Example Chapter - INFECTION AND BIOMATERIAL SURFACES

As discussed in Chapter 5, when bacteria accumulate at the site of an implant, there is a high
potential for infection. In the United States alone, there are around 1 million cases of implant
infection annually, imposing associated medical costs of around $3 billion USD each year.
As the amount of implanted medical devices increases, so too will the amount of
device-associated bacterial infections. These bacteria are attracted to implant surfaces due to
the presence of proteins and nutrients that adhere to and adsorb into the biomaterial surface.
As bacteria adhere to the surface of an implant, they may eventually accumulate in layers,
forming multilayered structures on the implant surface known as biofilms. Biofilms exhibit a
much higher resistant to traditional antibiotic treatments than individual bacteria due to the
inability of the antibiotic to penetrate into the deeper layers of the biofilm. Over time, the
antibiotic will eventually permeate throughout the biofilm, however by this point, the rapidly
mutating bacteria are likely to have become resistant to antibiotics; prolonged, ineffective
antibiotic exposure will naturally select for this trait in the bacterial colonies. As a result,
biofilms are notoriously difficult to remove from an implant, often requiring implant
resection to effectively treat the infection. Given the costs and risks associated with implant
revisions and resections, it is far more beneficial to prevent infections and biofilms rather
than treat them.

The difficulty associated with treating infections of implanted devices creates a need
for multiple effective techniques for the proactive treatment and prevention of these
infections. Methods such as bacteria repelling/antiadhesive surfaces, bioactive materials with
antibacterial properties, and biomaterials that actively deliver antimicrobial drugs are of
interest to this pursuit.

There are multiple avenues by which bacteria can adsorb or adhere to a material
surface. One of the most promising novel methods for the prevention of infection and the
formation of a biofilm is by selecting a surface material for the implant that is not conducive
to the adhesion of bacteria; preventing the bacteria from adhering to the implant material in
the first place eliminates the possibility of biofilm formation on the implant and decreases the
ability of bacteria to form a colony. The topographical characteristics of a surface may
influence how bacteria adhere to it. If the surface is porous or rough, there is more area
available for the bacteria to adhere to, resulting in a higher rate of bacterial infection
associated with these material properties. To combat this, surfaces can be coated with
bioactive materials that possess antibacterial properties. Silver, for example, has been found
to demonstrate antibacterial properties when used as a surface coating for implants. Many
other materials including metals such as copper and zinc, polymers such as chitosan, and
bioactive glasses possess this inherent cytotoxic property toward prokaryotic cells. There are
several concerns, however, with using materials such as these in medical implants. The
native cell-biomaterial interactions of these coatings and surfaces can impact over
biocompatibility with effects that are not well tolerated by the body. The concern with using
silver-coated implants, and other metal coatings, in particular is that areas with high activity,
such as joints, may produce wear debris. This debris is characterized by small particles that
shed from the implant and migrate into surrounding tissue. Silver itself may not only shed
wear debris, but is susceptible to corrosion. Ions released from silver corrosion are cytotoxic,
causing local cell death. The loss of host cells in the area of the body surrounding the implant
causes poor prognosis in implant success and implant-tissue integration. Other physiological
concerns for wear debris include accumulation of metal and polymer particles within the
body in even distant organs and tissues, which may result in a host of side effects associated
with any loss of function in those areas.

The charge of the surface of an implant material will also affect the adhesion rate of
bacteria to that surface. If the surface of an implant is charged, proteins will adsorb and
adhere to the biomaterial surface more effectively than they would to a more inert surface.
The presence of proteins on the surface of the biomaterial may allow for bacteria to attach to
these proteins, as the bacteria have a higher affinity for binding to them than the material
surface itself. This increases the potential for infection at the site of the implant by
facilitating the formation of bacterial colonies and eventually biofilms. To prevent the
adsorption of proteins on an implant, protein attachment can be reduced through utilizing a
material coating that presents non-charged, inert surface. The necessity of these coatings
depends on the specific physiological environment in which the implant is located and the
concentration of proteins in that area. For example, hydrogels present a very attractive
options for protein adhesions and adsorption; not only can proteins adhere to this material,
but they may also adsorbed to the point of permeating the material.

