1. INTRODUCTION:

Biodegradable polymers are a newly emerging field. A vast number of biodegradable polymers have been synthesized recently and some microorganisms and enzymes capable of degrading them have been identified. In developing countries, environmental pollution by synthetic polymers has assumed dangerous proportions. As a result, attempts have been made to solve these problems be including biodegradability into polymers in everyday use through slight modifications of their structures. ^[1]

One of the first problems to become apparent while over viewing the literature in this area is the fact that there are varying definition of 'biodegradation' and 'bioerosion. Ikada defines biodegradable polymers as those, which are degraded in these biological environments not through thermal oxidation, photolysis, or radiolysis but through enzymatic or non-enzymatic hydrolysis. ^[1] Williams ^[2] defines biodegradation as biological breakdown of polymeric material, as opposed to simple hydrolytic breakdown, a definition also held by Gilbert et al. ^[3]Gilding, on the other hand, reports that the phrase 'biodegradable polymer' is widely used for any polymer that undergoes in vivo degradation. ^[4] Graham and Wood define biodegradable system as those, which degrade after a period of time to soluble products easily removed from the implant site and excreted from the body. ^[5] A much more complete picture emerges with the various definitions listed according to their degradative pathway by Griffin. ^[6]In a strict sense, such polymers that require enzymes of microorganisms for hydrolytic or oxidative degradation are regarded as biodegradable polymers. This definition does not include polylactides in the category of biodegradable polymers, because polylactides are hydrolyzed at a relatively high rate even at room temperature and neutral pH without any help of hydrolytic enzymes if moisture is present. This often gives rise to confusion when we say that polylactides are biodegradable. Polylactides, especially polyglycolide, are readily hydrolyzed in our body to the respective monomers and oligomers that are soluble in aqueous media ^[4] and the whole mass of the polymers disappears, leaving no trace of remnants. Generally, such polymer that loses its weight over time in the living body is called an absorbable, resorbable, or bio-absorbable polymer, regardless of its degradation mode, in other words, for both enzymatic and non-enzymatic hydrolysis.

Bio-erosion is much less widely defined in the literature. Heller defines the term as the conversion of an initially water insoluble material to a water-soluble material, which may or may not involve major chemical degradation.^[7]Langer and Peppas on the other hand, initially made no distinction between bioerodible and biodegradable, but later discuss the term 'erodible' in the context of the ability of the polymer matrix degradation to control the rate of drug release.^{[8, 9]} According to Kumar, the term 'biodegradable polymer' refers to a polymer, which undergoes enzymatic degradation in a given physiological or microbial environment and where the secretion of degrading enzyme(s) is linked to a chemically recognizable cleavage of the molecular structure of the polymer. Also, according to him, bioerodible or bio-assimilable is mediated by less specific hydrolytic degradation process with no participation by enzymes.^[10] Vert et al. have described biodegradable as breakdown of the macromolecule with dispersion in animal body with no proof for elimination from the body (this definition excludes environmental, fungi or bacterial degradation).^[11] They refer to the term bioresorsable to material, which degrade and further resorb in vivo i.e. which are eliminated through natural pathways either because of simple filtration of degradation by-products or after their metabolism.

2. NEED FOR BIODEGRADABLE POLYMERS:

For many biomedical, agricultural and ecological uses, biodegradable polymers are preferred that undergo degradation in the physiological environment or by the microbial action in the soil. A classification of biodegradable polymers on the basis of the origin, that is, naturally occurring or synthetic is given below.The concept of a material, which can be proposed with the ease of conventional thermoplastics and which after performing a function as moisture or odor barrier or as a carrier for a payload of an active substance, simply erodes in a harmless way is an appealing one, and one which has recently been proposed for a number of problem areas in packaging, agro and pharmaceutical industries. Perhaps the greatest interest has stemmed from recent legislation in Italy against the non-degradable polyethylene grocery bags, and in a number of cases in USA against various conventional thermoplastics in uses, which result in obvious litter and ecological problems.^[12,13] These biodegradable polymers have currently two major applications, one is as biomedical polymers that contribute to the medical care of patients and the other is as ecological polymers that keep the earth environments clean. Most of the currently available biodegradable polymers are used for either of the two purposes, but some of them are applicable for both, as illustrated in Fig. 1.

Figure 1. Application of biodegradable polymers

PAA: Poly (acid anhydride), PBS: Poly (butylene succinate), PCA: Poly (cyanoacrylate), PCL: Poly (-caprolactone), PDLLA: Poly (D,L-lactide), Poly (D,L-lactic acid), PEA: Poly (ester amide), PEC: Poly (ester carbonate), PES: Poly (ethylene succinate), PGA: Poly (glycolide), Poly (glycolic acid), PGALA: Poly (glycolide-co-lactide), Poly (glycolic acid-co-lactic acid), PHA: Poly (hydroxyalkanoate), PHE: Poly (3-hydroxybutyrate), PLLA: Poly (L-lactide), Poly (L-lactic acid), POE: Poly (orthoester)

A variety of polymers have been used for medical care including preventive medicine, clinical inspections, and surgical treatments of diseases.^[14]Among the polymers employed for such medical purposes, a specified group of polymers are called polymeric biomaterials when they are used in direct contact with living cells of our body. Typical applications of biomaterials in medicine are for disposable products (e.g. syringe, blood bag, and catheter), materials supporting surgical operation (e.g. suture, adhesive, and sealant), prostheses for tissue replacements (e.g. intra-ocular lens, dental implant, and breast implant), and artificial organs for temporary or permanent assist (e.g. artificial kidney, artificial heart, and vascular graft). These biomaterials are quite different from other non-medical, commercial products in many aspects. For instance, neither industrial manufacturing of biomaterials nor sale of medical devices are allowed unless they clear strict governmental regulatory issues. Biocompatibility is highly desirable but not indispensable, most of the clinically used biomaterials lack excellent biocompatibility, although many efforts have been devoted to the development of biocompatible materials by biomaterials scientists and engineers. A large unsolved problem of biomaterials is this lack of biocompatibility, especially when they are used not temporarily but permanently as implants in our body. Low effectiveness is another problem of currently used biomaterials.

