Materials for Biological

and Biomedical Systems

Unit 4

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Biomaterial & Bioactivity

Biomaterial is any substance that has been

engineered to interact with biological systems for a
medical purpose - either a therapeutic (treat,
augment, repair or replace a tissue function
Bioactivity: The ability of an engineered biomaterial
to induce a physiological response that is
supportive of the biomaterial's function and
performance.
Refers to the ability of implanted materials to bond
well with surrounding tissue in either
osseoconductive or osseoproductive roles.
Medical Device

Any instrument, apparatus, appliance, material or other article,

including software, whether used alone or in combination,
intended by the manufacturer to be used for human beings
solely or principally for the following purposes:
Diagnosis, prevention, monitoring, treatment or alleviation of
disease;
Diagnosis, monitoring, treatment, alleviation of or
compensation for an injury or handicap;
Investigation, replacement or modification of the anatomy or
of a physiological process;
Control of conception

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Biocompatibility

Ability of a medical device or material to perform

with an appropriate host response in a specific
application.
A measurement of how compatible a device or
material is with a biological system
Is not an intrinsic property of any material, but the
characteristic of ‘implant-organism’ system
corresponding to their condition-specific contact.
ISO 10993-1: Biological evaluation of medical devices –
Part 1: Evaluation and testing within a risk management
process
Biocompatibility tests

Chemical Characterization (ISO 10993-17 and 10993-18 )

Cytotoxicity
Irritation / Intracutaneous Reactivity
Hemolysis Testing – Direct and Extract Method
Sensitization
Systemic Toxicity
ISO Acute Systemic Toxicity Test
Pyrogen Tests
Implantation Testing

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Implants

Implant: A medical device manufactured to replace a missing

biological structure, support a damaged biological structure,
or enhance an existing biological structure.
Types: Orthopedic , Cardiovascular, Electric, Cosmetic , Sensory and
neurological, etc.
Requirement of Implants:
Absolutely biocompatible
Chemically inert;
Excellent strength;
High fatigue resistance;
Low elastic modulus;
corrosion-proof / resistance
Good wear resistance;
Inexpensive.
 Biochemical processes:
Blood serum and Implant,
Protein macromolecules are adsorbed on the implant
• toxic – toxic damage of the tissue, i.e. necrosis, destructive
inflammation, dystrophy and atrophy, degeneration;
• bioinert – the tissue forms a fine in adherent fibrous capsule
round the implant;
• bioactive – the tissue is biologically linked with the implant at
the interface;
• implant dissolution – the tissue absorbs and substitutes the
implant
Materials for Implants: Metals

80% are Metals but only few due to their limited biocompatibility
The most common metal alloys used in orthopedic implants are stainless steel,
cobalt-chromium alloys, and titanium alloys.
Recently magnesium-containing alloys with biodegradable properties and
tantalum- based alloys with radiographic properties are in demand
Applications:

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Stainless steel
Stainless steel is used for non-permanent implants,
such as internal fixation devices, because of its poor
fatigue strength and liability to undergo plastic
deformation.

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Cobalt-based alloys
Cobalt-based alloys had largely replaced stainless steel as materials for permanent
implants.
More corrosion resistant, owing to the formation of a durable chromium
oxide surface layer.
Ion release in vivo is a major concern, as chromium, nickel and cobalt are known
carcinogens.
Cobalt-chromium (Co-Cr) alloys have two basic elements, up to 65 w/w % Co and
35 w/w % Cr. Molybdenum (Mo) can be also added to obtain finer grain sizes which
result in higher strength after casting or forging

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Titanium and its alloys
Titanium and its alloys are mostly preferred due to good mechanical strength,
relatively low density (4.5 g/cm3), excellent corrosion resistance, and remarkable
biocompatibility.
Additionally, the elastic nature of titanium and titanium alloys is lower than that of
the other metals used in knee implants. Because of this, the titanium implant
acts more like the natural joint, and as a result, the risk of some complications like
bone resorption and atrophy is reduced.
Titanium and titanium alloys have great corrosion resistance, making them inert
biomaterial (which means they will not change after being implanted in the body).
The most used titanium alloy in knee implants is Ti-6Al-4V which is Grade 5

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Tantalum

Tantalum is a pure metal which has a remarkable resistance to corrosion, and

excellent physical and biological characteristics.
It is a very hard, malleable, ductile, and one of the most unreactive metals.
It is extremely stable at temperatures lower than 150 °C, is corrosion
resistant, and has excellent biocompatibility. (oxides of tantalum on the surface of
the metal)
Tantalum has been used in making biomedical implants either in its commercially
pure form or as an alloying element in titanium alloys.
It has also been used as coating on other metallic devices due to its stable surface
oxide layer, such as in 316L stainless steel, to improve the corrosion resistance
of the substrate and enhance its biocompatibility.
Tantalum is used in artificial hips, knees, and other joints.
Pins, screws, staples, and other devices used to hold bones together are also
made of tantalum alloys.
Tantalum based sheets, plates, rods, and wires are also used in the production of
prosthetic devices for humans such as skull plates, meshes to repair the bone
defects after cancer surgery, suture clips, and stents for blood vessels.
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Dental implant with a titanium core and a
porous tantalum layer

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 Nickel-Titanium Alloy (Nitinol)
shape memory alloy of nickel and titanium, where the two elements are present
almost in equal atomic ratio.
The name nitinol is the acronym for nickel titanium Naval Ordnance Laboratory,
where this alloy was discovered.
have greater strength and a lower modulus of elasticity compared with stainless steel
alloys.
Nitinol wires have super-elastic behavior, and they return to their original shape
upon unloading the force that caused deformation and by performing an appropriate
heat treatment above its phase transformation temperature
Fig.2. Shape
memory effect as
shown with a 3D-
printed polymeric
structu

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Magnesium-Based Biodegradable Alloys
Magnesium (Mg) is s light weight (density is 1.7 g/cm3) and biodegradability.
Density, elastic modulus, yield strength, and fracture toughness are close to that of
the bone.
Mg is present naturally in the bone.
Approx. 50% of the total magnesium is stored in the bones.
However, rapid corrosion of the pure metal limits its use in load-bearing applications.
Magnesium degrades within the first few weeks after implantation in vivo
Mg + 2H2O → Mg(OH)2 + H2
Mg(OH)2 + 2Cl− → MgCl2 + 2OH−

