Biomaterials for tissue engineering

BiomaterialsforTissueEngineering
Introduction:
Biomaterials are substances rather than drug either natural, synthetic or both in origins,
which act as a whole or part of a system that augment, replace or repair any worn out tissue or
organ of the human body. In the first Consensus Conference of the European Society for
Biomaterials (ESB) in 1976, a biomaterial was defined as ‘a nonviable material used in a
medical device, intended to interact with biological systems’. The biomaterials create a
biomolecular and spatial environment that is needed for cell proliferation and vascularization in
Tissue Engineering (TE) and Regenerative Medicine (RM). Biodegradable scaffolds that aid in the
formation of nouvelle tissues serve as a proffered solution in TE. The various classes of
biomaterials in TE include natural, synthetic and composite biomaterials.
Biomaterials were defined as “any substance, other than a drug, or a combination of substances,
synthetic or natural in origin, which can be used for any period of time, as a whole or as a part of
a system, which treats, augments or replaces any tissue, organ or function of the body”
Classification of Biomaterials

Natural biomaterials:
Natural biomaterials which include protein-based biomaterials and polysaccharide-based
biomaterials are promising subsets of biomaterials employed in tissue engineering because of their
bioactivity, biocompatibility, tuneable degradation and mechanical kinetics and their intrinsic
structural resemblance of native tissue ECM. They also promote biological recognition which
helps cell adhesion, proliferation, cell differentiation and function.
Protein-based biomaterials are made from animal and human sources which include
bioactive molecules that mimic the extracellular environment
Polysaccharide-based biomaterials usually received from algae, as in the case of agar and
alginate or from microbial sources such as the case of dextran and its derivatives.
Another type is decellularized tissue-derived biomaterials made by the removal of all
cellular and nuclear materials from native tissue/organs, as in decellularized dermis, heart valves,
blood vessels, small intestinal submucosa (SIS) and liver, among others.
Protein-Based Biomaterials
1. Collagen

Collagen is a hard, insoluble, and fibrous protein that makes up one-third of the protein in
the human body. In most collagens, the molecules are packed together to form long, thin fibrils.
It is the main structural protein of most tissues in the animal kingdom and plays an important role
in maintaining the biological and structural integrity of the extracellular matrix (ECM) while also
providing physical support to cells and tissues. At a cellular level, collagen is secreted mainly by
fibroblasts and plays key roles in regulating cellular morphology, adhesion, migration and
differentiation.
In the human body, collagen comprises approximately 25–35% of the whole-body protein
content where it can be found mostly in fibrous tissues (skin, tendons and ligaments) and every
other tissue that require strength and flexibility, such as bones, cartilage, blood vessels, corneas,
gut, intervertebral discs and dentin (in teeth).
Currently, there are 29 known isoforms of collagen that have been described. Collagen’s
important biological role has driven this biomaterial to the center of tissue engineering research.
In fact, collagen is easily isolated and can be purified on a large scale. Moreover, it has well-
documented structural, physical, chemical and immunological properties. Additionally, collagen
is biodegradable, biocompatible and has non-cytotoxic proprieties.
Collagen can also be processed into a variety of forms including cross-linked films, steps,
beads, meshes, fibers, sponges and others expanding its potential applications. Many researchers
have illustrated the use of collagen as scaffolds for cartilage and bone as well as in bioprosthetic
heart valves, vascular grafts, drug delivery systems, ocular surfaces, and nerve regeneration.
Additionally, microcapsules containing collagen matrices have been designed in 3-D scaffolds for