2.1 Classification of biodegradable polymers

A) Natural Polymers

1. Plant origin

1.1 Polysaccharides: Cellulose, Starch, and Alginate

2. Animal origin

2.1 Polysaccharides: Chitin (Chitosan), Hyaluronate

2.2 Proteins: Collagen (Gelatin), Albumin

3. Microbe origin

3.1 Polyesters: Poly (3-hydroxyalkanoate)

3.2 Polysaccharides: Hyaluronate

B) Synthetic Polymers

1. Aliphatic polyesters

1.1 Glycol and dicarbonic acid polycondensates:

Poly (ethylene succinate), Poly (butylene terephthalate)

1.2 Polylactides:

Polyglycolide, Polylactides

1.3 Polylactones:

Poly (-caprolactone)

1.4 Miscellaneous:

Poly (butylene terephthalate)

2. Polyols

Poly (vinyl alcohol)

3. Polycarbonates

Poly (ester carbonate)

4. Miscellaneous

Polyanhydrides,

Poly (-cyanoacrylate)s,

Polyphosphazenes,

Poly (orthoesters)

Recently, biodegradable medical polymers have attracted much attention. ^{[15, 16, 17]} There are at least two reasons for this new trend. One is the difficulty in developing such biocompatible materials that do not evoke any significant foreign-body reactions from the living body when receiving man-made biomaterials. At present we can produce biomaterials that are biocompatible if the contact duration of biomaterials with the living body is as short as several hours, days, or weeks.^[18] However, the science and technology of biomaterials have not yet reached such a high level that allows us to fabricate biocompatible implants for permanent use. On the contrary, biodegradable polymers do not require such excellent biocompatibility since they do not stay in our body for a long term but disappear without leaving any trace of foreign materials.

The other reason for biodegradable polymers attracting much attention is that nobody will want to carry foreign materials in the body as long-term implants, because one cannot deny a risk of infection eventually caused by the implants.

2.2 Surgical use

Application of biodegradable polymers to medicine did not start recently and has already a long history. Actual and possible applications of biodegradable polymers in medicine are shown in Table 1. As is seen, most of the applications are for surgery. The largest and longest use of biodegradable polymers is for suturing. Suture materials are required to keep wounds together until they hold sufficiently well by themselves. They provide artificial fiber support until the natural fiber (collagen) is synthesized and woven in to a strong scar. Collagen fibers obtained from animal intestines have been long used as absorbable suture after chromium treatment. ^[19]

Throughout the history of surgery, absorbable sutures have been derived almost exclusively from various forms of collagen such as catgut. Catgut, however, produces an allergic reaction in a number of patients, along with other problems such as fast loss of mechanical strength, problems with knot holding etc. Baptist presented the idea of synthetic biodegradable sutures based on PHB and in 1966 Kulkarni et al. reported the manufacture of biodegradable Poly (L-lactic acid) sutures.^{[20, 21]}

Huggins ^[22]reported in 1954 the spinning of poly (glycolic acid) and in 1967 Schmitt and Polistina ^[23] obtained a patent on PGA sutures, which led in 1970 to the first commercial synthetic biodegradable suture (Dexon®) manufactured by American Cynamide Co.^[24] DuPont considered the polymer of homologous poly (lactide) (PLLA) for the same purpose.^[25] A copolymer of 92 mol % glycolide and 8 mol % lactide led to the development of the second commercial synthetic biodegradable suture (Vicryl®).^{[26, 27]}Both PGA/PLLA sutures are multifilament ones. Thick biodegradable monofilament sutures were developed from poly (p-dioxanone) (PDS) and from PGA/TMC (Maxon®). ^{[28, 29]}

Commercial polymers used for this purpose include polyglycolide, which is still the largest in volume production, together with a glycolide-L-Iactide (90:10) copolymer. ^{[4, 15]} The sutures made from these glycolide polymers are of braid type processed from multi -filaments, but synthetic absorbable sutures of mono-filament type also at present are commercially available. Biodegradable sutures have wide applications not only in closing wounds in soft tissues but also in repair of tendons, ligaments, and dislocation of joints. ^[30] Also, by constructing gauzes, felt or velour dressings from biodegradable fibers one can manufacture surgical dressing to protect a wound surface, such as burn, traumatic injury or surgical incision and adhesion to tissues. ^[31] Liquid-type products are mostly used for these purposes. Immediately after application of a liquid to a defective tissue where homeostasis, sealing or adhesion is needed, the liquid sets to a gel and covers the defect to stop bleeding, seal a hole, or adhere two separated tissues. As the gelled material is no longer necessary after healing of the treated tissue, it should be biodegradable and finally absorbed into the body. The biomaterials used to prepare such liquid products include fibrinogen (a serum protein), 2-cyanoacrylates, and a gelatin/ resorcinol/formaldehyde mixture. 2-Cyanoacrylates solidify upon contact with tissues as a result of polymerization to polymers that are hydrolysable at room temperature and neutral pH, but yield formaldehyde as a hydrolysis by-product. ^[4] Regenerated collagen is also used as a haemostatic agent in forms of fiber, powder, and assemblies.

Another possible application of biodegradable polymers is the fixation of fractured bones. Currently, metals are widely used for this purpose in orthopedic and oral surgeries in the form of plates, pins, screws, and wires, but they need removal after re-union of fractured bones by further surgery. It would be very beneficial to patients if these fixation devices can be fabricated using biodegradable polymers because there would be no need for a re-operation.

Table 1 Medical applications of bio-absorbable polymers

Applications	Trade Name	Composition	Manufacturer
Sutures	Dexon	PGA	Davis and Geck
	Maxon	PGA-TMC	Davis and Geck
	Vicryl	PGA-LPLA	Ethicon
	PDS	PDO	Ethicon
	Polysorb	PGA-LPLA	U. S. Surgical
	Biosyn	PDO-PGA-TMC	U. S. Surgical
	PGA Structure	PGA	Lukens
	Monocryl	PGA-PCL	Ethicon
Interference screw	Sysorb	DLPLA	Synos
	Arthrex	LPLA	Arthrex
	Bioscrew	LPLA	Linvatec
	Phusiline	LPLA-DLPLA	Phusis
	Biologically Quiet	PGA-DLPLA	Instrument Maker
	Endofix	PGA-TMC or LPLA	Acufex
Suture anchor	Bio-statak	LPLA	Zimmer
Suture anchor	Suretac	PGA-TMC	Acurex
Anastomosis clips	Lactasorb	LPLA	Davis and Geck
Anastomosis ring	Valtrac	PGA	Davis and Geck
Dental	Drilac	DLPLA	THM Biomedical
Angiplastic plug	Angioseal	PGA-DLPLA	AHP
Screw	SmartScrew	LPLA	Bionx
Pins and rods	Biofix	LPLA or PGA	Bionx
Pins and rods	Roser-pin	LPLA-DLPLA	Geistlich
Tack	SmartTack	LPLA	Bionx
Plates, mesh, screws	LactoSorb	PGA-LPLA	Lorenz
Guided tissue	Antisorb	DLPLA	Atrix
	Resolut	PGA-DLPLA	W. L. Gore
	Guidor	DLPLA	Procordia

