Biodegradable Polymers in Pharmacy and Medicine. Classification, Chemical Structure, Principles of Biodegradation and Use

by Jan Gajdziok (Author) Roman Goněc (Author) David Vetchý (Author)

Textbook 2016 110 Pages

Medicine - Pharmacology




Biodegradable polymers
Properties of biodegradable polymers
Changes in physical and chemical properties in the course of biodegradation
Molecular weight
Mechanic properties
Changes in dimensions and morphology
Chemical composition of the surface
Absorption of water and weight loss
Principles of hydrolytic degradation
Principles of enzymatic biodegradation

Scaffold constructions in tissue engineering and sutures
Advantages of biodegradable bone fillings, prosthetics, and fixations in orthopaedics
Biodegradable polymers in drug delivery systems
Polymeric delivery systems
Challenges in inhalation therapy
Targeted administration, local and topical administration, implants

Polymers degradable by hydrolysis
Poly(α -ester)s
Chemically synthesised aliphatic polyesters
Polyglycolide (PGA)
Polylactide (PLA)
Lactide glycolide copolymer (PLGA)
Polycaprolactone (PCL)
Polydioxanone (PDS)
Poly(trimethylene carbonate) (PTMC)
Polyhydroxyalkanoates (PHA)
Polyesters containing aromatic groups in their structure
Polyurethanes (PUR)
Poly(ester amides) (PEA)
Poly(ortho esters) (POE)
Polyanhydrides (PA)
Poly(phosphoester)s (PPE)
Polymers degradable by enzymes
Polysaccharides occurring in humans
Hyaluronic acid (HA)
Chondroitin sulphate
Polysaccharides not occurring in humans
Chitin and chitosan
Alginic acid and alginate
Cellulose derivatives and their mixtures
Proteins and poly(amino acids)
Natural poly(amino acids)
Poly(γ-glutamic acid) (γ-PGA)
Poly- ε - L -lysine (EPL)
Poly(aspartic acid) (PAA)
Elastin and similar peptides




Preface and Scope

The aim of this book is to provide a brief but comprehensive overview on the issue of biodegradable polymers. The introduction chapter is followed by a description of the general characteristics of biodegradable polymers and pathways of their degradation in the human body. Particular pitfalls and specifics of their various biomedical and pharmaceutical applications, especially in the field of pharmaceutical technology, are described in order to define the ideal carrier polymer system for specific types of therapy. Finally, the work presents the classification of these polymers based on the type of degradation mechanism. This section also includes the chemical structure of particular polymer molecules, their chemical or bio-synthesis and the description of their uses in specific biomedical and pharmaceutical applications.

The book could be used as a textbook for students of medical and pharmaceutical sciences as well as by researchers in this field or industrial area.


In the past few decades, biodegradable polymers have reached significant importance in fields of biomedical and pharmaceutical applications. They have become preferred candidates for the manufacture of therapeutic forms, for instance, orthopaedics devices, temporary bone screws and spins, three-dimensional scaffolds for tissue engineering or drug delivery systems for sustained and targeted release. Each of these applications requires material with specific physical, biological, and chemical properties, as well as specific degradation profile. These polymers (natural or synthetic) undergo hydrolytic or enzymatic degradation, which both have some advantages and disadvantages. Most widely used polymer materials in biomedical applications are listed, including their structure and degradation pathways.

Key words: polymer, biodegradation, hydrolytic degradation, enzymatic degradation, biomaterial


In recent decades, there has been significant progress in the development of biologically degradable polymer materials. Because of their biocompatibility and ability to decompose to non-toxic monomer units, these degradable polymers (both of natural and purely artificial origin) are preferred in the development of new and modern therapeutic systems. They are sought after in various fields of medicine – as elementary scaffold in tissue engineering, sutures (without subsequent need to extract stitches), or bone replacement as well as of pharmaceutics – their suitable properties play key role as carrier materials in the production of modern dosage forms with controlled or targeted release of drug in the organism. Any of these applications demands material with specific physical, chemical, biological, biochemical, and degradation properties that are essential for the therapy to be effective (1). The synthesis and design of new polymer combinations is a trend showing significant future potential, widening the range of perspective locations where new systems can deliver the drug in the organism (2).

