Bio-Design and Manufacturing
https://doi.org/10.1007/s42242-021-00170-3
REVIEW
A state‑of‑the‑art review of the fabrication and characteristics
of titanium and its alloys for biomedical applications
Masoud Sarraf1,2 · Erfan Rezvani Ghomi3
· Saeid Alipour2 · Seeram Ramakrishna3 · Nazatul Liana Sukiman1
Received: 15 April 2021 / Accepted: 24 September 2021
© Zhejiang University Press 2021
Abstract
Commercially pure titanium and titanium alloys have been among the most commonly used materials for biomedical applications since the 1950s. Due to the excellent mechanical tribological properties, corrosion resistance, biocompatibility,
and antibacterial properties of titanium, it is getting much attention as a biomaterial for implants. Furthermore, titanium
promotes osseointegration without any additional adhesives by physically bonding with the living bone at the implant site.
These properties are crucial for producing high-strength metallic alloys for biomedical applications. Titanium alloys are
manufactured into the three types of α, β, and α + β. The scientific and clinical understanding of titanium and its potential
applications, especially in the biomedical field, are still in the early stages. This review aims to establish a credible platform
for the current and future roles of titanium in biomedicine. We first explore the developmental history of titanium. Then, we
review the recent advancement of the utility of titanium in diverse biomedical areas, its functional properties, mechanisms
of biocompatibility, host tissue responses, and various relevant antimicrobial strategies. Future research will be directed
toward advanced manufacturing technologies, such as powder-based additive manufacturing, electron beam melting and
laser melting deposition, as well as analyzing the effects of alloying elements on the biocompatibility, corrosion resistance,
and mechanical properties of titanium. Moreover, the role of titania nanotubes in regenerative medicine and nanomedicine
applications, such as localized drug delivery system, immunomodulatory agents, antibacterial agents, and hemocompatibility,
is investigated, and the paper concludes with the future outlook of titanium alloys as biomaterials.
Graphic abstract
Keywords Titanium and titanium alloys · Biomedical application · Functional properties · Biocompatibility · Antibacterial
activity · Advanced manufacturing
Extended author information available on the last page of the article
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Bio-Design and Manufacturing
Introduction
In recent years, the number of patients in need of replacing failed tissue with artificial alternatives or implants,
such as arthroplasty, hip joints, craniofacial, maxillofacial, dental implants, prostheses, and surgical instrumental
applications, has increased [1]. Researchers estimate that
demand for the replacement of hip and knee arthroplasties
could reach 3.48 billion operations (673%) in 2030 compared to 2005 in the USA [2]. Therefore, many endeavors
have targeted recognizing appropriate biomaterials for the
fabrication of durable medical implants [3]. Biomaterials are utilizable owing to their superior mechanical and
thermal conductivity properties. The main essential factor for metals to be recognized as biomaterials should be
that no adverse reaction occurs when used in the targeted
biomedical application; that is, they act as biocompatible
materials. Metallic biomaterials are generally utilized for
load-bearing applications; thus, they should have adequate
fatigue strength. In comparison with ceramics and polymeric materials, using metals as biomaterials and the relevant technologies are continually enhancing because their
properties can be modified in the function of the manufacturing processes [4]. Among various types of materials, metallic biomaterials such as 316L stainless steels,
Co–Cr-based alloys, titanium, and its alloys have desirable
properties and hence remain the most adequate choice for
replacing failed hard tissue [5].
Grade 316L stainless steels (18Cr–14Ni–2.5Mo wt%)
have been used as implants since the 1920 s. The “L” in
316L stainless steel denotes low carbon content, which can
intercept the formation of chromium carbides and increase
the corrosion resistance. However, stress corrosion cracking, which cannot be prevented in 316L stainless steel, can
be triggered by the combined effect of tensile stress and
a Cl-rich environment such as human body fluid, resulting in an undesirable sudden failure of the implant under
stresses [6]. Moreover, although Co–Cr-based alloys have
a higher corrosion resistance compared to 316L stainless
steels in human body fluid, some undesirable ions such
as Cr and Co are released due to wear and corrosion [7].
There have been reports of Co exhibiting carcinogenicity in many animal researches and cases of neurological
symptoms in patients after implantation. The released Cr
could affect the blood cells, kidney, and liver by oxidative
reactions; therefore, Co–Cr-based alloys and 316L stainless steel have potential risks as implants [8]. Hence, these
two alloys may not be the best alternative for orthopedic
implants, making titanium (Ti) deserve more attention.
Titanium and its alloys have been used as medical
implants due to their long fatigue life, corrosion resistance, high biocompatibility, and lower Young’s modulus
13
compared to other implants [9]. Despite the advantages
of Ti alloys, supplementary development and modification are essential to devise clinically useful applications.
Owing to the inadequate biocompatibility of alloys in this
category, which are used in medical implant manufacturing, the risk of implant failure may be enhanced. This may
also cause the poisonous agglomeration of ion discharge
and wear debris entering the human body. To overcome
these drawbacks, different types of advanced manufacturing and surface modification have been proposed [10].
Consequently, it is necessary to conduct comprehensive
research on suitable biomaterials like titanium for biomedical applications. The present review focuses on the development of titanium and its multiple biomedical applications,
such as bone replacement, dental implants, craniofacial,
maxillofacial, surgical instruments, and prostheses. Then,
we explore its functional properties, such as biocompatibility, density, corrosion resistance in the biomedical environment, ductility, thermal expansion, yield strength, tensile
strength, magnetism, toxicity, host tissue response, protein
adsorption, and antibacterial activity. Moreover, we carefully
examine the different surface modifications and advanced
manufacturing technologies of titanium and its alloys to
improve its biomaterial properties. Finally, the applications
of Ti in nanomedicine are discussed along with the future
directions of research.
History of development of titanium alloys
The first reported application of commercially pure titanium (CP-Ti) in medicine originated from 1940, when this
metal was found to have excellent compatibility with bones
based on results from testing the reaction of bone to multiple
metallic implants on animals [11]. During the subsequent
decade of the 1940s, achievements made in industrial-scale
manufacturing processes for titanium paved the way for an
increasing number of studies on the medical applications
of titanium [12]. During the 1950s, discoveries were made
regarding the compatibility of titanium with soft tissue and
the bone of rabbits, as well as its non-cytotoxic properties
due to its remarkable corrosion resistance in biological
environments, where research on the surgical application
of titanium in dogs showed its excellent biocompatibility
[13]. Clinical evaluations further confirmed this advantageous characteristic of Ti in long-term animal testing [14].
Subsequently, the utility of CP-Ti was developed through
additional clinical reviews of its biocompatibility.
Observations on the long-term medical application of
CP-Ti in the human body established that it is prone to
fracture in this type of biological environment. However,
CP-Ti has currently many applications in the medical field,
Bio-Design and Manufacturing
such as an artificial tooth root, internal fixation plates, and
mandibular reinforcement plates. Therefore, the safety of
long-term applications prompts the appropriate design process for stress conditions [15–17]. Proposals were made
to utilize Ti − 6Al − 4V, which is the most widely utilized
titanium alloy in the aerospace industry and is an alternative biomaterial for artificial joints and bone fixators [18].
Subsequently, β-type and α + β-type titanium alloys possessing low Young’s modulus and free of vanadium (V)
or aluminum (Al) compounds were developed [19]. A new
α + β-type titanium alloy, Ti − 6Al − 7Nb, was created by
replacing the vanadium (V) in Ti − 6Al − 4V titanium alloy
with a safer element, niobium (Nb), to reduce the cytotoxicity of titanium and associated alloys [20]. The development
of other types of α + β-type titanium alloys also began during the 1970s using iron (Fe), molybdenum (Mo), and tantalum (Ta), which included Ti − 6Al − 2Nb − 1Ta − 0.8Mo
and Ti − 6Al − 2.5Fe [21–23].
The advancement of enhancing β-type titanium alloys for
biomedical applications was prolific in the USA and Japan.
Different β-type titanium alloys compounded with elements such as oxygen (O), silicon (Si), and zirconium (Zr)
to produce Ti − 13Zr − 13Ta (a near β-type titanium alloy),
Ti − 12Mo − 6Zr − 2Fe, T − 15Mo, and Ti − 15Mo − 2.8Nb −
0.2Si − 0.28O, were developed in the USA. On the Japanese
front, β-type titanium alloys such as Ti − 15Mo − 5Zr − 3Al,
Ti − 15Mo − 5Zr, and Ti − 15Zr − 4Nb − 4Ta were formulated [24–30].
The dentistry field has seen successful implementations
of CP-Ti from 1965 with the introduction of cast titaniumbase partial denture for use as dental implants, which was
based on research establishing the excellent compatibility of
titanium with hard tissue [31]. Further advances spurred the
use of titanium in dentistry from 1982, when the argon-arc
casting machine and magnesia-system investment material
were developed following the establishment of multiple dental casting systems utilized in dental restoratives [32].
At the turn of the century, attempts were made to develop
novel β-metastable titanium alloys by designing titanium alloys
through transformation-induced plasticity (TRIP) and twinning-induced plasticity (TWIP). The TRIP and TWIP concepts
originated from application on steels, which consequently
lead to their adaptation to titanium in the form of Ti–Ni shape
memory alloy. This opened the future possibility for β-type
titanium alloy with extremely high rates of strain-hardening to
be utilized in biomedical applications. In addition to the development of TRIP and TWIP concepts for titanium alloy-based
medical devices, extensive research is also being conducted
on the design and development of new β-type titanium alloys
as biomaterials for implants based upon the design theory of
d-electron [33]. The history of development of titanium alloys
for biomedical applications is summarized in Table 1.
Biomedical applications of titanium alloys
Titanium and its alloys are widely used in various biomedical
treatment scenarios, including arthroplasty and bone replacement, craniofacial, maxillofacial and dental implants, surgical
instruments, healthcare goods, or external and internal prostheses. The utilization of titanium alloys in medical devices
throughout the entire human body, as well as the specifications
of titanium alloys used in medical devices, is shown in Fig. 1.
Arthroplasty and bone replacement
Titanium is used extensively throughout the whole human
musculoskeletal structure. The most prevalent biomedical
application of titanium is currently for hip and knee replacements, with shoulder and elbow joint implants following
closely. Titanium has also seen frequent utilization in the spinal area for spinal correction parts, spinal fixation devices,
spinal fusion cages, and in recent years, replacements of spinal
disks [45, 46]. Rib cages for children made of titanium allow
the implant to expand as the body grows, thereby allowing
young patients to grow with the rib cage [47]. Finger and toe
implants, as well as tibial nails employed in the reinforcement
of lower leg fractures, are also made of titanium [48]. Fixation
and reconstructive devices that support broken bones, such as
bone plates, mesh, pins, screws, and rods made of titanium,
are frequently used nowadays [49]. To increase implant lifetime for younger patients, some of these applications utilize
roughened bioactive surfaces to limit resorption and stimulate
osseointegration.
Craniofacial and maxillofacial applications
Neurosurgical and cranioplasty applications of titanium
include cranial plates, mesh, and acrylic. The biocompatible
properties of titanium facilitate faster recovery and reduce
the chance of infection. Maxillofacial prosthetics made from
titanium alloys with appropriate levels of biocompatibility,
strength, and osseointegration are able to stabilize soft tissue
prostheses [50]. The application of maxillofacial prosthetics
after maxillofacial surgery may often be necessary to restore
the patients’ cosmetic appearance, their ability to eat or speak
and replace any missing facial features due to disease or accident damage [51]. A schematic briefly depicting the design
and fabrication process of a patient-specific mandibular prosthetic implant for defects related to maxillofacial clinical applications is shown in Fig. 2.
Dental implants
Titanium alloys are utilized in restorative dental practice
as dental implants, functioning as artificial roots to provide
13
Bio-Design and Manufacturing
Table 1 History of development of titanium alloys for utilization in biomedical applications
Year
Material
1940
1940
CP-Ti
Ductile Ti
1950
1957
1959
1960
1970
1979
1970s
1985
1996
1996
1997
1998
After 2000
After 2000
After 2000
After 2000
After 2000
After 2000
After 2000
After 2000
Application
Compatibility with bones as a metallic implant
Launching industrial production and smelting by the Kroll
process for medical applications
Ti
Compatibility of titanium with soft tissue and the bone of
rabbits as well as the non-cytotoxic properties of titanium
Ti
Non-toxicity with long term implantation
Ti–Ni
Shape memory alloy
Ti
Artificial joints
Ti-6Al-4V
Orthopedic implants
Ti − 6Al − 2Nb − 1Ta − 0.8Mo
Surgical implants
Ti − 6Al − 2.5Fe
Medical devices
Ti–6Al–7Nb
Joint replacement
Ti − 12Mo − 6Zr − 2Fe
Surgical implants
Ti-15Mo–2.8Nb–0.2Si
Prosthetic implants
Ti − 15Mo − 5Zr − 3Al
Dental casting and surgical implants
Ti–15Sn–4Nb–2Ta–0.2Pd
Medical implants
Ti − 13Zr − 13Ta
Implant
T − 15Mo
Biomedical
Ti − 15Mo − 2.8Nb − 0.2Si − 0.28O orthopedic
Ti − 15Zr − 4Nb − 4Ta
Implant
Ti–35.3Nb–5.1Ta–7.1Zr
Biomedical
Ti–29Nb–13Ta–4.6Zr
Biomedical
Ti–15Zr–4Nb–4Ta–0.2Pd
Medical implants
Ti–5Al–1.5B
Biomedical
Fig. 1 Titanium alloys used in medical devices throughout the entire human body
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Type of alloy
Reference
α type
α type
[11]
[12]
α type
[13]
α type
β type
α type
β-type and α + β-type
α + β-type
α + β-type
α + β-type
β-type
β-type
β-type
α + β type
β-type
β-type
β-type
β-type
β-type
β-type
α + β type
–
[14]
[34]
[35]
[36]
[21]
[37]
[38]
[25]
[39]
[28, 30]
[40]
[24]
[26]
[27]
[29]
[41]
[42]
[43]
[44]
Bio-Design and Manufacturing
Fig. 2 a-e Brief illustration of the design and fabrication process of a patient-specific mandibular prosthetic implant for defects related to maxillofacial clinical applications
a secure base for a single tooth to a complete dental arch.
The titanium dental root comprises biocompatible anchors
surgically implanted into the jawbone where the natural
tooth is missing to support the artificial crown once the
osseointegration period has occurred over time. During
this period, the bone grows into and surrounds the titanium
implant to create a firm structural support. Thereafter, the
higher assembly of tooth superstructure is attached onto
the implant as a dental replacement using cementation or
the screw-tightening retaining method. Orthodontic braces
made of titanium alloys are lighter, stronger, and feature
better biocompatibility than steel [52, 53]. In this regard,
pure titanium, Ti–6Al–4V, and Ti–6Al–7Nb are the primary
titanium alloys utilized in surgical and dental applications.
The mechanical properties of the various titanium alloys
used in dental applications are listed in Fig. 3 [54].