soft tissue engineering. Regarding liver tissue bioengineering, collagen-coated silicone scaffolds
represent an important tool for the development of viable 3D hepatocyte cultures. More recently,
Wang Y et al. were able to generate crypt-villus architecture of human small intestinal epithelium
using micro engineered collagen scaffolds.
2. Gelatin
Gelatin is a biocompatible, biodegradable and fully absorbable biopolymer derived from
the hydrolysis of collagen. Due to its biological nature, great solubility in aqueous systems and its
high commercial availability at low cost, gelatin has been commonly used and showed several
advantages compared to its parent protein.
Among its many formulations (mainly derived from porcine, fish, and bovine tissue) the
most used ones in biological fields include nanoparticles, microparticles, 3D scaffolds, electrospun
nanofibers and in situ gels.
Another important fact regarding this polymer is that it can be crosslinked and chemically
modified which expands even more its applications.
As an example of gelatin versatility, Tayebi L and co-workers, have recently characterized
a biocompatible and bio-resorbable 3D-printed structured gelatin/elastin/sodium hyaluronate
membrane with great biostability, mechanical strength and surgical handling characteristics which
hold great potential for engineered procedures.
Furthermore, several other authors have described other applications of gelatin-derived
biomaterials from cardiovascular, bone, skeletal muscle and hepatic tissue engineering to wound
healing and injectable fillers.
Another very interesting finding was attributed to Kilic Bektas C., and Hasirci V., who
recently developed a “corneal stroma system” using keratocyte-loaded photopolymerizable
methacrylated gelatin hydrogels which could serve as an important alternative to the current
products used to treat corneal blindness.

Gelatin as a biomaterial shows a wide range of applications. In stem cell research,
modifications in gelatin formulations have been shown to influence stem cell fate in injectable
cell-based therapies.
Gelatin-based delivery systems have also found to be successful in gene and siRNA
delivery, by inducing the expression of therapeutic proteins or trigger gene silencing, respectively.
Overall, with the significant progress that has already been made, along with others that
will be achieved in a near future, the safe and effective clinical implementation of gelatin-based
products is expected to accelerate and expand shortly.
3. Silk
Silks are biopolymers formed by different fibrous proteins (fibroin and sericin) that are
segregated by the glandular epithelium of many insects including silkworms, scorpions, spiders,
mites and flies. Silk fibers, in the form of sutures, have been used for centuries, and new research
into different formulations (gels, sponges and films) have been encouraging.

In the orthopedics medical field and cartilage tissue engineering, many studies have been
pointed out the enormous potential of this biomaterial. Recently found that the microenvironment
provided by the porous scaffolds based on silk fibroin (SF) and SF with gelatin/chondroitin
sulfate/hyaluronate scaffolds enhanced chondrocyte biosynthesis and matrix accumulation.
In this line, another silk derived scaffold (curcumin/silk scaffold) was also described as a
good candidate for cartilage repair and for meniscal replacement.
Another recent investigation conducted by Hu Y et al., lead to a silk scaffold with increased
stiffness and SDF-1 controlled release capacity for ligament repair. On the other hand, Bryan S.
Sack et al, described that silk fibroin derived scaffolds showed promising repair of urologic defects
in pre-clinical trials. Although silk fibers also showed broad applications, the more popular ones
seems to be related to cartilage engineering.
4. Fibrin

Fibrin is a non-globular protein, involved in blood coagulation, formed from the thrombin-
mediated cleavage of fibrinogen.
Numerous studies have exploited fibrin’s function as hemostatic plug and wound healing,
which suggests fibrin has potential applications in both the medical field and tissue engineering.
Among its applications, three-dimensional fibrin gels have been used as scaffolds for cell
proliferation and migration. Fibrin gels can serve as a useful scaffold for cardiac tissue engineering
with controlled degradation, excellent cell seeding effects and good tissue development. More
recently, 3D fibrin scaffolds effectively induced the differentiation of human umbilical cord
matrix- derived stem cells into insulin producing cells. Other studies reported that hybrid
fibrin/PLGA scaffolds may promote proliferation of chondrocytes as well as cartilaginous tissue
restoration and may eventually serve as a potential cell delivery vehicle for articular cartilage
tissue- engineering.
Additionally, a new biomaterial called fibrin glue or fibrin sealant, has been formulated by
combining fibrinogen and thrombin at very high amounts along with calcium and Factor XIII. This
material is currently used as an adjunct to hemo-stasis in patients undergoing different types of
surgeries.

