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xii Contributors
Kondaiah Gudimetla
Department of Mechanical Engineering
Pace Institute of Technology & Sciences
Ongole, India
Raghavendra Gujjala
Department of Mechanical Engineering
NIT Warangal
Telangana, India
Ramu Inala
Department of Mechanical Engineering
Vishnu Institute of Technology
Bhimavaram
Andhra Pradesh, India
S. Indran
Research Scientist, Department
of Materials and Production
Engineering
King Mongkut’s University of
Technology
North Bangkok, Thailand
Satish Jain
Department of Mechanical Engineering
NITWarangal
Telangana, India
Rakesh Kanakam
Department of Mechanical
Engineering
NIT Warangal
Telangana, India
Yugesh A. Kharche
Department of Mechanical
Engineering
Padmashri Dr.V.B. Kolte College of
Engineering
Malkapur, Maharashtra, India
Vishnu Vijay Kumar
International Institute of Aerospace
Engineering and Management
JAIN (Deemed-to-be-University)
Bangalore, Karnataka, India
Akanksha Mohanty
Department of Biomedical Engineering
NIT Rourkela
Odisha, India
Muhammad Akhsin Muikhun
Mechanical and Industrial Engineering
Department
Gadjah Mada University
Yogyakarta, Indonesia
M. S. Narayanan
Department of Biotechnology
Indian Institute of Technology Madras
Tamil Nadu, India
P. Navaneethakrishnan
Department of Energy Science and
Engineering
Indian Institute of Technology Bombay
Mumbai, India
Shakuntala Ojha
Department of Mechanical Engineering
Pace Institute of Technology & Sciences
Ongole, India
Mutlu Özcan
Center for Dental Medicine
Clinic of Masticatory Disorders and
Dental Biomaterials
University of Zurich
Zurich, Switzerland
R. G. Asuwin Prabu
School of Bioscience and Technology
Vellore Institute of Technology
Vellore, India
Department of Applied Mechanics and
Biomedical Engineering
Indian Institute of Technology Madras
Tamil Nadu, India
P. Syam Prasad
Department of Physics
NIT Warangal
Telangana, India
xiiiContributors
P. Phani Prasanthi
Department of Mechanical Engineering
PVP Sidhartha Institute of Technology
Andhra Pradesh, India
K. G. Prashanth
Department of Mechanical and
Industrial Engineering
Tallinn,Estonia
Shanmukha Raju
Department of Pharmacy
University College of Technology
Osmania University
Hyderabad, Telangana, India
Parthiban Ramaswamy
Erich Schmid Institute of Material
Science of the Austrian Academy of
Sciences
Leoben, Austria
H. Jeevan Rao
Department of Aerospace, AIAE
Amity University
Noida, India
P. Venkateswara Rao
Department of Physics
TheUniversity of West Indies
Mona Campus, Jamaica
Manuela Reben
Department of Glass Technology and
Amorphous Coatings
Faculty of Materials Science and
Ceramics
AGH University of Science and
Tech n ology
Kra kow, Pola n d
S. Shiva
Department of Mechanical
Engineering
Centre for Nanotechnology &
Sustainability
National University of
Singapore
Singapore
School of Bioscience and
Tech n ology
Vellore Institute of
Tech n ology
Vellore, India
Y. B. Sudhir Sastry
Department of Aerospace
Engineering
IIAEM, Jain University
Bangalore, Karnataka,
India
Santosh R. Shekokar
Department of Mechanical
Engineering
Padmashri Dr.V.B. Kolte College of
Engineering
Malkapur, Maharashtra, India
Nadeem Siddiqui
Department of Biotechnology
Koneru Lakshmaiah Education
Foundation
Andhra Pradesh, India
Ishika Singh Solanki
Scholar, Department of Aerospace
Engineering
Jain University
Bangalore, Karnataka, India
xiv Contributors
Shrishail B. Sollappur
International Institute of Aerospace
Engineering and Management
Jain deemed-to-be-University, JGI
Global Campus
Bangalore, Karnataka,
India
Marcin Środa
Department of Glass Technology and
Amorphous Coatings
Faculty of Materials Science and
Ceramics
AGH University of Science and
Technology
Krakow, Pola nd
Riessom Weldegiorgis
Institute of Research and
Development
Director for Flight Dynamics and
Control Center Bishoftu
Bishoftu, Ethiopia
1
Introduction to
Bioactive Materials
Metals to Non‑metals
Dheeraj K. Gara, Raghavendra Gujjala,
P. Syam Prasad, Madaboosi. Srinivasan.
Narayanan and Mutlu Özcan
1.1 METALS AS A BIOACTIVE MATERIAL
Basically, metals are used as biocompatible materials rather than bioactive materials
due to their bulk nature that a human body cannot afford. Conventional metals such
as aluminium, titanium, copper, mild steel, nickel and other transition block elements
which are anticorrosive in nature can be used as implants in bulk form as a support
system to enable the growth of the bone or sometimes as a permanent implant. This
literature dates back to the early 18th century of using metals as implants; however,
over more than a century, this practice was followed by the clinicians to treat mostly
various bone-related issues such as cartilage damages, osteoporosis and arthritis.
When titanium is considered, it is a popular material for bone implants due to its
biocompatibility, strength and light weight. It is also corrosion resistant and has a
low modulus of elasticity, which means it is exible enough to move with the bone