2.3 Pharmaceutical use

In order to deliver drugs to diseased sites in the body in more effective and less invasive way, a new dosage form technology, called drug delivery systems (DDS), was started using polymers. The objectives of DDS include sustained release of drugs for a desired duration at an optimal dose, targeting of drugs to diseased sites without affecting healthy sites, controlled release of drugs by external stimuli, and simple delivery of drugs mostly through skin and mucous membranes. Polymers are very powerful for this new pharmaceutical technology. If a drug is administered through a parenteral route like injection, the polymer used as a drug carrier should be preferably absorbable, because the polymer is no longer required when the drug delivery has been accomplished. Therefore, biodegradable polymers are widely used, especially for the sustained release of drugs through administration by injection or implantation into the body. For this purpose, absorbable nanospheres, microspheres, beads, cylinders, and discs are prepared using biodegradable polymers.^{[32, 33, 34]} The shape of the most widely used drug carriers is a microsphere, which incorporates drugs and releases them through physical diffusion, followed by resorption of the microsphere material. If the drug carrier is soluble in water, the polymer need not to be biodegradable, because this polymer will be excreted from the body, associated with urine or feces although excretion will take a long time if the molecular weight of the polymer is extremely high.

2.4 Use for tissue engineering

Tissue engineering is an emerging technology to create biological tissues for replacements of defective or lost tissues using cells and cell growth factors. Also, scaffolds are required for tissue construction if of the lost part of the tissue is so large that it cannot be cured by conventional drug administration. At present, such largely diseased tissues and organs are replaced either with artificial organs or transplanted organs, but both of the therapeutic methods involve some problems. As mentioned earlier, the biocompatibility of clinically used artificial organs is mostly not satisfactory enough to prevent severe foreign-body reactions and to fully perform the objective of the artificial organs aimed for patients. The biofunctionality of current artificial organs is still poor. On the contrary, the biofunctionality of transplanted organs is as excellent as healthy human organs, but the patients with transplanted organs are suffering from side effects induced by immunosuppressive drugs administered. Another major problem of organ transplantation is shortage of organ donors. The final objective of tissue engineering is to solve these problems by providing biological tissues and organs that are excellent in both biofunctionality and biocompatibility than the conventional artificial organs. Biodegradable polymers are required to fabricate scaffolds for cell proliferation and differentiation, which result in tissue regeneration or construction. ^[14] Biodegradable polymers are necessary also for a sustained release of growth factors at the location of tissue regeneration. Generally, scaffolds used in tissue engineering are porous and three-dimensional to encourage infiltration of a large number of cells into the scaffolds. ^[35] Currently the polymers used for scaffolding include collagen, glycolide-lactide copolymers, other copolymers of lactide, and crosslinked polysaccharides.

2.5 Ecological applications (Processing of plastic wastes)

The other major application of biodegradable polymers is in plastic industries to replace biostable plastics for maintaining our earth environments clean. The first choice for processing of plastic wastes is reuse. However, only some plastic products can be re-used after adequate processing, and many of them are very difficult to recycle. In these cases, wastes are processed by landfill or incineration, but these processes often pollute the environments. If biodegradation by-products do not exert adverse effects on animals and plants on the earth, biodegradable plastics can be regarded as environment-friendly or ecological materials. Therefore, much attention has been focused on manufacturing biodegradable plastics, which, however, should address several requirements. They are to be low in product cost, satisfactory in mechanical properties, and not harmful to animals and plants when biodegraded. The biodegradation kinetics is also an important issue of biodegradable plastics.

Applications of biodegradable polymers in plastic industries are listed in Table 2. As can be seen, the applications cover a wide range of industries including agriculture, fishery, civil engineering, and construction, out door leisure, food, toiletry, cosmetics and other consumer products. It is possible that the waste left as a result of outdoor activity and sports will stay for a long time in natural environments, possibly damaging them. On the other hand, when plastics are used indoors as food containers that are difficult to separate from the food remaining after use, the waste can be utilized as compost if it is biodegradable. ^[36]

Table 2 Ecological applications of biodegradable polymers

Application	Fields	Examples
Industrial Applications	Agriculture, Forestry	Mulch films, Temporary replanting pots, Delivery system for fertilizers and pesticides
	Fisheries	Fishing lines and nets, Fishhooks, Fishing gears
	Civil engineering and construction industry	Forms, Vegetation nets and sheets, Water retention sheets
	Outdoor sports	Golf tees, Disposable plates, cups, bags, and cutlery

Composting	Food package	Package, Containers, Wrappings, Bottles, Bags, and Films, Retail bags, Six-pack rings
	Toiletry	Diapers, Feminine hygiene products
	Daily necessities	Refuge bags, Cups

3. MODES OF BIODEGRADATION:

Polymer degradation takes place mostly through scission of the main chains or side-chains of polymer molecules, induced by their thermal activation, oxidation, photolysis, radiolysis, or hydrolysis. Some polymers undergo degradation in biological environments when living cells or microorganisms are present around the polymers.

The various modes of degradation of polymers are given below. Heller has classified the various biodegradation mechanisms at three distinct types Fig. 2. ^[37]

Type I: In these systems, water-soluble polymers are insolubilized by means of hydrolytically or enzymatically unstable cross-links. As a result the polymeric matrix is highly hydrophilic and completely permeated by water. Since the active agent is located in an aqueous environment, compounds with high water solubility will be rapidly leached out independent of the matrix erosion rate. A useful application of these systems is for the slow release of water-soluble macromolecules that can be entangled in these systems and consequently are unable to escape until a sufficient number of cross-links have cleaved and the matrix cross-link density has been reduced.