Fig.3. Orthodontic dental wires and vascular stents

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Ceramics

Bioceramics: resistance to heat,chemicals and corrosion, lower density, hardness and

stiffness, and ease of modification, and therefore they are commonly used in medical
applications especially in the treatment of hard tissue as bones and teeth
Classes of fixation of bioceramics
1. Morphological Fixation: Attachment of the implant to the tissue occurs by cementing
the device in the tissue or by press fitting into the defect. Single crystal or polycrystalline
Al2O3 can be examples of implants fixed in this fashion.
2. Biological Fixation: In this approach, porous and inert ceramics are fixed by bone
ingrowth into the pores and mechanically attach the bone and the material. As examples,
polycrystalline Al2O3 and hydroxyapatite coat on a porous metal can be stated.
3. Bioactive Fixation: Surface reactive ceramics can attach directly to the bone via chemical
bonds. E.g. bioglasses, glass ceramics, functionalized ceramics, bioactive glass ceramics and
hydroxyapatites.
4. Fixation of Resorbable Implants:The ceramics fixed with this approach are designed to
slowly degrade and be eliminated from the body, while the newly forming bone replaces
the ceramic.
Calcium sulfate and various calcium phosphates including tricalcium phosphate are some
examples of this category
 Fig.4 Stability and bioreactivity of
calcium phosphate salts

Alumina: commonly used bioinert, biocompatible and highly stable bioceramic.

It has low fracture toughness, high compressive strength, high hardness, and high
abrasion and wear resistance.
Alumina coatings yield smooth surfaces.
Aluminum oxide (Alumina) ceramics are formed by the simultaneous application of
pressure and temperature to a powder. This process, called hot-pressing, leads to a final
product with high density, small grain size and good mechanical properties.
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Fig.5. Alumina head in hip joints and artificial eye implant for use after
enucleation and before ocular prosthesis application

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Zirconia (ZrO2):

Zirconia (ZrO2): Zirconia, like alumina, is one of the inert bioceramics. It is

obtained from mineral zircon, a gemstone of many colors.
Addition of some oxides such as MgO, CaO, CeO, and Y2O3 stabilizes the
tetragonal crystal structure of zirconia.
It has a high mechanical strength and fracture toughness. It is produced
generally by hot press or by hot isostatic press processes.
Zirconia is generally used in orthopedic applications such as femoral head,
joint replacement, artificial knee, screws and plates, as well as dental crowns
and bridges
Zirconia has
superior wear
resistance hence Fig.6. Zirconium based
preferred over ceramic dental product
UHMWPE

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Calcium Phosphate Ceramics (CPC)

Calcium phosphate is naturally present in bone structure, CP salts

were successfully applied in replacing and augmenting bone tissue
Calcium phosphate bioceramics have bioresorption and bioactivity
properties
Most widely used calcium phosphate-based bioceramics are
hydroxyapatite (HAp) and β-tricalcium phosphate (β-TCP).
Hydroxyapatite chemistry is similar to natural apatite structure
present in the natural bone. Ca to P ratio in hydroxyapatite is 1.67,
higher than many phosphate ceramics.
Calcium phosphate ceramics can be prepared as powders, tissue
engineering scaffolds, self-setting bone cements, and as coating
materials for metals and heart valves to prevent blood clotting.
They are used as repair materials for bone damaged by trauma and
diseases, as filling materials after resection of bone tumors, as ocular
implants, as materials to repair maxillofacial and dental defects, and
as herniated discs and fusion of vertebra

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Fig.7. Biodegradable ceramics (a) Cerabone (hydroxyapatite), (b) Algipore
(hydroxyapatite),(c) Cerasorb (synthetic phase‐pure β‐TCP), (d) 3D printed
DCPA/monetite, (e) Craniomosaic (DCPA- 3D-printed titanium mesh)

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Polymers
Types of Polymerization Reactions
The chemical reaction in which high molecular weight molecules are formed
from monomers is known as polymerization reaction.
Polymerization can proceed according to two different mechanisms, chain
growth (or addition) and step growth (or condensation) polymerization.
Chain growth polymerization, reactions occur by addition of monomer
molecules to each other via unsaturated (double) bonds.
CGP is a combination of vinyl monomers such as ethene (ethylene), propene,
styrene, and vinyl chloride which form polyethylene, polypropylene polystyrene,
and polyvinylchloride, respectively.
Step growth polymerization involves a reaction between two different
functional groups of monomers.
Functional groups can undergo a condensation reaction where the
polymerization is called step growth polymerization.
Most condensation reactions result in the elimination of a small molecule like
water or methanol.
It applies to monomers with functional groups such as –COOH, –COOR, –
COOOC–, –COCl, –OH, –NH2, –CHO, –NCO, epoxy, etc

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Fig.8. Different polymer geometries

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Classification

Polymers are commonly defined by their thermal properties, (their

response against heat)
Thermoplastics are polymers composed of independent, linear, or
branched molecules which can melt (e.g., polyethylene, PMMA)
upon heating above their melting temperature and processed
(molded, extruded) by heating.
Thermosetting polymers are those with unsaturation or other
reactive groups which upon heating form covalent links
between chains.
They cannot be remelted once solidified (e.g., silicone elastomer)
Elastomers: If the number of these bonds between the chains, the
cross-links, is few, the polymer acts as an elastic material and
stretches reversibly upon application of tensile forces.
Thermal properties provide information on stability of form, effect of
sterilization methods, processing and shaping, and storage