The casting process is instrumental for the dental applications of Ti, with an emphasis on low elongation and high
strength [55]. Hydrogenation processing and dehydrogenation processing are efficient techniques to improve elongation without compromising the strength of cast titanium
alloys. These include thermochemical processing by postheat treatments such as broken-up structure or β and α-β
solution treatment [56]. Titanium alloys have a higher melting point and are more reactive than other dental alloys, such
as Ag- and Au-based alloys that are preferred for precision
dental castings.
External prostheses
Owing to the inherent properties of titanium, such as corrosive resistance, low weight, and toughness, its alloys are
used extensively for the fabrication of temporary or longterm external devices and fixations, including artificial limbs
and orthopedic calipers [57–59].
Internal prostheses
Titanium alloy pegs are used to secure false ears and eyes,
while pure titanium grid implants provide fixation for interorbital fractures. The aural applications of titanium include
bone conduction hearing aids anchored with devices made
of titanium that are connected to the middle ear [60].
The carrier structure for replacement heart valves, coronary angioplasty catheters, defibrillators, intravascular
stents, pacemaker cases, and vascular access ports are also
made of titanium alloys [61–66]. Infusion pumps utilize
titanium–nickel shape memory alloys that flex when the
applied electrical current enables the creation of a heating
and cooling cycle that changes the shape of the chamber
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Bio-Design and Manufacturing
Fig. 3 a-d Various titanium alloys used in dental implants and their associated mechanical properties
[67]. Urethral strictures are treated with urethral stents
made from titanium [68].
Surgical instruments
An extensive range of surgical instruments, such as dental
drills, forceps, and laser electrodes, often contain titanium
due to its antibacterial properties, resistance to corrosion,
compatibility with radiation, durability, and lightweight
nature [69]. The low weight of titanium reduces the
onset of fatigue for surgeons wielding the instrument for
extended periods of time [70]. For microsurgical operations, such as ocular surgery, titanium surgical instruments
are usually anodized to produce a non-reflecting surface
essential for such operations [70, 71]. The non-magnetic
property of titanium reduces the possibility for electromagnetic damage or interference to small and sensitive
implants during surgery [72]. The durability of titanium
surgical instruments enables them to withstand repeated
sterilization cycles without compromising their corrosive
resistance, strength, edge quality, and surface quality.
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Utilization in healthcare products
The utilization of titanium alloys for the fabrication of
healthcare goods is expanding. Such uses include external prostheses and wheelchairs, particularly those used
for sporting purposes, due to their outstanding biocompatibility, low weight, and high-strength properties. The
titanium alloys widely used in this aspect are TFCA
(Ti–4.0Fe–6.7Cr–3.0Al) and TFC (Ti–4.2Fe–6.9Cr) due to
their lower cost than pure titanium, as recycling titanium
with iron (Fe) contents, or low-cost ferrochrome (FeCr)
can be utilized for this purpose [73, 74].
Even though healthcare goods are not implanted into
the patient’s body, biocompatibility issues such as allergic reactions still need to be addressed, especially for the
elderly who have weaker immune systems and a higher
propensity to use these healthcare devices. A study involving pure titanium, Ti–6Al–4V, TFC and TFCA, has shown
that TFC and TFCA had greater cell viability among the
groups. As such, there is a potential for TFC and TFCA
to be used more widely in other types of healthcare goods
[75].
Bio-Design and Manufacturing
Functional properties of titanium alloys
used in biomedical applications
Tensile strength
Commercially pure titanium possesses several functional
properties that are particularly advantageous for various
biomedical uses. Here, we explore the characteristics that
make titanium a suitable option as a biomedical material
for such applications. Table 2 presents the properties of
titanium compared to other lightweight metals used in
the biomedical field. It can be seen that titanium has a
higher melting and boiling point compared to aluminum
and magnesium. The demand for biomaterials is related
to different parameters based on their applications, such
as elasticity modulus; hence, alloys with higher strength
have a broader usage in biomedicine [76].
Bio‑inertness (inert to chemical reactions
with human bodily fluids)
Titanium exhibits the highest strength ratio of any metal
suitable for medical application as a biomaterial [81, 82].
Titanium is lighter than stainless steel by approximately 56%
but possesses twice the yield strength and an ultimate tensile
strength that is approximately greater by 25% [83, 84].
Magnetism
Titanium is not susceptible to magnetization. Due to its
non-magnetic properties, the benefits for patients with titanium inserted into the human body include reducing complications when undergoing CT scan or X-ray, avoiding the
magnetization of titanium insert or prosthetic when near an
electromagnetic source (such as most modern electronics),
and not triggering metal detectors at airports [85].
Density
Decades of medical studies and evaluation performed on
titanium as a biomaterial demonstrated its excellent resistance to chemical reactions in the biological environment of
the human body under fatigue, stress, as well as in crevice
conditions [77]. The bio-inertness property of titanium is the
result of its ability to naturally form a protective oxide film
under the presence of even trace amounts of oxygen. This
protective film is chemically impermeable, highly adherent,
insoluble, and prevents chemical reactions between human
tissue and titanium under the biological environment of the
human tissues [78].
Titanium possesses the lowest density among the metallic biomaterials. Matching the density of the biomaterial
with that of the already low density of human bone also
contributes to the reduction of the stress shielding phenomenon by maintaining the proper distribution of body weight
throughout the skeletal structure. Moreover, these properties
enhance the image quality produced by computed tomography, magnetic resonance imaging (MRI), and X-ray [86].
Typically, β-type titanium alloys that have niobium and zirconium elements are utilized in applications where a low
modulus of elasticity is required, while α + β-type titanium
alloys are employed in cases where a high modulus of elasticity is required, such as for bone plate.
Ductility and malleability
Corrosion resistance
Pure titanium possesses a relatively high level of ductility
and malleability, which allows the use of conventional
metal processing techniques and tools to form, machine,
and join the biomaterial into functional biomedical
implants. Such level of workability enables sheet metal
techniques, such as tungsten inert gas welding performed
without vacuum, to fabricate biomedical implants with
larger and more complex designs [79, 80].
Table 2 Physical properties
of lightweight metals used as
biomaterials
Titanium exhibits excellent resistance to corrosion due to
the self-formation of a passive titanium dioxide film that
protects the metal from further oxidation, thereby inducing low toxicity in comparison with most other biometals.
However, the property of corrosion resistance alone is not a
determinant of the excellent tissue compatibility of titanium
[87, 88]. The electrical plating of titanium with platinum
improves its corrosion resistance at the cost of depleting
Metallic element Boiling
point
(°C)
Metal
density
(g·cm−3)
Melting
point
(°C)
Hardness
(HBW)
Elastic
modulus
(GPa)
Tensile
strength
(MPa)
Thermal conductivity
(W/(m·K))
Titanium
Aluminum
Magnesium
4.512
2.7
1.74
1678
660
650
716
160
44
120
70
45
220
90
175
26
238
156
3289
2520
1090
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Bio-Design and Manufacturing
the bone formation capability due to the surface property of
titanium being shielded [89, 90]. Several studies investigated
the corrosion resistance of Ti–6Al–4V and Ti–6Al–7Nb in
phosphate-buffered saline (PBS) solution. The corrosion
potential and current density of Ti–6Al–4V are − 0.143 V
and 4.334 × 10−5 μA·cm−2, respectively, and their values
are − 0.217 V and 4.83 × 10−5 μA·cm−2 for Ti–6Al–7Nb,
respectively, which demonstrated that the corrosion resistance of Ti–6Al–7Nb is better than that of Ti–6Al–4V for
biomedical purpose. This also results from the fact that niobium has higher corrosion resistance compared to vanadium
[88, 91].
Some atrophy change at the posterior of the tibial bone was
observed after week 20. Ti–6Al–4V ELI displayed similar
results, albeit at a slower rate. For SUS 316L stainless steel,
significant fracture calluses were detected that remained
until the end of the subsequent period. Observations of the
proximal tibial bone at week 10 showed bone atrophy at the
posterior part, which became more apparent every fortnight.
The posterior tibial bone at week 24 showed signs of the
bone structure becoming severely weakened. The low-rigidity titanium alloy Ti–29Nb–13Ta–4.6Zr has therefore shown
a potential to address the load transmission issue faced by
current implants [99, 100].
Resemblance of thermal expansion and elasticity
modulus of Ti to human bone
Elasticity and shape memory of titanium alloys
The coefficient of thermal expansion as well as the modulus
of elasticity of titanium closely resembles those of human
bone, which in turn significantly reduces the potential for
the patient receiving titanium implants to experience stress
shielding, as the loads will be comparatively well distributed
across the skeletal structure [92, 93].
Rigidity of titanium alloys
Most titanium alloys are designed with low rigidity as the
fundamental property for biomedical application as implants
and prosthetics [94]. Taking the cortical bone as an example,
it is important for the Young’s modulus of a biomaterial to
be as close as possible to that of cortical bone, as resorption
may occur if this value is higher [95]. The α + β-type titanium alloy Ti–6Al–4V is commonly utilized in biomedicine
[96]. Its Young’s modulus is lower than that of cobalt-based
alloys and stainless steel, but still much higher than that of
cortical bone. The Young’s moduli of β-type titanium alloys
have been established to be lower than those of α + β-type
or α-type titanium alloys, thereby allowing β-type titanium
alloys to feature the required property of low rigidity. Furthermore, these alloys display high strength and outstanding
cold workability [97].
The mechanical biocompatibility of titanium alloys with
low rigidity for biomedical use was established on rabbits.
In the relevant model, an experimental tibial fracture was
induced in the tibia beneath the tibial tuberosity through
the utilization of an oscillating saw [98]. The fracture was
treated with the insertion of an intramedullary rod into the
intramedullary canal, which was fabricated from Ti–6Al–4V
ELI, Ti–29Nb–13Ta–4.6Zr, or stainless-steel SUS 316L.
Atrophy, bone healing, and remodeling were monitored via
X-ray imagery every fortnight for a period of 24 weeks. The
shape of the fracture callus for Ti–29Nb–13Ta–4.6Zr was
discovered to be very smooth, gradually decreasing from
week 6, and traces of fracture disappearing by week 10.
13
Ti–Ni is a shape memory titanium alloy used extensively in
the wider industry beyond the field of biomedicine. In fact,
Ti–Ni has seen limited biomedical applications due to its
significant Ni content, which causes high rates of allergy.
However, Ti–Ni has the potential for applications as catheters or stents where shape memory and superelastic properties are desirable [101]. To address the issue of metallic
allergy due to the high Ni content, ongoing research and
development have been underway for non-toxic titanium
alloys with shape memory as well as superelastic properties.
A β-type titanium alloy known as “Gum Metal” (also
called TNTZ) has a similar chemical composition to
Ti–Nb–Ta–Zr system titanium alloys utilized in biomedical applications and has been used as flexible glass frames.
Modifications to the chemical composition of “Gum Metal”
may enable its potential for biomedical use. The superelastic feature of Ti–29Nb–13Ta–4.6Zr has been established
for biomedical application with reports describing the very
low density of dislocations post-deformation [102]. Developments are ongoing for Ti–Nb–Sn system titanium alloys
as shape memory Ni-free titanium alloys for biomedicine
[103]. Research and development on various β-type system titanium alloys for biomedical use, such as Ti–Mo–Ga,
Ti–Mo–Ge or Ti–Mo–Al, Ti–Ta, Ti–Ta–Zr, and Ti–Sc–Mo,
have also been intensive [104–108].
Bioactive surface treatments
Titanium alloys are generally treated with bioactive
surface modifications to enhance their biocompatibility. Despite demonstrating superior biocompatibility in
comparison with their metallic counterparts for biomedical use, titanium alloys exhibit similar bio-inertness to
ceramics such as alumina and zirconia. Therefore, bioactive materials including phosphate calcium (CaP),
β-CPP (β-Ca2P2O7), and β-TCP (β-Ca3 (PO4)2) coatings
are applied on the titanium alloy surface to facilitate the
Bio-Design and Manufacturing
formation of hydroxyapatite (HAP). The various bioactive
surface modification processes are categorized into dry or
wet processes [109–111].
Dry processes consist of direct and indirect HAP forming
methods. The former includes the ion beam dynamic mixing method, ion plating, the plasma spray method, the pulse
laser deposition method, the superplastic joining method,
and radio frequencies (RF) magnetron sputtering, whereby
the formation of HAP occurs directly on the surface of the
titanium alloy [112–116]. Indirect HAP forming methods
include calcium ion implantation, in which calcium alloys
are incorporated into titanium alloy, and the calcium ion
mixing method where calcium is deposited on the surface
of titanium alloy, followed by the implantation of argon ion.
These treatments enhance the precipitation of phosphate calcium on biomedical titanium alloy surfaces [117].
In a similar manner, wet processes consist of direct and
indirect HAP forming methods. Electrochemical treatment
is a direct HAP forming method, while alkali treatment is an
indirect HAP forming method that involves heating the titanium alloy during immersion in sodium hydroxide solution
(NaOH), followed by immersion of the said titanium alloy
in simulated body fluid [118, 119]. In addition, several other
methods have been applied to form an apatite layer on the Ti
surface in simulated body fluid (SBF) for various biomedical
applications, as follows: NaOH and heat treatments; NaOH,
CaCl2, heat and water treatments; H2SO4/HCl and heat treatments; NaOH, and acid and heat treatments [120].
Biocompatibility of and host tissue
responses to titanium alloys
Host tissue response
Observations on the structural interface located between the
titanium biomaterial and bone tissue both at the microscale
and the nanoscale facilitate the understanding of the osseointegration mechanism. The titanium substrate is covered
by several layers of materials in the following order: titanium
oxide with a thickness of a few nanometers; an amorphous
layer of proteoglycans with a thickness of 20–50 nm; a slim
layer of cells; a region with mild calcification; and bone
tissue. Researchers have recently investigated the reaction
mechanisms contributing to the capability of titanium for
osseointegration. The influencing factors found include
effects of healing and immune modulation; hydrophilicity
and wettability; increase in gene expression associated with
angiogenesis, neurogenesis and osteogenesis; inflammation–immunological balance; interactions between platelets
and red blood cells; and molecular signaling mechanisms
related to immune osteocytes [121–123].
Surface hydroxyl groups
The properties of the surface oxide film covering the titanium substrate govern reaction mechanisms at the interface
located between the titanium biomaterial and living tissue.
Hydroxyl groups are formed on the surface oxide film due to
interactions with moisture from the air, which in turn form
electric charges after dissociating in aqueous solutions, such
as bodily fluids. The pH of the surrounding solution determines the value of the electric charge, which becomes zero
at a certain pH value. This pH is also called point of zero
charge (PZC) that is dependent on the oxide and is an indicator showing acid or base property. In the case of titanium
oxide, the PZC of anatase is 6.2, while that of rutile is 5.3,
which translates to an almost neutral property that is neither
significantly acidic nor basic. The concentration of surface
hydroxyl groups on titanium oxide, at 4.9–12.5 nm−2, is relatively large [121, 124]. This large concentration or wettability increases post-immersion in an aqueous solution, which
promotes the absorption of proteins such as cytokines and
integrins.
