**2. Strategies for conferring enhanced bioactivity to titanium alloys**

So far most research efforts have been concentrated on improving the bone-implant interface, with the aim of enhancing bone healing and implant integration via either physical or chemical approaches [15]. The physical approach is focused on the modification of the implant surface morphology and topography using mechanical methods such as machining, acid-etching, plasma spraying, grit-blasting and anodization to improve the microtopography of the surface. The rationale behind this is that an increase in surface roughness of the implant material would provide a higher level of surface energy which would improve bone anchorage, matrix protein adsorption, osteoblasts functions and ultimately osseointegration [16].

The chemical approach is towards the creation of a bioactive implant surface via application of coatings onto the implant layer by biochemical and physicochemical techniques. In bio‐ chemical techniques, organic molecules such as growth factors, peptides or enzymes are incorporated to the implant layer to affect specific cellular responses [17]. While in physico‐ chemical techniques, the incorporation is achieved with inorganic phases such as calcium phosphate which may increase the biochemical interlocking between bone matrix proteins and surface materials thereby enhancing bone-bonding [16]. Many implant modifications may combine both physical and chemical engineering methods. In the following sections we will discuss some of the more popular strategies used to enhance implant integration and bonebonding.

#### **2.1. Inorganic coatings**

metal implant caused by fibroblast layer attachment. Fibrosis can also cause osteoclastindependent bone resorption by fibroblast-like cells. It has been shown that fibroblast-like cells, under pathological conditions, not only enhance but also actively contribute to bone resorption [14]. Successful implant integration into the surrounding tissue is highly dependent on the crucial role of native cells, chiefly osteoblast attaching to the implant surface. Therefore one of the key challenges in orthopaedics is the engineering of an implant with enhanced osseointe‐

**Figure 2.** Schematic figure of a hip implant. The femoral neck is the region at risk of compromised vascularity. Arrows

So far most research efforts have been concentrated on improving the bone-implant interface, with the aim of enhancing bone healing and implant integration via either physical or chemical approaches [15]. The physical approach is focused on the modification of the implant surface morphology and topography using mechanical methods such as machining, acid-etching, plasma spraying, grit-blasting and anodization to improve the microtopography of the surface. The rationale behind this is that an increase in surface roughness of the implant material would provide a higher level of surface energy which would improve bone anchorage, matrix protein

The chemical approach is towards the creation of a bioactive implant surface via application of coatings onto the implant layer by biochemical and physicochemical techniques. In bio‐

**2. Strategies for conferring enhanced bioactivity to titanium alloys**

indicate area of compromised vascularity where osseiointegration fails to take place.

adsorption, osteoblasts functions and ultimately osseointegration [16].

gration properties to reduce implant failure rates.

4 Titanium Alloys - Advances in Properties Control

Calcium phosphate coating has been widely used in the orthopaedic field due to their similarity with the mineral phase of bone [18] and are known for their bioactive properties which are beneficial in bone-bonding [19]. As calcium phosphate generally lacks the mechan‐ ical strength for use as bulk materials under loading conditions, they are often coated onto the surface of metallic implants. There are several studies published which have shown the favorable use of calcium phosphate coatings in increasing the biocompatibility of bone-implant interface, implant anchorage and integration [20]. The calcium phosphate layer functions as a physiological transition between the implant surface and the hosts' tissues which guides bone formation along the implant surface and the surrounding tissues. One of the most successful method for the application of calcium phosphate coatings is via the plasma-spraying method due to its advantage of extensive coating capability and high deposition rate. However despite numerous findings [21] that report the beneficial osteoinductive properties of plasma-sprayed calcium phosphate coatings, there are still some concerns regarding its use. Plasma-sprayed coatings are not uniform and there is poor control over thickness and surface topography, which may result in implant inflammation when particles are released from these heteroge‐ neous coatings. To overcome these drawbacks, various other deposition strategies have been developed and employed such as biomimetic, electrophoretic and electrospray deposition etc. However care should be taken when comparing the efficacy of each of these methods which would require a comprehensive evaluation of both biological response and clinical perform‐ ance. Although calcium phosphate coatings have been shown to be beneficial in enhancing bone-bonding, there is still no general consensus on the use of calcium phosphate coating systems. The main problems include large variation in the quality of calcium phosphate coatings, even between different batches and market forces which offer other cheaper alter‐ natives [22].