Type II: These systems include polymers that are initially water-insoluble and are solubilized by hydrolysis, ionization or protonation of a pedant group. Since no backbone cleavage takes place, the solubilization does not result in any significant changes in MW. Polymers in this category are only useful in topical applications where elimination of high molecular weight, water-soluble macromolecule proceeds with no difficulty. e.g. partial esters of methyl vinyl ether and maleic anhydride copolymers.

Type III: This category includes hydrophobic polymers that are converted to low molecular weight water-soluble molecules by backbone cleavage. e.g. the most commonly used biodegradable polymers of this category are PLA, PLGA copolymers, poly caprolactones, poly orthoesters, poly amino acids and poly anhydrides.^[38]

Type I

Type II

Type III

Fig. 2 Schematic representation of biodegradation mechanism

4. MODES OF POLYMER DEGRADATION:

4.1 Quantitative Aspect of Polymer Degradation

In order to successfully design chemically controlled drug release systems, it is necessary to understand the main factors that determine the overall rate of the erosion or the degradation process. Zaikov has reported the in vivo breakdown of a polymer in terms of three degradative components, these being water (diffusivity), salt content/ pH of the physiological environment, and lastly enzymatic attack. ^[39] It is important to know the potentials of each of these factors and to determine their respective contribution to the destructive process. Following are some of the major factors involved in the degradation process.

Fig. 3 Mechanism of polymer matrix degradation

Water

It is known that water permeates well in non-hydrophobic polymers (e.g. hetero chain polymers and those carbon chain polymers, which have hydrolysable side groups) and therefore may be an agent responsible for polymer degradation in the organism. For majority of polymers, water diffusivity at 37^oC varies from 10^-6 to 10^-9cm²/ s. ^[40]The hydrolytic degradation kinetics for various polymers has been established. Comparison of hydrolytic degradation rate constant indicates that hydrolytic degradation rate of poly (ethylene terephthalate) ^[41] is extremely slow while that of poly (glycolide) ^[42] is very fast.

Salts

The anions and cations in electrolytes (as well as the acidity and alkalinity of the environment) have an important effect on both hydrolytic and oxidative polymer degradation. ^{[41, 43]}Salt solubility in polymer is related to water solubility. Hydrophobic polymers do not absorb salts where as hydrophilic polymers have a salt diffusivity close to that of water. It is reported that salts and the pH of the environment may produce a sizable catalytic effect on the hydrolysis of ester and amide bonds. ^[41]The ionic composition of human fluid is shown in Table 3. ^[38]

Phosphate ions are especially effective as a catalyst for hydrolytic degradation of carbonyl containing polymers.^[38] As seen from Table 3, they are available in sufficient concentration in plasma, interstitial fluid and particularly cellular fluid.

Enzymes

Enzymes may contribute considerably to polymer degradation in an organism. Structurally, enzymes are highly specialized complex proteins, which are produced by the cell in order to catalyze specific types of chemical reactions of biological importance. As the size of the molecule is enormous, the enzymes generally attack the polymeric device from the surface on in a thin surface layer. The enzymes are classified within one of the categories according to the general type of reaction they catalyze Table 4. In each case the enzyme may be highly specific for a given type of chemical structure or substrate, and it can increase the rate of reaction of the substrate by a factor of from 10⁶to 10²⁰fields without creating undesirable reaction products. ^[44]

The presence of enzymes on the surface of polymeric implants or in their surface layers has been detected numerous times by various, entirely chemical techniques. Acid phosphatase, for example, is available in enormous amount in the first two months after the implantation of the polymer. ^[38] The contribution of hydrolases and oxidases is especially significant in the degradation of carbon chain polymers.

4.2 Chemical stability of the polymer

The susceptibility of the polymeric backbone towards hydrolytic cleavage is probably the most fundamental parameter. Susceptibility of the polymer backbone structure towards hydrolysis can be used to predict the rate of bioerosion. The predicted stability of the various labile bonds are as follows ^[45]

Hydrocarbon ≥ amide ≥ urea ≥ carbamate ≥ ester ≥ anhydride

Thus polyanhydrides will tend to degrade faster than polyesters, which in turn will have a higher tendency to bio-erode than polyamides.

4.3 Hydrophobicity of the polymer matrix

Erosion rate of drug loaded matrix system is strongly dependent on the water permeability into the polymer matrix. The hydrophobicity of the polymer, which is a function of the structure of the monomeric starting material as well as the nature and loading of the drug, can therefore have an overwhelming influence on the observed rate of degradation. For example, the erosion rate of polyanhydrides can be slowed by about three orders of magnitude when the hydrophilic monomer sebacic acid is replaced by hydrophobic bis (carboxy phenoxy) propane as the starting material. ^[46]

Table 3 Ionic compositions of body fluids (milligram equivalent)

Ion

Plasma

Interstitial

Fluid

Cellular

Fluid

Na ⁺

K ⁺

Ca ⁺²

Mg ⁺²

Cl^-

HCO₃^-

PO₄^-3

SO₄^-2

Organic acids

Proteins

138

102

141

4.1

115

1.1

3.4

150

100

Table 4 Different types of enzymes

Enzyme	Reaction catalyzed
Hydrolase	:	Hydrolysis reaction, especially those of esters, amides and acetals.
Esterase or amidase	:	Esterification or amidation reaction or ester or amide interchange reaction
Isomerase (transfarase)	:	Molecular reorganization reactions by transferring atoms or groups within molecules
Reductase or oxidoreductase	:	Electron transfer reactions, which result in either oxidation or reduction processes.
Ligase	:	Condensation reactions, which form new C-C, C-S, C-O, and C-N bonds.
Hydrogenase or dehydrogenase	:	Hydrogen addition or removal reactions

4.4 Polymer morphology

Two distinct morphological states (crystalline and amorphous) are identified in polymer molecules. In semicrystalline polymer, the crystalline regions are most densely packed and offer the highest resistance to the penetration of water. Consequently, the rate of backbone hydrolysis tends to be higher in amorphous regions of a semicrystalline polymer than in crystalline regions. E.g. Poly (L-lactic acid) degrades at a slower rate due to the fact that this stereo-regular polymer is semicrystalline, while the racemic Poly (D,L-lactic acid) degrades faster owing to the amorphous nature.^[47]

5. DESIGNING OF BIODEGRADABLE POLYMERS:

The synthesis and development of biodegradable polymers is one of the leading frontiers of research in polymer science at the present time. More recently, with the emphasis on reducing environmental pollution, attention has been directed toward biodegradable polymers. ^{[6, 48]} In addition, there is now a wide variety of medical applications of synthetic and natural polymers that are biodegradable. ^{[36, 49, 50]}