Protein adsorption
Since proteins carry charges depending on the pH environment, their conformation is altered via adsorption onto the
biomaterial surface. The relative permittivity of the surface
oxide film determines the electrostatic force between proteins and the metal surface; that is, a larger relative permittivity translates to a smaller electrostatic force. Titanium
oxide has a relative permittivity of 82.1, which is similar
to that of water at 80.0 and is significantly larger than that
of other oxides. Thus, the conformational fluctuations of
protein adsorbed on titanium oxide are comparatively small.
The absorption layer for fibrinogen is thicker, though the
absorption amount in aqueous solution is smaller on titanium than on gold. Titanium is covered with TiO2, whereas
gold is an exposed metal without surface oxide; hence, the
electrostatic force for titanium is much smaller than that
for gold. Therefore, the change in protein conformation is
smaller on titanium, and proteins adsorbed on titanium are
less susceptible to conformational changes compared with
those adsorbed on gold [125, 126].
Formation of calcium phosphate
While the surface oxide film is macroscopically stable,
its chemical state and composition vary based on the surrounding conditions. The composition of surface oxide
film continuously changes based on the environment; from
a microscopic viewpoint, it participates in a constant cycle
of partial dissolution and reprecipitation in the electrolyte.
In a biological environment, calcium phosphates easily
13
Bio-Design and Manufacturing
form on the surface of titanium and titanium alloys, while
under cell culture, they form sulfite and sulfide, respectively. The Ca/P atomic ratio to stimulate the generation
of a bone-like apatite layer is considered as a key feature
for rapid bone rehabilitation. Titanium is stabilized following calcium phosphate formation with a Ca/P atomic ratio
of around 1.6 when soaked in Hank’s solution, which is
close to the stoichiometric molar ratio of hydroxyapatite.
Furthermore, phosphorous and calcium can be detected at
the interface located between the titanium biomaterial and
bone tissue. The capability of titanium to form calcium
phosphate is one of the contributing factors to its outstanding hard-tissue compatibility [127, 128].
Osseointegration
For a patient’s body to successfully accept the biomedical
implant, it is instrumental to establish safe implant placement and shorten the postoperative healing period, as the
human body will begin to reject the implants after a response
to osseointegration for a minimum period [129, 130].
Due to the high dielectric constant of its surface oxide,
titanium possesses the capability to form a direct interface
with and bond well to living bone tissue without intervening soft tissue. This high dielectric constant does not
denature proteins when titanium biomedical implants are
inserted into the body. Such functional ankylosis enhances
the durability and mechanical stability of load-bearing
titanium implants as compared to biomaterials that require
the use of adhesives, as the amount of force required to
break the physical bond formed between the human bone
and titanium inset is considerable [129, 131]. However,
according to other researches, in early implementations
of implants into the human body made of CP-Ti, the surface of the biomaterial is unable to integrate with the
patient’s bone due to the bioinert surface property of titanium [132, 133]. This leads to a longer healing duration
and occasionally the surface encapsulation of the implant
over time. The possible consequences are the loosening of
the implant, the formation of wear debris or fibrous tissue
developing at the implant site, micromotion, and the possibility of fracture or delamination at the implant–bone
interface [134, 135].
The key factors that determine the successful osseointegration of implants include biological compatibility in that
the implant is not toxic to the surrounding living tissues,
mechanical compatibility in that the implant is able to transfer stress loads between the receiving living tissue and the
root of the placed implant, and morphological compatibility
in that the implant is able to promote bone cell growth at the
implant location [136, 137].
13
Strategies to enhance the antimicrobial
properties of titanium alloys
through ultraviolet (UV) irradiation
The surface of pure titanium shows signs of decreased histocompatibility over time. The application of UV irradiation reverses the effects of the biological aging phenomenon through the physiochemical alteration of the titanium
surface, a process known as photo-functionalization [138].
Titanium implants used in dental surgery are sterilized
via UV irradiation [139]. In addition, there is potential
in exploring the antibacterial effects of UV irradiation on
orthopedic biomaterials typically comprised of titanium
alloys, including Ti–6Al–4V. Accordingly, evaluations
have been performed on the antimicrobial and bactericidal
effects of UV irradiation, at a shorter and lower dosage
than in prior applications, to treat Ti and titanium alloy
Ti–6Al–4V for utilization in implant surgery [140, 141].
Postoperative infections involving the use of metallic biomaterials comprise a significant complication for
patients. Thus, multiple studies have attempted to develop
methodologies that can alter the surface of implants to prevent or reduce the initial bacterial adhesion. These alterations are based on the principle of hindering the ability of
microorganisms to form biofilms by enabling the patient’s
cells to attach to the implant surface first. Pure TiO2 substrates with photocatalytic properties have been demonstrated as capable to function as disinfectants and eliminate organic compounds when exposed to UV irradiation
[142, 143]. Prior studies have shown the bactericidal effect
of Ti–6Al–4V alloy surface exposed to UV subtype UV-C
light at 227 J/cm2 dosages for 15 h. Studies have also indicated that exposing Ti–6Al–4V alloy to UV irradiation
at lower duration and energy induces increased bioactivity and osteoconduction. However, the dimensions of the
implant are typically determined perioperatively, which
leads to challenges in preparing the implants by UV irradiation before surgery. The difficulties experienced in the
perioperative replication of the aforementioned antimicrobial strategies in clinical practice involving total implant
surgeries have led to the conclusion that it is necessary
to evaluate the antimicrobial and bactericidal effects of
exposing Ti and Ti–6Al–4V to UV irradiation of shorter
durations and energy levels [140].
Based on previous knowledge, one study investigated
how UV irradiation contributes to the antimicrobial effect,
which involved seeding Staphylococcus aureus 834 bacterial suspensions onto Ti and Ti–6Al–4V disks that had
been exposed to a 9 J/cm2 dosage of UV light for a period
of 15 min. The evaluation of the bactericidal effect of UV
irradiation involved seeding the bacteria onto the disks
at different time points after UV irradiation under the
Bio-Design and Manufacturing
same conditions. The time periods were 0, 0.5, 1, 6, 24,
and 48 h, followed by 3 and 7 days. After harvesting and
culturing the bacteria, the colonies were counted in both
groups. Findings showed the absence of colonies on the
UV-irradiated disks after seeding the bacteria. After the
addition of bacteria onto the UV-irradiated disks, the number of live bacteria initially decreased before showing a
steady rise. However, the antimicrobial effect faded over
time [140].
The conclusive results showed that UV-irradiated Ti and
Ti–6Al–4V exhibited similar antimicrobial properties, the
bactericidal effect was maintained for a week post-UV irradiation on both disks, and this effect was similar on both
types of disk. In addition, low-energy and short-duration UV
irradiation was determined to contribute to the bactericidal
effect on both Ti and Ti-6Al-4V [140].
Surface modifications of titanium
The detailed description of the surface properties of the biomedical implant, such as its surface morphology, structure,
and chemistry, is critical to determine the reactions between
the biomaterial implanted into the body and the associated
live tissues [144]. The biocompatibility of a biomaterial
is typically improved via modifying its surface properties
through a combination of biochemical coatings and morphological changes. The main aim of these surface modifications performed on implants is to avoid foreign body
response, decrease bacterial adhesion and inflammatory
reaction, as well as increase implant integration and tissue
adhesion [145].
Biocompatibility has shown to be dependent on the interrelation of various factors influencing the bulk and surface
properties of biomaterials, which include surface topography
(e.g., surface roughness), surface chemistry (e.g., surface
tension and purity for wetting), and nature of tissue integration (e.g., fibrous, osseous, or mixed) [146–148].
Roughness modifications commonly applied to titanium
and titanium alloys can yield significant improvements in
biomedical performance without compromising the bioinert nature of these materials. Furthermore, chemical modifications may be required to ensure rapid osseointegration.
These include deposition methods, such as precipitating
calcium phosphate through immersion into synthetic body
fluid, electrodeposition, protein absorption, and plasma
spray [149, 150]. Alternatives to chemical modification have
also been developed, such as the biomolecular functionalization of implant surface with various biomolecules, including
collagen, fibronectin, peptides, as well as bioengineered protein fragments. Regardless, the critical mechanism involved
pertains to how the bioactive molecule binds to the surface
of the implant, as well as the method of immobilization
[151–153].
The host environment has been reported to have the most
significant influence on the biomaterial-to-tissue interface
zone, where the interaction occurs between the implanted
biomaterial and recipient tissues. This interface zone, which
involves the implant surface layer and several nanometers
into the recipient tissues, determines the circumstances of
healing, as well as the clinical longevity of the implant’s
load-bearing function [121].
The mechanical methods generally used for titanium and
titanium alloys to obtain rough surfaces are subtraction processes, such as blasting, grinding, machining, and polishing,
while smoothing the surfaces requires attrition processes,
such as milling. The objective of such mechanical modifications is to produce a surface with specific topographies for
improved adhesion in bonding while cleaning or roughening
the surface, since the increased surface roughness of the
implant structure is deemed more conducive for biomineralization [154, 155].
Chemical methods, such as acid and alkaline etching,
biochemical surface coating methods, chemical deposition,
and electrochemical anodization, are generally utilized to
provide titanium and titanium alloys with bioactive surface
characteristics. The aim is to improve bioactivity, biocompatibility, corrosion resistance, and osteoconduction and
remove any contaminations. Obtaining irregular morphologies for titanium implant surfaces on the nanoscale can be
achieved through a multitude of chemical methods, while
electrochemical anodization is generally used when the aim
is to fabricate controlled nanostructures, such as nanodots,
nanorods, and nanotubes [156–158]. The fabrication process
of titanium dioxide nanotube (TNT) arrays by anodization
is shown in Fig. 4.
Physical surface modification methods do not require
chemical reactions to produce the desired engineered surface. Such methods include glow discharge plasma treatments, ion implantation, physical vapor deposition, and
thermal spraying. The resulting layer of coating or film
formation on the surface of titanium substrate is simply
a product of transferring various types of energy, such
as kinetic, electrical, or thermal, which is unique to each
method [159–161].
Titanium/silver physical vapor deposition (PVD)
coatings
The formation of biofilm and endoprosthesis infection are
regular issues pertaining to complications of implant surgeries. Adjustments to the implant surface prior to implantation
have been applied to overcome such postoperative infections.
One of the techniques for surface modification to improve
the biocompatibility and antimicrobial properties of titanium
13
Bio-Design and Manufacturing
Fig. 4 Schematic of anodization process to fabricate titanium dioxide nanotube (TNT) arrays: a oxide layer formation, b pit creation, c
pit growth, d oxidation and field-assisted dissolution of the metallic
region between the pores, e fully developed nanotubular configurations with f a corresponding top view and g cross-sectional view with
inner and outer oxides
is silver coating by PVD. Several researches have been conducted to develop antimicrobial coatings with titanium and
silver using PVD [162, 163]. Some of the recent studies
investigated the mixed system of anodization and PVD to
improve the titanium/silver coating, and the results showed
the deposition of Ag2O on the edges of highly ordered TiO2
nanotubular arrays (schematic shown in Fig. 5) [128].
Relevant techniques involve direct impregnation utilizing
antibiotics before implantation, or polymer coatings doped
with antibiotics or silver. The antimicrobial activity and
non-toxic nature of active silver ions to human cells have
been well established, as only a few bacteria are intrinsically resistant to silver via resistance mechanisms derived
from plasmids [162, 164]. The incorporation of silver ions
into polymeric materials has been extensively performed
for some time [165]. Urinary and central venous catheters
use silver coatings, while dialysis units or heart valves have
silver dotted surfaces to reduce infection [166]. Unfortunately, the relevant techniques may not meet the mechanical requirements for load-bearing biomedical implants, particularly those implanted into bone, due to the high levels
of abrasive and shear forces occurring at the implant-bone
interface.
Moreover, the PVD process is commonly utilized in
medical and technical applications due to the excellent
adhesiveness and wear resistance of ceramic and metallic coatings. In one study, silver–titanium was applied to
samples of titanium alloys by PVD and tested for bactericidal action, biocompatibility, and hardness. The objective
of the study was to assess the antimicrobial capability of
coatings with silver ion under an aqueous environment,
without compromising the hardness and biocompatibility
of titanium with soft and hard tissue, for utilization in
biomedical implants with load-bearing requirements, such
as knee joints or hip joints [167].
In one study, both titanium and silver were vaporized
in an atmosphere filled with inert argon, and antimicrobial
coatings with a thickness of about 2 µm were deposited on
the titanium surface. Through X-ray analysis, the silver
content of the coatings was determined to be about 0.7%
to 9%. Subsequently, eukaryotic culture cells and microorganisms were grown on these surfaces. After immersion
in phosphate-buffered saline (PBS), the coatings released
adequate amounts silver ions (between 0.5 and 2.3 ppb) and
displayed remarkable antimicrobial potency against Klebsiella pneumoniae and Staphylococcus epidermidis strains.
13
Bio-Design and Manufacturing
Fig. 5 a–c Schematic of a mixed system of anodization and PVD to deposit silver oxide on the edges of highly ordered TiO2 nanotubular arrays
on Ti64
Furthermore, the coatings had no cytotoxic effects on the
epithelial cells and osteoblasts [168].
Using commercial grade 2 pure titanium as control, the
reaction of Klebsiella pneumoniae and Staphylococcus epidermidis bacterial strains on surfaces dotted with silver was
observed. The datum for the adherence of bacteria to the
control surface was defined as 100%, and bacterial contamination on the surfaces containing silver was subsequently
recorded. Klebsiella pneumoniae displayed reduced adhesion (p < 0.05) on the surfaces with 0.7% silver to 4% silver
in the range of 32–64%, respectively. Meanwhile, Staphylococcus epidermidis displayed reduced adhesion (p < 0.01)
on the surfaces with 0.7–4% silver in the range of 43–52%,
respectively. Due to their similar mechanical performance
to pure titanium, titanium silver (Ti-Ag) coatings may be a
viable antimicrobial strategy for load-bearing implant surfaces [168].
Advanced manufacturing (AM) of titanium
alloys for biomedical application
The fabrication techniques of titanium alloys for biomedical application include casting and powder metallurgy, cold
working and hot working, machining, and additive manufacturing. Titanium alloys are manufactured into three types,
including α, β, and α + β. Some alloying elements are dissolved preferentially in α phase such as Zr, Al, Sn, O, and
Si raising the α + β-phase. The addition of these elements
results in the modification of alloy properties, such as in
hardening and tensile strength improvement. Oxygen plays
a dominant role controlling the range of strength of several
grades, which are collectively called CP-Ti. The β-phase
transformation stabilizes titanium alloys and makes them
suitable for biomedical application because of their subsequent low modulus (which is below that of the α- and
α + β-phase and near that of the human femoral bone), and
confers them high specific strength [76].