Polysaccharides-Based Biomaterials
1. Cellulose
Cellulose is the most abundant natural polymer on Earth; present in the cell walls of green
plants, some forms of algae, and can also be produced by bacteria.
Although cellulose is very abundant and has several readily available renewable natural
sources, major difficulties in its refinement make it a poor option for a naturally-derived
biomaterial, such is the reason why there are no physiological or pharmaceutical applications.
Research is currently focused on the simplification of the normally intensive methods for the
depolymerization of cellulose and the manufacture of its derivatives so that it may be used as a
biomaterial.
Recently, chemists were able to generate useful cellulose derivatives such as
carboxymethyl cellulose, cellulose nitrate, cellulose acetate, and cellulose xanthate which are all
gaining some interest in the medical and tissue engineering fields. Cellulose acetate for instance
has been used to produce cardiac scaffolds, while other forms were used for cartilage tissue
engineering.
One of the lastest and curious application of this biomaterial is to use heparinized bacterial
cellulose based scaffold for improving angiogenesis in tissue regeneration.
2. Chitin/Chitosan
Chitin is the second most abundant natural polysaccharide next to cellulose. It is mostly found in
the exoskeletons of arthropods and many insects. Its derivatives which includes chitosan,
carboxymethyl chitin, and glyco-chitin have all generated attractive interests in various fields such
as biomedical, pharmaceutical, food and environmental industries.
In recent years, considerable attention has been given to chitosan (CS)-based materials and their
applications in the field of orthopedic tissue engineering. It has garnered this interest because of
its intrinsic anti-bacterial nature, porosity, and the ability to be molded in various geometries which
are suitable for cell growth and osteocon-duction. Chitosan/alginate hybrid scaffolds have also
been developed in this field. Moreover, chitosan was also reported to promote angiogenesis and

accelerate wound healing response by promoting migration of inflammatory cells to the wound
site and collagen matrix deposition in open skin wounds. Thus, chitosan hydrogels have been
developed in medical therapeutics for third-degree burns.
3. Alginate
Alginate is extracted from brown seaweed, specifically Laminaria spp, Ascophyllum nodosum,
and Macrocystis pyrifera. It is a polysaccharide comprised of a set of linear copolymers with
blocks made of (1,4)-linked β-D-mannuronate (M) and α-L-guluronate (G) residues (shown in the
figure). These blocks can be composed of either consecutive G or M residues, or alternating G and
M residues. The ratio of G and M and the length of each block is determined by the specific source
from which it is derived. Only the G blocks cross-link, therefore the ratio of G/M and length of the
G block are extremely important in its mechanical strength. Recently, scientists have tried creating
alginate using bacterial biosynthesis from Azotobacter and Pseudomonas which they believe will
allow control over its chemical and physical properties which could lead to more applications and
control over its functions.
FIGURE: Bonded G and M residues of alginate
Alginate form a hydrogel that is crosslinked ionically with cations, most often calcium ions.
Hydrogels are 3D, crosslinked polymer networks that have a high water content. Alginate is often
used in wound healing, drug delivery, and cell transplantation. Wound dressings made of
alginate maintain a moist, bacteria-free environment. In addition, alginate hydrogels excel at
releasing molecules in a controlled manner, which is especially useful in tissue engineering to
deliver cells or signals to the desired area.
4. Agarose

