NanoMedical Systems

Diffusion under a concentration gradient is the most common driving force for molecular movement, including drug molecules being delivered both out of medical drug delivery devices (implants, depots, subcutaneous injections, etc.) and into the body’s lymph system, vascular system, and even cell walls. 

Under conventional diffusion physics, molecules in high concentration (the left of the top figure) will move in proportion to their concentration through a membrane.  The resulting rate (lower left figure) is high at first and lower later (as the concentration drops).  This results in a total mass moved (as shown in the bottom right) that rises fast at first, then goes slower and slower over time.

NMS overcomes this non-linear physics with nanotechnology effecting the basic (schematic) molecular movement through an NMS nanochannel chip (the green and gray areas). There is a continuous aqueous path (blue shading) from the fluid in the reservoir through the 100,000’s of channels and out to the subcutaneous space in the body.

The highly concentrated drug molecules in the reservoir move under 3-dimensional Brownian motion to find paths to the lower concentration in the body.  The molecules move easily through micrometer sized channels, but within the chip they encounter nanochannels that are just slightly larger in size than the molecule diameter.  Moving through these 2-dimensional spaces constrains the diffusion to a constant rate, independent of the concentration.

The effect is not unlike that of an hour-glass, through which sand moves at a constant rate, no matter how much sand is piled above (the physics is different, of course!). It should be noted, as shown at bottom left, that the nanochannel is not a “tube”, but rather a wide, flat space that is truly 2-dimensional.

As shown in the lower right chart, the nanochannels change the devices release from the blue “Fick’s Law” diffusion (initially fast and eventually slow) to the red “zero order” diffusion (constant).

Note that when the device is “empty” (that is, most of the molecules have diffused out), it is still “full” (that is, the inside is still full of the saline carrier fluid).

Nanochannel Chips

Increasing magnification (SEM’s):

• example chip (at top left)
• macrochannel on reservoir-side of chip (lower left)
• 100~1000’s of inlet microchannels at the bottom of each macrochannel
• outlet microchannels emerging on the body-side of the chip (nanochannels are buried)
• zooming down to the bottom of the outlet to see the nanochannel entering
• zooming down (at far right) to the size of a nanochannel (note that the cross-hatching that is seen in this transmission electron microscope (TEM) image is the atomic lattice of the crystalline silicon material). A typical peptide molecule is illustrated at scale for comparison.

NOTES:

• Chip can be any size and shape and the pattern and number of microchannels and nanochannels is fully customizable using semiconductor chip manufacturing methods.
• Atomic Force Microscope data shows that the surface of the floor of a typical nanochannel is atomically smooth, with roughness values of 1~2Å

In Vitro Release of Therapeutic Molecules

Many molecules have been successfully released in the laboratory. Some examples include:

LEFT:

Top: In vitro data to determine the rate of release of Interferon alpha 2b in 13nm  (also has been release through 20nm chips). 

Bottom: In vitro data for leuprolide through 3nm channels (smallest nanochannels ever fabricated for drug release at therapeutic-dosing)

RIGHT:

Top: Release curve for a small molecule

Bottom: Release data for the macro-molecule Bevacizumab, a monoclonal antibody (2 weeks release)

In Vivo Release of Therapeutic Molecules

Calcitonin in dogs

Interferon-a in rats

Leuprolide in dogs

STUDY GOALS