The CP-Ti and Ti-64 are manufactured via the traditional
routes, such as strips, sheets, plates, bars, billets, forgings,
and wires, specified according to the American Society for
Testing and Materials (ASTM) as grades 1–5. Grades 1–4
comprise the unalloyed CP-Ti, and grade 5 is the alloyed
Ti-64 [169]. One of the AM methods is the powder-based
additive manufacturing technology of titanium and its alloys,
with the advantages of low-cost, resource-saving, suitable
time, and customized parameters for fabrication, and has
received great attention for biomedical application [170].
The quality of additively manufactured implants highly
depends on the selected additive manufacturing technique
and the quality of titanium and its alloy powders. Additive
manufacturing techniques employed to fabricate the biomaterials include directed energy deposition [171], laser-based
powder bed fusion of metals (PBF-LB/M) [172], powder
fed system of binder jetting [173], electron beam powder
bed fusion of metals (PBF-EB/M) [174], plasma atomization
[175], gas atomization [176], and plasma rotating electrode
process [177].
Developments in porous titanium structures for biomaterial application have enabled design optimizations for
13
Bio-Design and Manufacturing
patient-tailored implants. The additive manufacturing techniques allow for the fabrication of porous surface structures
with predetermined, predictable unit cells for a biomedical
implant, which have the necessary capabilities such as promoting cell proliferation and osseointegration. Thus, biomedical implants can achieve mechanical properties similar
to those of human bone, such as compressive strength and
elastic modulus, thereby preventing post-implantation complications, like stress shielding effects [178, 179]. To achieve
such desired traits, it is necessary for biomedical implants to
have an accurate design of porosities and pores to replicate
the various mechanical properties and characteristics of the
two main categories of bones, namely cortical bone and trabecular bone [180]. Despite having a similar composition,
these two bone types vary in the degree of porosity and the
proportion of organic and inorganic materials. The combination and organization of these two categories of bone differ
according to the applied mechanical loading, as well as the
skeletal region. Cell differentiation and proliferation are also
affected by the morphology of pores, which is related to the
pore size, porosity, and pore quantity [181].
Cellular structures can be classified into two main types,
namely stochastic and non-stochastic. The cells in stochastic structures vary randomly in shape and size, while nonstochastic structures can be defined by the periodic repetition of the lattice structure with a unique shape and size of
cells. Due to the absence of random variations in their cell
shapes and sizes, non-stochastic metal structures are considered superior to stochastic metal foams on the basis of
fabrication via powder bed technologies, which leads to better mechanical properties and the ease of removal of unfused
powder [182, 183].
Evaluations have been performed on how variances in
non-stochastic structures, such as the shape and size of
pores, permeability, and porosity, affect the in vitro biological outcomes, as well as the mechanical properties of
Ti–6Al–4V scaffolds fabricated via selective laser melting
(SLM). The different pore shapes had an effect on cell permeability and consequently the number of cells attached to
the Ti–6Al–4V scaffold. Other studies also reported that
the circular cell growth pattern was not dependent on the
shape and size of pore, which was primarily attributed to
the amount of pore occlusion being higher on hexagonal
pores in comparison to rectangular or triangular pores [184].
Moreover, research has been carried out on titanium
hip implants with the aim of reducing the stress shielding
effects without compromising mechanical strength. This
was achieved by applying finite element analysis (FEA)
to the design process and utilizing electron beam melting
(EBM) fabrication technologies. A periodic lattice structure
was used to modify the solid stems to achieve the desired
reduction in implant stiffness. The comparisons between the
constructed model and the simulated model demonstrated
13
the possibility of utilizing EBM to fabricate non-stochastic
lattice structures. The orientation of lattice struts was also
instrumental to the fabrication process. Due to differences
among the surfaces of struts between the EBM-fabricated
model and the FEA-simulated model, the design of implants
had to incorporate safety factors. The FEA model featured a
consistent cross-section with a smooth surface, whereas the
fabricated struts exhibited cross sections with slight variances coupled with textured surfaces. The study involved
three model configurations, namely complete solid, hole
configuration, and mesh configuration. The mesh configuration incorporated into the Ti–6Al–4V stem was found to
possess better stress distribution characteristics at the proximal portion of the femur [185–188].
Another study was conducted to determine the properties of porous structures in terms of internal geometry, pore
size, and pore density in Ti–6Al–4V fabricated by continuous laser melting deposition (LMD) and pulsed LMD.
Both fabrication methods were shown to produce different
internal porous structures, while optimizing the parameters
such as laser power and powder mass flow rate yielded different densities in both cases. Ti–6Al–4V powder was used
as the deposition material on the substrate, and parameter
optimization resulted in the fabrication of suitable pores for
osseointegration. Analytical models of the processes built
by using Wolfram Mathematica software are also necessary
to find interacting, transient heat, temperature, and mass
flow models [189]. A more controlled porosity was obtainable by utilizing a pulsed beam fabrication methodology as
compared to a continuous beam. A regular structure was
instrumental to avoid premature failure [190].
Effect of alloying elements on biocompatibility,
corrosion resistance, and mechanical properties
In order to develop safer biological Ti alloys with high
strength and ductility, biocompatible alloying elements
were examined as alternatives to V and Al. The strength
of the alloy was found to increase with the Zr and Sn content. In this regard, Sn is more effective than Zr, while Nb,
Ta, and Pd are less potent; therefore, the tensile strength of
Ti–15Sn–4Nb–2Ta–0.2Pd is higher than that of Ti–6Al–4V
for medial implants [191, 192]. Elements such as Mo, Zr,
Ta, Sn, and Nb are selected as the safest alloying metals
to adjust the properties of the biomaterial and maintain its
suitability for implantation [76]. The β alloying elements
of titanium, including V, Mo, Nb, Ta, and Zr, improve its
corrosion behavior. Accordingly, it has been proven that
Ti–6Al–4V has higher corrosion resistance compared to
titanium alloyed with elements such as Co and Cr alloys,
while pure titanium has higher pitting corrosion resistance
rate. The β-phase stabilizing elements, such as Mo and V,
Bio-Design and Manufacturing
improve the stress corrosion cracking of titanium owing to
the increased heat treatment capability [193–195].
Titanium β-phase alloys, including Ta, Nb, Zr, and Sn,
have excellent mechanical properties, such as low Young’s
modulus, high strength, good cold workability, and good
biocompatibility and, therefore, have been more commonly
used in recent years [76, 196, 197]. Moreover, Mo in titanium is not suitable for biomaterial application in high
amounts due to the increased possibility of ion releasing to
the surrounding tissue, resulting in totally diminished cytoplasm content and reduced cell spreading. Therefore, this
element must be used in small quantities, just as Ni, V, and
Al [198]. Cell culture experiments on osteoblast cells with
Ti–5Nb–xFe alloys showed that the rate of cell proliferation
is related to the amount of Fe and the chemical bonding
between Fe and cells and that Fe with specific ratio has good
biocompatibility [199]. The ranking of elements added to Ti
in bioimplants regarding their cell viability enhancing effect,
from lowest to highest, is Cu < Al < Ag < V < Mn < Cr < Zr
< Nb < Mo < Cp-Ti, and that regarding their cytotoxicity is
Cp-Ti < Sn < Ta < Mo < Nb < Zr < Cr < Mn < V < Ag < Ni =
Al < Cu [200–204].
Potential of titanium alloys for regenerative
medicine and nanomedicine
Properties of titania nanotube arrays (TNA)
Nanomedicine aspires to supply a valuable set of research
tools and clinically functional devices for different biomedical applications. Titania nanotube arrays (TNA), also known
as titanium dioxide nanotube (TNT) arrays, are garnering
significant prominence as nanomedicine technique thanks
to improvements to orthopedic procedures due to its unique
properties, including a high specific surface area and the
capability to exhibit a positive cellular response. TNA can be
fabricated by various chemical, electrochemical, and physical methods. Self-assembled nanotube arrays grown using
anodic oxidation have been of particular interest due to the
cost efficiency and ease of fabrication, combined with the
exceptional electrical, optical, structural, and thermal properties exhibited by these nanotubes. The anodization layering process produces a continuous array of TiO2 nanotubes
vertically aligned on the surface of titanium alloy [205–207].
Applications in localized drug delivery systems
TiO2 nanotubes (TNT) comprise a viable option for localized drug delivery systems to address shortfalls in conventional drug delivery. Several methodologies can be utilized
to control extended drug release in small dosages for longterm therapies, such as adjustment of pore openings via
biopolymer coatings, modification of internal chemical characteristics, regulation of TNT dimensions, and utilization of
polymeric micelles as drug nanocarriers [208, 209]. Strategies to control drug delivery from TNTs are shown in Fig. 6.
Emergency conditions, such as the sudden onset of inflammation, osteomyelitis, and unexpected viral attack, may arise
with an imminent requirement for high concentrations of
drugs [210]. Such critical situations can be addressed by
employing stimuli-responsive drug delivery systems triggered by external conditions, such as magnetic, pH, radiofrequency (RF), temperature, ultrasound, ultraviolet (UV)
light, or voltage-sensitive drug delivery systems. The concept of stimuli release is based on the application of magnetic field, RF signal, ultrasonic wave, UV light, or voltage
field to induce the movement of related stimuli particles, and
forcing the release of polymer micelles out from the TNT.
External stimuli for on-demand and responsive drug delivery
can also be triggered via changes in the pH and temperature
of the surrounding bioenvironment. The internal volume of
TNT may be filled with biomolecules and chemicals, such
as proteins or enzymes. Extrapolating this approach, titania nanotube arrays (TNA) may be coated with drugs that
reduce inflammation, an example being dexamethasone, by
utilizing the physical adsorption or deposition of a drug via a
drug delivery system that is stimuli responsive. This application can work in conjunction with post-remission therapies,
such as stem cell transplant and radiation therapy [211, 212].
Some researchers have attempted to fabricate smart
implants with an on–off drug release capability using temperature as the external stimulus. It is assumed that the formation of a thermosensitive polymer coating on the surface
of TiO2 NTs endows a sustained release potential, resulting
in lower required drug dosages and decreased systemic toxicity. The schematic of the drug encapsulation and release
mechanisms is shown in Fig. 7. The polymer coating on
top of the nanotubes undergoes a rapid transition from a
hydrophilic state with coil-shaped polymer chains to hydrophobic globules at a specific temperature, which results in
the release of the drugs in a specific area of the human body.
This phenomenon leads to the partial removal of the protective shell from the surface of TiO2 NTs and the generation of
preferred trajectories for drug diffusion within the surrounding environment [213, 214].
Applications as immunomodulatory agents
Recent advancements in nanomedicine have facilitated
the development of new immunomodulatory agents that
include immunosuppressive agents or immunologically
active components. In conjunction with an immunosuppressive agent, the unique surface structure of TNA enables the
effective reduction of compromising immune responses that
would contribute to unsuccessful transplants as a result of
13
Bio-Design and Manufacturing
Fig. 6 Strategies for controlling drug release from TNTs. a Controlling the diameter and length of nanotubes; b surface chemistry
(hydrophobic, hydrophilic, charged); c tuning the nanotube opening
by plasma polymerization; d degradation of dip-coated polymer film
closing the nanotubes (PLGA or chitosan); e using drug nanocarriers
(micelles) for multidrug delivery; f delayed/sequential drug release of
drugs/drug carriers. External field-triggered drug release using g temperature, h magnetic field, i ultrasound, j light, and k radiofrequency
with gold nanoparticles. Only a single nanotube structure is shown to
present an array of TNTs
localized autoimmune or allergic reactions [205, 215]. Such
applications have the potential to significantly enhance clinical outcomes for a range of infectious and non-infectious
diseases.
100 nm) as compared to nanotubes with smaller diameters
(around 20 nm), which may potentially stunt the growth of
bacteria such as Staphylococcus epidermidis or Staphylococcus aureus [218].
Applications as antibacterial agents
Applications for hemocompatibility
Coating the TNA nanomatrix surface with drugs that
reduce infections, including streptomycin and penicillin,
can be utilized to mitigate the bacterial colonization of indwelling medical devices. The medical device surface is
aligned with TNA to act as an antimicrobial chemotherapy
agent. The internal cylindrical surface of the aligned TNA
is then coated with bactericidal antibiotics such as streptomycin and penicillin. This antibacterial surface provided
by the TNA coated with bactericidal antibiotics has proved
to inhibit and mitigate bacterial growth, thereby reducing
the risk of bacterial infection originating from the system [216, 217]. Nanomedicine approaches also provide an
enhanced solution to limit bacterial infection by delivering
traditional antibiotic treatments. Research has established
the utilization of nanotubes with larger diameters (30 to
13
TNA is a viable option as a nano-blood-contacting agent;
it has the ability to transform fibrinogen to fibrin, thereby
increasing the formation of a dense fibrin network and
subsequently reducing the clotting time. The topology of
TNA is conducive to enhancing the activation and adhesion of platelets, protein absorption of the blood serum,
and kinetics of blood coagulation. In addition, the surface
of TNA has the potential to act as a link between biological substances for propitious implants that are blood
related [219]. TNA also evokes low cytokine secretion and
monocyte activation. The adsorption of blood on TNA
enables further evaluation through the utilization of micro
bicinchoninic acid (BCA) assay, as well as X-ray photoelectron spectroscopy [220–222].
Bio-Design and Manufacturing
Fig. 7 Proposed mechanism of thermal-triggered drug release from
polymer-coated TiO2 nanotubular structures before a and after b
heating. At low temperatures, the polymer capping forms a uniform
protective layer on the nanotubes, resulting in a negligible level of
uncontrolled drug release. However, heating of the implant to a specific temperature leads to the coil-to-globule transition of the polymer
shell and the provision of preferred routes for drug diffusion
Conclusions and future directions
Ongoing research is being conducted on orthopedic
devices constructed from porous metal. Based on clinical studies using such porous metals like titanium foam,
the formation of vascular systems in a porous area seems
viable. The mechanisms of osseointegration in titanium
foams share similarities with that in bone grafts, whereby
the porous properties of the titanium foam facilitate considerable bone infiltration, allowing osteoblast activity to
occur. Furthermore, the porous structure enhances vascularization and the adherence of soft tissue within the
implant. Therefore, the utility of porous materials may see
a future expansion in replacement arthroplasty and dental
applications.
In the nanotechnology field, biomedical research and
development primarily target improvements to current
diagnostic and therapeutic methodologies. The ultimate
goal is to reduce the overall medical cost by improving the
efficiency and reusability of available practices. Thus far,
titanium nanostructures have proved to be a viable option
for advanced biomedical implants, as well as theragnostic
applications; however, a more in-depth understanding of the
biomolecular interactions involving titanium as a nanomaterial is necessary for further developments in this field.
