NSF-funded interdisciplinary research develops cutting-edge biomaterials to reduce the risk of infection around implants.

Working with a number of colleagues throughout the university, Professor Matthew Libera of Stevens Institute of Technology has introduced innovative hydrogel-treated surfaces, ones which may dramatically reduce the risk of infection that often occurs during orthopedic implant procedures. Such infections result from bacteria attaching to and proliferating on the implant surface where they can subsequently develop into structures known as biofilms. The new hydrogel-modified surfaces are designed to interfere with bacterial adhesion and the biofilm development process.

Implant infection is emerging as an extremely important medical problem. Current statistics indicate that infection is responsible for causing failure in approximately 1% of hip implants, 4% of knee implants, and more than 15% of implants associated with orthopedic trauma, where the wounds are typically quite open and inherently dirty from debris from an accident or battlefield injury.

With a market valued at more than $16 billion and a projected value exceeding $23 billion by the year 2012, orthopedic implant procedures are becoming increasingly widespread. They offer the potential for increased and/or restored mobility and play an increasingly crucial role in patient well being. With this continued growth, however, comes an ever increasingly critical need to reduce the associated risks. The research efforts at Stevens seek to introduce unique solutions to reduce implant infection and the catastrophic consequences associated with it.

Biomaterials-Related Infection: An Interdisciplinary Problem

a) Uncontrolled bacterial growth
b) PLL-primed test wafer
c) Wafer with PEG Hydrogel application

Fighting implant infection is far more complex than simply getting a prescription for antibiotics. Bacteria that grow in biofilm communities can be as much as 10,000 times more resistant to antibiotics than the so-called planktonic bacteria, which circulate around the body as individual cells. Resolving an implant infection usually requires that the implant be entirely removed, the surrounding tissue cured of infection, and then a second prosthetic device is implanted. This can take months and many tens of thousands of dollars. Solving this problem requires a broad range of expertise from many different disciplines.

"One of the most exciting aspects of our activities in this field is how so many Stevens research groups have been able to contribute new ideas about possible solutions," explains Prof. Libera. Over the past five years, more than eight different Stevens professors have started doing work on topics related to biomaterials-associated infection. It's situations like these when big advances can be made.

While hydrogels inhibit the growth of bacteria, osteoblasts will continue to grow and proliferate. This figure shows osteoblast growth in both a) confocal and b) SEM images

Libera is one of five investigators supported by a so-called NIRT grant from the National Science Foundation to help solve the implant-infection problem. The project has just started its third year and involves collaborators from Materials Science, Chemical Biology, and Biomedical Engineering.

The basic idea underlying the NIRT project is to modify the surface of an implant to simultaneously preserve the many desirable healing properties they have now but make bacteria less likely to adhere to them. Currently, implant surfaces are adhesive to both tissue cells and bacteria. In an ideal situation, the implant will be accepted by and integrated into the surrounding native tissue resulting in a healthy functioning joint. However, in cases where bacteria overtake surface colonization, infection can occur leading to failure of the implant as well as substantial health consequences.

The NIRT project exploits the concept of differential cell adhesion. "This is one of the holy grails of modern biomaterials science," says Prof. Libera. "It's now pretty easy to make a surface to which all different kinds of cells adhere. It's also pretty easy now to make a surface that repels pretty much all cells. The challenge is to make a surface that the good cells stick to but the bad cells avoid."

Biomaterials-Associated Infection and Hydrogels

One of the ways the Stevens team is trying to achieve differential cell adhesion is by patterning the implant surface at microscopic length scales. A human tissue cell (Eukaryotic) cell is typically on the order of 10 to 50 micrometers in diameter with a flexible, liquid like cell wall. Bacterial (Prokaryotic) cells on the other hand, are generally spherical in shape with rigid cell walls and an average size of 1 micrometer. Just as antibiotics exploit differences between bacteria and eukaryotic cells to preferentially kill bacteria, the Stevens effort is exploiting differences between their size and adhesion mechanisms to achieve differential cell adhesion.

Testing was done with specific Hydrogel patterns applied to silicon testwafers. Dr. Libera is able to control the growth of osteoblasts and inhibit bacterial formation by adjusting the densities of these patterns.

Libera's group has been patterning surfaces with various types of hydrogels. Hydrogels are polymers that absorb large amounts of water, and most bacteria, particularly the various types of Staph common to implant infection, do not adhere to most hydrogels. One of Libera's graduate students, Chris Wang, has learned how to make gel particles from poly(ethylene glycol) [PEG] and deposit them onto an implant surface by Electrostatic Self-Assembly. This is a bottom-up approach that exploits the fact that particles of one charge will be attracted to surfaces with the opposite charge. Stevens Professor Svetlana Sukhishvili is an authority on self assembly and is playing a key role in this aspect of the NIRT project. The goal is to deposit these gel particles onto surfaces at just the right size and spacing so bacteria get repelled by them but eukaryotic cells grow right over them. In collaboration with Biomedical Engineering Professor Xiaojun Yu and his students, Chris Wang has already shown that bone cells known as osteoblasts do in fact nicely grow on gel-modified surfaces that simultaneously reduce bacterial adhesion.

