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Biodegradable Polymers:

What is Polymer Degradation?

polymer degradation was viewed negatively as a process where properties and performance deteriorated with time.

Some of the important properties of a biodegradable

biomaterial can be summarized as follows The material should not evoke a sustained inflammatory or toxic response upon implantation in the body. The material should have acceptable shelf life. The degradation time of the material should match the healing or regeneration process. The degradation products should be non-toxic, and able to get metabolized and cleared from the body. The material should have appropriate permeability and processibility for the intended application.

Hydrolytically degradable polymers are polymers that have hydrolytically labile chemical bonds in their back bone. The functional groups susceptible to hydrolysis include 1) esters, 2) orthoesters,

3) anhydrides,
4) carbonates, 5) amides, 6) urethanes, 7) ureas,

Biodegradable Polymers
Carbonyl bond to O N S

A.
O R1 C X R2 H2O R1 O C OH

+ HX

R2

Where X= O, N, S
O R1 C O R2

O R1 C NH R2 R1

O C S R2

Ester

Amide

Thioester

B.

Biodegradable Polymers
O R1 X C X' R2 H2O R1 X O C OH

HX'

R2

Where X and X= O, N, S
O R1 O C O R2 R1 NH O C O R2 R1 NH O C NH R2

Carbonate

Urethane

Urea

C.

O R1 C X

O C R2

H2O R1

O C OH

+
O

HX

R2

Where X and X= O, N, S
O R1 C NH O C R2 R1 O O C R2 C

Imide

Anhydride

Biodegradable Polymers
H C H

Acetal:

R'

H2O

OH

+
H

C H

R'

OH

OH

OH

Hemiacetal:
Ether
R

C C

O
C OH
H O C H

OH

OH C

C H2O C OH OH C
H R C H

OH + H2O C OH C==O H
H OH

OH C
H C H

R'

H2O

R'

C H H

OH

Nitrile
R

H C C R N

H2O

H R C C H2N R O

H2O

C C HO

R O

Phosphonate
RO

O H2O P OR''
H R C H CN C C O OR'' H C H CN C C O OR''' R' H2O R H C H

O OR' R OH

+ HO

P OR''
CN C

OH

+ HO

R'

Polycyanocrylate

H C H OH

CN

C C O OR'''

R'

C O OR''

Synthetic or Natural Biodegradable Polymers Why Do We Prefer Synthetic Ones?


Tailor-able properties

Predictable lot-to-lot uniformity


Free from concerns of immunogenicity Reliable source of raw materials

Degradation:The process of polymer chain scission by the cleavage of bonds between the monomers in polymer backbone Biodegradation:The chemical breakdown of materials by the action of living organisms which leads to changes in physical properties. Erosion:The mass loss of a polymer matrix due to the loss of monomers, oligomersor even pieces of nondegraded polymer. Erosion can be the result of 1. biological, 2. chemical 3. or physical effects. Degradation is the most important part of erosion.

Degradable mechanism
Degradation is characterized by a loss of molecular weight and initiates polymer erosion. Four major modes of polymers degradations: 1. Photo-degradation 2. Mechanical-degradation 3. Thermal-degradation 4. Chemical-degradation Chemical degradation is the most important for biodegradable polymers

Hydrolysisis the most important mode of chemical degradation. Hydrolysis------breakdown of organic materials through the use of water Catalyzed by acids, based, salts, or enzymes. The result of its chemical structure, its morphology, its

dimensions and the bodys environment.

General stages of hydrolysis


A :Starts with water penetrates deeply into the interior areas B :The functional groups in polymer chains hydrolyze and absorb

the water. Water reacts with the polymer resulting in cleavage of


covalent chemical bonds

C :Polymer is broken down to oligomersand monomers

(transported from the polymer bulk controlled by diffusion)


D: The release of degradation products leads to the mass loss which is characteristic for erosion.

Factors affecting the velocity of degradation 1. Chemical bond nature: functional groups (depend on main chain structure: anhydride > ester > carbonate) 1. Water uptake: degradation rates increase when raising the content of the hydrophilic components 2. PH: change degradation rates of polyesters by orders of magnitude 3. Crystallinity (Amorphous phase is only accessible to permeants and susceptible to enzyme attack.