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Biodegradable polymers: important properties
The polymer should not cause any acute or chronic inflammatory
response after implantation in the body.
The degradation time and change in the properties of the polymer should
match the healing of the tissue.
The degradation products should not be toxic; they should be metabolized
andcleared from the body.
Preferred for developing temporary therapeutic devices such as 3D
scaffolds for tissue engineering and controlled release drug delivery
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UHMWE (ultra-high molecular-weight polyethylene) or high-density
polyethylene (HDP).
Polyethylene is the best material for articulating with metal or ceramic.
One major problem in polymers is the slow, temperature-dependent, deformation it suffers
under load, called “creep“.
Progressive wear.
Carbon fiber has been used for reinforcement of the mechanical strength of polyethylene.
Although creep and tensile strength could be improved, resistance to surface wear was
decreased.
In spite of the increasing implantation of cement-less devices, the use of self-curing bone
cement, which is an acrylic polymer, remains widespread.
Modern cementing techniques are responsible for the much-improved clinical outcome of
cemented prosthetic implants.
It should however be emphasized that cement does not act as a glue, but merely as a filler
which allows mechanical anchoring of the implant and transfer of load from the
prosthesis to the bone.
Compared to cortical bone, polymethylmethacrylate (PMMA) is relatively weak with
respect to nearly most mechanical properties.
low modulus of elasticity appears to be an advantage in that it allows a gradual transfer of
stress to bone.
Deformation-strength characteristics of
materials
Deformation-strength characteristics of
materials
Joint Implant Loosening: A1B2

A1B2 are SM and smart implant systems which (in response to

mechanical deformation) activate FBS initiating the implant structure
change.
Smart increase of the cross-section of joint implant (JI) stems fixed by
press-fitting of the bones into the marrowy canal will allow eliminate the JI
loosening syndrome.
Swiss orthopedic surgeon M. Muller. To solve this problems with adjustable
Poisson’s ratio – both positive and negative – are
required. Specimens of materials with negative Poisson’s ratio – auxetics
– expand in the plane normal to the direction of stretching and compress
along the normal to the direction of compression (Konek et al 2004).
The FBS in such SM is quite complex: it should respond not only to
loosening of the stem, but also take into account the bone strength at
biaxial stretching.
Fig. 9. Joint implant loosening syndrome
Human Joints: A2B32

A2B32 are the smart friction units equipped with FBS

initiating the Friction material biosynthesis
A human joint which operates under considerable loads for many
years with a very low friction coefficient (0.02 - 0.05) and
compensation of cartilage wear represents a ‘smart’ friction
unit.
Production of lubricating synovial liquid (SL) in the joint, its
circulation in the area of cartilage friction, etc.
Joint implants (implanted prosthesis of movable bones joint) differ
from the natural joints, mainly, by lack of cartilages – anti-
friction microporous bodies filled with SL.
When a healthy joint is loaded, SL is exuded from the microspores
on the friction surface areas which are under the heaviest load
and provides for their lubrication.
Fig.10. Lubricating synovial liquid
 Cross-section of UHMPE artificial cartilage
friction surface

Microporous
layer

UHMPE initial
structure
Bone cement: A8B12

A8B12 are SM formed as the result of chemical reactions which

thermal effect is controlled with FBS optimizing the material structure
Bone cement is used to stick implants to the bone tissue.
It is produced by mixture polymerization of powdered methyl
methacrylate and liquid polymerization initiator
Release of large amounts of heat at curing of the bone cement
standard (for the hip joint implant stem or socket) dose of 4 cm3, its
temperature reaches 100 °C in~15 minutes, such temperature is fatal
for the living tissues.
Evidently, there is a need to develop smart cement the preparation of
which the competitive chemical reaction would occur: the first one
(exothermic) with the heat release and the second one
(endothermic) with the heat absorption.
The product of the endothermic (second) reaction shall complement the
properties of the polymethyl-methacrylate-based basic bone cement
Bone Cement
Bioactive ceramics coatings: A9B2

A9B2 are SM which properties are directional changed

as the result of biological environment influence by the
control of FBS which regulates the material structure
change
Tricalcium phosphate Ca3 (PO4) 2 & hydroxyapatite
Ca5(PO4)3OH are designed for the implants
osteointegration
Hydroxyapatite (HOA) chemical and crystal structure is
identical to the bone tissue structure.
Provides for formation of strong bonds between the bone
and the coating.
After 7÷9 years :HOA-coated implants shows first indications
of their instability and loosening (gap 0.5-1 mm) are revealed.
To solve the task, it is necessary to implement a FBS regulating
HOA resorption (resolution) along the coating area.
HA Coating (Hip implant)

After 5 years
Implants with memory effect

A1B3 are the implants in which FBS-regulated

stresses occur under temperature change
Titanium nickelide dental implants , elasticity modulus E =
50-75 GPa ,is close to E value of the bone tissue
Practically impossible to regulate the temperature
of a human organ which the implant is implanted into.
Need for material implementing the memory effect under
another energy deposition
Implants made of these materials could change their form
under FBS control with a computer managing the
radiation intensity.
 Shape Memory Medical Devices:

Stent Basket
Targeted Drug Delivery

Administration: drugs, are administered through a variety of routes such as

oral, intravenous (i.v.), intramuscular (i.m.), intrathecal (i.t.),
intraperitoneal (i.p.), subcutaneous (s.c.), and topical or transdermal.
A drug administered in the form of tablets, creams, ointments, or
injectables has to pass through a large number of barriers to reach its
targeted site of action.
To achieve this, the drug is transported within the body through the vascular
system
The concentration of the drug molecule is decreased by distribution to the
tissues, metabolism in certain organs (e.g., liver), and excretion through a
variety of routes (e.g., skin, kidney, lungs).
−dA / dt = k A , A: concentration of the drug, t: time and k: rate constant
A = A0 e –kt ,A
0: drug concentration at time zero
Distribution: important in the efficacy of the drug and also in the elimination
kinetics
Distribution depends on the physicochemical properties of the drug such as
the hydrophilicity/hydrophobicity, charge, size, pKa, etc.
These determine the ability of the drug
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cell membranes and the
other physiological barriers (such as the blood-brain barrier, BBB), their
Metabolism: Drug molecules are unavoidably metabolized
Main goals of metabolism are to modify the drug to be more easily
eliminated (by conjugating with molecules like glucuronic acid
derivatives) and make them highly hydrophilic, to activate (if
prodrugs are used) or inactivate them.
Elimination and Excretion: The drug, is metabolized sometimes
even before showing its effect, and eliminated through the
kidneys by filtration, through the large intestines by excretion, by
exhalation from the lungs, or by diffusion through the skin.
The route of elimination depends on the physicochemical
properties (form, size, charge, etc.) of the drug.
As a result of these four processes, the drug concentration in the
body continuously changes after the administration, and this is not
well accepted by the patients due to the problems associated with
the “sawtooth” variation of the plasma drug concentration due to
repeated administrations as presented in Fig. 11.