Rodriquiz has discussed a number of possible approaches to biodegradable systems. ^[50] He suggested a search for new organism for conventional polymers, the introduction of vulnerable units in the polymer chain, or adding nutrients, e.g. cellulose or amlylose, on reinforcement in polymer composites. Gilbert et al. have reviewed two approaches towards the designing of biodegradable systems. ^[3] The first is concerned with the synthesis and in vivo studies of a series of polyesters e.g. PLA, PGA, poly (--caprolactone) and its copolymers. The second approach was based on the synthesis of block and graft copolymers containing naturally occurring segments e.g. cellulose and amylose, known to be biodegradable. Sudesh Kumar has classified the possible approaches in developing new biodegradable polymers in the following four areas. ^[51]

· Modification of natural polymer

· Biodegradable polymer composites

· Synthesis of new biodegradable polymers

· Modification of synthetic polymers

5.1 Modification of Natural Polymers

Chemical modification of the natural polymers serves the two-fold purpose of utilizing renewable, naturally derived products such as polysaccharides and proteins as replacement for synthetic, petroleum-based products and as biodegradable compositions, which can be tailored for slower or faster rate of degradation. Several new polymeric materials have been prepared by the chemical modification of the natural polymers.

Among the polysaccharides, the commonly employed polymers include cellulose, starch, dextran and amylose. Various cellulose ethers have been reported to be biodegradable by various microorganisms. ^{[52, 53]} Also the -1,4 linkage between the glucose units in the cellulose could be made susceptible to hydrolysis by introducing chemical modifications. One such product is periodate oxidized cellulose, which is formed by oxidizing cellulose with sodium periodate leading to the conversion of anhydro-D-glucose units to dialdehyde units. ^[54] Singh et al. have reported that this product is degradable in the physiological environment and the degradation products are glycolic acid and 2, 4-dihydroxy butyric acid. ^[55] Another approach reported by Gilbert et al. was the biodegradable graft and copolymers of cellulose and amylose. ^[21] Grafting reaction leaves the main chain of a polymer intact, and it can be expected to add new properties associated with the side chains without drastically changing the main chain properties. Regenerated cellulose, cellulose acetate and ethyl cellulose are commercially available and find application in packaging. Ferruti et al. reported succinic esters of starch and dextran as biodegradable drug release matrices. ^{[56,
57, 58]} Dextran as such is used clinically as plasma expander. ^[59]

Schacht has many questions concerning the immunological properties of polysaccharide derivatives. ^[60] Also, the strength of polysaccharide is not outstanding when compared to other classes of materials. Bishop reported that fibers useful in surgery could be prepared by extruding the ethyl ether of dextran. ^[61]

Among the proteins, collagen and gelatin based polymers are commonly employed. Collagen was used for a long time as a bioabsorbable suture. ^[62] Gelatin has found many application in biomedical field as bioabsorbable agent. For surgical use, gelatin is prepared as a foam or film and cross-linked with formaldehyde to decrease its solubility. It is used in the filling of voids after tissue resection. ^[51] A new surgical procedure was developed using cross-linked gelatin cup prosthesis, which participated in the temporary substitution of tissues.^[63]Kumar et al. investigated the biodegradation of gelatin graft copolymers with poly (methylacrylate) using pure cultures and mixed bacterial inoculums. ^{[64, 65, 66]}Being proteinaceous in nature, collagen and gelatin also have the potential for inciting immune response.

5.2 Polymer composites

Several polysaccharide plastic blends have been developed as degradable plastics, with the majority of them containing starch, cellulose or their derivatives as the polysaccharides. ^[67] The primary goal of that work was to replace plastic with inexpensive renewable resource materials derived from plants. These blends have been suggested as desirable alternatives to non-degradable plastics for which a number of solid waste disposal and environmental problem exists. The principal degradable materials are mixtures of starch and polyethylene or starch, polyethylene and ethylene-co-acrylic acid. ^{[68, 69]} Poly (vinyl chloride) compositions filled with starch are also reported. ^[70]

A significant development in this area is the development of a biodegradable ceramic plastic composite for use as a biomaterial for hard tissue or bone replacement therapy. ^[71]When a biodegradable additive is used, the additive undergoes rapid biodegradation leaving a porous and mechanically weakened undegraded polymer behind. The microorganisms once having gained a foothold on the residual polymer start degrading it slowly.

5.3 Synthetic polymers

The various classes of synthetic polymers explored as polyesters, polyamides, polyanhydrides, polyorthoesters, polyiminocarbonates, polyphosphazenes and polyphosphoesters.

Polyamide

Polyamides [-RCONH-]_n have received considerable attention as biodegradable polymers because of the general assumption that amide linkage is subject to attack by proteolytic enzymes. The utilization of polyamides in the preparation of biodegradable matrices began following the observation that nylon implants deteriorated with time in vivo. ^[72] Although nylon microcapsules have been used to study the release of several drugs, their slow rate of biodegradation has focused attention on more hydrolytically labile, hydrophilic polyamides. ^[73]

The naturally occurring proteins e.g. collagen, gelatin and albumin have been used for drug delivery applications. ^[74-75] However, problems can arise due to their potential antigenicity. ^[3]

The hydrolytic instability of the amide bond in synthetic amino acid polymers has been viewed in the formation of intentionally biodegradable polymers. As reviewed by Kopecek and Rejmanova, these polymers may be designed to give controlled biodegradation via the introduction of segments susceptible to specific enzymes. ^[76] For e.g. polymers of N- (2-hydroxypropyl)-methacrylamide and p-nitrophenyl esters of N-methylacrylolated amino acids are reacted with compounds containing an aliphatic amino group, with the formation of an amide bond. If this bond, originates in an amino acid specific for certain enzyme, an enzymatically cleavable bond is formed e.g. L-phenylalanine, L-tyrosine and L-leucine are degraded by chymotrypsin. A wide variety of biodegradable polymers have been prepared in this way.