The earliest proven application of biodegradable polymers for therapeutic purposes can be traced to Egypt, 3500 BC. The Egyptians used natural polymers – treated animal guts – to stitch wounds; these can be considered to be the earliest versions of surgical sutures based on collagen (3).

Polymers based on polyesters were the first synthetic biodegradable polymers to have properties suitable for biomedical application. At the beginning of 1930s, DuPont company manufactured high-molecular linear poly(lactide)s using ring-opening polymerization. Since 1960, as the result of subsequent oil crises, biotechnological procedures for polymer materials as poly(hydroxy alcanoate)s have been developed to be independent of petrochemical procedures to manufacture plastics and polymers. Shortly afterwards, at the beginning of 1970s, first co-polyesters were used in matrices for controlled release drugs or as sutures in surgery (4).

The term biodegradation is often used to describe degradation in biological environment. In the context of biomedical application, however, biodegradation is defined rather as gradual decomposition of material caused by specific biological activity. The correct meeting of requirements for medical devices depends to some extent on the stability of material that was used to produce them. Biodegradation has its strong position on the list of safety norms when choosing suitable material for particular biomedical application. The understanding of degradation of materials (degradation kinetics, the changes in mechanic properties in the course of degradation and subsequent identification of degradation products) is crucial for their development, choice and correct application (5).

This book aims at giving concise though complex overview of knowledge concerning biodegradable polymers. The introduction is followed by the description of general properties of biodegradable polymers and possible pathways of their biodegradation in the human organism. Besides classifying polymers in various groups, the book points out particular challenges and specifics of various biomedical and pharmaceutical applications, including the manufacture of dosage forms based on ideal carrier polymer system intended for particular therapeutical mean. The polymers are classified according to their degradation mechanism and for each polymer, its chemical structure, synthesis, and use in concrete biomedical and pharmaceutical applications are listed.


Biodegradable polymers

Biodegradable polymers are macromolecular compounds that are degraded in vivo (under suitable conditions also in vitro) to products of physiologic human metabolism or products that can be eliminated completely from the organism, either by a specific metabolic pathway or directly. These polymers can be natural, completely synthetic or of mixed origin (derived from natural polymers; semisynthetic). Based on the breakdown mechanism, polymers are either degradable by hydrolysi s or degradable by enzymatic reactions. Therefore, their structure has to contain bonds that are susceptible to hydrolytic or enzymatic cleavage, allowing for the breakdown (1) (2).

Natural polymers were the first biologically degradable biomaterials to be used in clinical practice. Most polymers of natural origin are degraded in the organism by enzymatic reactions. The rate and the velocity of in vivo breakdown of enzymatically degradable polymers depend significantly on the site of implantation or administration of the polymer in the organism and the availability and concentration of particular enzyme. Chemical modification of these polymers can have impact on the velocity of their degradation. Natural polymers are disadvantaged chiefly by the lack of uniformity of production batches (1). On the other hand, natural polymers include proteins which have several important advantages: mainly often pronounced biological activity, i.e. the ability to act as ligands and bond themselves to cellular receptors. Furthermore, they are liable to enzymatic degradation initiated by the cell. Protein structures can be remodelled easily. Nevertheless, there are disadvantages: strong immunological response and easier contamination with endotoxins (6).

On the contrary, the disadvantages of natural biopolymers are mostly absent in synthetic biomaterials that are usually biologically inert. Their properties are more predictable and their manufacture batches are more uniform. The largest advantage they have is the possibility to tailor the profile of their properties with respect to specific application. Usually, their breakdown is caused by hydrolysis (7).

