**2. Potential application of TNA in biomedical implants**

Several researchers have investigated a range of parameters associated with the physical and element properties of TNA. The physical parameters involve different crystal structures, nanotubes diameter and length, as well as surface roughness. The element contents are the core compositions of TNA. The effect of different parameters could solely or communally modulate diverse cellular responses of the cells adhesion, migration, proliferation and differentiation [3, 4].

**Figure 1. TNA nanomatrix observation by field emission scanning electron microscopy**. (A) The surface modification

top view; the formation of well-aligned nanotubular structure (nanotubes). The nanotubes were linked to each other and

layer (TNA) in vertical view and (B) nanoporous structure from

Interaction of these parameters may also result in the wettability factors of cellular interaction and biocompatibility [5]. Hence, these parameters need to be optimized before performing a detailed study of the material. This might also help in gaining an understanding of the cellnanostructure interactions and designing novel regenerative biomaterials that could favor-

The Ti surface readily reacts with oxygen upon contact and results in three titanium oxide crystalline phases such as rutile, brookite and anatase. These phases may also be responsible for the material biological properties [9]. Anatase phase is metastable and exhibit stronger interactions between metal and support, which would be advantageous for medical application [10]. Anatase phase shows better absorption properties of hydroxyl-OH- and phosphate-PO<sup>4</sup>

than rutile titania in simulated body fluid which could favor bonelike apatite component to be

3+

ably modulate cellular responses to enhance the tissue regeneration [6–8].

by anodization produced nanotubular structure of TiO2

470 Titanium Dioxide - Material for a Sustainable Environment

ripple marks occurred at the sidewalls.

Biomaterials are the core needs in diverse medical areas such as for the orthopedic, dental, cardiovascular, and craniofacial implants [59–64]. In the past, Ti or Ti alloys were commonly used as biomaterial implants [16]. Besides having great mechanical properties and excellent corrosion resistance, titanium possesses a good biocompatibility, which related to the behavior and function of nontoxic materials in living systems [17, 18].

This metal surface is known to be cytocompatible, which refers to the ability to bind with biomolecules and supported cellular attachment (adhesion), growth and proliferation [11, 19–22]. Conventionally, Ti alloys have a thin layer of titania also known as titanium oxide (TiO2 ) on the surface. This naturally occurring oxide of titanium (Ti4+) resulted from the reduction–oxidation action of surrounding oxygen (O2 4−) and water (H2 O) [23]. This oxidized layer of Ti is known to be bioactive which makes it possible to establish direct contact with bone cells and promote the formation of apatite (major component of bone tissue) [24].

To meet the expectation of successful biomedical implants, there is a critical need in reducing the post-operation healing time and safe placement of implants have become a major concern. This is because the human body has minimum time to react to osseointegration before the body starts rejecting the implants. The currently available implants possess these limitations. For instance, at the early stage of implantation of Ti implant materials into human body, the material surface cannot bind directly to living bone due to biologically inert metallic surface properties [25]. Hence, the healing period takes a longer time and sometimes the surface gets encapsulated over the time [26]. This attributes to poor osseointegration, leading to aseptic loosening of the implant, development of fibrous tissue (at interface of implant-bone), micromotion (at interface of bone implant) and/or wear debris formation (wear particles of bone implant interface) and further delamination (or fracture) between bone and implant material [26, 27].

The surface of implant materials plays a vital role in controlling osseointegration to decrease healing time; in this regard, scholars aim to improve or alter the biocompatibility of Ti implant surface for long-term clinical use [16]. Current studies focus on the potential of titania with a three-dimensional (3-D) microporous or nanoporous structure to enhance the formability of apatite (bone component) and the adherence speed of osteoblastic cells compared with that of a dense titania layer [28–30]. The nanometric scaled surface modification has shown to be critical for the tissue acceptance and cell survival.