without causing pain or discomfort. It is used in joint replacement, fracture xation,
spinal fusion and dental implants. Likewise, aluminium was found to be one of the
potential materials for biomedical applications due to its interesting properties such
as biocompatibility, light weight and strength; i.e., high strength to weight ratio, cor-
rosion resistance and Osseointegration potential make them more versatile. Unlike
the titanium, the Osseo integration potential of the aluminium makes it potential for
biological applications, since the process of Osseo integration involves the bonding
of the bone tissue and promoting the growth through exchange of ions. Such materi-
als are referred to as bioactive materials and lie in the interest of the current scientic
community. However, excess amount of aluminium can result in adverse effects such
as induced cytotoxicity due to degradation of excess aluminium ions and limited
applications such as dental and orthopaedic applications where their properties are
particularly benecial.
Considering one more potential material from the transition group, nickel also has
potential for use in biomedical applications as implants, but they were found to be
very limited due to their allergic reaction observed in many of the individuals who
are treated for the same. Hence, it is ensured that before using nickel as an implant,
1
2 Bioactive Glass Materials for Biological Applications
a previous medical history of the allergy reaction towards metals is to be taken into
consideration, whereas the most versatile material used in biomedical applications is
stainless steel. Stainless steel is a versatile and commonly used material for biomedi-
cal applications due to its excellent corrosion resistance, biocompatibility and good
mechanical properties. It is used in a wide range of medical devices that includes
orthopaedic implants, such as hip and knee replacements, as well as dental implants.
It is also used for some cardiovascular implants, such as stents and valves, and sur-
gical instruments, such as scalpels, forceps and clamps. It is also used for a variety
of other medical devices, such as needles, syringes and catheters, and sterilization
equipment, such as autoclaves and ovens. It is also used for laboratory equipment
and other medical equipment. The properties of the stainless steel include corrosion
resistance, biocompatibility, strength and durability and ease to clean and sterilize.
On the other side, other problems include wear and tear over time and inference for
medical imaging procedures due to their strong magnetic properties.
Cobalt-chromium (Co-Cr) alloys are a class of materials that have gained signi-
cant traction in the eld of biomedical applications due to their remarkable combina-
tion of properties. These alloys exhibit exceptional corrosion resistance, high strength
and toughness, biocompatibility and wear resistance, making them ideal candidates
for various medical implants and devices. Few properties of these alloys include cor-
rosion resistance, high strength and toughness, biocompatibility and excellent wear
resistance. They have foreseen few applications such as orthopaedic implants, den-
tal implants, cardiovascular devices and surgical instruments. Alongside, they also
have amenability towards inducing bioactivity in the form of Osseo integration and
biodegradation.
Another interesting material tantalum is valued for its remarkable properties
that make it an ideal material for various implants and devices. Tantalum is con-
sidered biocompatible, meaning it is well-tolerated by the human body and has a
low risk of triggering adverse reactions or causing tissue damage. This property
makes it suitable for long-term implantation without the risk of rejection or inam-
matory responses. Tantalum also exhibits exceptional resistance to corrosion in
various bodily uids, making it a durable and long-lasting material for implants.
Its inertness prevents the release of harmful ions into the body, further enhancing
its biocompatibility. It also possesses high strength and stiffness, making it suit-
able for load-bearing implants, such as orthopaedic components. Its mechanical
properties can be tailored through alloying and processing techniques to match
the specic requirements of different applications. Tantalum has demonstrated the
ability to bond with bone tissue, a process known as Osseo integration. This prop-
erty promotes the stability and long-term success of bone implants, particularly in
orthopaedic and dental applications. Tantalum is radiopaque, meaning it is visible
under X-rays and other imaging modalities. This property allows for easy tracking
of implants during surgery and follow-up assessments, aiding in patient care and
monitoring implant performance. Based on various applications, these different
materials are used in versatile locations in the human body as implants as shown
in Figure1.1.
