BIOACTIVE AND COMPATIBLE POLYMER

Introduction

Bioactive polymers are materials based on synthetic polymers with the additional
incorporation of a bioactive species, such as proteins, peptides, or carbohydrates, into
the polymer structure to induce a specific biological response. Such bioactive species
may be immobilized or releasable, depending on the mechanism of action of the
agent. Much of the current research in bioactive polymers has focused on polymers
that support biospecific cell adhesion, e.g., adhesion to an oligopeptide via a cell
surface receptor that specifically recognizes and binds to the amino acid sequence of
the oligopeptide. While many cell adhesion peptides recognize receptors on a broad
variety of cell types, some peptide sequences may be cell-type selective, thus allowing
the possibility to create materials that are adhesive towards one type of cell but not to
others. It may be possible to achieve a degree of cell-type specific adhesion based on
cell-surface receptor-mediated interactions with carbohydrates.
“a biomaterial that is designed to elicit or modulate biological activity” .

Biocompatibility: The polymer should be well-tolerated by the body, causing

minimal or no adverse reactions. Biocompatible polymers are designed to interact
with biological tissues without inducing inflammation or immune responses.
Bioactivity: The polymer should have properties that promote specific biological
responses, such as cell adhesion, tissue regeneration, or controlled release of bioactive
agents.
Degradability: Many bioactive compatible polymers are biodegradable, meaning
they can break down into non-toxic byproducts over time. This feature is
advantageous in applications where temporary support or controlled release is needed.

Examples of Bioactive Compatible Polymers:

Poly(lactic acid) (PLA): PLA is a biodegradable polymer commonly used in medical

applications. It is compatible with biological systems and is often employed in drug
delivery systems and tissue engineering scaffolds.
Poly(glycolic acid) (PGA): Similar to PLA, PGA is biodegradable and has been used
in various biomedical applications, including absorbable sutures and tissue
engineering.
Poly(lactic-co-glycolic acid) : PLGA is a copolymer of lactic acid and glycolic acid,
combining the properties of both. It is widely used in drug delivery systems and
medical implants.
Chitosan: Derived from chitin, a natural polymer found in the exoskeletons of
crustaceans, chitosan is biodegradable and has antimicrobial properties. It is used in
wound dressings, drug delivery, and tissue engineering.
Polyethylene glycol : PEG is a water-soluble polymer known for its biocompatibility.
It is often used as a coating to improve the biocompatibility of surfaces and as a
component in drug delivery systems.

Bioactive compatible polymers play a crucial role in the development of advanced

biomedical materials that can seamlessly integrate with living tissues, deliver
therapeutic agents, and support regenerative processes. The choice of a specific
polymer depends on the intended application and the desired biological interactions.

Biocompatible Polymers:

Biocompatible polymers are materials that do not elicit a significant immune response
or toxicity when in contact with biological systems. These polymers are well-tolerated
by the body and are used in various medical devices, drug delivery systems, and
implants. The goal is to minimize adverse reactions and ensure compatibility with the
biological environment. Examples of biocompatible polymers include:

 Polyethylene
 Polytetrafluoroethylene
 Polylactic acid
while bioactive polymers are designed to actively interact with biological systems,
promoting specific responses, biocompatible polymers focus on being well-tolerated
by the body, minimizing adverse reactions. These materials play crucial roles in
advancing medical technologies and improving the performance of various
biomedical devices and systems.
Blending of these biomaterials with synthetic polymers is non-ideal due to phase
separation. Hence, the creation of new hybrid materials with both biological and
mechanical properties, is critical to improvement of healthcare outcomes.