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Fig.11 The pharmacokinetics of drugs depending on the administration and
formulation type
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Smart drug delivery
Passive targeting:
Based on the accumulation of drug at areas around the site of
interest, such as in case of tumor tissues.
This is called Enhanced Permeability Retention (EPR) effect.
Such a types of targeting occurs with almost all types of drug
delivery carriers.
Passive targeting is actually a misnomer because it cannot really be
described as a form of selective targeting.
Although the EPR effect applies for nanoparticle administered, the
majority (>95%) of these nanoparticles tend to accumulate in
organs other than those of interest such as liver, lungs and spleen
(Fig.14)
It is the distribution of drug by blood circulation.
Active targeting :
Through the use of ligand-receptor interactions,
However, interactions between a ligand and a receptor are possible
only when the two are in close propinquity, (i.e. less than about
0.5mm)
The currently available drug delivery systems can reach the target
by the virtue of blood circulation and extravasation.
Medicinal agents (MA) entering the body go a long way before they
reach the effector organ or tissue
MA bioavailability: amount of MA dose absorbed by the effector
organ determines the degree MA bioavailability.
Injected MA: Reach the bloodstream quicker but painful
Oral MA: Slowly, elimination becomes a significant issue when the
drug is taken orally
At subcutaneous administration: the rate of MA delivery to the
diseased tissue is lower
Oral intake
Oral intake (only a small amount of MA reaches the
target

Stomach: Disintegrate in gastrointestinal Tract

bloodstream (absorbed MA amount)

LIVER
Biochemical transformation, highest metabolic activity

Retain in tissue
only a small amount of MA reaches the target
The target-oriented delivery: Presupposes the MA
placement directly into the effector organ by-passing
other systems and tissues of the organism.
This medical technology purpose is to achieve MA dose
optimization to increase therapeutic and reduce toxic
effects.
Properties of the Drug:
Aqueous solubility (hydrophilicity)
pKa (acid dissociation constant)
Partition coefficient (ratio in oil to that in
water, Kd)
Molecular weight (Mw)
Targeted Delivery

Almost all the drug administration applications introduce the drug to the
body at various rates, but the effect is in most cases systemic, except
may be the topical applications, the drug applied onto the skin.
Researchers aim to localize the bioactive agent at the site of the disease
Since the drugs are active molecules, their bioactivity could be harmful
on the healthy tissues which receive the drug as a result of its systemic
distribution.
Targeted drug delivery systems are designed to deliver their payload
directly to the desired site of action.
This is especially important for anticancer drugs which aim to kill the
cells into which they are taken up.
Targeting can be achieved by attaching the drug to a molecule which
is selectively taken up into the cells of the target tissue or by using
the properties of the drug carrier, such as chemistry and size.
A typical drug attached to a polymer: liposome-based study to prevent
systemic toxicity, an anticancer drug-carrying liposome was
conjugated with a RNA aptamer specific to the prostate-specific
membrane antigen (PSMA) expressed on the surface of prostate
cancer cells

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 Liposomes carried the
anticancer drug
Spacer Drug doxorubicin (Dox) and
were more toxic to the
targeted cancer cells
than to nontargeted
Polymer

cancer cells.
Targeting
Dox-carrying liposomes
moiety
administered to xenograft
nude mice were
selectively retained in the
tumor tissue indicating the
Hydrolysable
Adhesive endeffectiveness of the cell
link
membrane binding by the
Fig. 13. A targeted polymer-drug conjugated liposomes.
conjugate
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 EPR effect, drug carriers with
EPR (enhanced permeation and retention)
low nano size (ca. 100 nm or
less) can leak out of the
disorganized vasculature at the
cancer site
Since the vasculatures at the
healthy sites have tight cell-to-
cell contact at the capillaries, the
drug-carrying nanoparticles are
delivered/targeted to the cancer
tissue.

Fig.14 Targeting through EPR effect

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Methods to Achieve Prolonged or Sustained
Drug Delivery: a. Approcahes
Reservoir-
Rate controlling type :
membrane (Simplest) is
when the drug in
powder form
Drug carrier layer is mixed with
particles of an
inert (and
preferably
Spacer bioresorbable)
carrier and
compressed to
form a pill or a
film.
Rate controlling
membrane

Fig.15 Reservoir-type drug delivery

system (DDS)

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Monolithic systems

The carrier could erode

gradually and the drug is
released when the
aqueous medium
interacts and
solubilizes the drug.

Fig.14 Different types of biodegradation

used in delivery systems
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b. Processes: Encapsulation in Micro- and
Nanospheres or Capsules
Used to encase
Polymer solution particles, liquids, solids,
or gases, and several
approaches can be
employed to
encapsulate materials
Involves hydrophilic
and hydrophobic drugs
to be entrapped
Polymer
microcapsul
e
Non-solvent

Fig.16. Microcapsule production

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2. Entrapment in Micro- and Nanofibers by Electrospinning
Fig.17 Electrospinning to produce drug
delivery from fibrous materials
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Under the influence of the
potential, the polymer is
extruded in the form of thin
fibers which dry during the
trajectory toward the target or
soon after reaching there.
Depending on the polymer
concentration, solvent type,
distance between the injector
needle tip, the collector (a
rotating mandrel, a metallic
sheet or
parallel bars), and the potential
applied, the fiber thickness,
beading (formation of
bead-like formations along the
length of the fiber), and the level
of sticking of the
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fibers
determined
Stimuli–Responsive polymers

Stimuli–responsive polymers:
Polymers which respond with physical or chemical
transformations in response to changes in
environmental conditions,
temperature,
pH,
mechanical stress,
electric/magnetic response,
light,
Ionic strength
 Stimuli–responsive drug delivery system

