Chlorhexidine Nanoparticles in the Management of Peri-implant Diseases

The aim of this research is to design and optimise a coating for dental implants that prevents infection.

Dental implants can be used to replace a missing tooth or teeth. They are titanium screws which are surgically placed into the jaw, acting as an artificial root to which false teeth can be attached. They allow a patient to eat, speak and socialise more normally than they would without teeth. They are used to treat patients who have lost teeth due to decay, gum disease, major trauma such as road traffic accidents, and head and neck cancers. Approximately 1.5 million people in the UK have dental implants, with numbers increasing every year.

After implant placement in the jaw, bone cells (osteoblasts) attach to the surface, laying down new bone and securing the implant in position. This important process is known as 'osseointegration', and takes 6-12 weeks. It permanently anchors the implant in the bone.

Osseointegration can, however, be compromised by infection. During or after surgery the implant can be colonised by bacteria. This can lead to inflammation and discomfort (peri-implant mucositis), and, if untreated, can destroy surrounding gum and bone (peri-implantitis). This usually means that the implant is no longer functional, and requires removal. There is often not enough bone left to place a new implant, meaning that either a bone graft or denture is necessary to replace teeth. This can impact on the patient's confidence whilst eating, speaking and socialising. These implant infections can occur in any patient, but particularly affects older or unwell patients, such as those who have had cancer or major trauma.

An infection can develop at any point within the lifespan of the implant; immediately after placement in the jaw, or months to years later. Up to 43% of implants develop infection and there is no consensus among clinicians or scientists how to best prevent or treat it. Current methods include professional implant cleaning by a dentist, cleaning with one or more chemicals, and use of antibiotics.

Recently, tiny particles ('nanoparticles') have been developed that release an antiseptic agent, chlorhexidine. Chlorhexidine is already used widely in healthcare, including as a pre-operative skin cleanser, in mouthrinse to treat oral infection, in eye drops and in wound dressings. It treats infection by killing the organisms which cause it, including bacteria, fungi and some viruses.

Previous research has shown a benefit in using chlorhexidine in the prevention and treatment of dental implant infections, but it has not been investigated in nanoparticle form. During my research project, I will coat titanium with these nanoparticles to determine if they could be used to prevent dental implant infections.

I will develop methods to produce an even coating that leaves enough titanium uncovered to allow osseointegration. I will test this coating on bacteria taken from patients with implant infections to find the strength of its antibacterial effect. I will also clarify whether the nanoparticles are harmful to osteoblasts. Based on these combined results, I will optimise the coating for dental implants.

If the coating is shown to have a long-term antimicrobial effect, whilst not affecting osseointegration, it could offer a simple and effective prevention for dental implant infections. Information gained from this project could also be useful in other areas of medicine, including joint replacements for hips and knees which are also made from titanium and suffer from similar problems with infection. This means the research could have an impact on infection prevention for many types of implant, not just in dentistry.

With a rising number of dental implants in an ageing population, a straightforward method for prevention and treatment of implant infections is a priority for dentists. The global increase in antibiotic resistance means a strategy not reliant on antibiotics is essential.

Background: Dental implants can be affected by peri-implant bacterial infection, which may result in bone loss and implant failure.
Aims: To determine whether chlorhexidine hexametaphosphate nanoparticles (CHX-NPs) have potential for use as an implant coating to prevent peri-implant infection.
Objectives:
1. Apply a discrete, non-continuous CHX-NP coating to titanium
2. Investigate the antimicrobial efficacy and mechanism of the coating
3. Establish effects of the coating on osteoblast colonisation, growth and maturation
Methods: A CHX-NP coating will be applied to titanium coupons prepared to mimic a dental implant surface. Reactant concentrations, deposition parameters and aggregation control will be optimised for even coverage, assessed using SEM, TEM and AFM. Duration and level of CHX release will be characterised using UV spectrophotometry.
Antimicrobial efficacy of the coating will be assessed using clinically isolated microbes. TEM will identify potential mechanisms of bactericidal action, and will direct proteomics to identify changes in marker proteins/genes. A polymicrobial biofilm flow cell will be used with human saliva. FISH assay will elucidate temporal changes in biofilm.
HMSCs will be differentiated into osteoblasts and used to establish the effects of CHX-NP on osteoblast adhesion, metabolism, growth, proliferation, differentiation and toxicity. Dose-response of outcomes, and thresholds for adverse effects will be established.
Results from objectives 2 and 3 will inform changes to the coating to establish an ideal CHX release profile.
Scientific/medical opportunities: This research will elucidate the scope for CHX-NP coatings to be adapted for biomedical devices. It will identify the antibacterial mechanism of action of the coating, and reveal any toxicity towards human osteoblasts. These findings have potential to facilitate development of a CHX-NP coating for dental implants, and advance progression towards in vivo trials.

The aim of this project is to determine if recently developed chlorhexidine hexametaphosphate nanoparticles have potential for application to dental implants as a coating to prevent infection. Therefore the primary beneficiaries in the future will be patients having dental implants placed.

Over 1 million dental implants are placed annually worldwide, with an estimated 10% increase annually. Current data suggest that by the year 2020, approximately 1.8 million people in the UK will have at least one dental implant.

Peri-implant mucositis occurs in 30-50% of implants, and peri-implantitis is seen in 10-43% of implants. This would equate to around 834,000 people with peri-implant mucositis, and 264,000 with peri-implantitis in the UK by 2020. Hence, a very large number of patients could benefit from this research.

As the use of dental implants increases, and the UK population continues to age, an effective method for management of peri-implant disease is needed. This research proposes a simple, alternative approach to prevent infection. This will help minimise the discomfort and inconvenience caused to patients by these infections, and reduce both financial and health costs associated with the problem.

If this research shows the nanoparticle coating to be a safe and effective way of preventing infection, it will benefit;

1. patients, since implants will have lower risk of infection, produce less symptoms and last longer. Costs for ongoing remedial treatment, often met by the patients, will also reduce.
2. the NHS, by reducing number of patients requiring treatment for implant infections, meaning savings for hospital staff, appointment time, equipment required for treatment, and antibiotic prescription costs.
3. the UK economy by reducing missed work days for implant infection related illness and treatment time.
4. the global antibiotic resistance burden, by reducing the use of antibiotics in the treatment of implant infections.
5. dental implant manufacturers, by demonstrating a potential coating which could improve predictability.


Dental implant technology has relevance to, and crossover with, orthopaedic implants. Previous research on dental implant surface topography has had benefit in the field of orthopaedic implants, such as hip and knee replacements, and my research could have a similar cross-application in the future. Therefore this work could have an impact on the prevention of infection associated with various types of implant, not just within dentistry. Millions of orthopaedic implants are placed annually in the UK, and so this research could benefit patients having treatment in this area too.

This work will advance knowledge with regard to the use of nanotechnology in biomedical applications, particularly with respect to demonstrating compatibility of the nanoparticles with human tissues. This research will, of course, also have impact in the academic community, both within nanomedicine and the wider field of biomaterials; this is discussed further in the 'Academic Beneficiaries' section.