Synthesis of Bioactive polymers

Bioactive PCL-peptide and PLA-peptide brush copolymers for bone-tissue

engineering. Inspired by these positive outcomes, we sought to utilize ROMP to
construct peptide-containing bioactive polyethylene copolymers for use as
bioadditives in orthopaedic materials. The preparation of a series of “bioactive
polyethylene” brush copolymers via ROMP, consisting of PE side chains and
PEGylated RGD or . The “bioactive polyethylene” was formulated with ultra-high
molecular weight polyethylene and 3D-printed into coupons for biovalidation in
vitro and in vivo. It functions as a carrier for thermally sensitive biomolecules in high-
melting point polymers such as UHMWPE. Also, the biocompatibility of UHMWPE
is improved using this “bioactive polyethylene” without premature degradation of the
biomolecules RGD , which are present in the final PE formulation.
 Fig. 1 Schematic of a bioactive polyethylene-peptide brush copolymer.

Selection of Monomers:
Choose monomers that contain functional groups or structures with bioactive
properties. Monomers are the building blocks of polymers, and their selection is
crucial in determining the bioactivity of the resulting polymer.

Polymerization:
Use a suitable polymerization technique to link the selected monomers together to
form a polymer chain. Common polymerization methods include:

Free Radical Polymerization: Initiators generate free radicals that initiate the
polymerization process.
Ring-Opening Polymerization: Particularly used for cyclic monomers like lactides
and glycolides.
Living Polymerization Techniques: Such as atom transfer radical polymerization or
controlled radical polymerization, which allows for precise control over the polymer
chain length.

Incorporation of Bioactive Groups:

Modify the polymer by incorporating bioactive groups or molecules during or after
polymerization. This step is crucial for conferring specific bioactive properties to the
polymer. Common bioactive groups include peptides, proteins, carbohydrates, or
other functional groups that can interact with biological systems.

Crosslinking or Modification:
Depending on the application, the synthesized polymer may undergo crosslinking or
further modification to enhance its stability, mechanical properties, or bioactivity.
Crosslinking can be achieved through chemical reactions or physical processes.

Purification:
Purify the synthesized polymer to remove any unreacted monomers, by-products, or
impurities. This step is essential to ensure the final product's safety and effectiveness.

Characterization:
Characterize the synthesized bioactive polymer using analytical techniques such as
spectroscopy (e.g., NMR, FTIR), chromatography, and other methods to confirm its
structure and properties.

It's important to note that the synthesis of bioactive polymers can be highly
specialized and application-dependent. Researchers often tailor their synthesis
methods to achieve specific properties required for a particular biomedical
application, such as drug delivery, tissue engineering, or medical implants.
Additionally, safety considerations are crucial in designing bioactive polymers for use
in biological systems. Always follow appropriate ethical and safety guidelines when
working with bioactive polymers and other biomedical materials.
Neobiopolymers have been generated by a number of different polymerization
strategies. These include
 Radical polymerization
 Cationic polymerization
 Ring-opening polymerization
 Ring-opening metathesis polymerization
 The key mechanistic issues, advantages, and disadvantages of each method are
outlined in this chapter. In addition, the recent, significant advances in ring-
opening metathesis polymerization
for the synthesis of novel biopolymers will be discussed.

Methods Used to Generate Bioactive Polymers

Free radical polymerization was the first method used to generate neobiopolymers .
The polymerization reaction requires a radical initiator such as
tetramethylenediamine, ammonium peroxysulfate , or 2,2'-azobisisobutyronitrile .
Under optimized conditions, these compounds serve as initiators by forming the first
radical species. The resulting radical can then react with a substrate, generally an
electron deficient olefin such as acrylamide, which generates a new intermediate.
 From this radical species, the polymerization reaction propagates until the
monomer is completely consumed.
 The chemistry of this process has important advantages, including a tolerance for
monomers with polar, functional groups and the ability to conduct the reactions
of such monomers in water.
 Large drawbacks of the radical approach exist, however, in that the polymers
resulting from these processes often have high molecular weights and high
polydispersities .

