Preclinical Development of a Novel Bioactive Glass Cement for Bone Graft Substitution in Dentistry

When a tooth is extracted, the bone surrounding that tooth root no longer receives a physical stimulation connected to functions such as chewing or biting and its structure starts to alter. This remodelling (removing and replacing bone) of the bone results in net bone loss. Nowadays dental implants are the most common treatment for replacing a missing tooth. Dental implants consist of titanium screws that replace the root of a tooth once they are placed into the jawbone. They require bone tissue underneath and surrounding them for support to properly integrate into the jaw. People who have been edentulous (without teeth) for a prolonged period may encounter problems with dental implants as they may either not have enough bone left in the tooth socket or the insertion of the implant could be limited by the presence of areas of missing bone. To overcome these problems a bone like material is commonly used to entirely fill the bone socket after tooth extraction or fill a bone defect around the dental implant.

The most common materials available are synthetic calcium phosphate compounds. These offer the greatest potential for bone regeneration since they have a composition similar to the mineral components of the original bone. The rationale behind their use is that they will prevent the physiological remodelling/alteration of the bone after tooth extraction and promote new bone formation within the bone defect.

The aim of this research project is to assess the efficacy of a novel injectable material used to replace missing bone in implant dentistry. Its physical, chemical and biological properties have already been proven in our previous studies. Therefore, the next stage is to focus on specific clinical dental applications. We want to assess the in-vivo performance of two novel injectable calcium phosphate materials for bone replacement.

Currently all bone substitute materials are available for clinical use as granules that do not harden into a single construct. As a consequence the material can partially migrates from the site, coming out as small granules into the mouth, which leads to a failure of the procedure. Our materials is an injectable pastes similar to putty that can be easily moulded into the desired shape, they are essentially polyfillers for the skeleton. The novelty of our materials is the fact that they harden in a few minutes after being injected into the bone, ensuring a complete void filling of the site without any parts becoming dislodged after the implantation. Our materials show excellent handling properties and ease of use, which leads to a simplification of the surgical procedure and consequently, a shorter surgical time which benefits both patients and the surgical team involved. Initial investigations have demonstrated that our materials integrate well, bind strongly with bone and enhance the formation of new bone at a faster rate compared to other materials used for the same applications.

In this study we will use animal models to compare the performance of these two test materials with regard to their abilities to preserve the dimensions of the bone after tooth extraction and promote new bone formation around dental implants in direct comparison with a standard material commonly used in dentistry.

The introduction of these novel injectable materials in dentistry will help to overcome the limits of other synthetic materials currently available, such as low degradation rate, poor handling properties and low stability in the site of implantation, which are associated with failures of the surgical procedure. The clinical use of this material for implant dentistry will be beneficial for patients as it will lead to better outcomes, faster healing times and a shorter time required for completion of the final restoration. This project will provide all scientific data required for a CE mark, a requisite for licensing our products and will take the materials into clinical application.

To preserve the original alveolar ridge dimensions following tooth extraction and regenerate bone defects around dental implants, bone graft substitutes (BGS) are used to prevent physiological resorption of the alveolar ridge and promote new bone formation. Calcium phosphates are among the most widely used synthetic materials for this function.

A novel injectable BGS developed at QMUL is a mixture of bioactive glass and calcium phosphate (Ca(H2PO4)2) powder which reacts to form octacalcium phosphate. This novel cement can set hard in-vivo, and we have demonstrated a faster rate of osseointegration and replacement of new bone compared with other synthetic bone substitutes. We will compare the performance of two variants of the novel injectable biomaterial with their ability to (i) preserve the dimensions of the alveolar ridge and (ii) regenerate bone. Straumann BoneCeramic will be used as a control.

Our objective is to optimise an existing formulation for a CE-mark application (ISO10993) and medical device approval. We will achieve this through:
1. Manufacture and full chemical analysis of all cement powders (Milestone 1)
2. In vitro testing - cell culture tests confirming absence of in-vitro toxicity and osteotrophic impact (Milestone 2)
3. In vivo testing - A six month minipig in-vivo study involving alveolar socket grafting and simultaneous bone grafting around dental implants (Milestone 3)

In-vivo testing will be carried out in mini-pigs. The trephined core specimens and implants obtained after a healing period of 12 weeks respectively will be studied using three techniques:
1. X-ray microtomography - to determine the surface area of BGS covered with new bone and the amount of bone to dental implant contact (BIC).
2. Histology - to confirm bone formation and new blood vessel infiltration in the bone core specimen, and osseointegration between BGS and dental implant.
3. Scanning electron microscopy - to quantify the degree of osseointegration.

This research project has been designed to have an impact in clinical and academic environments as well as a social and economic impact.

The main beneficiaries of successful completion of this project are patients. These materials offer a potentially significant improvement upon current bone substitutes used in implant dentistry. The introduction of these materials into the market will reduce treatment times and costs of surgical dental treatments. The hypothesised higher clinical performances of the materials, compared to current bone substitutes, will lead to reduced complications and treatment failure rates. This ultimately reduces the costs and pain associated with these procedures and remarkably improves the quality of life of the patient.

The use of these materials offer significant benefits to the clinicians using them for a number of reasons. The materials offer improved outcomes during both surgery and healing. We expect this will reduce the failure rate of bone grafting procedures and associated dental implants. Reduced failure rates will significantly decrease patient discomfort and the economic costs of replacing the faulty implant. This is not only a benefit for the patient but also for the clinician who will be able to offer imrpoved treatment at a high level of care.

There are also benefits with regards to the ease of use of the materials. Clinicians will benefit from an injectable material which can be easily moulded to the exact shape required and can be used for filling bone defects ensuring better void filling compared to particulate bone substitutes. The injectability allows the clinician to accurately fill bone defects in difficult to treat areas such as the posterior sites of the maxilla.

The setting properties of the materials will allow the them to harden in a specific frame time and hamper the migration of the material from the site. All this means that the clinician will be able to offer an improved treatment in a shorter timeframe.

Researchers in the bone regeneration field will benefit from our research as novel materials will be introduced to the community for study and further development which will ultimately advance scientific knowledge in this field.

The dental students will also benefit from our research as they will have access to lectures, lab practical sessions and workshops designed to improve their clinical knowledge. These activities will also advance their skills which will benefit their careers and the patients they treat in the future. Additionally as this project is being conducted within a dental school by clinicians who are directly responsible for Restorative and Implantology Dentistry, the students will benefit from a high level of education given by clinicians actively involved in research projects in that area.

Given this project is being conducted by materials scientists, cell biologists, biophysicists, and clinicians they offer potential benefits to each other in respect to promoting interdisciplinary research and improving their knowledge in areas different from their academic background.

This research will also be beneficial for people already involved in this project who will receive academic training associated with the project and will be able to improve their experience and their background in preclinical research. This will further develop their curriculum and prepare them for future careers in academia. This will be beneficial as well for universities as that allows to better prepare people to enter the academic work force.

The economic impact is related with the downstream exploitation of these materials to introduce novel bone graft materials within the dental market. The UK will be at a forefront of bone graft in dentistry.
Dental companies seeking a novel bone substitute to commercialise with a clear commercial advantage would be particularly interested in our product.