Feng research outlines strategy to improve drug delivery to tissues
Lipid vesicles are small enclosed compartments made of fatty layers that effectively isolate their inner contents from the outside environment. They are ubiquitous in biology and vital for cellular function, but recently they have been engineered to act as a transport medium for precise and targeted delivery through small channels. This has many potential applications, such as delivering cancer treatments directly to tumors without damaging the surrounding healthy tissue. Lipid vesicles are especially well suited to these types of tasks because their extremely small size allows them to squeeze through tiny capillaries and the micro-scale gaps that exist within tissues. Lipid vesicles also have the added benefit of being easily modifiable so that molecules can be embedded onto their surface, allowing them to selectively prefer targeted tissues. The problem, however, is getting them there.
Typically, vesicles need to diffuse through tissues, similar to cream mixing into coffee, which can be a very slow process. This makes them of little use for applications like drug delivery, where both the amount of drug delivered and the time over which it is delivered are crucial for its effectiveness.
To speed up this transport process, Assistant Professor Jie Feng, in collaboration with Professor Sangwoo Shin at the University of Hawaii at Manoa, devised a system that slightly alters the outside environment to cause spontaneous movement of the vesicle in a given direction. The technique, called diffusiophoresis, is outlined in their Physical Review Applied paper, “Osmotic Delivery and Release of Lipid-Encapsulated Molecules via Sequential Solution Exchange.” During the process, vesicles exposed to a local solute gradient will experience an enhanced migration. This difference in concentration gradient causes the vesicles to move quickly away from the higher concentration solution (i.e. down the concentration gradient) at rates much faster than can be achieved by passive diffusion. To test this process, a microfluidics apparatus was constructed that mimics the geometry of common tumor tissue. They found that by using diffusiophoresis, they were able to cause the vesicles to penetrate the tissue model about 100 times faster than passive diffusion alone.
Although delivering drugs quickly is one important piece of the microtransport puzzle, getting vesicles to release their contents once they reach their destination is another important consideration. Vesicles in general are very stable structures and will not spontaneously open. It had been noted previously that when vesicles contain a photoreactive chemical, laser light can be used to alter the osmotic balance inside the cell. If the osmotic shock is extreme enough, the vesicle will swell and explode, delivering all of its contents immediately. If, however, the osmotic change is too mild, the vesicle will simply swell, burst to release a tiny bit of its contents, and reseal. Under what conditions a vesicle would explode and how the properties of the vesicle itself altered the explosion threshold was unknown.
In a new paper – “Light-triggered explosion of lipid vesicles,” published in Soft Matter – by graduate student Vinit Kumar and a team led by Feng – who runs the Fluids, Interfaces and Transport Lab at Illinois – engineers developed a theoretical model, unravelling the mystery around vesicle explosion. Vesicle swelling dynamics are driven by three energies: elastic energy, pore-edge energy, and bending energy.
When a vesicle swells, the elastic energy is stored until the membrane ruptures by creating a pore to relax the energy. At this point there is a competition between the pore edge energy that tries to reseal the pore and bending energy that prefers the pore to be open. If the swelling happens slowly (low strain loading rates) then the pore that opens will be small and the edge energy will quickly reseal it. Light reactions that cause extreme osmotic gradients, however, can cause the vesicle to swell at a very fast rate, leading to sudden high strain. At the moment the pore opens it becomes very large and the bending energy dominates, causing the pore to open wider and the vesicle to explode.
Feng and colleagues also found that small vesicles are more resistant to exploding—a finding that sets a lower bound for the feasible size of transport vesicles. Using these parameters, it now becomes possible to precisely design vesicles with the specific properties needed to ensure its contents will be delivered. Such designer vesicles could even be built into complex and multicompartment systems that mimic the structure of biological cells. This new theoretical framework can help bioengineers to program artificial cell systems to perform complex biological functions such as osmoregulation and osmosignaling. This could allow for more mechanistic understanding of how biological tissues grow, develop, and die.
Feng earned his PhD in mechanical and aerospace engineering from Princeton University in 2016. He joined MechSE in January 2019.