Fig. 1A,B. Application of radical polymerization to the synthesis of

neobiopolymers. A Y.C. Lee's approach to galactose-substituted polyacrylamide
gels. B The stages of radical polymerization

The product heterogeneity that results from radical polymerizations arises from
inefficient initiation, chain transfer and termination events. Ideally, each initiating
species, for example APS, would generate a reactive monomer, but initiation typically
does not occur with the desired efficiency. Vinyl polymerizations, which are common
for the generation of neoglycopolymers, typically have initiation efficiencies between
60% and 100% [9]. Under such conditions, control of polymer length is not feasible.
This problem is difficult to solve. Developing molecules that undergo more rapid
initiation is not enough; the intermediates generated are active enough to undergo
chain transfer (addition of two growing chains) or termination. These alternative
reaction processes add to the difficulty of generating materials of controlled lengths as
well as complicating the synthesis of mixed copolymers (polymers incorporating
different monomer templates). Despite these challenges, significant progress toward
developing living free radical polymerizations has been made [10], and these methods
have recently been applied to the synthesis of well-defined neoglycopolymers
Cationic Polymerization
Cationic Polymerization Another reaction that has been applied to the generation of
highly functionalized polymers is cationic polymerization [12–15]. Catalysts for
cationic polymerizations are aprotic acids, protic acids, or stable carbocation salts. In
these processes, the catalyst generally reacts with a cocatalyst to form an active
initiated species. Initiation takes place by protonation of the monomer (Fig. 2A).
Monomers that possess cation stabilizing groups, such as electron rich olefins, are
preferred as they more readily undergo the desired polymerization process
Fig. 2A,B. Application of cationic polymerization for neobiopolymer
synthesis. A Mechanism of polymerization. B Minoda's use of
Higashimura and Sawamoto's initiating system to generate a protected
glucose-substituted poly- mer
with minimal side reactions. Because of the high reactivity of the
carbocationic intermediates, an advantage of the electron-rich alkene
monomers is that the polymerization reactions can be conducted at or
below 0˚C, thereby minimizing byproducts [16]. While there have been
examples of living cationic polymerization and copolymerization,
these reactions will not tolerate key functional groups found in
biomolecules, such as multiple amides, nitrogen-containing
heterocyclic rings and alcohols [16]. For example, carbohydrate-
substituted polymers can be prepared by this method, but the hydroxyl
groups must be protected (Fig. 2B) [13]. For unique functional
groups, such as sulfate, found in biologically important natural
carbohydrates and glycoproteins, no suitable protecting group
strategy is available. Materials derived from peptides and nucleic
acid components would also be difficult to produce by this strategy,
given the diversity of nucleophilic functional groups relevant for
their biological activities. Moreover, even for the synthesis of
polymers displaying less functionalized saccharides, the need for
protection can complicate the synthesis. For example, the efficiency
of the protecting group removal for some masked polymers was shown to
be dependent on the type of protecting group used [17, 18]. Another
potential drawback is that the protecting group can interact with the
catalyst system, as was suggested for the phthalimide group in a
protected glucosamine monomer [13]. Therefore this method can be used
to generate some bioactive polymers, but its scope is limited.

Effects of fungal based bioactive compounds on human health

Alternatively, filamentous fungi, which can be easier to produce, play an active role in
the synthesis of some bioactive compounds, which are also important for health, as
well as being rich in protein content. Therefore, this review presents some important
bioactive compounds synthesized by fungal strains and their health benefits. In
addition, potential probiotic- and prebiotic fungi were researched to determine their
effects on gut microbiota. The current uses of fungal based bioactive compounds for
cancer treatment were also discussed. The use of fungal strains in the food industry,
especially to develop innovative food production, has been seen as promising
microorganisms in obtaining healthy and nutritious food.

Fungal-based bioactive compounds have various health benefits.Prebiotic fungi play

an active role in the regulation of gut microbiota.Anti-tumor effective fungal
components will contribute to alternative medicine.