4. GLASS TRANSITION TEMPERATURE: 1. The glassy / rubbery state of the polymer has a impact on chain mobility and permeability characteristics of the polymer. 2. The molecular chain mobility determines the vunerability of the polymer to enzyme attack.

3.

The lysed fragments are unable to diffuse through the polymer in the gassy state
leading to intensification of autocatalyticic hydrolysis as in polymer s like PLGA and PLA.

5. PHYSICAL DIMENSION: Size and surface to volume ratio are significant in biodegradation Particularly in important in primary stage of biodegradation when phagocytosis occurs

Factors Influence the Degradation Behavior


Chemical Structure and Chemical Composition Distribution of Repeat Units in Multimers Molecular Weight Polydispersity Presence of Low Mw Compounds (monomer, oligomers, solvents, plasticizers, etc) Presence of Ionic Groups Presence of Chain Defects Presence of Unexpected Units Configurational Structure Morphology (crystallinity, presence of microstructure, orientation and residue stress) Processing methods & Conditions Method of Sterilization Annealing Storage History Site of Implantation Absorbed Compounds Physiochemical Factors (shape, size) Mechanism of Hydrolysis (enzymes vs water)

Enzymatic degradation

Mainly effective for naturally polymers(polysaccharides and polypeptides) Serve a classic catalytic function, altering reaction rate (via ion or charge transfer) by modifying activation energy

Degradation Schemes
Surface erosion with polymer which are hydrophobic but

contains labile chemical groups that are hydrolysable (poly(ortho)esters and polyanhydrides)
Sample is eroded from the surface
SE maintains the bulk integrity Mass loss is faster than the ingress of water into the bulk

Bulk degradation (PLA,PGA,PLGA, PCL)


Degradation takes place throughout the whole of the sample Ingress of water is faster than the rate of degradation

Polymer Degradation by Erosion (1)

Erodible Matrices or Micro/Nanospheres

Classification based on Chemical mechanisms includes :

Type-I: This type of erosion is evident with water soluble polymers


that are cross linked to form water insoluble. When placed in water it swells to extent permitted to cross link density then cleavage of crsosslinks takes place polymer and finally dissolve. leading to further swelling of

Type-II: Occurs with polymers that were already water insoluble


but converted to water soluble by hydrolysis,Ionisation
Type-III :Polymer having high MW but transformed to small water soluble by hydrolytic cleavage of labile groups

Classification of Biodegradable Polymers

PLGA/PLA

Polyglycolide is a highly crystalline polymer (4555% crystallinity) The glass transition temperature of the polymer ranges from 35 to 40 1C . the melting point is greater than 200 1C. Due to its excellent fiber forming ability, polyglycolide was initially investigated for developing resorbable sutures. The first biodegradable synthetic suture called DEXONs that was approved by the United States (US) Food and Drug Administration Solubility: Insoluble with most organic solvent except Halogenated hydrocarbons,tetrahydrofuran,dioxane,ethylacetate. Polyglycolide is a bulk degrading polymer, degrades by the non-specific scission of the ester backbone.

The polymer is known to lose its strength in 12 months when hydrolyzed and losses
mass within 612 months. Rate of hydration and degree of degradation can be increased by increasing the glycolide ratio in copolymer.

In the body, polyglycolides are broken down into glycine which can be excreted in the urine or converted into carbon dioxide and water via the citric acid cycle
Polylactides

Unlike glycolide, lactide is a chiral molecule and exist in two optically active forms; L-lactide and D-lactide.

The polymerization of these monomers leads to the formation of


semi-crystalline polymers. The polymerization of racemic (D,L)-lactide and mesolactide however, results in the formation of amorphous polymers.

Among these monomers, L-lactide is the naturally occurring isomer. poly(L-lactide) (PLLA) is also a crystalline polymer (37% crystallinity) and the degree of crystallinity depends on the molecular weight and polymer processing parameters. It has a glass transition temperature of 6065 1C and a melting temperature of approximately 175 1C. Poly(L-lactide) is a slow-degrading polymer compared to polyglycolide. being more hydrophobic than polyglycolide, the degradation rate of PLLA is very low. It has been reported that high molecular weight PLLA can take between 2 and 5.6 years for total resorption in vivo

Poly(DL-lactide) (PDLLA) is an amorphous polymer due to the random distribution of Land D-lactide units

has a glass transition temperature of 5560 1C.