Poly (amino acids) based on synthetic amino acids such as poly (glutamic acid) has also been increasingly reported. Poly (glutamates) with increasing ester contents and with chemically or enzymatically degradable bonds, have been evaluated as drug carriers. ^[77] The poly (t-butyloxy carbonyl methyl) glutamates are obtained by partial esterification of polyglutamic acid with t-butyl bromoacetate. Asano et al. have studied the polymers and copolymers of -benzyl-L-aspartate and -methyl-L-glutamate. ^[78]

Other biodegradable nonpeptidic polyamides have also been reported. Vanderbilt et al. have reported the polyamides obtained by polymerization of 4, 4-spirobisbutyrolactone with amines. ^[79] Harris and Eury have obtained polyamides by the ring opening polymerization of 2, 2'-bis [5 (4h)-oxazolones] with diamines. ^[80]

Features

Polyamides are known to undergo chemical as well as enzymatic degradation. The hydrolytic degradation of polyamide follows the mechanism of bifunctional catalyses ^[38] as shown in Scheme 1

Scheme 1

The poly (glutamic acid) based polymers are generally hydrophilic, absorbing up to 50 mol % water.^[81]The biodegradation rate increased as the hydrophilicity increased. The 1:1 copolymer of -benzyl-L-aspartate and -methyl-L-glutamate showed maximum water up take as well as maximum rate of biodegradation. Poly (amino acids) have been used predominantly to deliver low molecular weight drugs for period up to 1 year. Although these polymers are biocompatible, their mildly antigenic nature makes their widespread use uncertain. ^[44]

Polyesters

Polyesters having ester (-RCOO-)_nlinkages in their main chain represent the most widely studied class of degradable polymers. Today the most important biodegradable polymers used in surgery and drug delivery are aliphatic polyesters (polymers/ copolymers) of --hydroxy acids. Table 5 lists some important biodegradable polyester.

The simplest biodegradable polyester synthesized was polyglycolic acid (PGA). Poly (lactic acid) (PLA) may be considered as an oxygen analog of polyalanine. Although the synthesis of poly (glycolic /lactic acids) was reported by the simplest polycondensation of glycolic/lactic acids with antimony trioxide, the resulting polymer has low molecular weight and optimum properties were not obtained. ^[82] The preferred method for producing high molecular weight polymer is ring opening polymerization of the cyclic diester glycolide/ lactide using antimony, zinc, lead or preferably tin catalyst.^{[83, 84, 85,
86, 87]}

The synthesis of relatively low molecular weight polyesters by direct polycondensation of -hydroxy acids or lactones are characterized by good biocompatibility e.g. polylactic acids ^{[88, 89]} poly (lactic-co-glycolic acid), ^[90]poly (lactic-co--caprolactone), ^[91] poly (lactic-co--valerolactone), ^[92] etc.

Poly (-hydroxybutyrate) (PHB) has recently been identified as a promising biomaterial. PHB is degradable, biocompatible and thermoplastic polyester made by microorganisms. ^[93] It is an intracellular storage polymer, whose function is to provide a reserve of carbon and energy. The poly (dioxanes) substituted or unsubstituted have been prepared from the corresponding dioxanes-diones by ring opening mechanism. ^[94]

Other ester containing polymers suitable for biomedical application are also reported. For e.g. poly (esters) such as poly (tartaric acid) and poly (-malonic acid) prepared via the anhydrosulphite derivative of the appropriate alpha-hydroxy carboxylic acid.^[94] Bailey et al. reported for the first time, an elegant way of introducing an ester group into the backbone of an addition polymer by free radical process.^[95] Thus, copolymerization of ethylene with ketene at 40^oC produced a copolymer containing about 10 % by weight of ring opened units containing ester groups.

Features

The in vitro and in vivo degradation of polyesters have been extensively studies.^{[2, 11, 96, 97]} Poly (esters) are generally known to undergo hydrolytic degradation with enzymatic involvement only in the later stages. (Scheme 2)

Scheme 2

The degradation mechanism is reported as bulk degradation. The kinetics of polyesters degradation have been established by monitoring the carboxyl ends group by either potentiometric titration or by colorimetric by dye interaction technique proposed by Palit and Mandal. ^[98] The polyester degradation was found to be auto catalyzed by the end carboxyl groups. The degradation is known to occur in four major stages:

a) Polymer hydration causing disruption of the primary and the secondary structure by altering hydrogen bonding and Van der Waals forces,

b) Strength loss caused by rupture of covalent bonds forming backbone,

c) Loss of mass integrity resulting in initiation of absorption, and

d) Solubilization of mass resulting in polymer dissolution and phagocytosis. ^[44]

The physico-mechanical properties of various polyesters has been reviewed recently by Engelberg and Kohn. ^[99]Poly (glycolide) the simplest polyester was the first synthetic suture material of choice because of its high tensile strength. However, its low solubility in common solvents has limited its application in drug delivery system. Poly (lactic acid) being soluble in common solvents is a preferred material. The most important difference between racemic Poly (D,L-lactic acid) and the stereo regular Poly (L-lactic acid) is that Poly (D,L-lactic acid) is amorphous, whilst Poly (L-lactic acid) is a semicrystalline material. Poly (D,L-lactic acids) have been extensively used as matrices for drug delivery. ^[44,99]Poly (L-lactic acid) on the other hand has poor permeability properties but high crystallinity and high mechanical strength and toughness and hence is more preferred as sutures and orthopedic devices.

Several copolymers of lactic acid and glycolic acid having a variety of properties have been reported. ^[100] The biodegradation of these copolymers is a function of their composition, the 1:1 copolymer showing maximum biodegradation rate in vivo.

Poly (-caprolactone) was one of the first biodegradable polymers examined for the in vivo drug delivery. Owing to the low T_g, (below body temperature) and crystallinity it has excellent permeability towards a wide range of drugs. Co-polymers of -CL with other lactones such as lactide, -valarolactone, etc. have been reported. A reservoir device fabricated from copolymer of -CL and D,L-lactide (Capronor®) is currently undergoing clinical trials as a subdermal delivery of contraceptive drug. ^[101] The properties of rapid biodegradability contributed by polylactic acid and the high permeability of p (-CL) make this a desirable copolymer. ^[102]

One of the drawbacks of polyesters derived from -hydroxy acids is their susceptibility to -radiation sterilization. -irradiation is known to bring about changes in polymer owing to main chain degradation and/or crosslinking.^[102]

