Osseointegration of Hafnium when Compared to Titanium-A Structured Review

Search methodology was comprehended using PICO analysis and a comprehensive search was initiated in PubMed Central, Medline, Cochrane, Ovid, Science Direct, Copernicus and Google Scholar databases to identify the related literature. Randomised control trials, clinical studies, case control studies and animal studies were searched for osseointegration of hafnium coated titanium implants versus conventional titanium implants. Timeline was set to include all the manuscripts published till December 2018 in this review.


INTRODUCTION
The advent of tissue engineering provides a novel approach for the repair and reconstruction of bone defects [1 -4]. An ideal implant material should have appropriate biocompatibility, corrosion resistance, elastic modulus, and favourable bone anchorage [5 -12]. One of the most commonly used materials is titanium for its low elastic modulus, good corrosion resistance and biocompatibility. Hence it has become the most commonly used biomaterial for dental implants [13 -15].
In various studies conducted to date, Tantalum has revealed superior properties fulfilling the criteria required for an implant [16 -20]. Tantalum has been shown to be a promising material for excellent chemical stability, fluid body resistance, biological inertness and remarkable osteocon-ductivity [16 -26]. Tantalum has higher elastic modulus than human bone tissue but it's prone to stress shielding effect [27]. To overcome this, porous forms of tantalum have been explored [28 -30]. However, the structure of porous tantalum renders it unsuitable for long-term use in the load-bearing structures [31]. Hence tantalum porous implants with titanium substructures have become more popular [18,31,32]. Similarly, plasma spraying tantalum over titanium is also reported [33].
In the periodic table by IUPAC 2016, tantalum belongs to period 6 (d block) of the periodic table [34]. Hafnium belongs to the same block as tantalum, in the periodic table, hence similar biological and chemical behaviour analogous to tantalum are expected and therefore, hafnium coatings and their biological applications have been vigorously researched upon. The metal was first identified by Dirck Coster and Georges de Hevesy in Copenhagen in 1923 and owed its name to 'Hafnia', the Latin name for Copenhagen. Hafnium is always found in association with zirconium in mineral ores [35 -37]. The main mineral where it is found in zircon, with a ratio Hafnium/Zirconium of about 2.5% [38]. Hafnium is a passive metal with various properties, such as high ductility, strength, resistance to corrosion and mechanical damage. Due to a number of interesting properties such as high ductility and strength, as well as resistance to corrosion and mechanical damage, it has attracted interest for a number of applications [37]. For instance, it is used as a control material for nuclear reactors and as an alloying element in some superalloys used in aircrafts engines [39,40].
Hafnium has also been investigated as an alloying element in titanium alloys. Different proportions of Titanium-Hafnium binary alloys have been studied and reported in the literature [41]. These alloys have shown a low elastic modulus which is beneficial in order to reduce the stress shielding effect and to enhance bone growth. It has also been shown that cold work can be used to decrease the elastic modulus of this type of alloy, reaching values close to the elastic modulus of cortical bone [42].
In 1984, Marcel Pourbaix proposed hafnium as a metal to be considered for surgical implants due to the passive state of the metal. However, due to the lack of information about its toxicity to the human body at that time, it was discarded from the final list of metals to be theoretically considered. More recently, the properties of hafnium as an implant material have been investigated. Studies have shown that hafnium metal had both good biocompatibility and osteogenic potential.To date, the literature illustrating the behaviour of hafnium as a surface coating in biological environments has been scarce. Thus, further studies of hafnium coating under biological conditions are needed in order to determine the suitability of this material, as a surface coating for biomedical applications. The aim of the current review is to systematically analyse the scientific evidence on osseointegration of hafnium coatings in titanium implants.

Structured Question
Is osseointegration in hafnium significantly greater than titanium?

Data Collection and Analysis
The studies selected were based on the data extraction and analysis of quality and publication bias. The data collection form was customized. The outcome measure was bone implant contact.

Sources Used
For identification of studies included or considered for this systematic review, detailed search strategies were developed for the database searched. The search methodology applied was a combination of MESH terms and suitable key words. The key words employed in this search were broadly classified into four categories describing population, intervention, outcome and the type of study. Key words within each group were combined using Boolean operator [OR] and the searches of individual groups were combined using Boolean operator [AND] to retrieve articles electronically. The protocol is registered in PROSPERO (acknowledgements of receipt (166932)).