Pure titanium (Ti) and its alloys have been used extensively as medical implants owing to their high biocompatibility, fatigue life, corrosion resistance, and lower Young’s
modulus compared to other medical implants. With the
development of AM technologies over recent years,
the fabrication of medical devices has not only become
cheaper and faster in comparison with conventional manufacturing techniques, but also these products have demonstrated superior mechanical properties with reduced
tooling operations and material wastage. The biomedical
application of AM technologies has garnered considerable
popularity in recent years due to improved capabilities in
the fabrication of implants specifically tailored to individual patients. AM technologies using biomaterials such
as titanium can replicate patient organs and tissues with
precision, which allows for the reproduction of complex
porous structures that enable tailored cell morphologies,
promote cell differentiation and proliferation, a requirement for bone in-growth, and act as an antimicrobial agent.
These benefits consequently reduce the risk of implant
rejection and accelerate the healing process.
13
Bio-Design and Manufacturing
Acknowledgements The authors would like to acknowledge the
National University of Singapore, Sharif University of Technology, and
University of Malaya for providing necessary resources and facilities
for this study. This project was supported by the University of Malaya
(UM) Research Grant: (FRGS/1/2020/TK0/UM/02/40).
11.
12.
Author contributions MS was involved in conceptualization, investigation, validation, writing—original draft, writing—review and editing,
and visualization. ERG was involved in conceptualization, validation, writing—original draft, and writing–review and editing. SA was
involved in conceptualization, investigation, writing—original draft,
and visualization. SR was involved in writing—review and editing and
supervision. NLS was involved in writing—review and editing and
supervision.
13.
Declarations
16.
Conflict of interest The authors declare that they have no conflict of
interest.
17.
Ethical approval This study does not contain any studies with human
or animal subjects performed by any of the authors.
References
1. Goncalves AD, Balestri W, Reinwald Y (2020) Biomedical
implants for regenerative therapies. Biomaterials. https://doi.
org/10.5772/intechopen.91295
2. Kurtz S, Ong K, Lau E et al (2007) Projections of primary and
revision hip and knee arthroplasty in the United States from 2005
to 2030. J Bone Joint Surg Am 89(4):780–785. https://doi.org/
10.2106/JBJS.F.00222
3. Khosravi F, Khorasani SN, Khalili S et al (2020) Development
of a highly proliferated bilayer coating on 316L stainless steel
implants. Polymers 12(5):1022. https://doi.org/10.3390/polym
12051022
4. Santos G (2017) The importance of metallic materials as biomaterials. Adv Tissue Eng Regen Med Open Access 3(1):300–302
5. Sarraf M, Zalnezhad E, Bushroa AR et al (2014) Structural and
mechanical characterization of Al/Al2O3 nanotube thin film on
TiV alloy. Appl Surface Sci 321:511–519. https://doi.org/10.
1016/j.apsusc.2014.10.040
6. Xu WC, Yu F, Yang LH et al (2018) Accelerated corrosion of
316L stainless steel in simulated body fluids in the presence of
H2O2 and albumin. Mater Sci Eng C 92:11–19. https://doi.org/
10.1016/j.msec.2018.06.023
7. Yamanaka K, Mori M, Kartika I et al (2019) Effect of multipass
thermomechanical processing on the corrosion behaviour of biomedical Co–Cr–Mo alloys. Corrosion Sci 148:178–187. https://
doi.org/10.1016/j.corsci.2018.12.009
8. Biesiekierski A, Munir K, Li YC et al (2020) Material selection for medical devices. Metallic Biomater Process Med Dev
Manuf 2020:31–94. https://doi.org/10.1016/B978-0-08-1029657.00002-3
9. Su EP, Justin DF, Pratt CR et al (2018) Effects of titanium nanotubes on the osseointegration, cell differentiation, mineralisation and antibacterial properties of orthopaedic implant surfaces.
Bone Joint J 100-B(1 Supple A):9–16. https://doi.org/10.1302/
0301-620X.100B1.BJJ-2017-0551.R1
10. Kopova I, Kronek J, Bacakova L et al (2019) A cytotoxicity
and wear analysis of trapeziometacarpal total joint replacement
implant consisting of DLC-coated Co-Cr-Mo alloy with the
13
14.
15.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
use of titanium gradient interlayer. Diamond Related Mater
97:107456. https://doi.org/10.1016/j.diamond.2019.107456
Bothe R (1940) Reaction of bone to multiple metallic implants.
Surg Gynecol Obstet 71:598–602
Kroll W (1940) The production of ductile titanium. Trans Electrochem Soc 78(1):35. https://doi.org/10.1149/1.3071290
Leventhal GS (1951) Titanium, a metal for surgery. J Bone
Joint Surg Am 33(2):473–474. https://doi.org/10.2106/00004
623-195133020-00021
Beder OE, Stevenson JK, Jones TW (1957) A further investigation of the surgical application of titanium metal in dogs.
Surgery 41(6):1012–1015 (PMID: 13442870)
Martola M, Lindqvist C, Hänninen H et al (2007) Fracture of
titanium plates used for mandibular reconstruction following
ablative tumor surgery. J Biomed Mater Res B Appl Biomater
80(2):345–352. https://doi.org/10.1002/jbm.b.30603
Van Noort R (1987) Titanium: the implant material of today. J
Mater Sci 22(11):3801–3811. https://doi.org/10.1007/BF011
33326
Venkatesh B, Chen D, Bhole S (2008) Three-dimensional fractal analysis of fracture surfaces in a titanium alloy for biomedical applications. Scripta Mater 59(4):391–394. https://doi.org/
10.1016/j.scriptamat.2008.04.010
Ran J, Jiang FC, Sun XJ et al (2020) Microstructure and
mechanical properties of Ti-6Al-4V fabricated by electron
beam melting. Curr Comput-Aided Drug Des 10(11):972.
https://doi.org/10.3390/cryst10110972
Fu Y, Xiao WL, Wang JS et al (2021) A novel strategy for
developing α+β dual-phase titanium alloys with low Young’s
modulus and high yield strength. J Mater Sci Technol 76:122–
128. https://doi.org/10.1016/j.jmst.2020.11.018
Semlitsch MF, Weber H, Streicher RM et al (1992) Joint
replacement components made of hot-forged and surfacetreated Ti-6Al-7Nb alloy. Biomaterials 13(11):781–788.
https://doi.org/10.1016/0142-9612(92)90018-J
Whittenberger JD, Moore TJ (1979) Elevated temperature
flow strength, creep resistance and diffusion welding characteristics of Ti-6Al-2Nb-1Ta-0.8 Mo. Metallurgical Trans A
10(11):1597–1605. https://doi.org/10.1007/BF02811691
Hanawa T (2012) Research and development of metals for medical devices based on clinical needs. Sci Technol Adv Mater
13(6):064102. https://doi.org/10.1088/1468-6996/13/6/064102
Maehara K, Doi K, Matsushita T et al (2002) Application of
vanadium-free titanium alloys to artificial hip joints. Mater
Trans 43(12):2936–2942. https://doi.org/10.2320/mater trans.
43.2936
Aguilar C, Arancibia M, López LA et al (2019) Influence of
porosity on the elastic modulus of Ti-Zr-Ta-Nb foams with a
low Nb content. Metals 9(2):176. https://doi.org/10.3390/met90
20176
Wang KK, Gustavson LJ, Dumbleton JH (1996). Microstructure and properties of a new beta titanium alloy, Ti-12Mo-6Zr2Fe, developed for surgical implants. In: Brown SA, Lemons
JE (Eds.), Medical Applications of Titanium and Its Alloys: the
Material and Biological Issues, American Sociery for Testing
and Materials, USA, p. 76–87. https://doi.org/10.1520/STP16
071S
Im YD, Lee YK (2020) Effects of Mo concentration on recrystallization texture, deformation mechanism and mechanical properties of Ti–Mo binary alloys. J Alloys Compd 821:153508. https://
doi.org/10.1016/j.jallcom.2019.153508
Pellizzari M, Jam A, Tachon M et al (2020) A 3D-printed ultralow Young’s modulus β-Ti alloy for biomedical applications.
Materials 13(12):2792. https://doi.org/10.3390/ma13122792
Koizumi H, Ishii T, Okazaki T et al (2018) Castability and
mechanical properties of Ti-15Mo-5Zr-3Al alloy in dental
Bio-Design and Manufacturing
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
casting. J Oral Sci 60(2):285–292. https:// doi. org/ 10. 2334/
josnusd.17-0280
Okazaki Y (2001) A new Ti–15Zr–4Nb–4Ta alloy for medical applications. Curr Opin Solid State Mater Sci 5(1):45–53.
https://doi.org/10.1016/S1359-0286(00)00025-5
Matsuda Y, Nakamura T, Ido M et al (1997) Femoral component made of Ti-15Mo-5Zr-3Al alloy in total hip arthroplasty. J
Orthop Sci 2(3):166–170. https://doi.org/10.1007/BF02492973
Bruschi M, Steinmüller-Nethl D, Goriwoda W et al (2015)
Composition and modifications of dental implant surfaces.
J Oral Implants 2015:527426. https:// doi. org/ 10. 1155/ 2015/
527426
Ida K, Togaya T, Tsutsumi S et al (1982) Effect of magnesia
investments in the dental casting of pure titanium or titanium
alloys. Dent Mater J 1(1):8–21. https://doi.org/10.4012/dmj.1.8
Marteleur M, Sun F, Gloriant T et al (2012) On the design of new
β-metastable titanium alloys with improved work hardening rate
thanks to simultaneous TRIP and TWIP effects. Scripta Mater
66(10):749–752. https://doi.org/10.1016/j.scriptamat.2012.01.
049
Buehler WJ, Gilfrich JV, Wiley R (1963) Effect of low-temperature phase changes on the mechanical properties of alloys near
composition TiNi. J Appl Phys 34(5):1475–1477. https://doi.org/
10.1063/1.1729603
Luo Y, Yang L, Tian M (2013) Application of biomedical-grade
titanium alloys in trabecular bone and artificial joints. In: Davim
P (Ed.), Biomaterials and Medical Tribology. Woodhead Publishing, Elsevier, p. 181–216. https://doi.org/10.1533/9780857092
205.181
Xue L, Koul AK, Bibby M et al (1970) A survey of surface treatments to improve the fretting fatigue resistance of Ti-6Al-4V.
WIT Trans Eng Sci 8:265–272. https://doi.org/10.2495/SURF9
50311
Hanawa T (2019) Overview of metals and applications. In
Niinomi M (Ed.), Metals for Biomedical Devices, Woodhead
Publishing, p.3–24. https://doi.org/10.1533/9781845699246.1.3
Semlitsch M, Staub F, Weber H (1985) Titanium-aluminiumniobium alloy, development for biocompatible, high strength surgical implants - Titan-Aluminium-NIOB-Legierung, entwickelt
für körperverträgliche, hochfeste implantate in der chirurgie.
Biomed Eng Biomed Technik 30(12):334–339. https://doi.org/
10.1515/bmte.1985.30.12.334
Bhambri SK, Shetty RH, Gilbertson LN (1996) Optimization
of properties of Ti-15Mo-2.8Nb-3Al-0.2Si & Ti-15Mo-2.8Nb0.2Si-.260 beta titanium alloys for application in prosthetic
implants. In: Brown SA, Lemons JE (Eds.), Medical Applications
of Titanium and Its Alloys: the Material and Biological Issues.
American Sociery for Testing and Materials, USA, p. 88–95
Niinomi M (1998) Mechanical properties of biomedical titanium
alloys. Mater Sci Eng A 243(1–2):231–236. https://doi.org/10.
1016/S0921-5093(97)00806-X
Elias L, Schneider SG, Schneider S et al (2006) Microstructural
and mechanical characterization of biomedical Ti–Nb–Zr (–Ta)
alloys. Mater Sci Eng A 432(1–2):108–112. https://doi.org/10.
1016/j.msea.2006.06.013
Hao Y, Yang R, Niinomi M et al (2003) Aging response of the
Young’s modulus and mechanical properties of Ti-29Nb-13Ta-46
Zr for biomedical applications. Metallurgical Mater Trans A
34(4):1007–1012. https://doi.org/10.1007/s11661-003-0230-x
Xu L, Chen YY, Liu ZG et al (2008) The microstructure and
properties of Ti–Mo–Nb alloys for biomedical application. J
Alloys Compd 453(1–2):320–324. https://doi.org/10.1016/j.jallc
om.2006.11.144
Yang R, Hao Y, Li S (2011) Development and application of lowmodulus biomedical titanium alloy Ti2448. Biomed Eng Trends
10:225–247. https://doi.org/10.5772/13269
45. Warburton A, Girdler SJ, Mikhail CM et al (2020) Biomaterials
in spinal implants: a review. Neurospine 17(1):101. https://doi.
org/10.14245/ns.1938296.148
46. Tan JH, Cheong CK, Hey HWD (2021) Titanium (Ti) cages
may be superior to polyetheretherketone (PEEK) cages in lumbar interbody fusion: a systematic review and meta-analysis of
clinical and radiological outcomes of spinal interbody fusions
using Ti versus PEEK cages. Europ Spine J 30(5):1285–1295.
https://doi.org/10.1007/s00586-021-06748-w
47. Alvarez AG, Evans PL, Dovgalski L et al (2021) Design, additive manufacture and clinical application of a patient-specific
titanium implant to anatomically reconstruct a large chest wall
defect. Rapid Prototyping J 27(2):1355–2546
48. Baltatu MS, Tugui CA, Perju MC, et al (2019). Biocompatible titanium alloys used in medical applications. Rev Chim
70(4):1302–1306. https://doi.org/10.37358/RC.19.4.7114
49. Vijayavenkataraman S, Gopinath A, Lu WF (2020) A new
design of 3D-printed orthopedic bone plates with auxetic structures to mitigate stress shielding and improve intra-operative
bending. Bio-Des Manuf 3:98–108. https:// doi. org/ 10. 1007/
s42242-020-00066-8
50. Shakir DA, Abdul-Ameer FM (2018) Effect of nano-titanium
oxide addition on some mechanical properties of silicone elastomers for maxillofacial prostheses. J Taibah Univ Med Sci
13(3):281–290. https://doi.org/10.1016/j.jtumed.2018.02.007
51. Cevik P, Eraslan O (2017) Effects of the addition of titanium
dioxide and silaned silica nanoparticles on the mechanical properties of maxillofacial silicones. J Prosthodontics C 26(7):611–
615. https://doi.org/10.1111/jopr.12438
52. Asserghine A, Filotás D, Németh B et al (2018) Potentiometric scanning electrochemical microscopy for monitoring the pH
distribution during the self-healing of passive titanium dioxide
layer on titanium dental root implant exposed to physiological
buffered (PBS) medium. Electrochem Commun 95:1–4. https://
doi.org/10.1016/j.elecom.2018.08.008
53. Das R, Bhattacharjee C (2019). Titanium-based nanocomposite
materials for dental implant systems. In Asiri AM, Inamuddin,
Mohammad A (Eds.), Applications of Nanocomposite Materials
in Dentistry, Woodhead Publishing, p.271–284. https://doi.org/
10.1016/B978-0-12-813742-0.00016-X
54. Niinomi M (2003) Recent research and development in titanium
alloys for biomedical applications and healthcare goods. Sci
Technol Adv Mater 4(5):445. https:// doi. org/ 10. 1016/j. stam.