At the end of 1960s, the first suture system based on poly(glycolic acid) was introduced, which led to the design and development of numerous types of biodegradable materials intended to be used as transitory implants for orthopaedic and similar use. Since that time, research has progressed to custom design of biodegradable polymer systems with predictable erosion kinetics suitable as vehicles for drugs or genes or as scaffolds for tissue engineering. In case a material with some level of biological activity is required, it is possible to incorporate biologically active compound (for example, a segment of natural polymer) in a completely synthetic polymer. These hybrid materials belong to semisynthetic polymers (8).

The classification of biodegradable polymers used to manufacture polymer materials for biomedical use is shown in Table 1.

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Table 1: Examples of polymers used in biomedical and pharmaceutical applications (2)

Properties of biodegradable polymers

A crucial property of biodegradable polymers, biocompatibility is the ability of material contained in specific application to elicit adequate natural physiological reaction of the organism that has to be maintained uninterruptedly for the whole period of therapy. In contrary, chemical, physical and mechanical properties of biodegradable material can change in time and the biocompatibility of degradation products can be different from the biocompatibility of original polymer matrix (9).

Biodegradable polymer has to meet following elementary requirements:

- polymer has to be manufactured from compound that is soluble in water;
- polymer has to be non-toxic and free of endotoxins so as to minimize undesired reaction of the organism to foreign body or molecule;
- the time necessary for material breakdown should be similar to the expected tissue recovery time or required therapeutic time;
- degradation products have to be non-toxic and their elimination from the organism has to be easy;
- mechanical properties have to be suitable for desired role and the product has to be easy to manufacture (4) (10).

Other properties of polymer materials that can have impact on their biocompatibility include chemical structure, molecular weight, crystallinity, solubility, hydrophilicity/hydrophobicity, slipperiness, surface chemistry, the ability to absorb water, the rate of this absorption, and breakdown mechanism. With respect to the complexity of these properties and the range of application of polymer biomaterials in use, no polymer system can be described as ideal biomaterial (4).

The properties listed above point out the need to go on with developing wide range of new biodegradable materials that will be able to meet specific and unique requirements of each particular medicinal application. Nowadays, the synthesis and manufacture of new biodegradable materials is focused on tailoring the products to customers' needs, i.e. designing polymers with properties suitable for particular application. This goal can be reached by: (a) developing new synthetic polymers with unique chemical structure that will increase structure diversity and thus improve the properties; (b) using biosynthetic approach, building polymer structures with some degree of biological activity; (c) using combinatorial and computational approach in designing new biomaterials so as to accelerate their invention and development (11).

Changes in physical and chemical properties in the course of biodegradation

In the course of their breakdown, biodegradable polymers undergo a whole range of changes concerning their physical and chemical properties. These changes can have negative impact on their desired effect and can provoke undesired tissue reaction. Therefore, it is very important to characterize and quantify any changes that may occur in applied biomaterial in different phases of degradation and to evaluate the reaction of tissue because tissue reaction is likely to change in the course of breakdown process. On the other hand, the impact of adjacent tissue on an implant is more or less constant and does not change significantly in time (5) (12).

In the first phase of degradation, the most important factor is the gradual penetration of aqueous solution into polymer matrix, which leads to increased absorption of water by matrix, while weight, molecular weight and tensile strength of polymer do not change much. Main changes can be observed on the surface of polymer which becomes rough. Chemical changes due to hydrolysis can occur, as well. The second phase of degradation is characterised by decrease in molecular weight of polymer because of cleavage of polymer chain, followed by the spread of fragments in neighbouring aqueous environment. This leads to matrix weight loss and decrease in porosity and tensile strength. In advanced phases of degradation, polymer matrix collapses and molecular weight decreases significantly. Crystalline structures almost disappear, which leads to the loss of mechanic properties (5).

The most important methods used to evaluate degradation products of biodegradable materials include surface analysis (infrared spectroscopy, X-ray photoelectron spectroscopy, measurement of contact angle) that is of more use in the first phases of degradation, and bulk analysis (measurement of molecular weight, measurement of transition temperature of mechanic properties) that is more suitable in the later phases of degradation (5).


