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Tuning Viruses Creates Complex Biological Tissues

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BERKELEY, Calif., Oct. 20, 2011 — A benign virus has been turned into an engineering tool for assembling structures that mimic collagen, considered one of the most important structural proteins in nature. Researchers say this process eventually could be used to manufacture materials with tunable photonic, optical, biomedical and mechanical properties.

The materials created with the help of viruses eventually could be used to create complex biological tissues, such as cornea, skin and bones. (Image: Woo-Jae Chung, UC Berkeley)

By controlling the physical environment alone, a researcher team led by University of California, Berkeley, bioengineer Seung-Wuk Lee and his student and lead author Woo-Jae Chung caused the viruses to self-assemble into hierarchically organized thin-film structures with complexity that ranged from simple ridges to wavy, chiral strands to truly sophisticated patterns of overlapping strings of material — results that also may shed light on the self-assembly of biological tissues in nature.

Each film presented specific properties for bending light, and several films were capable of guiding the growth of cells into structures with precise physical orientations.

“We took our inspiration from nature,” Lee said. “Nature has a unique ability to create functional materials from very basic building blocks. We found a way to mimic the formation of diverse, complex structures from helical macromolecules, such as collagen, chitin and cellulose, which are the primary building blocks for a wide array of functional materials in animals and plants.”

For example, a number of blue-skinned animals, including the mandrill monkey, derive their coloring not from pigment, but from the specific scattering of light formed when thin fibers of collagen are bundled, twisted and layered in its skin.

Building blocks illustration. (Image: Zina Deretsky, National Science Foundation)

In contrast, aligning collagen in a perpendicular, gridlike pattern creates transparency and is the basis of corneal tissue. And corkscrew-shaped fibers, mineralized after interacting with calcium and phosphate, can generate the hardest parts of our body: bones and teeth.

“The basic building block for all of these functional materials — corneas, skin and teeth — is exactly the same. It’s collagen,” Lee said. “I was mesmerized when I saw the brilliant skin color and sharp teeth of blue-faced monkeys at the San Francisco Zoo. It is stunning that the way the collagen fibers are aligned, twisted and shaped determine their optical and mechanical functions. What had not been well understood, however, is how such a simple building block can create such complicated structures with diverse functions.”

The researchers began to study the factors influencing the formation of hierarchical structures and noticed that collagen is secreted in confined spaces and that it’s assembly into tissues can be influenced by its environment. “Unfortunately, collagen is a difficult material to study because it is hard to tune its physical and chemical structures,” Chung said. “We needed a convenient model system to solve this problem.”

That model system turned out to be a soup of saline solution containing varying concentrations of a common bacteria-attacking virus called the M13 bacteriophage. The researchers chose the M13 virus (harmless to humans and a model organism in research labs) because its long, chopsticklike shape with a helical groove on its surface closely resembles collagen fibers.

Professor Seung-Wuk Lee and Dr. Woo-Jae Chung analyze the ramen noodlelike nanostructure fabricated through self-templated materials assembly process of viral particles using an atomic force microscope. (Image: University of California, Berkeley)

The technique they developed entails dipping a flat sheet of glass into the viral bath, then slowly pulling it out at precise speeds. The sheet emerges with a fresh film of viruses attached to it. At a pulling rate ranging from 10 to 100 µm per minute, it could take one to 10 hours for an entire sheet to be processed.

By adjusting the concentration of viruses in the solution and the speed with which the glass is pulled, the researchers could control the liquid’s viscosity, surface tension and rate of evaporation during the film-growth process. Those factors determined the type of pattern formed by the viruses. The investigators created three distinct film patterns using this technique.

With a relatively low viral concentration of up to 1.5 mg/ml, regularly spaced bands containing filaments oriented at 90° to each other were formed.

With a slower pulling rate came increased physical constraints to the movement and orientation of the viruses. The viruses spontaneously bunched together, and as they stuck to the sheet, they started to twist into helical ribbons, much like curled ribbon used for gift wrap.

The most complex pattern — described as “ramen noodlelike” by the researchers — was formed using viral concentrations ranging from 4 to 6 mg/ml. By using the Advanced Light Source at Lawrence Berkeley National Laboratory (LBNL), they discovered that this highly ordered structure could bend light like a prism in ways never before observed in nature or other engineered materials.

In one expression of those differences, structures built using faster-pulled substrates yielded patterns that reflected ever-shorter wavelengths of light — 50 µm/min yielded material that reflected light in the orange color range of the spectrum (600 nm), while 80 µm/min yielded blue light (450 nm). The process was precise, allowing the researchers to tune the films to various wavelengths and colors and to induce polarization.

Viruses attach to the thin sheet of glass as it is pulled out of the solution. This new process creates materials that mimic collagen, one of the most fundamental structural proteins in nature. (Video: Woo-Jae Chung, UC Berkeley)

“We can determine the type of structure we get through this technique by fine-tuning the factors that influence the kinetics and thermodynamics of the assembly process,” Chung said. “We can control the levels of order, direction of the twist as well as the width, height and spacing of the film patterns.”

The researchers further showed that the virus assembly process could be used in biomedical applications. They genetically engineered the virus to express specific peptides, which influence the growth of soft and hard tissue. They used the resulting viral films as tissue-guiding templates for the biomineralization of calcium phosphate, forming a tooth-enamellike composite that, in the future, could be applied as a regenerative tissue material.

The simplicity of the technique bodes well for adapting it for use in manufacturing, the investigators say. Once the parameters are set, it is possible to step aside and let the self-assembly process take place.

“We let this run overnight, and by the next morning, there were trillions of viral filaments arranged in patterns on our substrate,” Lee said. “One of the most important aspects of our work is that we have started to understand nature’s approach to creating such complex structures, and we have developed an easy way to mimic and even extend it.”

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Oct 2011
The transparent front layer of the eye. Light entering the eye is refracted (converged) by the outer surface of the cornea.
Pertaining to optics and the phenomena of light.
Advanced Light SourceAmericasBasic Sciencebiological tissuesbiomedicalBiophotonicscalciumcellulosechitincollagencollegen fiberscorneaindustrialLBNLM13 bacteriophageM13 virusmandrill monkeymechanicalMicroscopynanoopticalopticsphosphatePrismsResearch & TechnologySeung-Wuk Leeskinteethtunable photonicstuning virusesUniversity of California Berkeleyviral concentrationsWoo-Jae Chung

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