Fig.12. Schematic illustration of the on–off drug Glucose-dependent

release in a stimuli-modulated drug delivery modulated insulin release
system
Thermo responsive Polymers

Temperature: 37 deg.
Temperature sensitive polymers = presence of a hydrophobic
group (methyl, ethyl, & propyl )
LCST (lower critical solution temperature): polymer solution
undergoes a phase transition from a soluble to an insoluble
state.
Solubility increase with temp.
Polymers having LCST, increase in temperature decreases the
water solubility due to hydrophobic associations of polymer
molecules and reduction in hydrogen bonding between polymer
and water molecules.
Eg. poly(N-isopropylacrylamide) (PNIPAAm), poly(N,N′-
diethylacrylamide) (PDEAAm), & poly(2carboxy isopropyl
acrylamide) (PCIPAAm)
pH-Sensitive Polymers

The pH-sensitive polymers include ionizable groups

such as carboxylic, sulfonic acid, or basic amino
groups that can accept or release protons in response to
the environmental pH
Stomach: pH 1–2 (fasting condition) & 4 (during
digestion)
Duodenum: pH 5.5
Cancer targeted drug delivery, most cancers are more
acidic (about pH 6.7 and pH < 7.0, respectively) than in
normal tissues or cells
Biomacromolecule-Sensitive Polymers
Glucose: Treatment of diabetes caused by malfunction
of pancreas.
self-regulated insulin-delivery systems based on blood
glucose concentration (refer stimuli response dia.)
Microneedles A1B32:

A1B32 are smart systems for mechanical

delivery (into the human body) of MA which
propagate in the disease-affected organ by
concentration diffusion mechanism
Subcutaneous administration of MA micro amounts is
exercised with hollow needles (with diameter up to 10
micron) made of metals, ceramics, glass or polymers
Alternative to medicamental therapy with
acupuncture
Entered to a depth of 10-15 mm from corneal
layer which causes no pain, no nerve endings
there
Nanotechnology

Nanotechnology, in combination with diverse

targeting strategies, can bring advantages to drug
delivery, overcoming the limitations of conventional
therapeutics .
Advantages:
delivery of much higher therapeutic payloads per
target biorecognition event;
the ability to carry multiple, potentially different
targeting agents for enhanced selectivity;
Bypass biological barriers; and the localized
delivery of multiple agents, resulting in targeted
combination therapy.
Nanoparticle A6B22:

A6B22, A6B25, A6B32 are smart magnetic

nanoparticles whose movement in the organism
under external magnetic field gradient action is
controlled with the FBS; initiates their fixation on the
disease affected cells by means of adsorption and
immune reactions.
Magnetic nanoparticles – the diseased tissues markers –
are made of Fe & its oxides, Ni or Co isolated with
coatings of Au or bioinert polymers; functional
chemical (proteins) or biological (antibodies)
agents are grafted to the coating.
Small particles (500-100 nm) are injected into the blood
stream
Carbon nanoparticles

A8B13 are smart carriers of chemotherapeutic

agents which are adsorbed (using the grafted groups)
on the malignant target and release the MA under
the action of external radiation
Used as a means of MA delivery to the cells affected by
cancer
Chemotherapy: Fullerene (in 1985), carbon nanotubes
(in 1991) and graphene (in 2004)
Interact with malignant tissues by mechanism of
endocytosis,( i.e. absorbed by the cells)
Advantages of a TDDS:
Tissue growth

The pioneers of the field, Robert Langer and Charles

Vacanti, have defined it in 1993 ““an interdisciplinary field
that aims at the development of biological substitutes that
can be used to replace, restore or improve tissue function”
ASTM came up with a range of definitions in the field
(Designation: F2312–11, Standard Terminology Relating to
Tissue Engineered Medical Products) and defined tissue
engineering as “the application, in vivo and in vitro, of
scientific principles and technologies to form tissue
engineered medical products (TEMPs) used for medical
treatments and diagnoses as diagnostics”.
The tissue-engineered medical product (TEMP) is “a medical
product that repairs, modifies or regenerates the
recipient’s cells, tissues, and organs or their structure
and function, or both.”
APP COEP
Fig.19 A scheme showing the relation between tissue engineering, regenerative
medicine, and the contributing fields

APP COEP
Fig.20 The scheme for tissue engineering of meniscus

APP COEP
 Three components achieve the goals of Tissue Engineering are available
(Fig.21)
1. A scaffold or a cell carrier to house the cells and serve as their
microenvironment
2. Appropriate cells to fill the empty scaffold and convert it into the target
tissue
3. Certain bioactive compounds (growth factors) to guide the cells in their
attachment to the scaffold or during their proliferation and
differentiation

Fig.21 Components
of tissue
engineering APP COEP
Scaffolds
An ideal tissue repair environment is created by reproducing the
intrinsic properties of the natural tissue or the autografts.
Scaffolds are needed for the cells to attach and then to serve as their
microenvironment, and their form (fibrous, foam, with and without
chemical and physical surface decorations) and chemistry
(hydrophobic, hydrophilic, carrying certain functional groups) are of
utmost importance.
A scaffold is anticipated to possess certain properties:
The scaffolds are 3D structures; they have to be highly porous to
allow penetration of cells, culture medium, growth factors, and other
compounds into the scaffold body and the metabolic waste products
to move out.
The pores have to be of an optimum size (generally 200–300 µm
wide) and interconnected to allow complete population by the cells.
They have to be resorbed in a time span paralleling that of healing
(Fig. 22).
The scaffold surface chemistry should be suitable for cell adhesion.

APP COEP
 Fig.23 Tissue healing and
scaffold resorption relation

Fig.24 Various 3D macroporous scaffold types. (a) Rapid prototyped (AM) (b) wet
spun (c) lyophilized sponge,(d) fibrous , (e) lamellar , (f) channel
APP COEP
Cell Types
Primary Cells: Primary cells, mature, differentiated cells that are obtained
from tissues and have not undergone any passaging (expansion in the lab),
are used in tissue engineering
Classified according to their source:
Autologous cells: Autologous cells are isolated from the diseased or
damaged tissue of the patient.
The extracellular matrix of the biopsy specimen is removed, the cell density is
increased, and then they are seeded on a scaffold.
Since they originate from the donor, there is no risk of immune response or
pathogen transmission.
Disadvantage: harvesting of cells causes a new damage at the donor site.
The pain, the risk of infection, and the limited availability of suitable donor
sites make autologous cells not a very practical source.
Allogeneic cells: Allogeneic cells are obtained from a donor of the same
species and, in this case, from another human being.
In using this source, there is a risk of pathogen transmission and immune
rejection, but at least donor site morbidity and associated pain are not an
issue for the patient in using this cell source.