Agarose is a part of the agar that is obtained by separating the agar–peptide. Various factors such
as molecular weight, concentration, and lateral groups significantly a
ect the melting and gelling temperature. Overall, 1.5% of each agarose type, such as types II, VII,
and IX-A, have di erent gelling and melting temperatures, at 26, 26–30, and 17˚C, respectively.
The agarose gelation process is divided into three stages: induction, gelation, and quasi-
equilibrium. The mechanism of gelation is usually characterized using rheological experiments,
and it includes nucleation and growth of nuclei. Several agarose nuclei are formed in the first step
followed by the growing of nuclei, which gradually form agarose-rich networks. In agarose, the
formation of gel is related to the agarose molecule twisting linked to the transplantation of
hydrogen and electrostatic penetration. In the end, it is essential to note that the concentration of
the agarose gel determines its permeability.
FIGURE: The molecular structure of agarose and schematic of its gelling process
Recent findings pointed agarose as an excellent candidate for applications involving neural tissue
engineering. Agarose scaffold loaded with matrigel could promote the regeneration of axons and
guide the reconnection of functional axons after spinal cord injury in rats. In cardiac
bioengineering and stem cell biology, agarose was shown to promote cardiac differentiation of
human and murine pluripotent stem cells. In other study, high quality valvular interstitial cell

aggregates were generated, in agarose micro-wells, which were able to produce their own ECM,
resembling the native valve composition.
Glycosaminoglycans
Glycosaminoglycans (GAGs) represent a group of long unbranched polysaccharides consisting of
repeating disaccharide units. There are several types of GAGs components including hyaluronic
acid (HA), chondroitin sulfate (CS), dermatan sulfate, heparan sulfate, and keratan sulfate.
Among these GAGs, HA and CS are the two most studied in regenerative medicine and tissue
engineering field. Some of its applications are described briefly.
1. Hyaluronic Acid
Hyaluronic acid (HA) is a molecule comprised of repeating disaccharide units of N-acetyl-d-
glucosamine and d-glucuronic acid being widely distributed in the most connectives tissues and
some body fluids (such as synovial fluid and the vitreous humor of the eye). Its chemical properties
(solubility and the availability of its reactive functional groups) make this molecule an excellent
candidate for chemical modifications and a very biocompatible material for use in medicine and
tissue regeneration.
Research has found that intra-articular injections of MSCs and HA in rabbits showed statistically
significant improvements in osteochondral defect healing. In current orthopedics medical practice,
HA has a prominent place. In fact, HA injections have been shown to ameliorate osteoarthritis
symptoms and shown the ability to delay prosthetic surgeries. Moreover, HA has also become
popular as dermatological fillers for treatment of face aging.

In tissue engineering, cartilage biodegradable scaffolds made of HA were engineered and HA-
collagen hybrid scaffolds were proven robust and offered freely permeable 3-D matrices that
enhance mammary stromal tissue development in vitro. Hydrogel had a neuroprotective effect on
the spinal cord of rats by decreasing the magnitude of secondary injury after a lacerating spinal
cord injury.
2. Chondroitin Sulfate
Chondroitin sulfate (CS) consists of repeating disaccharide units of d-glucuronic acid and N-acetyl
galatosamine, sulfated at either 4- or 6-positions and represents the second most used GAG as
biomaterial. CS could be obtained from bovine, porcine, chicken, shark and skate cartilage after
various extraction and purification processes. In biomedical applications, CS has been associated
with bone and cartilage metabolism and regulation, presenting both anti-inflammatory effects and
accelerated bone mineralization capabilities.
In animal studies, CS combined with HA and other GAGs administered after arthroscopy were
described as beneficial to equine cartilage health by increasing the number of repair cells and
decreasing the number of apoptotic cells.
In this line research, other biomaterials combinations have been hypothesized. According to Liang
WH, et al., CS-Collagen scaffolds could be used to cartilage and skin applications.
Recent study group has designed combined scaffolds,
CS-Collagen scaffolds could be used to cartilage and skin applications
Silk-CS scaffold proved as a good anti-inflammatory effects both in vitro and in vivo, promoted
the repair of articular cartilage defect in animal model. Thus, CS also constitutes one of the FDA
approved skin substitute component.