Polymer crystallinity is the ability to reach certain degree of order and possess specific supramolecular structure. Polymer can be considered crystalline in case its structure contains rather regions with three-dimensional structure on atomic level than on macromolecular level. The latter level arises usually only through intramolecular bending and/or stacking of adjacent chains. Usually, polymers contain both crystalline and amorphous parts and the degree of crystallinity can be given as weight or volume ratio of crystalline material. It does not matter if their origin is synthetic or natural; there are only a few completely crystalline polymers (13).

Polymer crystallinity is characterised by the degree of crystallinity that can range from 0 (0 %) (completely non-crystalline polymer) to 1 (100 %) (completely crystalline polymer). Polymers that contain in their structure microcrystalline regions tend to be tougher (it is possible to bend them more without cracking) and more resistant to impact than amorphous polymers. The rates of biodegradation and drug liberation kinetics from polymer matrix depend on chemical composition, morphology, and crystallinity of constituent polymers (14) (15).

In case of semicrystalline polymers, an increase in crystallinity was observed during the first phases of degradation (16). Absorbed water has plastifying effect, making polymer chain more mobile, thus leading to crystallization, because crystalline structure is suddenly thermodynamically more stable. On the other hand, hydrolysis runs preferentially in the amorphous part of polymer as these areas are more accessible to molecules of water and enzymes. Initial increase in crystallinity can be observed also after crystalline monomer and oligomer fragments were formed in the course of degradation (8). When the cleavage of chain reaches crystalline areas, decrease in total crystallinity of polymer can be expected (5).

Changes in crystallinity of biodegradable materials can be observed and measured using various methods and equipment, above all differential scan calorimetry (DSC) and wide array X-ray diffraction (WAXD) (5).

Molecular weight

Measuring molecular weight of a polymer (Mw) in the course of degradation is one of the most important analyses that have to be performed when studying degradation mechanisms of polymer materials. Many other properties are influenced by changes in molecular weight, including mechanical properties, crystallinity and morphology. During the breakdown process, molecular weight can be measured by gel permeation chromatography (GPC) or viscosimetric methods. The analysis yields two important parameters – mean number of molecules (Mn) and mean molecular weight (Mw). The ratio of Mw and Mn is called polydispersity index and describes the distribution width of molecular weight (5).

Mechanic properties

Some biological applications of biodegradable polymers, for instance, hard tissue replacements, demand biodegradable material with the same (in order of magnitude) mechanical properties as tissue it ought to replace. Furthermore, the material should degrade in such a way that it retains some mechanic strength and is able to support the formation of new tissue. Therefore, it is important to evaluate mechanical properties of applied biomaterial in the course of degradation. Suitable methods are described, for example, in standards by ASTM International. Tensile, compressive, and flexible properties of polymer biomaterials are tested by means of texture analysis (5).

Changes in dimensions and morphology

Changes in surface morphology of biomaterials in the course of degradation (the formation of rough surface, cracks, and micropores) are observed using microscopic methods, for instance, optical microscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM). AFM has the advantage of providing information on sample topography also in case of low magnification and enables the quantification of surface properties and shape (17).

The measurement of dimensions of applied sample of biomaterial in the course of degradation is an important item. In some cases, the breakdown process can cause significant changes that could pose a threat to morphologic properties of the final implant (for instance, bone cements or other filling or cementing devices). This type of analysis can help to identify the modus and direction of degradation. Usually, biomaterial is observed and analysed in sample cut obtained by deep-freeze drying and cutting in liquid nitrogen (5).

Chemical composition of the surface

Surface composition of biodegradable polymers before and during degradation can be analysed by various methods – Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and contact angle measurement. Main difference between these methods lies in the amount of provided information and the depth of observed material they are able to penetrate (5).

