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Adaptation Of HA Chemistry
The fact that natural bone comprises Hydroxyapatite (HA) has led to extensive research in developing synthetic HA as bone replacement materials. To make metal implants more compatible with the body, surgeons use HA powders as coatings on these implants. The application of HA powders as metal implant coatings not only increases the compatibility of the implants with the body but also promotes stronger bonding between the bone and the implant, thus eventually increasing the durability of the implant. The development of porous HA granulates is an effort to make implants comprising HA alone. These granulates are utilized in filling bone voids caused by trauma or disease. However, they have their own issues such as migration or exfoliation.
A 3-D porous synthetic HA structure that would perfectly fit into defect voids would fulfill needs in terms of bioactivity, anti-bacterial properties, suppression of hostile immune system responses, superior mechanical properties to reduce failure and stress shielding, porosity, and the ability to create bespoke shaped 3-D bone sections.
A sacrificial skeletal structure with the aforementioned properties initially demonstrates mechanical integrity and then dissolves as new bone grows. This approach opens avenues where metal alloys and inorganic powder/soluble polymer composites can also be used as candidate materials. This white paper investigates the role of (multi-element) substitution in HA and its impact on HA behavior in aqueous physiological conditions.
Adaptation Of HA Chemistry
Specific inclusion of target ions can alter the HA lattice. The properties of the substituting ion can distort the HA lattice to some extent. Even a subtle distortion to the lattice can largely affect the final properties, for example, surface charge and dissolution rates.
At present, Ceram explores the development of multisubstituted (2- or 3- ion additions) HAs. Preliminary studies at Ceram focus on the impact of mean deviations from the ionic radius and charge in pure HA on the ability for the retention of the HA structure and the distortion to the HA lattice. Initial findings show that there are areas and potential trends that allow increased loading. Graph 1 illustrates the volume Deviation versus HA Yield.
Graph 1. Volume Deviation Vs HA Yield
Besides investigating ionic volume changes, Ceram has also studied the impact of mean ionic charge variations due to substitutions. Graph 2 illustrates the charge deviation versus HA yield.
Graph 2. Charge Deviation Vs HA Yield
Once Ceram completes studying the impact of ion substitution to retain the HA crystalline structure, it will investigate the correlation between this data and bioactivity. SBF immersion trial test is the simple test that is deployable according to ISO 23317.
To better quantify fresh HA deposition rate versus time, Ceram looks forward to use low angle XRD analysis for the improvement of the test. The company also has plans to observe the concentration of key soluble ions with respect to time to confirm the role of HA dissolution in bioactivity.
While it has been noted that SBF tests reproduce the chemical environment of the implant, it is also observed that they do not replicate the deposition process of fresh HA growth. Observations through the scanning electron microscopy (SEM) revealed that the morphology of cell-deposited HA is different from crystals grown in SBF. The introduction of cell activity leads to a range of measurements for characterizing and understanding the HA re-precipitation method. The MTT test for cytotoxicity assesses the healthiness of a cell when exposed to powdered zirconia, HA. While MTT presents a measure of cell proliferation across a surface, tests such as Alkaline Phosphatase (ALP) assays are employed to measure the quantity of an enzyme and make a comparison with a DNA count to obtain an enzyme/cell count. To sum up, an ALP assay with HOB can strongly indicates the level of conductivity of a material surface to osteoblast activity.
Ceram also plans to build on its relations with CRANN in Dublin through the utilization of high resolution SEM analysis. This will enable the company to gain micrographs of cells adhered to various HA surfaces. Analysis of the way cells adhere and assume shapes could indicate their bioactivity. Graph 3 demonstrates the bioactivity by measurement of wt% HA detectable by XRD with a bio- inert polymer as substrate.
Graph 3. Demonstration of bioactivity by measurement of wt% HA detectable by XRD in the top ~30 µm. HA* and HA** are novel multi- substituted HA materials currently under investigation. The substrate is a bio-inert polymer.
Ceram’s liaison with Queen Mary University in London will enable the initial zeta potential analysis of HA powders dispersed in water and aqueous media. Graph 4 illustrates the zeta potential versus pH profiles for sintered HA in different aqueous media.
Graph 4. Zeta Potential vs pH profiles for sintered HA in a variety of aqueous media (DIW = De-ionized water; MEM = Minimum Essential Eagles Medium (a cell culture medium with salts, amino acids and vitamins); SBF = Simulated Body Fluid (inorganic apart from the component TRIS – Tris-hydroxymethyl aminomethane)
Preparing multi-substituted HAs is the initial step in developing synthetic bone solutions. There is much work required to (a) define correlations to bioactivity and put forward mechanisms of improved bioactivity and (b) transform primary HA powders into fashioned porous structures usable by surgeons.
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This information has been sourced, reviewed and adapted from materials provided by Ceram.
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