Searched Databases
The electronic databases included were: PubMed, Google Scholar, Medline, Ovid, Science Direct, Copernicus, Cochrane database of systematic reviews and no limitation regarding publication type and the publication date was set. pure hafnium and titanium, review articles, studies with metal coatings other than hafnium and titanium, studies with metal alloys other than titanium and hafnium.

Article Selection
The title and abstract of the entries yielded from the initial electronic database searches were read. After this initial filter, the full-text versions of the studies that could be potentially included in this review were read and a final selection of articles was made after applying the eligibility criteria.

RESULTS
Out of the 25 articles obtained from searching all databases, 5 studies were excluded based on title and abstract.
Out of the remaining 20 studies, 16 were excluded based on the inclusion and exclusion criteria of our interest and 4 were included on the basis of core data ( Table 1). The 4 articles were reviewed and were consolidated as depicted in the flowchart below (Fig. 1).
The treatment effects measured in these studies were boneimplant contact, percentage of new bone formation, cellular adhesion, and osteoblastic activity ( Table 2).
The data of the selected studies were extracted using standardized abstraction tables. Information extracted from each study included the following in one table as general characteristics of the study: 1) Title 2) Author and year 3) Study design 4) Duration 5) Intervention 6) Groups 7) Sample size 8) Types of statistical methods used 9) Outcome measures Table 3.The outcome variables of the extracted data from the studies were interpreted in detail ( Table 4). The level of evidence, according to Oxford Centre for Evidence-Based Medicine 2011, was also tabulated ( Table 5).

DISCUSSION
This Systematic review reveals four articles evaluating osseointegration of hafnium over the gold standard metal titanium [43 -45]. The studies show evidence that hafnium appears to have equivalent biocompatible properties as compared to Tantalum, Rhenium and other implant materials. However, the exclusions were not statistically significant and so larger studies with the stronger design are required to provide conclusive evidence on the exact effectiveness of Hafnium on osseointegration in human osseous tissues. A Meta-analysis could not be performed with the studies included, as the outcome parameters measuring the osseointegration were different in all the studies. Fig. (1). Image presenting flowchart of the search methodology describing the total number of articles obtained, the ones that were excluded, inclusion of handpicked articles and finally the total number of articles that were retrieved for analysis.
The studies included in this review show significant bone gain with hafnium implants. All four included studies evaluated different outcome parameters making it difficult to consolidate the results over a single outcome measure. The outcome parameters used to study osseointegration in the studies included in this review were bone-implant contact, percentage of new bone formation, alkaline phosphatase levels in blood, cellular adhesion and cellular proliferation [26, 46 -48].     It is well established that measuring bone implant contact is the standard gold technique for the measurement of osseointegration in animal models [49 -51]. Similarly, measuring the cell proliferation of osteoblastic cell lines is the gold standard technique for in vitro studies [52 -54]. Hence it is justifiable to give more weightage to the studies measuring the gold standard outcome measures [55 -59]. Apart from the above-mentioned parameters, the biochemical marker alkaline phosphatase is also considered an adjunct aid to prove significant osseointegration [52,60,61].The current evidence in the available literature shows that hafnium also promotes superior osteogenic cell proliferation when compared to titanium. The limitations of this review are the in vitro nature of the studies included with level 5 evidence, in vivo intervention in animal models and the absence of randomized control human trials with both titanium and hafnium coatings over the implant surfaces in varying clinical situations [58,62]. Hence the inference needs to be interpreted prudently [63 -67].

CONCLUSION
Based on this systematic review, hafnium is a very promising surface coating intervention that can augment osseointegration in titanium implants. However, this needs to be validated through rigorous long-term clinical trials. Owing to its biocompatibility and osseointegrative properties, hafnium could be an alternative to titanium, in the near future.

CLINICAL SIGNIFICANCE
Hafnium is a very promising surface coating intervention that can augment osseointegration in titanium implants. If research could be widened including in vivo studies on hafnium as a metal for coating over dental implants or as a dental implant material itself to enhance better osseointegration, it could explore possibilities of this metal in rehabilitation of both intra and extra oral defects and in medically compromised patients with poor quality of bone.

CONSENT FOR PUBLICATION
Not applicable.

STANDARDS FOR REPORTING
PRISMA guidelines and methodology were followed.

FUNDING
None.

CONFLICT OF INTEREST
The author declare no conflict of interest, financial or otherwise.