APP COEP
Xenogeneic Cells

Xenogeneic cells are obtained from donors from another species; in

the case of tissue engineering, this means nonhuman cells.
These are especially useful in the preparation of generic, off-the-shelf,
engineered tissues.
The human use of xenogeneic cells is associated with serious
problems (disadvantages):
Risk of transmission of known and unknown pathogens, with the
potential risk of introducing new infectious diseases into the general
population.
Risk of immunological rejection.
Maintaining the survival and functions of the cells in the long term.
Use of immunosuppressive treatment leads to weakening of the
host defense
system.
Careful choice of the donor animal.
Uncertainty of the transplanted cells to provide the desired function in
the long term
APP COEP
Transplantation of organs and tissues as a surgical method has
been known since antiquity to modern times.
Tissues transplant to a patient
Perform another (additional and quite painful) surgical operation
on tissues extraction.
Alternative solutions are transplantation of tissues taken from the
tissues bank (banks of bone tissues exist since 1970s, banks of
soft tissues are not available yet) and growing of tissue
implants by living cells multiplication.
Which is called the tissues engineering, presupposes availability
of a special scaffolds where a tissue embryo could develop by
assuring biocompatibility and sufficiently long ‘lifetime’ of the tissue
implant.
Biodegradable scaffolds are transplanted together with the grown
tissues, and they exert influence upon biological coherence of a
new tissue with the multitude types of the surrounding cells
Bone grafting: A9B32

A9B32 taxon: environment (in vitro it is the cultural medium and

scaffold which the cells have been inseminated onto, in vivo it is the
patient’s organism) exerts biological action upon the tissue embryo by
initiating its growth.
Scaffolds on the base of natural tissues are used in many medical
technologies
Bone grafting: is a set of surgical procedures for locomotor apparatus
rehabilitation using plastic materials in the form of bone tissue
Auto transplant (bone tissue belonging to the patient ) is used quite
rarely,
Allotransplant (living tissues belonging to other people or
xenotransplants (tissues of some other origin) are used more
frequently.
In all condtions the implanted tissues serve as a matrix where
amplification of human cells takes place.
 Bone grafting is a
surgical procedure
that uses
transplanted bone to
repair and rebuild
diseased or
damaged bones.
A bone graft is a choice
for
repairing bones almost
anywhere in your
body.
Surgeon might
take bone from your
hips, legs, or ribs to
Fig. 25 Bone grafting perform the graft.
Articular cartilage rehabilitation: exercised by
transplanting the mature cells of the patient’s cartilage
tissue (chondrocytes) into the cartilage defects.
Eg. knee joint arthroscopy
Bioptate (biopsy slice) of the cartilage tissue is taken from
the non-load area of medial condyle.
Bioptate is crushed, chondrocytes are filtered, mixed with
the patient’s blood serum and grown in the nutrient
medium.
In 2-3 weeks, a suspension is formed which is used to
close the cartilage defects.
Bioceramic coatings: A9B2

A9B2 taxon scaffold which activatesn development of the bone

tissue cell (osteocytes).
Applied onto the implants to stimulate the bone tissue
implantation.
Scaffold which activates development of the bone tissue cells
CaP: stimulate osteocytes growth and have micro porous
structure which is convenient for the FBS implementation in such
bio-system function is performed
by therapeutic agents, proteins and growth factors introduced into
the micro pores.
They control the cells structure of the surface layer, suppression
of infections, the graft’s ‘lifetime’
Ethical aspect of implementation of the genetic engineering smart
systems
Fig. 26 Acetabular cup
with CaP coating
Packaging

Basic Function:
protection of materials and products against damage and loss
protection of environment against pollution with the package
content
product maintenance during movement, i.e. during
transportation, warehousing, storage and sales
Mandatory information on the product:
allergen city,
freshness,
health benefits,
ethics of the foodstuff production,
evidence that the packaged product is not a counterfeit
Key application areas for Plastics
Active packages
Active packaging materials exert (upon the packaged
product) influence of chemical, physical or
biological nature by changing the content of gas
medium inside the package or by transforming the
surface layer structure of the packaged products or
materials.
Inhibited polymer film contains a micro porous layer
which includes a complex of contact and volatile corrosion
inhibitors (CI); the film is intended for anticorrosion
protection of metal ware
A1B6 is the film which (at deformation
producing the contact with the packaged
product)
exudes and transfer the contact CI to the product
surface preventing adsorption of moisture vapors
and corrosion
in theagents inside the package;

