PRINT (Particle Replication in Non-wetting Templates) Technology

Particle Replication in Non-wetting Templates (PRINT) technology is an advanced nanofabrication method designed to produce uniform, shape-specific, and monodisperse particles for applications in drug delivery, biotechnology, diagnostics, and materials science. Developed at the University of North Carolina at Chapel Hill by Professor Joseph DeSimone and his research group, PRINT represents a breakthrough in precise particle engineering.
This technology allows for the replication of particles with controlled size, shape, composition, and surface functionality, overcoming the limitations of traditional particle synthesis methods. It has become a cornerstone technique in the field of nanomedicine and polymer science for creating particles with predictable biological behaviour.

Background and Concept

The PRINT process was developed in the early 2000s to address the challenges of fabricating nanoscale particles with precise control over their physical and chemical attributes. Conventional particle fabrication techniques—such as emulsion polymerisation or spray drying—often produce heterogeneous particles with variable sizes and shapes, limiting their performance in targeted applications such as drug delivery.
PRINT was inspired by microfabrication techniques used in the semiconductor industry, where templates or moulds define precise geometries. By adapting these techniques using non-wetting, fluoropolymer-based templates, researchers were able to “replicate” particles in a controlled and reproducible way.
The name “Particle Replication in Non-wetting Templates” reflects its core principle — the use of a non-wetting mould surface that prevents adhesion between the material and the template, allowing easy release of the final particles.

Working Principle and Process

The PRINT technology involves a templating and replication process that allows precise control over particle formation. The method can be broken down into key stages:

1. Template Fabrication:
   • A non-wetting fluoropolymer mould (commonly made of perfluoropolyether, PFPE) is created using lithographic techniques.
   • The mould contains cavities or features that define the shape and size of the final particles (e.g., spheres, rods, cubes, discs).
2. Filling the Template:
   • The mould cavities are filled with a particle precursor material, which may include polymers, therapeutic drugs, proteins, or nanoparticles.
   • The filling can be achieved through methods such as capillary action, doctor blading, or solvent evaporation.
3. Solidification or Curing:
   • The precursor material is solidified using heat, UV light, or solvent removal, depending on its chemical composition.
   • This process locks the material into the desired shape within each cavity.
4. Particle Harvesting:
   • Because the template is non-wetting, the particles do not adhere to the mould surface.
   • The solidified particles are gently released or harvested from the mould, resulting in monodisperse, shape-specific particles.
5. Surface Modification (Optional):
   • The particle surfaces can be chemically modified for enhanced stability, targeting, or compatibility.
   • This step is critical in drug delivery applications where functionalisation allows for cell-specific targeting or controlled drug release.

Key Features and Advantages

PRINT technology offers several advantages over conventional particle fabrication methods:

• Precise Shape and Size Control: Enables fabrication of particles with well-defined geometry, ranging from nanometres to micrometres in size.
• Monodispersity: Produces particles of uniform size and shape, improving reproducibility in biological and industrial applications.
• Versatility in Materials: Applicable to a wide variety of materials including polymers, proteins, nucleic acids, and inorganic compounds.
• Controlled Composition: Allows incorporation of multiple components—such as drugs, imaging agents, or targeting ligands—within the same particle.
• Scalability: The templating approach can be adapted for large-scale manufacturing through roll-to-roll processing.
• Customisable Surface Chemistry: Enables modification of particle surfaces for targeted delivery or specific interactions with biological systems.
• Non-Wetting Mould Advantage: Prevents particle sticking and deformation, ensuring high yield and fidelity of replication.

Applications of PRINT Technology

PRINT has wide-ranging applications across scientific and industrial domains, particularly in biomedicine and nanotechnology.
1. Drug Delivery Systems

• PRINT enables precise design of drug-loaded nanoparticles with tailored release profiles.
• Particle geometry influences biodistribution, cellular uptake, and circulation time in the body.
• Used to encapsulate chemotherapy drugs, vaccines, and therapeutic proteins for targeted delivery.
• PRINT-based nanoparticles can be engineered for controlled drug release or pH-responsive behaviour.

2. Gene and RNA Delivery

• PRINT allows fabrication of particles carrying DNA, siRNA, or mRNA, used in genetic therapies.
• The uniform particle size aids in consistent gene transfer efficiency.

3. Vaccine Development

• PRINT-fabricated particles are used as antigen carriers or adjuvants, ensuring precise dosing and enhanced immune response.

4. Diagnostics and Imaging

• Particles designed for fluorescent tagging or contrast enhancement improve sensitivity in medical imaging techniques.
• PRINT nanoparticles serve as quantitative standards in flow cytometry and other analytical methods.

5. Materials Science and Industry

• Used in producing functional polymers, photonic materials, and nanocomposites.
• Applications extend to cosmetics, electronics, and catalysis, where control over particle morphology is crucial.

Influence of Particle Shape and Size

One of the greatest strengths of PRINT technology is the ability to study and optimise the influence of particle geometry on biological and physical performance.

• Shape: Elongated particles (e.g., rods, ellipsoids) often exhibit longer circulation times in blood and enhanced cellular uptake compared to spherical particles.
• Size: Smaller nanoparticles (50–200 nm) show improved tissue penetration, while larger microparticles are better for localised or sustained release applications.
• Surface Texture: Rough or porous surfaces enhance drug loading and interaction with cells.

PRINT thus enables precision medicine, allowing researchers to design drug carriers that match specific therapeutic requirements.

Manufacturing and Scalability

PRINT technology is compatible with industrial-scale roll-to-roll manufacturing, similar to techniques used in the production of flexible electronics and films. This scalability has been crucial in transitioning from laboratory-scale production to commercial pharmaceutical applications.
Process Advantages for Manufacturing:

• High-throughput continuous production.
• Consistent particle uniformity across batches.
• Reduced material waste due to template reuse.
• Compatibility with automation and GMP (Good Manufacturing Practice) standards.

Commercial adoption has been driven by companies such as Liquidia Technologies, which applies PRINT for pharmaceutical nanocarriers and vaccines.

Limitations and Challenges

While PRINT is a highly advanced technology, it faces certain limitations:

• High production costs compared to conventional synthesis.
• Complex template fabrication requiring specialised facilities.
• Material compatibility constraints, as not all polymers or drugs are easily processed.
• Potential scalability barriers for very high-volume, low-cost products.

Ongoing research aims to address these challenges through improved materials, simplified processing, and integration with complementary nanofabrication techniques.

Significance and Future Prospects

PRINT technology represents a paradigm shift in particle engineering and nanomedicine. Its precision and reproducibility enable the systematic study of how particle properties affect biological interactions, paving the way for highly customised therapeutic solutions.
Future developments focus on:

• Designing multi-functional nanocarriers capable of simultaneous therapy and diagnostics (theranostics).
• Expanding into personalised medicine for patient-specific drug delivery systems.
• Integrating with microfluidics and AI-driven design platforms to optimise particle fabrication.