Categories of bioactive material

As with the pathways of biocompatibility, the bioactivity pathways are not entirely
new biological phenomena, but biological processes that normally contribute to the
performance of living systems, and which can be identified as being, at least partly,
responsible for a biomaterial's performance. In each situation where bioactive
materials may have beneficial clinical outcomes, the most appropriate way to identify
putative pathways for that activity would be to start with the fundamental mechanisms
associated with the inherent biological characteristics of the target tissues and/or cells
and then identify any way in which the biomaterial could possibly influence those
characteristics. This is surely better than the phenomenological process of observing
some outcomes under experimental conditions and extrapolating to potential clinical
outcomes.
 Materials that promote or inhibit cell adhesion in soft tissues
 Materials that promote endothelialization
 Materials that modulate inflammation
 Immunomodulatory materials
 Materials with antioxidant activity
 Materials that promote wound healing
 Anti-infective materials
 Anti-thrombogenic materials

Biomaterials in bone regeneration assess a range of critical parameters to obtain the

optimal outcome for future translational use. Engineered tissues have developed as a
viable methodology for the rehabilitation and recovery of bones severely impaired
due to external injury, cancer, or aging.

Mechanism of activity

The underlying mechanisms that enable bioactive glasses to act as materials for bone
repair have been investigated since the first work of Hench et al. at the University of
Florida. Early attention was paid to changes in the bioactive glass surface. Five
inorganic reaction stages are commonly thought to occur when a bioactive glass is
immersed in a physiological environment:
A step by step image of the integration of bioactive glass with bone Ion exchange in
which modifier cations in the glass exchange with hydronium ions in the external
solution.
Hydrolysis in which Si-O-Si bridges are broken, forming Si-OH silanol groups, and
the glass network is disrupted.
Condensation of silanols in which the disrupted glass network changes its
morphology to form a gel-like surface layer, depleted in sodium and calcium ions.
Precipitation in which an amorphous calcium phosphate layer is deposited on the gel.
Mineralization in which the calcium phosphate layer gradually transforms into
crystalline hydroxyapatite, that mimics the mineral phase naturally contained with
vertebrate bones.
Later, it was discovered that the morphology of the gel surface layer was a key
component in determining the bioactive response. This was supported by studies on
bioactive glasses derived from sol-gel processing. Such glasses could contain
significantly higher concentrations of SiO2 than traditional melt-derived bioactive
glasses and still maintain bioactivity . The inherent porosity of the sol-gel-derived
material was cited as a possible explanation for why bioactivity was retained, and
often enhanced with respect to the melt-derived glass.
Subsequent advances in DNA micro array technology enabled an entirely new
perspective on the mechanisms of bioactivity in bioactive glasses. Previously, it was
known that a complex interplay existed between bioactive glasses and the molecular
biology of the implant host, but the available tools did not provide a sufficient
quantity of information to develop a holistic picture. Using DNA micro arrays,
researchers are now able to identify entire classes of genes that are regulated by the
dissolution products of bioactive glasses, resulting in the so-called "genetic theory" of
bioactive glasses. The first micro array studies on bioactive glasses demonstrated that
genes associated with osteoblast growth and differentiation, maintenance
of extracellular matrix, and promotion of cell-cell and cell-matrix adhesion were up-
regulated by conditioned cell culture media containing the dissolution products of
bioactive glass.