Alongside these metals, we shall discuss most common metal ions used as a
dopants in the bioactive glasses that are displayed in Figure1.2. These are used in
3Introduction to Bioactive Materials: Metals to Non-metals
analogues to the bioactive glasses. However, a comprehensive list of the metals and
their applications towards biological applications can be inferred in Table1.1.
1.2 BIOACTIVE GLASSES
The spongy centre of the bone consists of stem cells that progenitors into mesenchy-
mal stem cells aiding in the repair, development and growth of the bone through the
supply of osteogenic cells [42]. When a biomaterial is implanted in the site of the
fracture or defect, it requires a delivery vehicle for the carrying of proteins to the
bone marrow where mesenchymal cells promote bone regeneration. The most abun-
dant protein in the bone is Type I Collagen, and interestingly, this is synthesized by
osteoblasts. However, there is a lot of disambiguation in the scientic text, whether
osteoblasts directly synthesize Type I Collagen or by forming precursors of osteo-
cytes. From our earlier understanding, osteocytes perform traverse control of ions
from minerals into bone via canaliculi, realizing that matured osteoblast differenti-
ated from osteoblasts will synthesize the Type I Collagen protein. One more strong
FIGURE1.1 Various metals used as implants in bone tissues
4 Bioactive Glass Materials for Biological Applications
TABLE1.1
List of metal‑based bioactive materials for versatile biological applications
Groups Elements Bioactivity References
Alkali metals Lithium Angiogenesis and osteogenesis [1–4]
Sodium Improved hydroxyapatite formation
Potassium Delays the tendency of crystallization
Rubidium Cell adhesion, proliferation and ALP activity.
Alkaline earth
metals
Magnesium Antimicrobial activity, enhanced apatite layer
formation
[5–8]
Calcium Major constituent mineral of the bone which
forms apatite.
Strontium Early osseointegration
Barium Better biological radiation resistance/better
opacier
Transition metals Yttrium Improves chemical durability [9–24]
Titanium Lesser or no bioactivity
Zirconia Increases antibacterial activity
Vanadium Cerium ions improve the blood vessel
formations and no antibacterial activity but
lower angiogenesis
Niobium Enhanced cell proliferation and stimulated
osteogenic differentiation
Tantalum Antibacterial and antifungal, non-toxic and
simulated Osseo integration.
Chromium No bioactivity
Molybdenum Promotes the osteogenic gene expressions of
collagen I secretion and bone sialoprotein in
ADSCs.
Manganese Antibacterial activity/improves adhesion and
proliferation of osteoblastic-like cells
(MC3T3E1)
Rhenium Biocompatibility and osteoconductivity
Iron Bone cancer nanotherapeutics
Cobalt Enhances the hydroxyapatite layer formation
Nickel Better density and mechanical properties can
be increased
Copper For antimicrobial properties to the bioglass
Silver Antimicrobial property to the bioglass
Gold Optimal cellular proliferation, decent
angiogenesis, enhanced vimentin positive
cells
Zinc and
Cadmium
Able to stimulate osteoblast differentiation and
mineralization by enhancing the osteogenic
genes expression.
(continued)
5Introduction to Bioactive Materials: Metals to Non-metals
Groups Elements Bioactivity References
Post-transition
metals
Aluminium Accelerates the rate of osteoprogenitor cell
differentiation and formation of osteoid
nodules alongside inhibiting mineralization.
[25–27]
Gallium Absence of antibacterial activity/lower
angiogenesis.
Bismuth Antimicrobial activity, promotes osteogenic
cell proliferation, differentiation and
mineralization.
Metalloids Boron An excellent substrate for cell adhesion,
differentiation and proliferation and capable
of promoting osteogenesis and
neovascularization.
[28–31]
Silica Main constituent of bone, formation of
hydroxyapatite.
Germanium Treatment of cancer, arthritis and senile
osteoporosis due to the therapeutic attributes
such as immune enhancement, oxygen
enrichment and heavy metal detoxication.
Tellurium Antibacterial, antioxidant and radiation
shielding properties.
Reactive
non-metals
Phosphorous Main constituent in human body and enables
ion transfer.
[32, 33]
Selenium Drug-delivery system for bone therapy, tissue
regeneration, accelerates mineralization
process.