Modern contact lenses are composed of hydrogels and the surface of the eye exposes
the biomaterial to many proteins present in the tears. Protein adsorption in this material is
reduced through use of contact soaking solutions. Those who wear monthly-use contact
lenses place the contacts in these solutions overnight. These soaking solutions may contain
chemicals such as hydrogen peroxide to facilitate the removal proteins from the surface of
the material. When performed regularly, as indicated in the recommended use of contact
lenses, this prevents protein buildup on the surface of the lens and reduces the possibility of
bacterial infection. A method such as this only works for devices that can be regularly
removed. For implants, which are more or less permanently placed in the body or at least not
intended to frequent resection, this method of combating protein buildup and bacterial
adhesion is not feasible. Methods of reducing bacterial infection in implants might instead
include the integration of controlled release and delivery of antibiotic drugs. Integrating
antibiotics directly into the implant material allows local and targeted delivery of the drugs at
a controlled release rate. This is beneficial because it is more effective than an all-at-once
systemic delivery and also reduces the need of a patient having to remember to take an
antibiotic when prescribed to a regimen. The controlled, slow release of antibiotics reduces
the potential of incomplete treatment and more effectively prevents infection.

Nanoconstruction of materials presents another method of preventing bacterial

adhesion to implant surfaces. The surface of these materials can alter the three-dimensional
conformation of proteins that adsorb to them, preventing bacteria from adhering to these
proteins. The adsorption rate of proteins depends on the specific surface chemistry of the
nanoparticles. These surfaces can be altered to be very hydrophobic, which reduces the
possibility of attracting proteins and bacteria to the surface. In addition, the large surface to
volume ratio of nanoparticles can be used to increase antimicrobial action because there is
more surface area for the antibacterial particles to be incorporated into. Due to the
incorporation of antibacterial properties, the increased surface area is more beneficial
because it allows increased loading of the antibacterial molecules.

The primary drawbacks of using nanoparticles and nanoconstructed technology in

infection-resistant implants is the unknown toxicological effect that these methods have on
the body itself. In general, the mechanism by which nanoparticles provide bacterial
resistance is not well understood. Leading theories suggest that nanoparticles damage the cell
membranes of bacteria and also produce reactive oxygen species. Gold nanoparticles, in
particular, are known to disrupt ATP synthase and inhibit ribosomal binding. These
mechanisms may also affect host cells cause localized cytotoxicity and tissue damage. Much
like the silver ions discussed earlier in this chapter, there may also be a possibility of
nanoparticle accumulation throughout the body, in distant organs and tissues, causing
unknown side effects.

Summary
The potential of bacterial infection and biofilm formation, coupled with the challenge of
treating these conditions, provides a high incentive for novel methods of preventing bacteria
from colonizing medical implant materials and material surfaces. Several of these novel
methods, such as designing implant materials with inherent antibacterial properties, address
bacterial colonization at its root to prevent bacterial adhesion to the material. Though these
methods show great promise, many are not well characterized and raise challenges and
concerns over long-term effects on the body.

References
Campoccia, D., Montanaro, L., & Arciola, C. R. (2013). A review of the biomaterials
technologies for infection-resistant surfaces. ​Biomaterials,​ ​34​(34), 8533-8554.
doi:10.1016/j.biomaterials.2013.07.089

Hetrick, E. M., & Schoenfisch, M. H. (2006). Reducing Implant-Related Infections: Active

Release Strategies. ​ChemInform,​ ​37​(48). doi:10.1002/chin.200648272

Bibliography/Suggested Reading
Campoccia, D., Montanaro, L., & Arciola, C. R. (2013). A review of the biomaterials
technologies for infection-resistant surfaces. ​Biomaterials,​ ​34​(34), 8533-8554.
doi:10.1016/j.biomaterials.2013.07.089

Arciola, C. R., Campoccia, D., Speziale, P., Montanaro, L., & Costerton, J. W. (2012).
Biofilm formation in Staphylococcus implant infections. A review of molecular mechanisms
and implications for biofilm-resistant materials. ​Biomaterials,​ ​33​(26), 5967-5982.
doi:10.1016/j.biomaterials.2012.05.031

Costerton, J., Montanaro, L., & Arciola, C. (2005). Biofilm in Implant Infections: Its
Production and Regulation. ​The International Journal of Artificial Organs,​ ​28​(11),
1062-1068. doi:10.1177/039139880502801103

Discovery Activities
1. Explore the properties of biofilms with respect to how they resist traditional antibiotic
treatments. In what ways can drug delivery be designed to combat these formations?
Are there drugs other than antibiotics that might be useful?
2. What types of ​in vitro ​and ​in vivo​ experiments could be used to evaluate short-term
cytotoxicity to host tissues for modified implant surfaces and nanoparticles?
3. What types of ​in vitro ​and ​in vivo​ experiments could be used to evaluate long-term
cytotoxicity to host tissues for modified implant surfaces and nanoparticles? What ​in
vitro​ models and animals models could be used to simulate human tissues and
physiological conditions?
4. Search for examples of currently developing or marketed products that utilize
biomaterials with inherent antimicrobial properties in their design.
5. The study of nanoconstruction and nanoparticles is a relatively new field. Envision a
future where these techniques are well characterized and discuss what possibilities
and applications this technology might have on medical devices and implants
commonly used today.