XPS provides information on elements and chemical groups on the surface of the material (top 10 nm of surface) (18). FTIR enables the detection and quantification of chemical groups in top 5 µm of surface. Furthermore, when FTIR is combined with attenuated total reflection (ATR) it is possible to analyse samples in wet state, which is more significant from the point of view of biological systems (19).

Measurement of contact angle can provide information on changes in hydrophilicity of the material surface. Increasing values of contact angle suggest that the surface is becoming more hydrophobic in the course of degradation (5).

Absorption of water and weight loss

Main factors that have impact on the wettability of polymers are related to their crystallinity, chemical composition and character of aqueous medium the material is subjected to (8). The measurement of water absorption provides information on hydrophilicity or hydrophobicity of particular polymer material and thus information if the polymer is likely to be degraded by hydrolysis. Values representing water absorption are measured usually when the equilibrium between polymer and aqueous environment is reached. However, in some cases this never happens because before equilibrium can be reached the material degrades. In such cases the degree of water absorption increases usually in the course of degradation due to growing permeability of the material and the formation of porous structures caused by liberation of degradation products (5).

In the course of breakdown, polymer material loses weight. The rate of this loss can be observed by measuring sample weight in the course of degradation. Prior to the measurement of initial weight, the sample has to be dried until constant weight so as to avoid biased results due to residual moisture. However, drying temperature must not exceed temperature causing irreversible changes in polymer material (for example, melting point). On the other hand, for any measurement during or after degradation, the sample has to be washed thoroughly with deionized water to remove any residual degradation products, enzymes, salts, or other impurities. After cleaning, the sample is dried in vacuum until constant weight. The degree of degradation is then calculated as loss on weight (5).


Biodegradation or biological breakdown is a specific case of degradation. Polymers are degraded by biological means and agents. In medicinal terminology, biodegradation is often incorrectly united with the term hydrolysis (20).

Principles of hydrolytic degradation

Polymers that can be degraded by hydrolysis have to contain chemical bonds that are prone to hydrolysis in their structure. Compounds prone to hydrolysis include α -esters, ortho esters, anhydrides, carbonates, amides, and urethanes (8). Hydrolysis can run not only in the main chain of the polymer but also in other parts of the polymer. Whereas enzymatic degradation breaks down the material from the surface inwards (mainly because macromolecular enzymes are not able to penetrate polymeric structure), hydrolysis can occur in any part of the structure with the exception of very hydrophobic polymers. The most important parameters that have impact on hydrolytic degradation and polymer erosion include: (a) type of chemical bond; (b) pH of the environment; (c) temperature of the environment; (d) composition of copolymer; (e) hydrophilicity (20).

A) Bulk degradation and surface erosion

In the course of bulk erosion water diffuses into polymer matrix faster than the polymer is degraded. Bonds that can be hydrolysed are cleft within the whole bulk of polymer matrix at the same rate and homogeneously. Therefore, mean molecular weight of the polymer decreases evenly (Figure 1). In these polymers, constant rate of erosion is unlikely (21). In case of surface erosion , the velocity of water diffusion into polymer matrix is slower than the degradation of macromolecular components. Degradation process is running only in thin surface layer and molecular weight of the polymer does not change in the rest of the matrix. Surface erosion is heterogeneous process that depends significantly on the shape of polymer matrix (21) (22).

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Figure 1: C hanges in polymer matrix in bulk and surface erosion (21)

Recent findings have shown that degradation rate can be influenced also by many other parameters, for instance, copolymer composition, autocatalysis by acidic degradation products inside polymer structure, the presence of proteolytic active substance or excipients. However, the impact of these parameters on the decrease or increase of erosion and degradation rate remains still unclear (21) (23).

There is only one well documented phenomenon of this kind. Polyesters, one of the most frequently used hydrolytically degradable polymer classes, are degraded to oligomers with terminal carboxylic groups. This causes local increase in the acidity of the environment, resulting in autocatalysis and accelerated ester bond hydrolysis (24).