Lanthanides Lanthanum Enhanced osteoblast performance by
promoting differentiation and proliferation,
by raising protein expression.
[34–40]
Cerium Absence of antibacterial activity
Samarium Improved osteoblastic cell response and higher
cell proliferation
Europium Can be used for labelling bone marrow stromal
cells, enhanced osteogenic gene expression
Gadolinium Promotes osteogenic differentiation of human
bone marrow-derived mesenchymal stem
cells.
Terbium Radiation shielding characteristic
Erbium Radiation shielding characteristic
TABLE1.1
(Continued)
6 Bioactive Glass Materials for Biological Applications
understanding is that the protein concentration is lower in interstitial uid present in
bone marrow and thus osteocytes participate in mineralization and osteoblasts par-
ticipate in bone strengthening. An understanding of ion behaviour in osteocytes and
osteoblasts can be realized from Figure1.3.
The biomechanics of the bone is controlled and monitored at a micro and some-
times at mesoporous scale through altering mineral and protein nutrient ions. It is
clinically evident that transition metals due to their advantage of electronic congu-
rations are best suitable for the protein ions, whereas alkali earth metals for min-
eral ions [43, 44]. The implants made of these materials in the current scientic
community are referred to as bioactive glasses. Bioglass 45S5 is the rst of its kind
in bioactive glass which received wide attention in terms of clinical compliance.
Classic Bioglass [45] constitutes the composition of 45 wt% SiO
2
, 24.5 wt%CaO,
24.5 wt%Na
2
O and 6 wt%P
2
O
5
.
This bioglass is implanted at the fracture sight, where ion transport is disconnected
and growth factors’ accumulation will be very slow or sometimes may not be possible
if the intensity of crack magnitude is severe. Immediately the sodium and calcium ions
on the glass surface rapidly begin exchange of ions with the hydrogen ions present
in the physiological body uid particularly intracellular. This intracellular uid has
more charged macromolecules and high alkali ion concentrations that are referred to
as cytosol [46]. Cytosol is involved in various cell signalling, pertaining to the current
context; calcium and sodium signalling are few amongst others and enable exchange of
ions with hydrogen carriers to the bioglass comprising of calcium and sodium. This ion
exchange takes place until silane groups condense to the silica gel layer which forms
the bridge between the fracture mode as displayed in Figure1.3.
FIGURE1.2 Biologically active ions used for biological applications [41]
7Introduction to Bioactive Materials: Metals to Non-metals
Now calcium and phosphate (either from body uid or from simulated body uid
(SBF)) ions pleat at the silica gel and assimilate carbonate and hydroxyl ions from
the extracellular uid that forms a layer modifying the silica network with rich car-
bonated hydroxyapatite (HA). This phase, in coalescence, works with the native
tissue for the regeneration through exchange of ions and hence BAGs are referred
to as bio-coalescent materials. Most commonly observed phosphorus apatite min-
eral conguration is hydroxyl apatite, however few other apatite congurations such
as uorapatite and chlorapatite are also cited in the literature for tissue regenera-
tion applications. From the literature, it can be pursued that hydroxyl apatite shows
greater ability to form apatite compared to that of uorapatite but has lower osteo-
calcin synthesis [47]. Nevertheless, chlorapatite received contemplation in literature,
but it hasn’t shown much potential for clinical compliance. One must realize that
sodium used in the current bioglass assimilates with chlorine thus forming a salt,
sodium chloride, which actually tunes the bone resorption rate relative to bone for-
mation rate. Since the percentage of chlorine present is very minute, the chlorapatite
is ignored, but at an ionic scale its impact is decipherable. Hence, a bioglass combi-
nation with the addition of uorine and chlorine is also of equal importance where
biomimicking is desired. There is no such work cited in the literature as in contrast
to the bone tissue engineering applications in this combination and hence an under-
standing in this context can show some signicant potential. We shall now discourse
on the development of materials that exhibit bioactivity, biocompatibility and bio-
mimicking. It is understood by nature that the human body poses a large number of
materials in appropriate compositions with respect to the majority of elements within
the body. The term biocompatibility in context to the bone tissue engineering refers
to cytotoxicity and genotoxicity. Metals that are used as a constituent in process-
ing the bioglass should be biocompatible and bioactive in nature. Table1.2 displays
various classic bioglass congurations with different dopants as metals, and their
characteristic enhancements in terms of mechanical and biological parameters are
emphasized [47–57].
FIGURE1.3 ECM-BG coalescence for tissue regeneration