Due to its amorphous nature the polymer shows much lower strength (1.9 GPa) compared to poly(L-lactide). This polymer loses its strength within 12 months when hydrolyzed and undergoes a loss in mass within 1216 months . Being a low strength polymer with faster degradation rate compared to poly(L-lactide), it is a preferred candidate for developing drug delivery

Polylactides undergo hydrolytic degradation via the bulk erosion mechanism by the

random scission of the ester backbone. It degrades into lactic acid a normal
human metabolic by-product, which is broken down into water and carbon dioxide via the citric acid cycle

PLGA
A co-polymer containing glycolic acid (GA) and L-lactic acid (LA). Both L- and DL-lactides have been used for co-polymerization. In the composition range of 2575%, poly(L-lactide-co-glycolide) forms amorphous polymers. The

intermediate co-polymers were found to be much more unstable compared to the


homopolymers. Thus, 50/50 poly(DL-lactide-co-glycolide) degrades in approximately 12 months, 75/25 in 45 months and 85/15 in 56 months. PuraSorbsPLG is a semicrystalline bioresorbable co-polymer of L-lactide and glycolide with a monomer ratio of 80L:20G. PLGA has been shown to under go bulk erosion through hydrolysis of the ester bonds and the rate of degradation depends on a variety of parameters including the LA/GA

ratio, molecular weight, and the shape and structure of the matrix. PLGA demonstrates
good cell adhesion and proliferation making it a potential candidate for tissue engineering applications

Several drug delivery vehicles composed of PLGA, such as microspheres, microcapsules, nanospheres and nanofibers have been developed for the controlled release of drugs or proteins. Depending on the nature of the PLGA used, the drug or protein has been shown to have varying extents of interactions with the base polymer resulting in rapid or prolonged release profiles .However, due to the bulk degradation of the polymers, the achievement

of zero-order release kinetics from these polymer matrices has been found to be difficult.
Another concern with using PLGA as a protein delivery vehicle is the possibility of protein denaturation within the delivery vehicle due to the bulk degradation mechanism of the polymer and the acidic degradation products produced.

This has led to the search for surface eroding polymers as ideal candidates for developing drug delivery vehicles. Surface eroding polymers have a greater ability to

achieve zero-order release kinetics for molecules delivered from the matrix and are able
to protect hydrolytically sensitive molecules by encapsulation.

Poly Carpo Lactones

PCL is a biodegradable and nontoxic polyester . Carpolactone is prepared by oxidation of cyclohexanone with peracetic acid. which is then polymerized by ring-opening polymerization in presence of tin octate

catlyst.
Polymerization may be by anionic, cationic ,coordination and radical type. PCL is soluble in a wide range of solvents. Its glass transition temperature is low,around -60 C, and its melting point is 60 65 C. PCL is a semi-rigid material at room te mperature PCL is a semicrystalline polymer due to its regular structure

Degradation Nonenzymatic Hydrolysis of PCL yields 6-hydroxycaproic acid which enters the citric acid cycle and is metabolized.

1. PCL has been used clinically as a degradable staple for wound closure 2. 1-year drug delivery system for contraceptives 3. Biodegradibility can be increased by copolymerisation 4. Have good permeability to low MW drugs(<400D) 5. PCL typically has the highest percent crystallinity and the slowest degradation rate as compared to the most common biodegradable polymers typically used for drug delivery such as PLA or PLGA.

Chitin and chitosan. Structurally chitosan is a linear polysaccharide consisting of b (1-4) linked D-glucosamine with randomly located N-acetylglucosamine groups depending upon the degree of deacetylation of the polymer. Chitosan is derived from chitin which is a fully acetylated polymer and forms the exoskeleton of arthropod

Enzymes, such as chitosanase, lysozyme and papain are known to degrade chitosan

in vitro .
The in vivo degradation of chitosan is primarily due to lysozyme and takes place through the hydrolysis of the acetylated residues. The rate of degradation of chitosan inversely depends on the degree of crosslinking, acetylation and crystallinity of the polymer ,. The highly deacetylated form exhibits the lowest degradation rates and may last several months

Poly(ortho esters)
Poly(ortho esters) were developed by the ALZA corporation (Alzamers) as a hydrophobic, surface eroding polymer designed specifically for drug delivery applications. Although the ortho ester linkages are hydrolytically labile, the polymer is hydrophobic enough such that its erosion in aqueous environments is very slow. The unique feature of poly(ortho esters) is that in addition to its surface erosion mechanism, the rate of degradation for these polymers, pH sensitivity, and glass transition temperatures can be controlled by using diols with varying levels of chain

flexibility.
The pH sensitivity of the poly(ortho esters) has lead to the development of several drug delivery systems using this polymer. The rate of drug release is predominantly controlled by the rate of polymer hydrolysis through the use of acidic or basic excipients.