Extracellular Matrix-Derived Biomaterials
1. Cell-Derived Matrices
In recent years, the development of decellularized ECM has made the fields of cell biology,
regenerative medicine and tissue engineering advance beyond the use of simple natural derived
biomaterials.
Cell-derived matrices (CDMs) consist of an acellular complex of different natural fibrillar proteins,
matrix macromolecules and associated growth factors that often recapitulate, at least to some
extent, the composition and organization of native ECM microenvironments. As an ECM derived
material, CDMs provide mechanical and biological support allowing cellular attachment,
migration and proliferation; paracrine factor production and differentiation in a tissue-specific
manner.
The unique ability to produce CDMs de novo based on cell source and culture methods makes
them an elegant alternative to conventional allogeneic and xenogeneic tissue-derived matrices that
are currently harvested from cadaveric sources, suffer from inherent heterogeneity, and have
limited ability for customization
The production of CDMs have undergone several evolutions. There are several ways these
matrices can be produced through the use of different decellularization strategies that includes
chemical, enzymatic, physical, mechanical, or a combination of methods. Due to the toxicity of
this approach, some physical and mechanical methods have therefore been developed. These
methodologies include the use of temperature (for example, freeze-thaw cycles) or pressure
treatments (such as high hydrostatic pressure or supercritical CO2 content).
2. Small Intestinal Submucosa (SIS) and Bladder Submucosa (BS)
One such CDM being extensively used is the Small Intestinal Submucosa (SIS) or the Bladder
Submucosa (BS). These are naturally occurring ECM, derived from the thin and translucent tunica
submucosa layer of the porcine small intestine or urinary bladder, which remains intact after
removing the mucosal and muscular layers. SIS and BS have been shown to be biologically active
and its unique combination of intrinsic growth factors, cytokines, GAGs and structural proteins

(mainly collagen fibers, fibronectin, vitronectin, etc) provide strength, structural support, stability
and biological signals which allow overall cell ingrowth.
Once the SIS or BS biomaterial is harvested, it is carefully processed to remove all living cells,
disinfected and sterilized, and then able to be used as scaffold or for long-term storage in their
lyophilized form.The first application of SIS was associated to Lantz and colleagues, who first
used SIS in animal studies as a vascular patch, reported a great tissue-specific regeneration in both
arteries and veins. Within the urology field, SIS and BS are also very popular biomaterials.
3. Acellular Dermis
The acellular dermis (AD) is another example of a CDM, which consists of a soft tissue substitute
derived from donated human skin tissue. As the others CDMs, AD undergoes a multi-step process
which includes epidermis removal, disinfection and sterilization minimizing the risk for an anti-
genic or rejection response. AD was initially used as a type of graft material for the management
of burn wounds. AD has been used for various applications in reconstructive surgery including
head and neck reconstruction as well as chest and abdominal wall reconstruction. Currently, AD
has become an integral part of implant breast reconstruction being one of its most important
applications in regenerative medicine field.
4. Heart Valves
The origin of decellularized cardiac valves matrices may come from xenotransplants or
allotransplants showing different outcomes. It shows immunological differences depending on
whether the valves came from human or porcine, showing that decellularized porcine pulmonary
valve does not represent a completely non-immunogenic heart valve scaffold.
In other studies, the aim was to develop and optimize decellularization protocols to obtain viable
scaffolds for this type of applications. For example, mitral valves can be decellularized to obtain
structures that generally preserved their microarchitecture, biochemistry, and biomechanics. These
CDMs are currently widely studied and tested being now available many commercial options on
the market such as Acellular porcine heart valve leaflets from Epic™ and SJM Biocor®; porcine
acellular valve from Prima™ Plus or porcine acellular heart valve tissue from Hancock® II,
Mosaic®, and Freestyle®.

