Implantable medical devices – including access catheters, heart valves and stents – are integral to supporting and maintaining patient health. Unfortunately, devices that come in contact with the patient’s blood are susceptible to failure due to the body’s tendency to form blood clots or mount inflammatory responses at the site of the implant.
In the case of device failure due to an adverse reaction, the only currently-available option is complete device replacement. In order to improve the outcomes for patients who rely on these implantable devices, researchers from Harvard have developed a biochemical method capable of regenerating a protective bioactive film which prevents the body from attacking the implant.
What’s more, this method allows select bioactive compounds to be rapidly and repeatedly regenerated in situ, potentially prolonging the life of an implantable device and preventing additional surgery. The researchers also suggest that their method could be used for controlled drug delivery.
Modern implantable medical devices are coated with ultrathin films of bioactive compounds, which help prevent localized inflammation at the site of the implant. These films can also inhibit bacterial growth on the implant, thereby preventing dangerous infections. Despite the merits of these film-coated devices, they do still suffer from a number of limitations.
“Not only do they have a finite reservoir of bioactive agents, but the surface components of the thin films also degrade or lose their effectiveness when exposed to the physiological environment over time. Presently the only solution is to replace the entire device,” said Dr. Elliot Chaikof, Chair of Surgery at Beth Israel Deaconess Medical Center (BIDMC), and lead author on the study. The researchers published their results in the journal, Nature Communications.
To extend the biological activity of the medical device coating, the investigators used an enzyme – known as Sortase A – which was purified from Staphylococcus aureus. By introducing several mutations into the gene encoding Sortase A, the researchers were able to generate a new enzyme – eSrtA – with 120 times higher catalytic activity over the wild type enzyme. The new enzyme is also able to repeatedly link peptides as well as break them apart.
“We found that through a two-step process of removing and replacing bioactive coatings, eSrtA enables rapid, repeated thin-film regeneration in the presence of whole blood in vitro and in vivo,” said Dr. David Liu, Professor of Chemistry and Chemical Biology at Harvard University. “We also developed a series of new enzymes that recognize a variety of distinct peptide sequences that could be put to work in a similar manner.”
The researchers admit that further experimentation is necessary before the biochemical technique could be applied to implantable devices. Among the unanswered questions is how long the bioactive compounds would last.
“Many thousands of people depend on implantable devices with bioactive constituents for their health and well-being, so finding a strategy that will ensure the long-term efficacy of these devices is of paramount importance,” said Chaikof. “While this research is relatively early stage, it opens the door to a new way of approaching and addressing this clinical challenge.”