#### **2.2. Organic coatings**

Surface modification of implant materials with growth factors and peptides is gaining popularity in the recent years [23, 24]. Various therapeutic biomolecules of interest can be immobilized onto implant surfaces to enhance the bone-implant interface interactions. Currently more popular approaches would include the immobilization of bone growth factors such as bone morphogenetic proteins (BMPs) to enhance osteogenesis and the deposition of peptide sequences to induce specific cellular functions. Growth factors immobilized on orthopaedic devices have been reported to enhance osteoblastic activity and favor implant integration [25]. The most commonly used growth factors in orthopae‐ dics are members of the transforming growth factor beta (TGF-β) superfamily including the BMP family, especially BMP2 and BMP7. Growth factors may be physically adsorbed or covalently grafted onto the implant surface and various studies have shown that the loading of implant with these factors can enhance interactions at the bone-implant interface and aid the remodeling process ultimately improving implant integration [26-28]. Howev‐ er critical factors in the successful use of growth factors in orthopaedic devices are the optimum dosage, exposure period and release kinetics, all have to be considered careful‐ ly to avoid the detrimental effects associated with growth factor use such as high initial burst rate, ectopic bone formation and short half-life. More recently, peptide sequences with the ability to target specific osteogenic cellular functions of differentiation and mineraliza‐ tion have been developed [29, 30]. These short functional fragments derived from the original protein have increased shelf life, can be synthetically produced and are more resistant to denaturizing effects. Their usage would provide significant clinical benefits over the use of conventional proteins. They can be linked to the implant surface to provide biological cues for bone formation. Additionally other peptide sequences in use include the RGD, YIGSR, IKVAV and KRSR which have been used to improve cellular adhesion and bone matrix formation [31-33].

**3. Osseointegration of the implants**

as adhesion, growth and differentiation are desired.

crucial in improving the successful integration of implants [41, 42].

The clinical strategies to manage musculoskeletal defects would center around three compo‐ nents: cells, structure and growth factors. For the design of implant materials, cells and proteins at the implant interface plays a critical role [38]. The utilization of biosignal proteins such as growth factors for development of bioactive implant materials holds great potential. Especially due to the scarcity of stem cells in the body, materials which regulates cellular functions such

Titanium Alloys in Orthopaedics http://dx.doi.org/10.5772/55353 7

One of the most important process in determining the success of an orthopaedic implant is osseointegration. Osseointegration is defined as the formation of a direct structural and functional connection between the living bone and the surface of a implant [39, 40]. An implant is considered osseointegrated if there is no progressive relative movement between the implant and the bone it has direct contact with [40]. Under ideal conditions, implants could perma‐ nently become incorporated within the bone and persist under all normal conditions of loading, that is the two could not be separated without fracture. Vascularization which is the provision of blood supply is a critical component for the process of osseointegration. The differentiation of osteogenic cells is highly dependent on tissue vascularity and ossification is closely linked to the vascularization of differentiating tissue [40]. Therefore the success of tissue healing, regeneration and integration lies in the key process of revascularization which is

Bone healing around implants involves a cascade of cellular and biological events that take place at the bone-implant interface until finally the entire surface of the implant is covered by newly formed bone. This cascade of biological events is regulated by differentiation of cells stimulated by growth factors secreted at the bone-implant interface [40]. There has been considerable interest in modifying implant surfaces with growth factors to improve their cell functions and tissue integration capacity at the bone-implant interface. Enhanced cell functions and cell substrate interactions have been demonstrated with growth factors immobilized onto implant materials [26-28]. One of the more important growth factors for stimulating neovas‐ cularization (i.e. formation of new blood vessels) in target areas [43] would be angiogenic growth factors, crucial in improving the successful integration of implants both *in vitro* and *in vivo* [41, 42]. Of these angiogenic factors, vascular endothelial growth factor (VEGF) is the most potent and widely used key regulator of neovascularization [43, 44]. VEGF is a crucial factor in not only angiogenesis regulation but also in osteoblast [45] and osteoclast function [46-48] during bone repair. VEGF acts directly on osteoblasts, promoting cell functions such as proliferation, migration and differentiation [49, 50]. In addition, VEGF also indirectly affect osteoblasts via its influences on endothelial cells [51, 52]. VEGF is known to induce endothelial cells in surrounding tissues to migrate, proliferate and form tubular structures [53] and is an essential survival factor for endothelial cells [51] and new vessel formation [54]. Endothelial cells are needed to provide complex interactive communication networks in bone for gap junction communication with osteoblasts crucial to their formation from osteoprogenitors [55]. Furthermore VEGF stimulates endothelial cells in the production of beneficial bone forming

#### **2.3. Organic–inorganic composite coatings**

Research in the recent years have concentrated on the development of bioactive compo‐ site coatings which mimics the structure of the bone tissue. These composite coatings would combine calcium phosphate with growth factors, peptides, antibodies etc. to enhance interactions at the bone-implant interface. However due to the fact that often high temperature or non-physiological conditions are needed in the preparation of calcium phosphate coatings, only physical adsorption is employed in deposition of the biomole‐ cules on the implant surface [34, 35]. However with physical adsorption techniques, initial high burst rate is often observed, which is not desired [36]. Therefore coating techniques that create a gentle sustained release kinetics are preferred. A recently published paper have shown that calcium phosphate coating combining slow release of antibiotics, aids in early success at recruitment of bone cells [37]. Many other studies have shown that depositing BMP2 and TGF-β onto the implant surface would greatly enhance bonebonding at the bone-implant interface [25, 34]. The biological efficacy of orthopaedic implants can be improved greatly by both physical and chemical modifications. The use of a wide multitude of engineering techniques in the manipulation of surface topography, morphology and incorporating the use of various inorganic and organic components would directly influence the response in the local bone-implant interface and the apposition of new bone. With the development of new techniques and strategies on composite coatings to better mimic the human bone structure this would result in a new generation of orthopaedic implants with improved implant integration and bone healing.