A3B9 is the film in which (under the change of

temperature driving the moisture
condensation in the packaging area) the FBS
operates initiating emergence of stresses in the
film porous layer and release of CI in liquid or gas
phases from the pores;
Antistatic packaging films
A5B17 are the films with the FBS which takes away
the charge spontaneously accumulated on the
package in the process of its circulation
Antistatic packaging films are convenient in operation
because they decrease dust adhesion to the
package and eliminate the possibility of spark
discharges occurrence.
The latter provides them for primarily using
gunpowder and explosive powders as the
material for packaging
Oxygen absorbing plastics
A7B29 are the smart packaging materials in which the FBS ‘operates’
optimizing the gas medium content inside the package by oxygen
absorption
Oxygen absorbing plastics: are used in foodstuffs and beverages packaging.
Low-cost technological additives on the base of iron salts and active UV-
responding substances are introduced into the plastics binder & they must
be ‘friendly’ to the plastics processing technology
Ube Industries, Japan, developed the manufacturing technology without
additives: oxygen-capturing molecular centers are engrafted to the polymer
chain.
These plastics can be used for manufacturing beer bottles, containers for
juices, sauces and dressings, films for bread packaging
Materials of this kind are used in plastic corks for wines and beverages.
The FBS function in these plastics is performed by non-linear temperature- and
pressure-dependent changes in absorption characteristics of absorbents
Packaging films for meat products
A9B29 are the materials which regulate the microbial composition of the medium inside
the package by the actions of chemical nature.
Packaging films for meat products: contain natural and synthetic food preservatives.
Maximum storing term for chilled (T ≈ 5-7 ºC) pork and beef packaged in the active film
modified with mustard or coriander oil is 2-3 times higher than when packed in the
standard.
Such storage does not affect the meat organoleptic properties,
The meat products microbial damage processes is usually accompanied by the pH abrupt
jump (in the alkaline area ) along with an increase of the volatile fatty acids content in the
meat.
Introduction of preservatives (ascorbic and nicotinic acid, glucose, complexes of ‘salt –
conjugated carboxylic acid’ type) into the packaging film stabilizes the product pH at the
initial stage during the long-term storage period and has favorable effects on the meat
products quality
The generation of plastics with the antimicrobial activity has been under development since
1990s.
These materials are used in the production of ship plating, walls and roof coverings, boiler
casings, kitchen boards, children’s toys, sandals, shower curtain, stationery, waste
containers, etc.
Biocidal packaging films

Biocidal packaging films : Used for medicinal, sanitary and

hygiene purposes.
Medical instruments, disposable razors, creams are
packed in them.
Biocidal adhesive films are applied onto the skin areas to
be surgically dissected.
Such films contain additives which suppress the growth of
microbes; the films are manufactured in ‘clean’ rooms
The films with antimicrobial activity are typical active
materials.
They could become smart ones if equipped with the FBS
which regulates the recovery of antimicrobial agents upon
the signal of sensors controlling the microbial media
status.
Biodegradable packaging

Synthetic polymers: Long time to decompose under

natural conditions
Thrown away packaging films make up a considerable part
(in various countries 10 to 60 %) of domestic solid
wastes become a constant source of pollution of surface
soil and coastal waters of the oceans.
Time: Very High
Biodegradable plastics

Natural polymers – starch, dextrin's, pectin's, chitine-chitosan, cellulose, lignin,

gelatin, casein, etc., which raw material resources are constantly renewed
Polymers which are similar in structure to biopolymers, obtained by
polymerization of monomers – derivatives of nontraditional raw
material base or by inoculation of the functionalized oligomers to the
synthetic polymers chain of high-molecular compounds which are the
product of microbiological synthesis of organic raw materials and chemical
products (butylene glycol, butyrolacton, butyric and chlorine-butyric acids)
Composite material – synthetic polymers filled with natural polymer
(starch, cellulose, chitin) or non-organic substances containing elements
which are attractive for microbes – Ca, N, K, P, etc.
Electret polymer materials – the sources of the constant electric field
which facilitates immobilization and growth of the soil microbes in the
buried film an assists in its accelerated biodegradation
Antimicrobial materials
According to the European Centre for Disease Prevention and Control,
more than four million people are estimated to acquire a healthcare-
associated infection (HCAI) every year in Europe (1.7 million in the USA)
deaths occurring as a direct consequence of these infections is estimated to be at
least 37,000, and these infections are thought to contribute indirectly to an
additional 110,000 deaths each year (in the USA, a total of 99,000 deaths is
estimated) [C. Adlhart et al. / Journal of Hospital Infection 99 (2018)]
AMiCI (AntiMicrobial Coating Innovations) currently comprises participants
of more than 60 universities, research institutes and companies across 30 European
countries (www.amiciconsortium.eu)
Antimicrobial, bactericidal properties of biologically active metals - biometals
(silver, copper, zinc, etc.) - in the form of salts, complexes, colloid particles,
"silver" water are known to humans for a long time
Strategies to achieve antimicrobial coatings classified according to their functional
principle as: (i) antiadhesive, (ii) contact active, and (iii) biocide release
 Anti-adhesive surfaces can reduce the
Fig. 27 Established adhesion force between bacteria
(black) and and a solid surface to enable the easy
potentially
upcoming strategies
removal of bacteria before a
(blue) for biofilm layer is formed on the surface
antimicrobial
coatings classified Contact-active surfaces exhibit
by their functional antimicrobial activity without
principle releasing biocidal substances

Biocide-releasing surfaces : disadvantages since they are toxic by design in terms of

releasing biocidal substances.
gradually become inactive and they may induce the formation of resistance
Catalytically active surfaces, such as photocatalytically active surfaces (e.g. TiO2) which
regenerate reactive oxygen species upon UV radiation, provide an alternative
APP COEP
Effective antimicrobial coating must achieve a multitude of characteristics:
(i) be able to control the pathogenic population of a surface;
(ii) be stable (mechanically, tribologically and chemically) in the wide
range of hospital settings;
(iii) minimize (eco)toxicological hazards and risks of antimicrobial
resistance emergence;
(iv) be affordable and easily implemented
Antimicrobial coatings are developed to prevent the growth of bacteria
and germs on several surfaces
mostly applied to walls, counters, door handles as well as other high-
touch areas, mechanicals and HVAC vents and many more surfaces
They are sprayed onto gloves, masks, carpeting, and textiles.
Paints

APP COEP
Biocides-containing plastics
Cover handrails in the public transport, tables in public
spaces (post offices and baggage services, kitchen
furniture in public catering facilities), in medical
institutions (first-aid and medical treatment rooms,
operating rooms).
Trays, chopping boards and containers for foodstuff,
children’s toys, office appliances (phones, keyboards,
mouses), toilet bowls, sinks and other sanitary ware.
biocides-containing varnishes and paints are applied to
prevent biological fouling of ships (periphyton).
The periphyton base consists of bacterial slime which
plants and animals (algae, crustaceans, mussels, hydroids,
sponges, etc) are attached to.
Antimicrobial synthetic fibers
Used in new generation of textile products
whose protective properties are adapted to the modern human habitat.
The smart clothes are characterized by multifinctionality: ideally they should protect
humans not only against pathogenic microbes, but also against ultraviolet light
electromagnetic waves, static electricity, etc.
Antimicrobial synthetic fibers can be added to any fabric – on the base of cotton,
lint, silk, wool.
They make the fabric crease-resistant & wear-proof and add to it antiseptic
properties
Long-term preservation of the antimicrobial effect, is complicated due to textile
products are periodically laundered.
Introduce antimicrobial substances into synthetic fibers by the mechanism of crazing.
Phenomenon which occurs at the fibers drawing in surface-active liquids
Colloidal particles of antimicrobial substance available in the craze & adsorbed
on the newly formed walls, closing of craze
Benefits of antimicrobial coatings