Polyanhydrides

Polyanhydrides were first reported by Butcher and Slade who discovered the formation of high melting material when isophthalic or terephthalic acid were heated with acetic anhydride.^[103] Later Hill and Carothers investigated polyanhydrides of simple aliphatic dicarboxylic acid in their course for development of new material for textile application. ^[104,105] However, being hydrolytically unstable they were of little interest. Much later in the 1980s Langer recognized the broad potential of this class of polymers as biodegradable materials for drug delivery and other medical applications. ^[106,
107]

Polyanhydrides have been synthesized by the following methods. (a) bulk melt condensation of activated diols, (b) ring opening polymerization, (c) reaction between dibasic acids and diacid chlorides and (d) interfacial polymerization. ^[108,109]

Features

The polyanhydrides have been well characterized with respect to their chemical composition and structure, crystallinity and thermal properties, mechanical properties and hydrolytic stability. The copolymer based on sebacic acid (SA) and (p-carboxy phenoxy propane) (CPP) are found to be semicrystalline and have T_g in the range of 60^o to 96^oC depending on the composition. ^[110]The polyanhydrides are hydrolytically more unstable polymer and are currently being investigated for medical applications. The hydrolytic degradation essentially occurs by surface erosion and the mechanism is as follows. ^[44] (Scheme 3)

Scheme 3

Although the purely surface eroding mechanism makes these polymers advantageous over other class of polymer, they have certain limitations. First, the poor solid state stability of the aliphatic anhydrides, and second, the high inherent reactivity of the anhydride linkage towards nucleophiles makes the formulation of these polymers with amine containing drug difficult. ^{[111, 112]}

Despite these limitations polyanhydrides form CPP-SA have been approved by the FDA and are in the Phase III of clinical trials as an implantable delivery device for controlled release of BCNU (a chemotherapeutic agent) in the treatment of malignant brain tumors. ^[112]

Polyorthoesters

Polyorthoesters are family of synthetic degradable polymers that have been under development for a number of years. ^[113] They have the general formula

Polyorthoesters in biomedical applications were first described in patents assigned to the Alza Corporation.^[114] Until now, four families of polyorthoesters have been prepared.^[115] They are as follows:

¨ Polyorthoesters-I are prepared by transesterification of diethoxy tetrahydro furan with diols. These are available commercially as Alzamers® or Chronomers®

¨ Polyorthoesters-II reported by J. Heller are prepared by the condensation of 3, 9-bis (ethylidene-2, 4, 8, 10-tetraoxaspiro [5, 5] undecane) (DETOSU) with diols to produce a linear polymer or with a triol to produce a crosslinked polymer.

¨ Polyorthoesters-III are prepared by the condensation of a rigid triol with an alkyl orthoacetate to produce ointment like materials

¨ Polyorthoesters-IV are prepared by the condensation of a rigid triol with an alkyl orthoacetate to produce solid materials.

Features

Polyorthoesters have been reported with a wide range of physical characteristics (from glassy T_g>37^oC to rubbery T_g<37^oC) and erode heterogeneously (surface eroding). These polymers were shown to undergo general acid catalyzed hydrolysis as follows. ^[115]

Scheme 4

The release of acidic bi-products further autocatalyze the degradation process. Polyorthoesters II with T_g's ranging from 20 to 115^oC have been reported by J. Heller. ^[44] Also, these polymers are fabricated at lower temperatures as they undergo thermal rearrangement at T > 135^oC. Upon hydrolysis these polymers do not release acidic by-products and hence do not exhibit auto-catalytically increasing degradation rates. Thus, to accelerate the polymer hydrolysis and concomitant release of incorporated therapeutic agents, excipients, either acidic or basic are incorporated in the matrix. ^[115]

Drugs that have been formulated using polyorthoesters include narcotic analogues e.g. Naltrexone, contraceptive steroids e.g. Levonorgestrel, anticancer agents e.g. 5-Fluorouracil, and polypeptide e.g. insulin. ^{[116, 117]}

Being pH sensitive polymer polyorthoesters are particularly useful in the formulation of self-regulated insulin device for treatment in diabetics. In such a device, insulin is dispensed in an acid sensitive polymer, which is surrounded by hydrogel containing immobilized glucose oxidase. ^[117] When glucose diffuses in to the hydrogel it is oxidized by the enzyme glucose oxidase to glucoronic acid and the consequent pH will accelerate polymer erosion and concomitant insulin release.

Polyiminocarbonates

Polyiminocarbonates (-OROC (=NH)-)_n are little known polymer that in a formal sense are derived from polycarbonates by the replacement of the carbonyl oxygen by an imino groups. This backbone modification is known to dramatically increase the hydrolytic liability of the backbone, without appreciably affecting the physicochemical properties of the polymer.

Kohn first reported the use of polyiminocarbonates for medical purposes. ^[118] He has reported a series of polyiminocarbonates obtained from tyrosine dipeptide derivatives, referred to as pseudo poly (amino acids).

Kohn et al. have initially reported the synthesis of poly (BPA-iminocarbonate) which degraded within 9-12 months when implanted subcutaneously. ^[119] However, due to its limited tissue compatibility it was not recommended as biomaterial. To reduce the potential toxicity of poly (BPA-iminocarbonate), BPA was replaced with derivatives of tyrosine dipeptide. ^[120] The iminocarbonate bond was formed between the phenolic hydroxyl groups present at the tyrosine side chain. These tyrosine-derived polymers are referred to as pseudo polyamino acids. (Scheme 5)

Scheme 5

The synthesis of pseudo-poly (amino acids) was reported by both solution and interfacial polymerization procedures giving high molecular weight (80,000 - 150,000) polymer.

Features:

The relation between the structure of several tyrosine-derived monomers and the properties of the resulting polyiminocarbonates has been investigated. ^[121]The replacement of carbonyl oxygen by -NH group leads to increased hydrolytic instability while retaining the mechanical properties. However, there is a sharp reduction in the thermal stability in case of polyiminocarbonates due to the inherent tendency of the iminocarbonate bond to dissociate at temperatures of about 130-150^oC into a hydroxyl group and an organic cyanate.^[88]This imposes limitation on the processability of these polymers by melt fabrication techniques. The T_g of polyiminocarbonates is reported to be between 60 – 70^oC. Polyiminocarbonates are found to be stronger but little brittle as compared to the corresponding polycarbonates.

