Microfluidic apparatus to control liposome formation
Inventors
Gaitan, Michael • Jahn, Andreas • Locascio, Laurie E. • Vreeland, Wyatt • Reiner, Joseph E.
Assignees
National Institute of Standards and Technology NIST
Publication Number
US-8715591-B2
Publication Date
2014-05-06
Expiration Date
2024-07-21
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Abstract
An apparatus to create a homogenous liposome population without post-processing using laminar flow/diffusive mixing, and for reducing waste discharge of the therapeutic or compound to be encapsulated and delivered by the liposomes.
Core Innovation
The invention is a microfluidic apparatus designed to create homogeneous liposome populations without the need for post-processing. It uses laminar flow and diffusive mixing of miscible fluids to produce liposomes with controlled size and encapsulation efficiency, reducing waste of the therapeutic or compound encapsulated by the liposomes. The apparatus comprises multiple inlet and outlet channels etched into a silicon wafer and sealed by a glass wafer, enabling controlled flows of lipid, delivery compound, and buffer streams to form liposomes in a reaction channel with a convective diffusive mixing interface.
The problem addressed is the inability of prior art methods and devices to control liposome size, encapsulation amount, and loading efficiency effectively. Existing liposome production techniques often rely on viscous shearing under turbulent flow conditions, producing heterogeneous populations and requiring costly secondary processes like sonication or membrane extrusion for size control. Additionally, these methods have poor loading efficiency, leading to significant waste of delivery compounds, which is economically disadvantageous especially in drug delivery applications.
This invention solves the problem by employing laminar flow conditions in microfluidic channels where miscible fluid streams interact at convective diffusive mixing interfaces, enabling reproducible diffusive mixing and controlled liposome assembly. By adjusting volumetric flow rates and channel design parameters, the apparatus controls liposome size (40 to 300 nm diameter with low size deviation), the concentration of encapsulated compounds, and minimizes discharge waste. This approach eliminates the need for post-assembly size modification and enables scalable production of nanometer-scale liposomes.
Claims Coverage
The patent includes one independent apparatus claim and one independent method claim that describe the structural features of the microfluidic device and the method of controlling loading efficiency for liposome formation. Four inventive features characterize the claims.
Microfluidic apparatus with channels supporting laminar flow and specified depth-to-width ratio
The apparatus comprises a substrate including lipid, delivery compound, and buffer channels each having a channel depth to width ratio greater than 2:1. These channels carry miscible fluid streams and have dimensions that support laminar flow, enabling controlled, non-overlapping streams and diffusive mixing for liposome formation.
Convective diffusive mixing interfaces formed by channel intersections at angles maintaining laminar flow
Buffer channels and delivery compound channels intersect to form a miscible fluid mixing channel at an angle between 30 to 150 degrees sufficient to maintain laminar flow. This miscible fluid mixing channel further intersects the lipid channel to create a reaction channel with a convective diffusive mixing interface, ensuring diffusive mixing and liposome assembly under laminar flow conditions.
Control of liposome size, encapsulation, and loading efficiency through flow rate and channel length adjustments
Loading efficiency is varied by adjusting the ratio of volumetric flow rates through buffer and delivery compound channels. The method also includes controlling delivery compound concentration in the delivery compound stream by adjusting the length of the delivery compound channel, thereby controlling the extent of diffusion prior to liposome formation.
Sealing component bonded to substrate for fluid containment and apparatus integrity
The apparatus includes a sealing component bonded to the top surface of the substrate (silicon wafer) to enclose channels and maintain microfluidic conditions necessary for laminar flow and controlled liposome formation.
These inventive features collectively describe a microfluidic apparatus and method that produce homogeneous nanometer-scale liposomes with controlled size and loading efficiency by maintaining laminar flow conditions through specific channel geometries, flow rates, and fluid mixing interfaces, thereby overcoming limitations of prior art liposome formation technologies.
Stated Advantages
Production of homogeneous liposome populations on a nanometer scale without the need for post-processing such as sonication or membrane extrusion.
Increased loading efficiency reduces waste of encapsulated delivery compounds, lowering commercial costs especially for drug delivery applications.
Controlled liposome size and size distribution through adjustment of volumetric flow rates and channel design, enabling precise encapsulation.
Use of laminar flow and diffusive mixing provides reproducible and controllable liposome formation, avoiding the drawbacks of turbulent flow methods.
Documented Applications
Encapsulation of drugs, quantum dots, salts, nutrients, therapeutic agents, proteins, and contrast agents for medical applications such as drug delivery and enhanced magnetic resonance imaging.
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