for a high level of control to tune the size, aspect ratio, and shape of particles for drug payloads. With this precise control, monodisperse particles can be generated which allows for more accurate control over drug release rates from particle payloads. This is a tremendous advantage over the more established self-assembly or “bottom-up” approaches which generate a distribution of particle sizes and shapes.
A group recently reported a hot embossing technique followed by phase inversion to create nanoporous membranes with pores of approximately 20–60 nm. These nanofabrication methods allow for controlled nano-pore sizes to achieve zero-order drug release. This nanofabrication approach precludes the need for continuous therapeutic injections since a nanoporous delivery device can sustain release up to 6 months in vitro. This is a remarkable advantage over the gold standard treatment for diseases such as wet macular degeneration, for example, where patients currently receive eye injections once a month. Therefore, with only one surgery to implant the nanoporous device, this approach would lead to improved patient compliance since it would reduce the pain associated with frequent injections.
Delivery larger Molecules
Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
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