The chemical mechanism of the hydrolytic degradation of polyiminocarbonates has been studied previously and had been shown to lead to the formation of ammonia, carbon dioxide and the regeneration of the diphenol used in the synthesis of the polymer. ^[121] (Scheme 6) An important side reaction during the degradation process was the formation of carbonate linkages whose presence can be readily ascertained by IR spectroscopy of partially degraded polyiminocarbonate.

Scheme 6

The tyrosine-derived polyiminocarbonates were found to swell considerably in the media. These polymers exhibit a biphasic degradation, which includes an initial rapid phase followed by a slow process. Thus, although 75% reduction in molecular weight occurred in a matter of days, the complete degradation took one year. On the other hand, the hydrolytic degradation of tyrosine derived polycarbonates was very slow with little or no water uptake. ^[121]

Poly (Dat-Tyr-Hex-iminocarbonate) and poly (Dat-Tyr-Hex-carbonate) were identified as strong and readily processible materials with excellent engineering properties and these polymers were specially recommended for applications as temporary scaffold materials, bone fixation device (bone pins or screws) etc. ^[121]

Polyphosphazenes

Polyphosphazenes having the general structure [- P (R)₂= N - ]_n, R being an organic substituent that can undergo in vitro hydrolysis over a period of several weeks has been proposed as biodegradable polymers for controlled release by Allcock and coworkers, who have extensively explored the field of polyphosphazene synthesis. ^[122,123]

Polyphosphazenes are usually prepared by substitution of the chlorine atoms in polydichlorophosphazene (- N = PCl₂ -)_n by nucleophiles, such as amino acid esters it is possible to chemically link the drug to the polymer backbone. Imidazole substituted polyphosphazenes are also reported for production of bioerodable matrix system.

Features

These polymers are known to biodegrade to nontoxic products such as phosphate, ammonia, and the side group substituent. ^[122] (Scheme 7)

Scheme 7

Polyphosphazenes were first reported as drug carrier in 1983 to deliver Naproxen, which was chemically linked to it. Naproxen substitutes polyphosphazenes of different molecular weights were prepared. ^[124] However, a spontaneous decline in the molecular weight on storage at room temperature was observed. Storage at -35^o C, however, did not affect the molecular weight of these polymers.

Polyphosphazene microcapsules formed by complexation by calcium chloride have also been recently reported by Langer et al. ^[125] This procedure was employed for microencapsulation of living cells, such as healthy pancreas cells for diabetic treatment. Ionic crosslinking between Ca⁺⁺ ions and the carboxylate groups of the adjacent polymer chain takes leading to formation of microcapsule matrix.

Poly (phosphoester)

Poly (phosphoester) having represents another class of compound to which the drugs can be chemically linked.

The use of poly (phosphoesters) as pedant drug delivery system has been implicated by Penczek on the early 1980s. ^[126,127] Poly (propylene phosphonate) was synthesized by an anionic polymerization of 2-hydro-2-oxo-1,3,2-oxaphosphorinane ^[128] and further linked to model compounds such as benzoic acid, aniline, thiophenol, and p-nitro phenol via chlorination and subsequent dehydrochlorination. Studies on the model compounds demonstrate the feasibility of dealing with drugs having carboxylic, amino sulfhydryl or hydroxyl group.

An anticancer drug 5-fluorouracil (5-FU) has also been linked to the polymer via trimethyl silyl derivatization. ^[129]Leong et al. have reported poly (phosphoester urethanes) copolymers with a view to combine biodegradability and desired mechanical strength.^[130] The polyurethane part was made more hydrolytically labile by incorporating a bisglycolphosphite as part of chain extender. The release of a steroid drug, cortisone acetate through poly (phosphoester) matrices is reported. ^[77]

Features

These polymers are found to undergo essentially enzymatic degradation process in vivo. ^[131] Theoretically the polymer would breakdown in to phosphate, a diol and another alcohol if the side chain is a phosphate ester bond. Not much is reported on the properties of these polymers. Most of the physical and biological characterization has been performed on the bisphenol-A based poly (phosphoesters).

5.4 Modification of Synthetic Polymers

One approach involves the copolymerization of a desired monomer with a monomer possessing polar functional group, which might serve as a point of attack for microbial enzymes. The polymers can also be modified by substitution to enhance the degradability. It is reported that poly (vinyl butyrate) was rapidly degradable and with a rate comparable to catgut. ^[61] Also, it was shown that amide bonds in side chains of synthetic polymers are cleaved by enzymes if they originate from the L-amino acids specific for the given enzymes. ^[132,133]Kopecek et al. have reported the water-soluble copolymer based on N-2-hydroxypropyl methacrylamide and p-nitro phenyl esters of N-methacrylolylated oligopeptides, bearing in their side chains a chromogenic substrate for chymotrypsin. ^[134] The substrate was L-phenylalanine-4'-nitro aniline linked by its amino group to the terminal carboxyl group of the side chain. They have critically investigated the influence of both the detailed oligopeptide structures and structural and steric factors on the degradability of the polymeric substrates both in vivo and in vitro. ^{[135, 136]} Kumar et al. have reported the approach to render the polybutadiene moiety biosusceptible by incorporating ester linkages by the condensation of the carboxy terminated polybutadiene with glycerol. ^[137] It was thought that the enzyme would get a foothold on the polymer surface. Thus leading to progressive scissoring of C₂-units form the carbon chain, similar to well-known -oxidation of fatty acids.

6. CONCLUSIONS:

It is thus apparent that the development of the natural and synthetic biodegradable polymers has progressed in response to increasingly clearer definition of needs for materials with special characteristics. For example, exceptionally strong fibers are required for sutures, bulky, perhaps porous masses are indicated for tissue void filling or scaffolding, flexible but rapidly absorbing forms are suitable for drug release vehicles. It is to be expected that the wide variety of polymer systems with varied and special characteristics presently available will allow increasingly successful applications to many problems in medicine and surgery requiring such materials.

CONFLICT OF INTEREST STATEMENT:

We declare that we have no conflict of interest.

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Received on 19.12.2016 Modified on 16.01.2017

Research J. Pharm. and Tech. 2017; 10(2): 625-640.

DOI: 10.5958/0974-360X.2017.00121.4

A) Natural Polymers

Examples

Ion

Enzyme

Reaction catalyzed

Polyamide

Scheme 1

Polyesters

Scheme 2

Polyanhydrides

Scheme 3

Polyorthoesters

Polyiminocarbonates

Scheme 5

Polyphosphazenes

Poly (phosphoester)