pH-Responsive temperature. Thermoresponsive polymers are used for biomedical

pH-Responsive polymers are systems that its solubility, volume, and chain conformation can
be manipulated by changes in pH, co-solvent, and electrolytes. pH-sensitive polymers kind of
polyelectrolytes that include in their structure weak acidic or basic groups that accept or
release protons in response to a change in the pH. The acidic or basic groups of these
polyelectrolytes ionized like acidic or basic groups of monoacids or monobases. pH-
responsive polymers contain either weakly acidic ( carboxylic acid) or basic (ammonia)
groups, these either release protons or accept free protons in response to pH. 9

pH-responsive amphiphilic block copolymers are promising candidates for preparing
responsive soft materials due to their self-assembling properties . They contain a number of
ionizable groups in their main chains and pendants;thus their domains can be set to respond
to aqueous environments.

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The human body presents variations on pH along the gastrointestinal (GI) tract, and sub-
cellular compartments. The polymer–polymer and the polymer–solvent interactions (the

Fig. 2 – Types of Stimuli Materials 8

solvent in biomedical applications will usually be water) show an abrupt re-adjustment in
small ranges of pH. Changes in polymer conformation are manifested by alterations to
surface wettability, charge state or solubility. 10 These unique properties of pH-responsive
polymer systems consequently make them very useful in bio related applications such as drug
delivery, biotechnology, chromatography, and they have been used in several biomedical
applications, such as drug and gene delivery systems and glucose sensors.

2.1.1 – Synthesis of pH Responsive Polymers

Emulsion polymerization is among the most popular synthetic routes to pre-pare vinyl-based
pH-responsive polymers, especially microgel systems. This technique use a radical chain
polymerization methodology to form latexes of narrow particle size dispersion. The
emulsion polymerization systems are commonly composed of monomer(s), water, water-
soluble initiator and surfactant .One of the disadvantages of this technique is the use of
surfactants which may need to be removed at the end of the polymerization reaction, but it is
not always easy to carry out. 11

a)Mini-emulsion polymerization
b)Micro-emulsion polymerization
c)Group transfer polymerization (GTP)
d)Reversible addition-fragmentation chain transfer (RAFT) polymerization
e)Atom transfer radical polymerization (ATRP)

2.2 – THERMO RESPONSIVE POLYMERS

Thermoresponsive polymers are a class of “smart” materials that have the ability to respond
to a change in temperature. Thermoresponsive polymers are used for biomedical applications
including drug delivery, tissue engineering and gene delivery . Temperature-responsive
polymers exhibit a volume phase transition at a certain temperature, which causes a sudden
change in the solvation state. Polymers, which become insoluble upon heating, have a so-
called LCST. Systems, which become soluble upon heating, have an UCST. LCST and UCST
systems are not restricted to an aqueous solvent environment, but only the aqueous systems
are of interest for biomedical applications.

Typical LCST polymers are based on NIPAM , DEAM , MVE , and NVCI as monomers. 12
A typical UCST system is based on a combination of AAm and AAc. The combination of a
thermoresponsive monomer like NIPAM with one of a pH-responsive monomer yields
double-responsive copolymers . Most applications use the change from e.g. room temperature
to body temperature in order to induce a change in the physical properties for e.g. gelation,
especially in topical applications and in injectable biodegradable scaffolds.

Thermo responsive polymers are used for drug delivery,gene delivery,tissue engineering and
etc. Importance of deliver the drug to the right area, at the right time and at the right
concentration. The “smart” polymeric carriers are used to deliver drugs. These carriers allow
delivery of the drug at the right time and concentration by only releasing the drug in response
to an external stimulus. For example the polymer chains of a carrier may expand as a result of
the temperature increasing, thus enabling the drug to diffuse out and be released from the
carrier .

Gene therapy aims at the treatment of many genetic diseases as it is a technique for correcting
defective genes that are responsible for these genetic diseases. Specifically, the delivery of
the appropriate, therapeutic gene (DNA) into the cells that will replace, repair or regulate the
defective gene that causes the disease is a vital step for gene therapy.

Thermoresponsive polymers in tissue engineering are commonly used in two situations: as
substrates that enable the cell growth and proliferation and as injectable gels, for in situ of the
scaffold.

Thermoresponsive polymers offer great advantages in drug delivery. Instead of acting
passively as pure drug carriers, they will interact and respond to the environmental setting.
This allows us to aim further for tailor-made drug delivery with superior pharmacokinetics
while having all safety questions addressed. 13

2.2.1 – Selected Thermoresponsive Polymer Classes

a) Poly(N-alkylacrylamide)s
b)Poly(N-vinyl caprolactam) PVC
c) Poly(N-ethyl oxazoline) PEtOx

d) Poly(methyl vinyl ether) PMVE
e) Poly(acrylic acid-co-acrylamide)
f)Elastin-like oligo- and polypeptides
2.3 – BIOMOLECULE RESPONSIVE POLYMERS

Organs must respond to the existence of specific molecules and chemical changes for
maintaining the life. Biomolecule Responsive Polymers are the next generation of
biomaterials and drug delivery systems recognition of specific molecules and chemical
changes. Even though there is polymers in response to specific biomolecules like glucose,
enzyme etc. , they still need to further research for development. 14

Glucose responsive hydrogels are crucial for treatment of diabetes because of glucose

responsive hydrogels are very useful for the development of self-regulated insulin delivery

systems. Researchers using monomers for synthesizing glucose responsive hydrogels like,

“Ethylene-co-vinyl acetate (EVAc), N,N-diethylaminoethyl methacrylate (DEA), 2-

hydroxypropyl methacrylate (HPMA), MAAc, poly(ethylene glycol) monomethacrylate” 14
15

Biodegradable polymers have become important in biomedical research areas because of
their potential for usage in tissue engineering and drug delivery. Since some polymers can be
digested by specific enzymes, enzyme responsive hydrogels gained importance. Thus,
enzyme responsive hydrogels became using enzyme sensors and enzyme-sensitive drug
delivery systems. 14 There are monomers for synthesizing enzyme responsive hydrogels like,
“N,N-dimethylacrylamide (DMAAm), tert-butylacrylamide (AAc), combination of

PNIPAAm with enzymatic degradation consisting NIPAAm, DMAAm, butyl methacrylate
(BMA).” 14 16 17

Also, we can gave some examples to biomolecule responsive monomers like18;

–  NIPAm, MAA, AAm, MBAA for Cyt C or Lys response (Bulk) 19

–  HEMA, EGDMA for Hydrocortisone response (Bulk)20

–  NSA, AAm, MBAA for Alpha-fetoprotein response (Particle)21

–  Acryloyl-lectin, AAm, MBAA for Alpha-fetoprotein response (Hydrogel)22

–  AM, MBAA for Thrombin response (Hydrogel) 23

–  NIPAm, AAc, MBAA for DL-Norepinephrine Hydrochloride or DL-Adrenaline
Hydrochloride response (Hydrogel) 24 

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