2003.09.002
55. Herrmann H, Kern JS, Kern T et al (2020) Early and mature biofilm on four different dental implant materials: an in vivo human
study. Clin Oral Implants Res 31(11):1094–1104. https://doi.org/
10.1111/clr.13656
56. Wu C, Wang Q, Mao T et al (2019) Relationship between lattice
defects and phase transformation in hydrogenation/dehydrogenation process of the V60Ti25Cr3Fe12 alloy. Int J Hydrogen Energy
44(18):9368–9377. https://doi.org/10.1016/j.ijhydene.2019.02.
097
57. Shahryari L, JavidSharifi B, Dabaghmanesh M (2019) A case
study of performance improvement of femur prosthesis. J Struct
Eng Geo-Techn 10(2):57–75
58. Kumari N, Kumar K (2017). Mechanisms and materials of
orthotic calipers for polio infected patients—a review. Proc 2nd
International Conference for Convergence in Technology (I2CT),
p.7–9. https://doi.org/10.1109/I2CT.2017.8226086
59. Zhu Y, Liu DD, Wang XL et al (2019) Polydopamine-mediated
covalent functionalization of collagen on a titanium alloy to
promote biocompatibility with soft tissues. J Mater Chem B
7(12):2019–2031. https://doi.org/10.1039/c8tb03379j
60. Hol MK, Cremers CWRJ, Coppens-Schellekens W et al (2005)
The BAHA softband: a new treatment for young children with
13
Bio-Design and Manufacturing
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
bilateral congenital aural atresia. Int J Pediatr Otorhinolaryngol
69(7):973–980. https://doi.org/10.1016/j.ijporl.2005.02.010
Ferreira CC, Ricci VP, Sousa LL et al (2017) Improvement of
titanium corrosion resistance by coating with poly-caprolactone and poly-caprolactone/titanium dioxide: potential application in heart valves. Mater Res 20:126–133. https://doi.org/10.
1590/1980-5373-MR-2017-0425
Aikawa Y, Kataoka Y, Kanaya T et al (2018) Procedural challenge of coronary catheterization for ST-segment elevation
myocardial infarction in patient who underwent transcatheter
aortic valve replacement using the CoreValveTM. Cardiovasc
Diagn Ther 8(2):190–195. https://doi.org/10.21037/cdt.2018.
04.02
King MW, Bambharoliya T, Ramakrishna H et al (2020) Evolution of angioplasty devices. In Coronary Artery Disease and the
Evolution of Angioplasty Devices, Springer, New York
Meininghaus DG, Kruells-Muench J, Peltroche-Llacsahuanga H
(2020) First-in-man implantation of a gold-coated biventricular
defibrillator: difficult differential diagnosis of metal hypersensitivity reaction vs chronic device infection. HeartRhythm Case
Rep 6(6):304–307. https://doi.org/10.1016/j.hrcr.2020.02.004
Kashin OA, Krukovskii KV, Lotkov AI (2018). Opportunities
and prospects for the use of porous silicon to create a polymer-free drug coating on intravascular stents. AIP Conf Proc
2051(1):020119–020119–4.
Suzuki T, Tokuda Y, Kobayashi H (2017) The development of
yellow nail syndrome after the implantation of a permanent cardiac pacemaker. Intern Med 56(19):2667–2669. https://doi.org/
10.2169/internalmedicine.8769-16
Olin C (2001) Titanium in cardiac and cardiovascular applications. In: Brunette DM, Tengvall P, Textor M et al (Eds.), Titanium in Medicine, Springer, p.889–907. https://doi.org/10.1007/
978-3-642-56486-4_26
Martov AG, Plekhanova OA, Ergakov DV et al (2020) Thermoexpandable urethral nickel–titanium stent memokath for managing urethral bulbar stricture after failed urethroplasty. J Endourol
Case Rep 6(3):147–149. https://doi.org/10.1089/cren.2019.0146
Froes F, Qian M (2018) Titanium in medical and dental applications. Woodhead Publishing
Froes FS (2018). Titanium for medical and dental applications—an introduction. In Froes FH, Qian M (Eds.), Titanium in
Medical and Dental Applications, Woodhead Publishing, p.3–21.
https://doi.org/10.1016/B978-0-12-812456-7.00001-9
Abecassis IJ, Sen RD, Ellenbogen RG et al (2021) Developing
microsurgical milestones for psychomotor skills in neurological
surgery residents as an adjunct to operative training: the home
microsurgery laboratory. J Neurosurg 135(1):318–326. https://
doi.org/10.3171/2020.5.JNS201590
Glenn CA, Baker CM, Burks JD et al (2018) Dural closure in
confined spaces of the skull base with nonpenetrating titanium
clips. Operative Neurosurg 14(4):375–385. https://doi.org/10.
1093/ons/opx140
Gunawarman B, Niinomi M, Akahori T et al (2005) Mechanical
properties and microstructures of low cost β titanium alloys for
healthcare applications. Mater Sci Eng C 25(3):304–311. https://
doi.org/10.1016/j.msec.2004.12.015
Hong SH, Hwang YJ, Park SW et al (2019) Low-cost beta titanium cast alloys with good tensile properties developed with
addition of commercial material. J Alloys Compd 793:271–276.
https://doi.org/10.1016/j.jallcom.2019.04.200
Abdalla AO, Amrin A, Muhammad S et al (2017) Iron as a promising alloying element for the cost reduction of titanium alloys: a
review. Appl Mech Mater 864:147–153. https://doi.org/10.4028/
www.scientific.net/AMM.864.147
Khorasani AM, Goldberg M, Doeven EH et al (2015) Titanium in biomedical applications—properties and fabrication:
13
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
a review. J Biomater Tissue Eng 5(8):593–619. https://doi.org/
10.1166/jbt.2015.1361
Stepanovskaa J, Matejka R, Rosina J et al (2019) Treatments
for enhancing the biocompatibility of titanium implants: a
review. Biomed Pap Med Fac Univ Palacky Olomouc Czech
Repub 164(1):23–33. https://doi.org/10.5507/bp.2019.062
Khodaei M, Kelishadi SH (2018) The effect of different oxidizing ions on hydrogen peroxide treatment of titanium dental
implant. Surface Coatings Technol 353:158–162. https://doi.
org/10.1016/j.surfcoat.2018.08.037
Huang J, Chen HZ, Pan W et al (2020) Effect of nitrogen on the
microstructures and mechanical behavior of Ti-6Al-4V alloy
additively manufactured via tungsten inert gas welding. Mater
Today Commun 24:101171. https://doi.org/10.1016/j.mtcomm.
2020.101171
Baig MN, Khan FN, Junaid M (2007) Comparison of microstructure, mechanical properties, and residual stresses in tungsten inert gas, laser, and electron beam welding of Ti–5Al–2.5
Sn titanium alloy. Proc Inst Mech Eng Part L J Mater Des Appl
233(7):1336–1351
Paranthaman V, Dhinakaran V, Swapna Sai M et al (2021) A
systematic review of fatigue behaviour of laser welding titanium alloys. Mater Today Proc 39(1):520–523. https://doi.org/
10.1016/j.matpr.2020.08.249
Kumar SR, Kulkarni SK (2017) Analysis of hard machining of titanium alloy by Taguchi method. Mater Today Proc
4(10):10729–10738. https://doi.org/10.1016/j.matpr.2017.08.
020
Sadeghpour S, Abbasi SM, Morakabati M et al (2018) A new
multi-element beta titanium alloy with a high yield strength
exhibiting transformation and twinning induced plasticity
effects. Scripta Mater 145:104–108. https://doi.org/10.1016/j.
scriptamat.2017.10.017
Hao X, Dong HG, Xia YQ et al (2019) Microstructure and
mechanical properties of laser welded TC4 titanium alloy/304
stainless steel joint with (CoCrFeNi) 100−xCu x high-entropy
alloy interlayer. J Alloys Compd 803:649–657. https://doi.org/
10.1016/j.jallcom.2019.06.225
Al-Murshdy JMS, Ghayyib BJ (2019) Effect of heat treatment
on properties of titanium biomedical alloy. J Univ Babylon Eng
Sci 27(1):232–246
Koizumi H, Takeuchi Y, Imai H et al (2019) Application of
titanium and titanium alloys to fixed dental prostheses. J Prosthodont Res 63(3):266–270. https:// doi. org/ 10. 1016/j. jpor.
2019.04.011
Łęcka K, Gąsiorek J, Mazur-Nowacka A et al (2019) Adhesion
and corrosion resistance of laser-oxidized titanium in potential
biomedical application. Surface Coatings Technol 366:179–189.
https://doi.org/10.1016/j.surfcoat.2019.03.032
Sarraf M, Sukiman NL, Nasiri-Tabrizi B et al (2019) In vitro
bioactivity and corrosion resistance enhancement of Ti-6Al-4V
by highly ordered TiO2 nanotube arrays. J Aust Ceramic Soc
55(1):187–200. https://doi.org/10.1007/s41779-018-0224-1
Cora ÖN, Koç M (2019) Micromanufacturing. Mod Manuf Process 7:149–184. https://doi.org/10.1002/9781119120384.ch7
Verma RP (2020) Titanium based biomaterial for bone implants:
a mini review. Mater Today Proc 26:3148–3151. https://doi.org/
10.1016/j.matpr.2020.02.649
Rafieerad A, Bushroa AR, Zalnezhad E et al (2015) Microstructural development and corrosion behavior of self-organized TiO2
nanotubes coated on Ti–6Al–7Nb. Ceramics Int 41(9):10844–
10855. https://doi.org/10.1016/j.ceramint.2015.05.025
Gong D, Wang HL, Obbard EG et al (2020) Tuning thermal
expansion by a continuing atomic rearrangement mechanism in a
multifunctional titanium alloy. J Mater Sci Technol 80:234–243.
https://doi.org/10.1016/j.jmst.2020.11.053
Bio-Design and Manufacturing
93. Heary RF, Parvathreddy N, Sampath S et al (2017). Elastic
modulus in the selection of interbody implants. J Spine Surg
3(2):163–167. https://doi.org/10.21037/jss.2017.05.01
94. Suzuki G, Hirota M, Hoshi N (2019) Effect of surface treatment of multi-directionally forged (MDF) titanium implant on
bone response. Metals 9(2):230. https://doi.org/10.3390/met90
20230
95. Fousova M, Vojtech D, Jablonska E et al (2017) Novel approach
in the use of plasma spray: preparation of bulk titanium for bone
augmentations. Materials 10(9):987. https:// doi. org/ 10. 3390/
ma10090987
96. Kholgh Eshkalak S, Rezvani Ghomi E, Dai YQ et al (2020) The
role of three-dimensional printing in healthcare and medicine.
Mater Des 194:108940. https://doi.org/10.1016/j.matdes.2020.
108940
97. Niinomi M, Liu Y, Nakai M et al (2016) Biomedical titanium
alloys with Young’s moduli close to that of cortical bone. Regenerative biomaterials 3(3):173–185. https://doi.org/10.1093/rb/
rbw016
98. O’Brien T, Weisman DS, Ronchetti P et al (2004) Flexible titanium nailing for the treatment of the unstable pediatric tibial
fracture. J Pediatr Orthop 24(6):601–609. https:// doi. org/ 10.
1097/00004694-200411000-00001
99. Niinomi M, Nakai M, Hieda J (2012) Development of new
metallic alloys for biomedical applications. Acta Biomater
8(11):3888–3903. https://doi.org/10.1016/j.actbio.2012.06.037
100. Niinomi M (2011) Low modulus titanium alloys for inhibiting
bone atrophy. Biomater Sci Eng. https://doi.org/10.5772/24549
101. Kondoh K, Umeda J, Soba R, et al (2018). Advanced TiNi shape
memory alloy stents fabricated by a powder metallurgy route.
In Froes FH, Qian M (Eds.), Titanium in Medical and Dental
Applications, Woodhead Publishing, p.583–590. https://doi.org/
10.1016/B978-0-12-812456-7.00027-5
102. Plaine AH, da Silva MR, Bolfarini C (2019). Microstructure and
elastic deformation behavior of β-type Ti-29Nb-13Ta-4.6Zr with
promising mechanical properties for stent applications. J Mater
Res Technol 8(5):3852–3858. https:// doi. org/ 10. 1016/j. jmrt.
2019.06.047
103. Li P, Ma XD, Tong T et al (2019) Microstructural and mechanical properties of β-type Ti–Nb–Sn biomedical alloys with low
elastic modulus. Metals 9(6):712. https://doi.org/10.1016/j.jallc
om.2019.152412
104. Kim HY, Ohmatsu Y, Kim JI et al (2004) Mechanical properties
and shape memory behavior of Ti-Mo-Ga alloys. Mater Trans
45(4):1090–1095. https://doi.org/10.2320/matertrans.45.1090
105. Miyazaki S, Kim HY, Hosoda H (2006) Development and characterization of Ni-free Ti-base shape memory and superelastic
alloys. Mater Sci Eng A 438:18–24. https://doi.org/10.1016/j.
msea.2006.02.054
106. Shinohara Y, Matsumoto Y, Tahara M et al (2018) Development
of <001>-fiber texture in cold-groove-rolled Ti-Mo-Al-Zr biomedical alloy. Materialia 1:52–61. https://doi.org/10.1016/j.mtla.
2018.07.008
107. Maeshima T, Nishida M (2004) Shape memory and mechanical properties of biomedical Ti-Sc-Mo alloys. Mater Trans
45(4):1101–1105. https://doi.org/10.2320/MATERTRANS.45.