Notably, the proposed TNA structure has adaptive features which are required to successfully improve cell interaction with the implant materials. The continuous and vertically aligned TNA topography demonstrates extremely larger surface area than the flat titanium surface and has been assumed to overcome current clinical implants limitations [31]. Moreover, this improved bioactive layer of inward growth TiO2 nanotubes on Ti provides good adherence of the nanotube layer to the titanium metal which eventually rectifies the problems of existing ceramic coatings arising from weak interfacial bonding [28]. Besides that, TNA topography may provide similar characteristic as a natural bone topography (pore size/diameter ~ 60–100 nm) that might improve the interference of bone cells response [15].

Cardiovascular implants use Ti metals for the replacement of heart valves (pacemaker cases and defibrillators), endovascular stents, and stent-graft combinations. These implants help to overcome cardiovascular diseases which physically damage the heart, resulting in loss of cardiac function. The types of implants are classified as temporary internal, temporary external and permanent internal devices. One of the demands is stents which include the bare metal stents, drug-eluting stent, and bioabsorbable stents [49]. Craniofacial implants are important in the application of craniofacial prostheses or also known as an epistheses. Epistheses may be used to repair or improve absence of facial structures due to malformation present at birth, operations that involve treatment for cancer, or trauma. The osseointegrated titanium implant

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Further development and improvement on the implant is required for complete compatibility with the area of implantation, for shorter surgical duration and improved cosmesis [30, 50].

The application of nanotechnology in medicine has led to a new concept termed as nanomedicine. Nanosized materials exhibit extraordinary functional characteristics due to their unique dimension properties. This nanomaterial technology could lead to advances in medical therapies various diseases, especially cancers. TNA might improve efficiency of an existing therapies and diagnostic methods. In addition, this it could also reduce the total medical care expenses. The further prospect of TNA will be discussed in this section especially for

New nanoengineering approaches allow target drug delivery, improve drug solubility, increase therapeutic index, extend drug half-life, and decrease drug immunogenicity. Nanotherapeutics enables the delivery of drugs to specific cells by using nanostructured materials [51]. This property overcomes the limitations of systemic drug administration and may potentially revolu-

such as enzymes or proteins. Subsequently, TNA could be applied into new drug-releasing implants for emerging therapies for localized drug delivery [53, 54]. Whereby, the TNA topology can be coated with inflammation-reducing drugs, such as dexamethasone, by using simple physical adsorption or deposition of the drug by magnetic stimuli-responsive drug delivery system as described in **Figure 2**. This technology may act together radiation therapy and even stem cell transplant for an intensification therapy which also known as consolida-

nanotubes can be also filled with chemicals and biomolecules,

is one of the common types of implants used in epistheses [45].

**3. Potential application of TNA in nanomedicine**

**3.1. Nanotherapeutics: Nanomedicine in therapy**

tionize treatment of numerous diseases [52].

*3.1.2. Nanomatrix therapeutic induction*

The inner volume of TiO2

tion or postremission therapy.

*3.1.1. Nanodrug delivery agents*

nanotherapeutics, nanodiagnostics, and nanobiosensors applications [42].

Furthermore, the unique structure of TNA exhibit surface area that is three times higher than that of flat titanium, creating additional spaces for cell interaction particularly at the cell extracellular matrix level; this structure may also address the limitations of existing clinical implants [14, 21, 32, 33]. Moreover, the improved bioactive layer of the oxide nanotube structures on Ti allows the nanotube layer to adhere to the titanium metal (metastable), leading to stronger interfacial bonding that that of existing ceramic coatings [34]. These nanostructure properties can increase the surface energy and improve interactions with various proteins (such as vitronectin and fibronectin), resulting in enhanced specific cell adhesion and osseointegration [13, 35–38]. Yu et al. [13] reported that anatase TNA elicits optimal biological responses for cell adhesion, spreading, proliferation, and differentiation. Furthermore, the surfaces of these nanostructures can effectively reduce inflammatory responses compared with surfaces of conventional implants [39–41]. Therefore, the proposed TNA structure possesses adaptive features that can successfully improve cell interaction with the implant materials and may potentially enhance osseointegration [42–44].