Exist in 4 forms

(POE III polymer : gel-like material at room temperature) this viscous nature helps
in incorporation of therapeutic agents into the polymer matrix without the need for solvents . POE IV has been considered to be the biomaterial with greatest potential having well controlled release profiles for a wide range of pharmaceutical agents, including proteins.

Upon exposure to aqueous environments, the latent acid will undergo hydrolysis,
and the liberated lactic or glycolic acid will catalyze further polymer hydrolysis

Chitosan is soluble in weekly acidic solutions resulting in the formation of a cationic polymer with a high charge density and can therefore form polyelectrolyte complexes with wide range of anionic polymers The strong positive charges on chitosan makes it a very effective mucoadhesive as it can strongly interact with the negatively charged mucous membrane.

Chitosan has the ability to act as a permeation enhancer through its interaction with the
cell membrane resulting in a structural reorganization of tight-junction associated proteins. This, along with its mucoadhesive property, makes it a suitable candidate for use in both oral and nasal vaccination formulations.

chitin and chitosan have shown to have stimulatory properties on macrophages, and chemoattractive properties on neutrophils . These properties, along with its antibacterial, hemostatic properties give chitosan enourmous potential as a natural polymer for wound healing applications.

Alginic acid. Alginic acid present within the cell walls and intercellular spaces of brown algae Due to its non-toxicity, alginate has been extensively used as a food additive and a thickener in salad dressings and ice creams Alginate is a non-branched, binary copolymer of (1-4) glycosidically linked b-Dmannuronic acid and a-L-guluronic acid monomers. They are high molecular weight polymers having molecular weights up to 500 kDa. Aqueous solutions of alginates show non-Newtonian behavior.

Main disadvantages of using alginate-based materials is their inability to undergo enzymatic degradation by mammals. Poor bioadhesive property. Developing alginate gels by gamma irradiation has been reported to be another elegant way for developing degradable alginate gels
Another method to induce biodegradation to alginate-based materials is by chemical modification, which involves oxidation of the polymer backbone by

periodate resulting in formation of hydrolytically labile bond and the rate of


hydrolysis of the resulting polymer depends on pH and temperature

Fibrin
Fibrin is a biopolymer similar to collagen that is involved in the natural blood clotting process. Fibrin is derived from fibrinogen It has excellent biocompatibility, biodegradability, injectability

the presence of several extracellular matrix proteins, such as fibronectin, that


favorably affects cell adhesion and proliferation. Due to its injectability and biodegradability, fibrin has also been investigated as a carrier vehicle for bioactive molecules. Several cross-linking techniques are also currently under investigation to control the release profile of bioactive molecules from the fibrin matrix. Fibrin matrices have also been found to be excellent cell carrier vehicles. Bioseeds is

a fibrin-based product obtained by mixing keratinocytes with fibrin and is used to treat chronic wounds.
The fibrin clot, once formed, can undergo degradation called fibrinolysis in the body initiated by a complex cascade of enzymes present in the human body

Albumin Albumin is the most abundant protein in human blood plasma accounting to almost 50% of total plasma mass. Albumin is a water soluble-protein with a molecular weight of 66 kDa.

All tissues in human body have the ability to degrade albumin, making it a highly
preferred degradable biopolymer for medical applications. Due to its solubility and the presence of functional groups along the polymer chain, albumin can be easily processed into various shapes and forms such as membranes, microspheres, nanofibers and nanospheres. Due to its excellent blood compatibility, albumin has been extensively investigated as a carrier vehicle for intravenous drug/gene delivery . Albumin has also been investigated as coating materials for cardiovascular devices.

Gelatin Heterogenious product obtained by irreversible hydrolytic Extraction of treated animal collagen Physicochemical properties depends on source of collagen, Thermal degradation , pH value,extraction method, Electrolyte content Advantages Easy availability Low antigen profile Low temperature preparation technique Poor binding to drug molecules