1101
108. Li B, Xie R, Lu X (2020) Microstructure, mechanical property
and corrosion behavior of porous Ti–Ta–Nb–Zr. Bioactive Mater
5(3):564–568. https://doi.org/10.1016/j.bioactmat.2020.04.014
109. Dorozhkin SV (2017) Calcium orthophosphate coatings and
other deposits. Front Nanobiomed Res 3:1–84. https://doi.org/
10.1186/2194-0517-1-1
110. Gallinetti S, Kihlstrom Burenstam Linder L, Åberg J et al
(2021) Titanium reinforced calcium phosphate improves bone
formation and osteointegration in ovine calvaria defects: a
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
comparative 52-weeks study. Biomed Mater 16(3):035031.
https://doi.org/10.1088/1748-605X/abca12
Domínguez-Trujillo C, Peón E, Chicardi E et al (2018) Sol-gel
deposition of hydroxyapatite coatings on porous titanium for
biomedical applications. Surface Coatings Technol 333:158–
162. https://doi.org/10.1016/j.surfcoat.2017.10.079
Hu C, Aindow M, Wei M (2017) Focused ion beam sectioning
studies of biomimetic hydroxyapatite coatings on Ti-6Al-4V
substrates. Surface Coatings Technol 313:255–262. https://doi.
org/10.1016/j.surfcoat.2017.01.103
Ke D, Vu AA, Bandyopadhyay A (2019) Compositionally
graded doped hydroxyapatite coating on titanium using laser
and plasma spray deposition for bone implants. Acta Biomater
84:414–423. https://doi.org/10.1016/j.actbio.2018.11.041
Cao J, Lian R, Jiang XH (2020) Magnesium and fluoride doped
hydroxyapatite coatings grown by pulsed laser deposition for
promoting titanium implant cytocompatibility. Appl Surface
Sci 515:146069. https://doi.org/10.1016/j.apsusc.2020.146069
Ambrogio G, Palumbo G, Sgambitterra E et al (2018) Experimental investigation of the mechanical performances of titanium cranial prostheses manufactured by super plastic forming
and single-point incremental forming. Int J Adv Manuf Technol
98(5):1489–1503. https://doi.org/10.1007/s00170-018-2338-6
Alagarsamy K, Vishwakarma V, Kaliaraj GS (2019) Synthesis
and characterization of bioactive composite coating on titanium by PVD for biomedical application. IOP Conf Ser Mater
Sci Eng 561:012027. https:// doi. org/ 10. 1088/ 1757- 899X/
561/1/012027
Won S, Huh YH, Cho LR et al (2017) Cellular response of
human bone marrow derived mesenchymal stem cells to titanium surfaces implanted with calcium and magnesium ions.
Tissue Eng Regener Med 14(2):123–131. https:// doi. org/ 10.
1007/s13770-017-0028-3
Karimi N, Kharaziha M, Raeissi K (2019) Electrophoretic deposition of chitosan reinforced graphene oxide-hydroxyapatite
on the anodized titanium to improve biological and electrochemical characteristics. Mater Sci Eng C 98:140–152. https://
doi.org/10.1016/j.msec.2018.12.136
Lu M, Chen H, Yuan B et al (2020) Electrochemical deposition of nanostructured hydroxyapatite coating on titanium with
enhanced early stage osteogenic activity and osseointegration.
Int J Nanomed 15:6605–6618. https:// doi. org/ 10. 2147/ IJN.
S268372
Kokubo T, Yamaguchi S (2016) Novel bioactive materials
developed by simulated body fluid evaluation: surface-modified
ti metal and its alloys. Acta Biomater 44:16–30. https://doi.org/
10.1016/j.actbio.2016.08.013
Hanawa T (2019) Titanium–tissue interface reaction and its
control with surface treatment. Front Bioeng Biotechnol 7:170.
https://doi.org/10.3389/fbioe.2019.00170
Surender L, Rekha RK, Veerendra NRP et al (2011) Surface characteristics of titanium dental implants for rapid osseointegration.
Indian J Dent Adv 3(3):602–612
Le Guéhennec L, Soueidan A, Layrolle P et al (2007) Surface
treatments of titanium dental implants for rapid osseointegration.
Dent mater 23(7):844–854. https://doi.org/10.1016/j.dental.2006.
06.025
Yu M, Gong JX, Zhou Y et al (2017) Surface hydroxyl groups
regulate the osteogenic differentiation of mesenchymal stem cells
on titanium and tantalum metals. J Mater Chem B 5(21):3955–
3963. https://doi.org/10.1039/c7tb00111h
Paradowska E, Arkusz K, Pijanowska DG (2019) The influence
of the parameters of a gold nanoparticle deposition method on
titanium dioxide nanotubes, their electrochemical response, and
protein adsorption. Biosensors 9(4):138. https://doi.org/10.3390/
bios9040138
13
Bio-Design and Manufacturing
126. Jia E, Zhao X, Lin Y et al (2020) Protein adsorption on titanium
substrates and its effects on platelet adhesion. Appl Surface Sci
529:146986. https://doi.org/10.1016/j.apsusc.2020.146986
127. Hiji A, Hanawa T, Shimabukuro M et al (2021) Initial formation
kinetics of calcium phosphate on titanium in Hanks’ solution
characterized using XPS. Surface Interf Anal 53(2):185–193.
https://doi.org/10.1002/sia.6900
128. Sarraf M, Dabbagh A, Abdul Razak B et al (2018) Highlyordered TiO2 nanotubes decorated with Ag2O nanoparticles for
improved biofunctionality of Ti6Al4V. Surface Coatings Technol
349:1008–1017. https://doi.org/10.1016/j.surfcoat.2018.06.054
129. Souza JC, Sordi MB, Kanazawa M et al (2019) Nano-scale modification of titanium implant surfaces to enhance osseointegration. Acta Biomater 94:112–131. https://doi.org/10.1016/j.actbio.
2019.05.045
130. Rezvani Ghomi E, Eshkalak Saeideh K, Singh S et al (2021)
Fused filament printing of specialized biomedical devices: a
state-of-the art review of technological feasibilities with PEEK.
Rapid Prototyping J 27(3):592–616. https:// doi. org/ 10.1108/
rpj-06-2020-0139
131. Stacchi C, Barlone L, Rapani A et al (2020) Modified orthodontic
bone stretching for ankylosed tooth repositioning: a case report.
Open Dent J 14(1):235–239. https://doi.org/10.2174/1874210602
014010235
132. Wang C, Wang SN, Yang YY et al (2018) Bioinspired, biocompatible and peptide-decorated silk fibroin coatings for enhanced
osteogenesis of bioinert implant. J Biomater Sci Polymer Ed
29(13):1595–1611. https:// doi. org/ 10. 1080/ 09205 063. 2018.
1477316
133. Romanov DA, Sosnin KV, Filyakov AD et al (2021) The effect
of bioinert electroexplosive coatings on stress distribution near
the dental implant-bone interface. Mater Res Expr 8(1):015016.
https://doi.org/10.1088/2053-1591/abd664
134. Siddiqi A, Payne AGT, De Silva RK et al (2011) Titanium
allergy: could it affect dental implant integration? Clin Oral
Implants Res 22(7):673–680. https:// doi. org/ 10. 1111/j. 16000501.2010.02081.x
135. Wang X, Lu L, Feng Y et al (2019) Macrophage polarization
in aseptic bone resorption around dental implants induced by
Ti particles in a murine model. J Periodont Res 54(4):329–338.
https://doi.org/10.1111/jre.12633
136. Civantos A, Domínguez C, Pino RJ et al (2019) Designing bioactive porous titanium interfaces to balance mechanical properties
and in vitro cells behavior towards increased osseointegration.
Surface Coatings Technol 368:162–174. https:// doi. org/ 10.
1016/j.surfcoat.2019.03.001
137. Wang Q, Zhou P, Liu SF et al (2020) Multi-scale surface treatments of titanium implants for rapid osseointegration: a review.
Nanomaterials 10(6):1244. https://doi.org/10.3390/nano100612
44
138. Taniyama T, Saruta J, Rezaei NM et al (2020) UV-photofunctionalization of titanium promotes mechanical anchorage in a rat
osteoporosis model. Int J Mol Sci 21(4):1235. https://doi.org/10.
3390/ijms21041235
139. Zhang H, Komasa S, Mashimo C et al (2017) Effect of ultraviolet treatment on bacterial attachment and osteogenic activity to alkali-treated titanium with nanonetwork structures. Int J
Nanomed 12:4633. https://doi.org/10.2147/IJN.S136273
140. Itabashi T, Narita K, Ono A et al (2017) Bactericidal and antimicrobial effects of pure titanium and titanium alloy treated with
short-term, low-energy UV irradiation. Bone Joint Res 6(2):108–
112. https://doi.org/10.1302/2046-3758.62.2000619
141. Javadhesari SM, Alipour S, Akbarpour M (2020) Biocompatibility, osseointegration, antibacterial and mechanical properties
of nanocrystalline Ti-Cu alloy as a new orthopedic material. Colloids Surfaces B Biointerf 189:110889
13
142. Bono N, Ponti F, Punta C et al (2021) Effect of UV irradiation
and TiO2-photocatalysis on airborne bacteria and viruses: an
overview. Materials 14(5):1075. https://doi.org/10.3390/ma140
51075
143. Guo C, Wang K, Hou S et al (2017) H2O2 and/or TiO2 photocatalysis under UV irradiation for the removal of antibiotic resistant
bacteria and their antibiotic resistance genes. J Hazardous Mater
323:710–718. https://doi.org/10.1016/j.jhazmat.2016.10.041
144. Chouirfa H, Bouloussa H, Migonney V et al (2019) Review of
titanium surface modification techniques and coatings for antibacterial applications. Acta Biomater 83:37–54. https://doi.org/
10.1016/j.actbio.2018.10.036
145. Sarraf M, Dabbagh A, Razak BA et al (2018) Silver oxide nanoparticles-decorated tantala nanotubes for enhanced antibacterial
activity and osseointegration of Ti6Al4V. Mater Des 154:28–40.
https://doi.org/10.1016/j.matdes.2018.05.025
146. Wang Y, Zhang MJ, Li KM et al (2021) Study on the surface
properties and biocompatibility of nanosecond laser patterned
titanium alloy. Optics Laser Technol 139:106987. https://doi.org/
10.1016/j.optlastec.2021.106987
147. Taherian M, Rezazadeh M, Taji A (2021) Optimum surface
roughness for titanium-coated PEEK produced by electron beam
PVD for orthopedic applications. Mater Technol. https://doi.org/
10.1080/10667857.2020.1868209
148. Hwang YJ, Choi YS, Hwang YH et al (2021) Biocompatibility and biological corrosion resistance of Ti–39Nb–6Zr+045Al
implant alloy. J Funct Biomater 12(1):2. https://doi.org/10.3390/
jfb12010002
149. Fathyunes L, Khalil-Allaf J, Moosavifa M (2019) Development
of graphene oxide/calcium phosphate coating by pulse electrodeposition on anodized titanium: biocorrosion and mechanical
behavior. J Mech Behav Biomed Mater 90:575–586. https://doi.
org/10.1016/j.jmbbm.2018.11.011
150. Vogel D, Dempwolf H, Baumann A et al (2017) Characterization of thick titanium plasma spray coatings on PEEK materials
used for medical implants and the influence on the mechanical
properties. J Mech Behav Biomed Mater B 77:600–608. https://
doi.org/10.1016/j.jmbbm.2017.09.027
151. Lukaszewska-Kuska M, Wirstlein P, Majchrowski R et al (2018)
Osteoblastic cell behaviour on modified titanium surfaces.
Micron 105:55–63. https://doi.org/10.1016/j.micron.2017.11.010
152. Guillem-Marti J, Boix Lemonche G, Gugutkov D et al (2018)
Recombinant fibronectin fragment III8-10/polylactic acid hybrid
nanofibers enhance the bioactivity of titanium surface. Nanomedicine 13(8):899–912. https://doi.org/10.2217/nnm-2017-0342
153. Sarraf M, Razak BA, Nasiri-Tabrizi B et al (2017) Nanomechanical properties, wear resistance and in-vitro characterization of
Ta2O5 nanotubes coating on biomedical grade Ti–6Al–4V. J
Mech Behav Biomed Mater 66:159–171. https:// doi. org/ 10.
1016/j.jmbbm.2016.11.012
154. Zhou L, Pan M, Zhang ZH et al (2021) Enhancing osseointegration of TC4 alloy by surficial activation through biomineralization method. Front Bioeng Biotechnol 9:120. https://doi.org/10.
3389/fbioe.2021.639835
155. Sarraf M, Razak A, Crum R et al (2017) Adhesion measurement
of highly-ordered TiO2 nanotubes on Ti-6Al-4V alloy. Proc Appl
Ceramics 11(4):311–321. https://doi.org/10.2298/PAC1704311S
156. Sarraf M, Zalnezhad E, Bushroa AR et al (2015) Effect of microstructural evolution on wettability and tribological behavior of
TiO2 nanotubular arrays coated on Ti–6Al–4V. Ceramics Int
41(6):7952–7962. https://doi.org/10.1016/j.ceramint.2015.02.
136
157. Praharaj R, Mishra S, Rautray TR (2020) The structural and bioactive behaviour of strontium-doped titanium dioxide nanorods.
J Korean Ceramic Soc 57(3):271–280. https://doi.org/10.1007/
s43207-020-00027-y
Bio-Design and Manufacturing
158. Zalnezhad E, Maleki E, Banihashemian SM et al (2016) Wettability, structural and optical properties investigation of TiO2
nanotubular arrays. Mater Res Bull 78:179–185. https://doi.org/
10.1016/j.mater resbull.2016.01.035
159. Kunrath MF, Vargas ALM, Sesterheim P et al (2020) Extension
of hydrophilicity stability by reactive plasma treatment and wet
storage on TiO2 nanotube surfaces for biomedical implant applications. J Royal Soc Interf 17(170):20200650. https://doi.org/10.
1098/rsif.2020.0650
160. Sarraf M, Razak BA, Dabbagh A et al (2016) Optimizing PVD
conditions for electrochemical anodization growth of welladherent Ta 2O 5 nanotubes on Ti–6Al–4V alloy. RSC Adv
6(82):78999–79015. https://doi.org/10.1039/C6RA11290K
161. Cui C, Liu H, Li YC et al (2015) Fabrication and biocompatibility of nano-TiO2/titanium alloys biomaterials. Mater Lett
59(24–25):3144–3148. https:// doi. org/ 10. 1016/j. matlet. 2005.
05.037
162. Smeets R, Precht C, Hahn M et al (2017) Biocompatibility and
osseointegration of titanium implants with a silver-doped polysiloxane coating: an in vivo pig model. Int J Oral Maxillofac
Implants 32(6):1338–1345. https://doi.org/10.11607/jomi.5533
163. Rashid S, Sebastiani M, Zeeshan Mughal M et al (2021) Influence of the silver content on mechanical properties of Ti-Cu-Ag
thin films. Nanomaterials 11(2):435. https:// doi. org/ 10. 3390/
nano11020435
164. Bui VD, Mwangi JW, Meinshausen AK et al (2020) Antibacterial coating of Ti-6Al-4V surfaces using silver nano-powder
mixed electrical discharge machining. Surface Coatings Technol
383:125254. https://doi.org/10.1016/j.surfcoat.2019.125254
165. Gaviria J, Alcudia A, Begines B et al (2021) Synthesis and deposition of silver nanoparticles on porous titanium substrates for
biomedical applications. Surface Coatings Technol 406:126667.
https://doi.org/10.1016/j.surfcoat.2020.126667
166. Mandakhalikar KD, Wang R, Rahmat JN et al (2018) Restriction
of in vivo infection by antifouling coating on urinary catheter
with controllable and sustained silver release: a proof of concept study. BMC Infect Dis 18(1):1–9. https://doi.org/10.1186/
s12879-018-3296-1
167. Kheur S, Singh N, Bodas D et al (2017) Nanoscale silver depositions inhibit microbial colonization and improve biocompatibility
of titanium abutments. Colloids Surf B Biointerf 159:151–158.
https://doi.org/10.1016/j.colsurfb.2017.07.079
168. Ewald A, Glückermann SK, Thull R et al (2006) Antimicrobial
titanium/silver PVD coatings on titanium. Biomed Eng Online
5(1):1–10. https://doi.org/10.1186/1475-925X-5-22
169. Sidambe AT (2014) Biocompatibility of advanced manufactured
titanium implants—a review. Mater 7(12):8168–8188. https://
doi.org/10.3390/ma7128168
170. Jang TS, Kim DE, Han G et al (2020) Powder based additive
manufacturing for biomedical application of titanium and its
alloys: a review. Biomed Eng Lett 10(4):505–516. https://doi.
org/10.1007/s13534-020-00177-2
171. Chen Y, Clark S, Sinclair L et al (2021) Synchrotron X-ray imaging of directed energy deposition additive manufacturing of titanium alloy Ti-6242. Addit Manuf 41:101969. https://doi.org/10.