Electron-Beam Patterned Hydrogel Surfaces

Altida PatimethaIn an alternate technique, Prof. Libera employs Electron-Beam processing for the surface patterning of hydrogels. "It was a Stevens undergraduate student who got the group started on e-beam patterning about 7-8 years ago," comments Libera, "and we've had a series of different projects that have built on that early work." One of them is differential cell adhesion. Whereas self-assembly results in a coating of the entire surface, electron-beam processing is a top-down approach that can create very specific patterns and distributions of hydrogel particles in specific areas of a surface. The electron-beam processing approach thus enables the group to pursue really well-controlled experiments about the effects of surface patterning on differential interactions with tissue cells and bacteria.

One set of experiments is being led by graduate student Eva Wang. She uses a custom-configured scanning electron microscope to create surface-patterned hydrogels of PEG on glass microscope slides. The patterned surfaces are then studied in flow-cell systems integrated into advanced optical microscopes. The microscopes enable researchers to observe how different types of cells interact with surfaces. In addition to cell-culture experiments at Stevens, Eva Wang is working in collaboration with Prof. Henk Busscher and his colleagues at the University Medical Center in Groningen in the Netherlandson the flow-cell experiments. She spent part of the summer of 2009, together with Stevens undergraduate students Altida Patimetha and Harinder Bawa, in Busscher's lab learning some of these new imaging methods. The trans-Atlantic collaboration continues today. It's showing conclusively that, relative to an unmodified glass surface, specimens treated by e-beam patterning to create hydrogel particles at specific spacings are able to repel bacterial proliferation while encouraging eukaryotic cell growth. These tests are helping to identify the regime where bacterial growth can be significantly reduced while eukaryotic adhesion can be preserved.

More than just hydrogels – Stevens has become a leader in the infection technology landscape

"One of the exciting things at Stevens right now is the environment that has been built to study the many different aspects of biomaterials-associated infection," Dr. Libera comments. This environment involves a range of interdisciplinary research groups on campus. For example, Woo Lee (Materials Science) and Hongjun Wang (Biomedical Engineering) have been developing innovative 3-D tissue models to test advanced cell-interactive materials. James Liang (Chemical Biology) is working with antimicrobial peptides and learning how to bind these to synthetic surfaces to make them infection resistant. Svetlana Sukhishvili (Chemistry) and her students are designing new types of cell-interactive thin films, including temperature and pH-responsive drug-loaded hydrogel films, by self-assembly processes. Xiaojun Yu (Biomedical Engineering) has been working with chitosan-based materials with novel anti-infective properties to make nanofiber structures for advanced tissue-engineering applications. Libera explains, "One of the newest concepts is to create active surfaces, ones where some kind of switch gets toggled and the surface changes. There are some really creative ideas along these lines coming out of the Stevens nanofabrication groups in Mechanical Engineering."

The focus on infection started in late 2004 when Prof. Woo Lee came back from a Keck Foundation conference where he had heard about biofilms. He and Prof. Libera then did a lot of homework to identify some of the key issues surrounding what they now know is biomaterials-associated infection. They concluded that:

  • Bacteria will find immune-compromised or synthetic surfaces (such as open wounds, yeast infections, cystic fibrosis, catheters, orthopedic joints, contact lenses, heart valves)
  • Hospital-acquired infections currently strike 2 million people and kill over 90,000 in the U.S.
  • The prevention of biofilm formation is the best method of eliminating the risk of infection
  • There is not yet any clear government policy or corporate strategy to resolve these problems
  • Biomaterials-associated infection is an international problem
  • The problem will get worse as bacterial resistances to antibiotics increases (e.g. MRSA)

This sort of analysis convinced Lee, Libera, and others at Stevens that working on infection and cell-material interactions is a problem where Stevens can have some real impact. Furthermore, Stevens is partnering with collaborators at the nearby University of Medicine and Dentistry of New Jersey (UMDNJ) and the Public Health Research Institute (PHRI) to tap into regional expertise in infectious diseases and microbial cell biology. Prof. Libera says, "What we are doing is right in line with the Stevens historical tradition of solving real-world engineering problems that goes back to the roots of the Stevens family in the Revolutionary War era." The extended group now has research funding such sources as the National Science Foundation, the National Institutes of Health, the Army Research Office, and the Department of Defense and continues to make innovations and advances.

For more information about this research and other activities in health care at Stevens, please contact Dr. Peter Tolias.

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