Lasting protection against microbes : provide adequate and long-

lasting protection against fungi, mold, and bacteria. This minimizes
terrible odors, staining, and degradation of material on surfaces where
they are applied.
Longer Lifespan: Once antimicrobial coatings have been applied to a
surface, they cause no discoloration, leech or affect the final look of the
surface.
Antimicrobial has a lifespan that will last more than expected on the
covers..
Cost-Effective : Medical facilities, public institution, and building
managers stand a chance of saving an incredible amount of money since
they reduce the maintenance costs associated with replacement of
unsanitary items.
Improved Cleanliness and Health: There is a continuous trend of
germs and bacteria spreading where there is significant population.
Office and hospital having substantial human interactions every day.
Filters for water cleaning

Water filtration: is the process of removing or reducing the

concentration of particulate matter, including
suspended particles, parasites, bacteria, algae, viruses,
and fungi, as well as other undesirable chemical &
biological containments from contaminated water to
produce safe and clean water for a specific purpose.
Such as drinking, medical, and pharmaceutical applications
Community Water Treatment

1. Coagulation and flocculation:

Chemicals with a positive charge are
added, neutralizes the negative
charge of dirt and other dissolved
particles in the water
2. Sedimentation
3. Filtration: Filters like bio sand,
gravel, and charcoal such as dust,
parasites, bacteria, viruses, &
chemicals
4. Disinfection: Added chlorine,
chloramine to kill any remaining
parasites, bacteria, and viruses,
and to protect the water from
germs
A8B31,32 taxons Microbiological utilization of
admixtures found in the wastewater cleaned through
biofilters simulates the natural biochemical phenomenon of
‘self-cleaning’ in nature.
Wastewater is mechanically cleaned.
Its organic contaminants are settled on the filtering
material grains and are used as nutrients and source of
energy for microorganisms
Biofilter is a smart biosystem which removes admixtures
from the water and cleanses itself owing to the FBS
whose functions are performed by metabolism of
immobilized microorganisms
Biofilter for aerobic water treatment

flow meters

cover
layer of the carrier
sprayer unit with the immobilized
biomass
casing

flow meters

supporting grid
level indicator
Efficiency and reliability of biofilter operations are
determined by multifunctionality of the biomass
carrier.
Most significant parameters of the carrier are as per below,
porosity, developed surface, satisfactory mechanical
strength, chemical stability, & biocompatibility
For industrial biofilters: Fibrous polymer structural
elements obtained by depositing (with gas flow) the fibers
of polymer melt onto the shape-generating scaffolds (melt
blowing technology) possess these properties.
the optimal carriers are rings made of polypropylene or
polyamide fibers welded in the points of contact
Activated carbon Filtration (charcoal)
The most common type of water filter, particularly for household use.
Factors such as molecular weight, pH, particle size, surface area, and flow rate significantly
determine carbon’s purification ability.
Within carbon’s molecular surface area, several attractive forces exist to attract other
molecules.
These forces function similarly to that of a gravitational force, where contaminants within the
water adhere to the large surface area of carbon.
The interaction of these forces depends upon carbon’s non-polar nature, where the electrical
charges surrounding a single molecule of carbon are evenly distributed, canceling out any
charge to the molecule.
Arsenic, copper, fluoride, and some viruses (Toxins) are not successfully removed
Due to these restrictions, carbon filters can be made with iron, manganese, hydrogen sulfide,
or a sediment pre-filter in order to enhance the removal of certain harmful particles
within water.
Chlorine, along with other deleterious chemicals such as benzene, radon, solvent
trihalomethane compounds, & volatile organic chemicals such as pesticides, are all
successfully filtered out of drinking water in the presence of a carbon filter.
However, carbon filters are not particularly effective in removing compounds that exceed the
size of carbon itself.
Ceramic Water Filtration

Inexpensive and effective method of filtration used

throughout the world.
While there are numerous styles and forms of CWF
Ceramic water filters have proven to be particularly useful in
preventing early childhood diarrhea (ECD) in developing
countries.
Filters are often impregnated with colloidal silver in order to
ensure the complete removal of bacteria, viruses, and
protozoa.
While effective at removing larger protozoan and
bacterial organisms, smaller viral organisms are often
unable to pass through the pores of a ceramic water
filter.
Sand filtration

Rapid sand filtration and slow sand filtration.

Most often used in conjunction with each other water purification methods.
Rapid sand filtration uses the mechanism of physical straining to trap large
particles between the sand grains.
Within the slow sand filter, microorganisms such as bacteria, viruses, &
parasites are able to travel through the sand and are absorbed onto the sand
particles.
Often referred to as a bio-sand filter for its presence of biological activity, slow
sand filters contain very find sand, allowing for the removal of particles that are
smaller than the spaces between the sand grains.
The term “bio-sand filter” comes from the dense biological zone that forms within the
top layers of the sand following water filtration.
While slow sand filtration is often used in the treatment of groundwater, its principal
use is in the removal of pathogenic organisms and organic matter in surface
waters.
WHO claims that slow sand filters offer the greatest quality in the improvement
in the physical, chemical, and bacteriological of treated surface water.
Nanofibers
Nanoporous graphene membranes could be considered an
ideal separation membrane for water filtration and
desalination at a removal efficiency of 33%–100%,
depending on the pore size and applied pressure
Challenges in membrane technology
identify or to create new materials (e.g., high durability,
low cost and fewer environmental concerns) that can
fabricate more cost-effective membranes
Design and to optimize structure and morphology in
existing membranes that can lead to a substantial
increase in filtration efficiency (e.g., high permeation flux,
high retention and low pressure drop)
APP COEP