1016/j.addma.2021.101969
172. Dong Y, Li YL, Zhou SY et al (2021) Cost-affordable Ti-6Al-4V
for additive manufacturing: powder modification, compositional
modulation and laser in-situ alloying. Addit Manuf 37:101699.
https://doi.org/10.1016/j.addma.2020.101699
173. Barthel B, Janas F, Wieland S (2021) Powder condition and
spreading parameter impact on green and sintered density in
metal binder jetting. Powder Metall. https:// doi. org/ 10. 1080/
00325899.2021.1912923
174. Bieske J, Franke M, Schloffer M et al (2020) Microstructure and
properties of TiAl processed via an electron beam powder bed
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
fusion capsule technology. Intermetallics 126:106929. https://
doi.org/10.1016/j.intermet.2020.106929
Kalayda T, Kirsankin A, Ivannikov AY et al (2021) The plasma
atomization process for the Ti-Al-V powder production. J Phys
Conf Ser 1942:012046
Perminov A, Bartzsch G, Franke A et al (2021) Manufacturing
Fe–TiC Composite powder via inert gas atomization by forming reinforcement phase in situ. Adv Eng Mater 23(3):2000717.
https://doi.org/10.1002/adem.202000717
Nie Y, Tang JJ, Ye XJ et al (2020) Particle defects and related
properties of metallic powders produced by plasma rotating electrode process. Adv Powder Technol 31(7):2912–2920. https://
doi.org/10.1016/j.apt.2020.05.018
Taniguchi N, Fujibayashi S, Takemoto M et al (2016) Effect of
pore size on bone ingrowth into porous titanium implants fabricated by additive manufacturing: an in vivo experiment. Mater
Sci Eng C Mater Biol Appl 59:690–701. https:// doi. org/ 10.
1016/j.msec.2015.10.069
Wang X, Xu SQ, Zhou SW et al (2016) Topological design
and additive manufacturing of porous metals for bone scaffolds
and orthopaedic implants: a review. Biomaterials 83:127–141.
https://doi.org/10.1016/j.biomaterials.2016.01.012
Ragone V, Canciani E, Arosio M et al (2020) In vivo osseointegration of a randomized trabecular titanium structure obtained
by an additive manufacturing technique. J Mater Sci Mater Med
31(2):1–11. https://doi.org/10.1007/s10856-019-6357-0
Barba D, Alabort E, Reed R (2019) Synthetic bone: design by
additive manufacturing. Acta Biomater 97:637–656. https://doi.
org/10.1016/j.actbio.2019.07.049
Egan DS, Dowling DP (2019) Influence of process parameters
on the correlation between in-situ process monitoring data and
the mechanical properties of Ti-6Al-4V non-stochastic cellular
structures. Addit Manuf 30:100890. https://doi.org/10.1016/j.
addma.2019.100890
Trevisan F, Calignano F, Aversa A et al (2018) Additive manufacturing of titanium alloys in the biomedical field: processes,
properties and applications. J Appl Biomater Funct Mater
16(2):57–67. https://doi.org/10.5301/jabfm.5000371
Dhiman S, Sidhu SS, Singh P et al (2019) Mechanobiological
assessment of Ti-6Al-4V fabricated via selective laser melting
technique: a review. Rapid Prototyping J 25:1266–1284. https://
doi.org/10.1108/RPJ-03-2019-0057
Ameen W, Al-Ahmari A, Mohammed MK et al (2018) Design,
finite element analysis (FEA), and fabrication of custom titanium alloy cranial implant using electron beam melting additive
manufacturing. Advn Prod Eng Manage 13(3):267–278. https://
doi.org/10.14743/apem2018.3.289
He Y, Burkhalter D, Durocher D et al (2018). Solid-lattice hip
prosthesis design: applying topology and lattice optimization to
reduce stress shielding from hip implants. 2018 Design of Medical Devices Conference p.9–12. https://doi.org/10.1115/DMD20
18-6804
Murr L (2017) Open-cellular metal implant design and fabrication for biomechanical compatibility with bone using electron
beam melting. J Mech Behav Biomed Mater 76:164–177. https://
doi.org/10.1016/j.jmbbm.2017.02.019
Weißmann V, Drescher P, Bader R et al (2017) Comparison of
single Ti6Al4V struts made using selective laser melting and
electron beam melting subject to part orientation. Metals 7(3):91.
https://doi.org/10.3390/MET7030091
Soylemez E (2020) High deposition rate approach of selective
laser melting through defocused single bead experiments and
thermal finite element analysis for Ti-6Al-4V. Addit Manuf
31:100984. https://doi.org/10.1016/j.addma.2019.100984
Grabovetskaya GP, Stepanova EN, Mishin IP et al (2020) The
effect of irradiation of a titanium alloy of the Ti–6Al–4V–H
13
Bio-Design and Manufacturing
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
system with pulsed electron beams on its creep. Russian Phys J
63(6):932–939. https://doi.org/10.1007/s11182-020-02120-5
Adamovic D, Ristic B, Zivic F (2018). Review of existing biomaterials—method of material selection for specific applications
in orthopedics. In: Zivic F, Affatato S, Trajanovic M (Eds.), Biomaterials in Clinical Practice, Springer, Cham, p.47–99. https://
doi.org/10.1007/978-3-319-68025-5_3
Wang J, Li QQ, Xiong CY et al (2018) Effect of Zr on the martensitic transformation and the shape memory effect in Ti-Zr-NbTa high-temperature shape memory alloys. J Alloys Compounds
737:672–677. https://doi.org/10.1016/j.jallcom.2017.12.003
Cui YW, Chen LY, Liu XX (2021) Pitting corrosion of biomedical titanium and titanium alloys: a brief review. Curr Nanosci
17(2):241–256. https://doi.org/10.2174/15734137169992011252
21211
Chui P, Jing R, Zhang FG et al (2020) Mechanical properties and
corrosion behavior of β-type Ti-Zr-Nb-Mo alloys for biomedical
application. J Alloys Compounds 842:155693. https://doi.org/10.
1016/j.jallcom.2020.155693
Tardelli JDC, Bolfarini C, Dos Reis AC (2020) Comparative
analysis of corrosion resistance between beta titanium and
Ti-6Al-4V alloys: a systematic review. J Trace Elements Med
Biol 62:126618. https://doi.org/10.1016/j.jtemb.2020.126618
Konopatsky A, Dubinskiy SM, Zhukova YS et al (2017) Ternary
Ti-Zr-Nb and quaternary Ti-Zr-Nb-Ta shape memory alloys for
biomedical applications: structural features and cyclic mechanical properties. Mater Sci Eng A 702:301–311. https://doi.org/10.
1016/j.msea.2017.07.046
Wei K, Wang Z, Zeng X (2018) Effect of heat treatment on
microstructure and mechanical properties of the selective laser
melting processed Ti-5Al-2.5 Sn α titanium alloy. Mater Sci Eng
A 709:301–311. https://doi.org/10.1016/j.msea.2017.10.061
Eisenbarth E, Velten D, Müller M et al (2004) Biocompatibility of β-stabilizing elements of titanium alloys. Biomaterials
25(26):5705–5713. https://doi.org/10.1016/j.biomaterials.2004.
01.021
Hsu HC, Hsu SK, Wu SC et al (2010) Structure and mechanical properties of as-cast Ti–5Nb–xFe alloys. Mater Charact
61(9):851–858. https://doi.org/10.1016/j.matchar.2010.05.003
Chen S, Tsoi JKH, Tsang PCS et al (2020) Candida albicans aspects
of binary titanium alloys for biomedical applications. Regener Biomater 7(2):213–220. https://doi.org/10.1093/rb/rbz052
Iijima Y, Nagase T, Matsugaki A et al (2021) Design and development of Ti–Zr–Hf–Nb–Ta–Mo high-entropy alloys for metallic
biomaterials. Mater Des 202:109548. https://doi.org/10.1016/j.
matdes.2021.109548
Nagase T, Iijima Y, Matsugaki A et al (2020) Design and fabrication of Ti–Zr-Hf-Cr-Mo and Ti–Zr-Hf-Co-Cr-Mo high-entropy
alloys as metallic biomaterials. Mater Sci Eng C 107:110322.
https://doi.org/10.1016/j.msec.2019.110322
Park YJ, Song YH, An JH et al (2013) Cytocompatibility of
pure metals and experimental binary titanium alloys for implant
materials. J Dent 41(12):1251–1258. https://doi.org/10.1016/j.
jdent.2013.09.003
Cremasco A, Messias AD, Esposito AR et al (2011) Effects of
alloying elements on the cytotoxic response of titanium alloys.
Mater Sci Eng C 31(5):833–839. https://doi.org/10.1016/j.msec.
2010.12.013
Mydin R, Hazan R, FaridWajidi AF et al (2018). Titanium dioxide nanotube arrays for biomedical implant materials and nanomedicine applications. In Yang DF (Ed.), Titanium Dioxide—
Material for a Sustainable Environment, p.469–483. https://doi.
org/10.5772/intechopen.73060
Kafshgari MH, Goldmann WH (2020) Insights into theranostic
properties of titanium dioxide for nanomedicine. Nano-Micro
Lett 12(1):1–35. https://doi.org/10.1007/s40820-019-0362-1
13
207. Sarraf M, Nasiri-Tabrizi B, Yeong CH et al (2020) Mixed oxide
nanotubes in nanomedicine: a dead-end or a bridge to the future?
Ceram Int 47(3):2917–2948. https://doi.org/10.1016/j.ceramint.
2020.09.177
208. Kunrath MF, Hubler R, Shinkai R et al (2018) Application
of TiO2 nanotubes as a drug delivery system for biomedical
implants: a critical overview. Chem Select 3(40):11180–11189.
https://doi.org/10.1002/slct.201801459
209. Dabbagh A, Hedayatnasab Z, Karimian H et al (2019) Polyethylene glycol-coated porous magnetic nanoparticles for targeted
delivery of chemotherapeutics under magnetic hyperthermia
condition. Int J Hyperthermia 36(1):104–114. https://doi.org/
10.1080/02656736.2018.1536809
210. Nancy D, Rajendran N (2018) Vancomycin incorporated chitosan/gelatin coatings coupled with TiO2–SrHAP surface modified cp-titanium for osteomyelitis treatment. Int J Biol Macromol 110:197–205. https://doi.org/10.1016/j.ijbiomac.2018.01.
004
211. Wang Q, Huang JY, Li HQ et al (2017) Recent advances on smart
TiO2 nanotube platforms for sustainable drug delivery applications. Int J Nanomed 12:151–165. https://doi.org/10.2147/IJN.
S117498
212. Wang Q, Huang JY, Li HQ et al (2016) TiO2 nanotube platforms
for smart drug delivery: a review. Int J Nanomed 11:4819–4834.
https://doi.org/10.2147/IJN.S108847
213. Jia H, Kerr LL (2015) Kinetics of drug release from drug carrier
of polymer/TiO2 nanotubes composite—pH dependent study. J
Appl Polymer Sci 132(7):41570. https://doi.org/10.1002/APP.
41570
214. Wang T, Weng ZY, Liu XM et al (2017) Controlled release and
biocompatibility of polymer/titania nanotube array system on
titanium implants. Bioactive Mater 2(1):44–50. https://doi.org/
10.1016/j.bioactmat.2017.02.001
215. Ma A, You YP, Chen B et al (2020) Icariin/aspirin composite
coating on TiO2 nanotubes surface induce immunomodulatory
effect of macrophage and improve osteoblast activity. Coatings
10(4):427. https://doi.org/10.3390/coatings10040427
216. Zhang X, Zhang Y, Yates MZ (2018) Hydroxyapatite nanocrystal
deposited titanium dioxide nanotubes loaded with antibiotics for
combining biocompatibility and antibacterial properties. MRS
Adv 3(30):1703–1709. https://doi.org/10.1557/adv.2018.114
217. Mesbah M, Sarraf M, Dabbagh A et al (2020) Synergistic
enhancement of photocatalytic antibacterial effects in highstrength aluminum/TiO 2 nanoarchitectures. Ceramics Int
46(15):24267–24280. https://doi.org/10.1016/j.ceramint.2020.
06.207
218. Sm RB, Sreekantan S, Hazan R et al (2017) Cellular homeostasis
and antioxidant response in epithelial HT29 cells on titania nanotube arrays surface. Oxid Med Cell Longevity 2017:3708048.
https://doi.org/10.1155/2017/3708048
219. Zhang J, Li GL, Zhang XR et al (2020) Systematically evaluate
the physicochemical property and hemocompatibility of phase
dependent TiO2 on medical pure titanium. Surface Coatings
Technol 404:126501. https://doi.org/10.1016/j.surfcoat.2020.
126501
220. Salimi E (2019) Superhydrophobic blood-compatible surfaces:
state of the art. Int J Polymeric Mater Polymeric Biomater
69(6):363–372. https://doi.org/10.1080/00914037.2019.1570510
221. Cao Y (2019). Engineering therapeutic biomaterials for medical
implants. PhD Thesis, University of California, San Francisco,
USA.
222. Woodbury JM (2015), Hemocompatibility of polymeric materials
for blood-contacting applications. PhD Thesis, Colorado State
University, USA.
Bio-Design and Manufacturing
Authors and Affiliations
Masoud Sarraf1,2 · Erfan Rezvani Ghomi3
· Saeid Alipour2 · Seeram Ramakrishna3 · Nazatul Liana Sukiman1
* Erfan Rezvani Ghomi
erfanrezvani@u.nus.edu
* Seeram Ramakrishna
seeram@nus.edu.sg
1
Centre of Advanced Materials, Department of Mechanical
Engineering, Faculty of Engineering, University of Malaya,
50603 Kuala Lumpur, Malaysia
2
Department of Materials Science and Engineering, Sharif
University of Technology, Azadi Ave., P.O. Box 11365-9466,
Tehran, Iran
3
Center for Nanotechnology and Sustainability, Department
of Mechanical Engineering, National University
of Singapore, Singapore 117581, Singapore
13