Bimetallic Coupling for Electrochemical Control of Cell Fate at Metal Implant Surfaces

MD&M East 2011 Event Coverage
bimetallic coupling at implant surface
An SEM image shows a preosteoblast-like cell cultured on a titanium surface that is electrically connected to a magnesium wire also immersed in the medium.

Dr. Jeremy L. Gilbert, a professor in the department of biomedical and chemical engineering at Syracuse University, will present “Bimetallic Coupling for Electrochemical Control of Cell Fate" on Wednesday, June 8, as part of the MD&M East University Medical Innovation Showcase. Discussing a variety of exciting advancements in medical device research and development, scientists from several New York–based research institutions will present their innovative technologies to new venture development and established industry professionals. Organized with the intention of fostering medical device innovation, the event aims to promote licensing, joint R&D, and venture funding for university startups and emerging technologies.

MPMN: What is reduction electrochemistry?
 
Gilbert: Electrochemistry (redox reaction) is any chemical reaction that includes the transfer of charge from one species to another, usually across an electrode interface. Electrochemical reactions have two parts: oxidation and reduction. Oxidation is where the chemical reaction results in the release of electrons and the increase in the valence of a reacting species, while reduction is where the reaction takes up or consumes electrons and lowers the valence of the reacting species. So, reduction electrochemistry is that part of a so-called redox reaction where reduction occurs.

MPMN: How does this relate to implants?

Gilbert: At metallic implant surfaces, there is both oxidation and reduction that takes place in vivo. The metal oxidizes—raises its valence to become a cation—and the electrons given up will go to engage in a reduction reaction. The species that can reduce are usually in the solution adjacent to the metal. In the body, the solution is the extracellular fluid and, perhaps, the tissues immediately adjacent to the metal implant. There are many species that can engage in reduction reactions in vivo, including oxygen, reactive oxygen species, hydrogen peroxide, proteins, enzymes, etc.

For most studies of metallic biomaterials in the body, the focus has been on the products of the oxidation reactions—the metal cations and metal-oxide particles formed from oxidation—and how these products affect the cells and tissues in the body. Metal-ion toxicity and biological response to particles have been the focus of these studies. There have been very few studies focused specifically on the reduction reactions that are also present and may be affecting the biological interaction, however.

When the rate of oxidation of the metal of an implant increases, there is a corresponding increase in the rate of reduction that occurs as well. For metal implants, what happens is that, for example, mechanical abrasion of the oxide film will expose fresh metal to the body solution and will dramatically increase the rate of oxidation. The released electrons will result in a negative shift in the voltage of the implant and an increase in the rate of reduction reactions. So, wear processes cause increased rates of reduction reaction. Also, with newer degradable implant alloys, e.g. magnesium (Mg) alloys, the rate of oxidation is very high and, therefore, the corresponding rate of reduction is also very high.

MPMN: What is the impact of reduction electrochemistry at implant surfaces?
 
Gilbert: Many of the consequences of reduction electrochemistry at implant surfaces are not known, since we have not, until recently, appreciated the fact that these reactions may be important. There are a few things that had been known from prior work. First, it is known that negative voltages—where reduction reactions take place—can stimulate the formation of bone. So-called dc electrical stimulators are used to stimulate the formation of bone in areas where fracture nonunions have developed, such as with spinal-fusion procedures. It is likely that reduction electrochemistry will stimulate bone formation if it is applied in the vicinity of bone.

However, our work has shown that reduction reactions can result in the killing of cells immediately adjacent to a metal surface engaged in reduction reactions. We have also shown that, in the presence of inflammatory molecules like hydrogen peroxide, we can reduce these species at the metal surface with reduction processes. We are also likely able to generate reactive oxygen species at an implant surface engaged in reduction reactions.

MPMN: What has your work in this area focused on?
 
Gilbert: Our work has investigated the role of electrochemistry on the behavior of mammalian cells cultured on the metal surface engaged in the reactions. In our experiments, we culture mouse preosteoblasts on titanium (Ti) and cobalt-chromium alloy surfaces; surfaces are held at fixed electrode potentials, where either net-oxidation or net-reduction reactions are taking place. We have found that cells cultured on titanium will be driven to cell death by a process that appears to be apoptosis, or programmed cell death, when the potential of the surface is held at or below –400 mV versus an Ag/AgCl reference electrode. Above this potential, the cells remain viable and relatively indifferent to the potential up to 1000 mV. However, at or below –400 mV, the cells go through a process of cell death over time. The time needed to induce 100% cell death decreases the further below –400 mV you go, where –1000 mV will induce cell death in about two hours.

Our work is also focused on whether bimetallic coupling of a very active metal such as magnesium to a biocompatible metal such as titanium will result in a similar outcome when cells are cultured on the Ti surface. We have found that it takes very small relative quantities of Mg to cause the voltage of the surface of the Ti to become very negative, below –1.2 V, and that similar cell death processes occur if the Mg is in electrical contact with the Ti. We have also found that with the appropriate combination of Mg and Ti, we can keep a very negative voltage present for up to five days and likely longer. We have also found that particles of Mg and Ti-Mg combinations can also result in cell death in the vicinity of the particles when cells are cultured on tissue culture plastic but are near to the bimetallic particles.

Our idea is to develop two basic medical approaches to the use of bimetallic couples. In the first, we think that by coupling an active alloy to a biocompatible metal alloy, we may be able to kill living cells such as bacteria that are at the implant surface while also stimulating bone formation in the near-bone region. In the second, we believe that bimetallic particles coupling active metals with biocompatible ones may be able to be delivered locally to either kill infection or cancer cells. Thus, we feel that we may have an approach to the treatment of two very significant problems in healthcare: dealing with implant-centered infection and providing a therapy for cancer treatment. In both cases, the duration of the treatment will be limited by the lifetime of the active metal. When the small amount of active metal corrodes, the electrochemical processes will cease, and all that will be left are relatively biocompatible materials.
 
MPMN: What is the advantage or benefit of bimetallic coupling with biodegradable metals?
 
Gilbert: The advantage of this approach is that we may be able to make a metal implant surface a treatment vehicle for killing bacterial biofilms that may be infecting the surface. This will not rely on systemic antibiotics and could be applied to the metal implant directly through the attachment of the active metal to the surface. The duration of treatment can be limited or controlled by the amount and distribution of the active metal attached to the surface and does not require external power to occur. For cancer therapy, we can create particles that will be active for a day or two, with the possibility of targeting these particles with surface-chemistry approaches. Local delivery of the particles to the site of the tumor or infection and/or preferential attachment to the cells in question will deliver the killing effect.