Synthetic biomaterials:
Poly (α-hydroxy acids) include polylactic acid (PLA), polyglycolic acid (PGA) and their
copolymer such as poly(lactic-co-glycolic acid) (PLGA) are synthetic biomaterials widely used as
matrices and templates in biomedical engineering and bioengineering to mimic ECM systems of
human beings that in other words control or coy the functions of the biomaterials. These synthetic
polymers have been nontoxic degrading products (lactic acid and glycolic acid) and produced via
simple chemical hydrolysis of the polymers which cleared away by normal metabolic pathways.
These materials possess tensile strength, mechanical modulus and degradation properties which
can be utilized for target applications by changing the lactide/glycolide proportions and
polymerization parameters. They have been used to produce urethral tissue as well as bladder
material for replacement in patients suffering from idiopathic detrusor or neurogenic bladder. They
do not give an immune response due to lack of biologically functional domains. However, some
synthetic polymer templates incorporate biologically functional domains in order to develop
biomimetic scaffolds. For instance, collagen or serum coating and the synthetic polymeric scaffold
allow initial cell attachment and ECM deposition while ceramic (calcium phosphate) and coating
synthetic polymeric scaffolds work well for bone tissue engineering. Other relevant techniques
have been applied and are still in the developmental process for proper treatment of diseases. Some
typical biomaterials (both natural and synthetic) for applications in TE are presented in the below
table.

1. Silicon Rubber:
Silicones are polymers that contains any inert, synthetic compound made up of repeating units of
siloxane. Siloxane is a chain of alternating silicon atoms and oxygen atoms, frequently combined
with carbon and/or hydrogen. Silicones consist of an inorganic silicon-oxygen backbone chain (-
Si-O-Si-O-Si-O-) with organic side groups attached to the silicon atoms.
Silicones exhibit many useful characteristics as:
3. They have low thermal, chemical conductivity with low toxicity.
4. Thermal stability (temperature range of −100 to 250 °C).
5. Hydrophobic and form watertight seals.
6. Does not stick to many substrates, but adheres very well to others, e.g. glass.
7. Does not support microbiological growth.
8. Resistance to oxygen, ozone, and ultraviolet (UV) light.
9. Electrical insulation properties.
10. High gas permeability: at room temperature (25 °C).

11. Biocompatibility and Biodurability.
Silicon Rubber applications:
Internal devices
 Intravenous catheters
 Drainage tubes
 Hip implants
 Pacemakers
 Artificial heart valves
Silicone rubber is commonly used in implanted cuff electrodes for both recording and
stimulating peripheral nerves, and these electrodes are for long-term implantation. It can also be
found in cardiac pacemakers, cochlear implants, artificial skins, contact lenses, oxygenators,
catheters, and drug delivery systems. In artificial skins, a bilayer of cross-linked collagen and
chondroitin 6-sulfate is placed over a top layer of silicone. It serves well for traumatic and
regenerative stages of skin replacement and prevents fluid loss and the proliferation of bacteria.
Using its high oxygen and CO2 permeability, it is used in the blood oxygenator membrane, as well
as long wear contact lenses. Silicone rubber is also being used in tissue engineering, and used in
scaffolds, which are structures or framework that hold cells or tissues. The material must allow the
adhesion, distribution, and proliferation of the cells, which reflects the difference with other
applications (see discussion to follow: Interaction between Silicone Rubber and Cells, Tissues).
Taking advantage of the hydrophobic nature of silicone rubber, certain compounds can be
encapsulated in the scaffold for use as a slow release agent or platform for drug delivery.
2. Hydrogels:

Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of absorbing large
amounts of water or biological fluids. Due to their high water content, porosity and soft
consistency, they closely simulate natural living tissue, more so than any other class of synthetic
biomaterials. Hydrogels may be chemically stable or they may degrade and eventually disintegrate
and dissolve.
The so-called ‘moisture donor’ effect of hydrogels helps autolytic debridement, increasing
collagenase production and the moisture content of necrotic wounds. They can absorb and retain
contaminated exudate within the gel mass through expansion of crosslinked polymer chains
resulting in isolation of bacteria, detritus and odour molecules in the liquid. Their high water
content allows vapor and oxygen transmission to the wounds such as pressure sores, leg ulcers,
surgical and necrotic wounds, lacerations and burns. For example, Burnshield hydrogel burn
dressing (Levtrade International) present even in first aid kits is a polyurethane foam containing
96% of water and 1.06% Melaleuca alternifolia extract.
Synthetic materials capable of forming hydrogels suitable for tissue engineering include
poly(ethylene oxide), poly(vinyl alcohol), poly(acrylic acid), poly(propylene fumarate-co-

ethylene glycol), and polypeptides. Agarose, alginate, chitosan, collagen, fibrin, gelatin, and
hyaluronic acid are naturally derived polymers that could also be used for this purpose
Tissue engineering scaffold with the benefits of microporous and nanoporous scaffolds,
comprising a nanofibrous and nanoporous hydrogel formed from self-assembling peptides, which
are non-immunogenic, biodegradable, and capable to interact with cells. They were able to
stimulate tissue ingrowth and vascularization, and furthermore, this hydrogel could be used for
slow-diffusion drug delivery. The self-assembling peptides used to form hydrogels should have
alternating hydrophobic and hydrophilic amino acids (more than 8). For instance, one of them had
the following amino acid sequence: Arg–Ala–Asp–Ala–Arg–Ala–Asp–Ala–Arg–Ala–Asp–Ala–
Arg–Ala–Asp–Ala. This peptide is commercialized as ‘PURAMATRIX’ (3-D Matrix, Inc.,
Cambridge, Mass.) Its self-assembly could easily take place in tissue culture medium (Dulbecco
Modified Eagle’s Medium, Gibco BRL, Gaithersburg, Md) containing calf serum. The scaffolds
presented might also be applied to open wounds or be surgically implanted. One of the most
important future challenges in tissue engineering is how polymers could be used to stimulate the
blood vessel network formation in the desired tissue, essential to supply its needs. Hydrogels could
represent a valid option to effectively control the vascularization process, by local delivery of both
angiogenic factor and endothelial cells to the intended area.
3. Titanium:
Titanium is a lightweight, high-strength, low-corrosion structural metal and is used in alloy form
for parts in high-speed aircraft. Titanium is thus widely used for implants, surgical devices and
pacemaker cases. Its use for hip replacements and other joints, has been well established for some
40 years. Titanium not only fosters Osseointegration (joins with bones & tissues), it is non-
magnetic and non-radio opaque. Titanium instruments are used for micro-surgical operations and
in military light weight field trauma relief kits.
References:
1. Salati, Mohammad Amin, Javad Khazai, Amir Mohammad Tahmuri, Ali Samadi, Ali
Taghizadeh, Mohsen Taghizadeh, Payam Zarrintaj et al. "Agarose-based biomaterials:

opportunities and challenges in cartilage tissue engineering." Polymers 12, no. 5 (2020):
1150.
2. Brovold, Matthew, Joana I. Almeida, Iris Pla-Palacín, Pilar Sainz-Arnal, Natalia Sánchez-
Romero, Jesus J. Rivas, Helen Almeida et al. "Naturally-derived biomaterials for tissue
engineering applications." Novel Biomaterials for Regenerative Medicine (2018): 421-
449.
3. https://www.simtec-silicone.com/biocompatibility-liquid-silicone-rubber-lsr/
4. Caló, Enrica, and Vitaliy V. Khutoryanskiy. "Biomedical applications of hydrogels: A
review of patents and commercial products." European Polymer Journal 65 (2015): 252-
267.
5. https://titanium.org/page/MedicalTechnology#:~:text=of%20metal%20contamination.-
,Titanium%20is%20thus%20widely%20used%20for%20implants%2C%20surgical%20d
evices%20and,magnetic%20and%20non%2Dradio%20opaque.

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