Structure and Features of Chitosan

Chitin is a polysaccharide, which is formed of as the result of binding of 2 –

acetamide – 2 deoxy – D – glucopyronose and 2 – amino – 2 deoxy – D –
glucopyronose units with β (1-4) bond . Chitosan is a compound, which commercially
obtained by applying chemical reaction, which include demineralization,
deproteinization, declorization, and deacetylation processes . Chitin 70% de- astyle
chitosan solution is obtained after deasetylation of chitin for 1 – 3 hours in 40%
sodium hydroxide solution under 120 °C. T Chitosan is a compound, which is not
soluble in many organic solutions and water with neutral pH. However, it can be
dissolved in organic acid solutions such as acetic acid, formic acid, tartaric acid,
valeric acid, glycolic acid, and citric acid and also in diluted inorganic acid solutions
such as hydrochloric acid and sulfuric acid. The fact that chitosan is not soluble in
water constitutes a significant impediment against it can have an extensive
antibacterial effect.
Chitosan is a compound, which is not soluble in many organic solutions and water
with neutral pH. However, it can be dissolved in organic acid solutions such as acetic
acid, formic acid, tartaric acid, valeric acid, glycolic acid, and citric acid and also in
diluted inorganic acid solutions such as hydrochloric acid and sulfuric acid. The fact
that chitosan is not soluble in water constitutes a significant impediment against it can
have an extensive antibacterial effect.

Figure 2. Chemical process of Chitosan production

Its Antimicrobial Feature

Start of the studies on chitosan in modern ages goes back to 1990s and its first feature,
which was discovered, was its antimicrobial feature. Chitosan and chitosan
derivatives show antimicrobial activity in a wide spectrum on human pathogens and
on bacteria, which cause food borne intoxication. It was found out in the first studies
on the antimicrobial activity of chitosan that it had an inactivating effect on both
Graham positive and Graham negative bacteria in a wide spectrum . In the further
studies conducted in the following years, six different mechanisms regarding the
antimicrobial feature of chitosan were explained:
 Positive loaded amine groups of chitosan interact with negative loaded microbial
cell membranes. That enables compounds with protein and other inner cell
compounds to leak out. Chitosan blocks active parts of various enzymes and
causes enzyme inhibition and activates some protective
 With its binding feature, chitosan binds some metals to itself and that enables to
suppress the toxin production and stopping microbial growth in the cell.
 Chitosan with low molecule weight interferes with the penetration of
microorganism through stazole in order to bind DNA and with the mRNA and
protein synthesis.
 Chitosan breaks the physiologic activities such as adsorbtion in the
microorganism cell and flocculation of electronegative substances and causes the
death of the microorganisms
Usage in Bioactive Packing

Packing is of great importance for foods with short live such as sea food. Although
traditional packing methods are used for packing those products, alternative packing
materials have been sought because of the known negative effects of traditional
methods both on the food and on environment. As it is known that packing materials
have effect on costs and causes increase in the sale price of the final product, the
alternative packing materials are required as low cost materials. In accordance with
that requirement, production of edible bioactive packing materials has accelerated
especially in the recent years.
 Chitosan is one of the materials, which is frequently used in the production of
those bioactive materials. Chitosan films tend to show resistance against lipid
diffusion and differential permeability of gasses.
 Because of this quality, it has a fine protection for oxygen, nitrogen and carbon
dioxide permeability in the food. It is reported that chitosan forms a barrier
between the food and the atmospheric gasses around and delays the lipid
oxidation by slowing down the diffusion of oxygen in the food in that way.
Its Usage in Pharmaceutics

Chitosan has significant usage area in pharmaceutics. Chitosan is a material, which is

frequently used in developing especially nasal, vaginal and ophthalmic transdermal,
parenteral, colon specific medicines and the medicines taken from human body. For
that reason, these qualities of the polymer are stated as the qualities to be considered
in choosing the appropriate quality chitosan to be used as specific medicine cover
agent. The quality of not being soluble in mineral and organic acids of this
biodegradable polymer increases its usage as medicine cover agent in medicine
industry . Usage areas of chitosan in pharmaceutics can be listed as follows:
 Usage as diluents agent in compressed medicine.
 Usage as binding agent for wet granulation,
 In tablets and granules of slow release medicine,
 Usage as medicine carrier in micro particle system,
 In the films that control the medicine release,
 In preparation of hydro gels an agent that increases the viscosity in the
solution,
 Usage as auxiliary agent for the active ingredients whose dissolution capacity
are low in solution,