B) Chemical and enzymatic oxidation

In the course of inflammatory reaction caused by the presence of foreign body in tissue or in corporal liquid, cells participating in the inflammatory process (in this case leucocytes and macrophages) produce highly reactive oxygen species (ROS), for example, superoxide radical (O2-), hydrogen peroxide (H2O2), nitric oxide (NO), and hypochlorous acid (HOCl) (25). Oxidative activity of these molecules can cleave the bonds of polymer chains and accelerate hydrolytic degradation. There have been several studies researching the effect of reactive oxygen species on polymer material degradation. Superoxide was found to accelerate the degradation of absorbable sutures manufactured from aliphatic polyesters by cleaving ester bonds with nucleophile attack of O[2]- (26).

The impact of oxidative enzymes (plant horseradish peroxidase; human c atalase and xanthine oxidase) on the degradation of polyurethane materials was also studied. These enzymes were found to be able to cause the breakdown of polymer chain (27). There are also enzymes that catalyse the hydrolysis of synthetic polymers (5).

Degradation rate of polymer materials under in vivo conditions is higher than under in vitro conditions. The catalytic impact of hydrolytic enzymes has to be taken in account also in completely synthetic polymer materials. Nevertheless, it is not enzymatic degradation in the strict sense because the enzyme itself is not able to degrade the whole polymer molecule completely (28).

Principles of enzymatic biodegradation

The breakdown of polymer biomaterials catalysed by enzymes runs chiefly along the lines of surface erosion. This is valid chiefly in case of highly crystalline and hydrophobic homopolymers. Because of their large size, the molecules of enzymes are not able to penetrate the dense structure of some polymers. This is the reason why enzymatic catalysis occurs solely on the polymer-enzyme boundary. However, in the course of degradation, the surface becomes rougher or even fragmented, surface area available for the enzymes is growing and the rate of enzymatic degradation can increase (29).

The process of enzymatic degradation is influenced by several variables, the most significant being the interaction between enzyme and polymer matrix. Enzymatic breakdown usually includes four steps: (a) diffusion of enzyme to the surface of polymer material; (b) adsorption of enzyme on substrate leading to the formation of enzyme-substrate complex; (c) catalysis of degradative reaction (for example, hydrolysis); (d) diffusion of degradation products from the bulk of matrix to the environment (30).

Beside physical and chemical properties of the polymer (molecular weight, crystallinity, chemical structure, surface area, etc.), there are properties that are interesting from the pharmaceutical point of view; for instance, chemical modifications during the manufacturing process (cross-linking, removal or introduction of chemical groups within the polymer) that can have significant impact on the degree of enzymatic degradation, protecting the modified substrate from the enzyme. For example, lysozyme (enzyme that acts as N-acetylmuramide glycanhydrolase and degrades peptidoglycans or chitin) does not degrade chitosan efficiently if the polymer is cross-linked or completely deacetylated (31) (32).

The most frequent and, in fact, the first ever interaction of biomaterial with host tissue is the adsorption of proteins. Plasma contains more than 150 types of protein and any of them can be adsorbed on the surface of biomaterial with respect to the binding potential of particular protein (33). Adsorbed proteins can decelerate the rate of enzymatic degradation of polymer biomaterials by occupying sites available to enzymes, obstructing the contact of enzymes with bonds prone to hydrolysis, or preventing degradation production from leaving the surface of polymer. For instance, if fibrinogen is adsorbed on poly(ether urethane)s in advance, the polymer is protected for some time from the hydrolytic action of cholesterolesterase mediated by inflammatory cells (34).

A) Extracellular enzymatic biodegradation

Enzymes present in plasma can be divided into two categories: (a) specific plasmatic enzymes and (b) specific non-plasmatic enzymes. The former group has some physiological function in plasma (participating on blood coagulation, complement activation, or lipoprotein metabolism), the latter group is present in plasma without functioning there its substrates or cofactors are usually absent in plasma. Non-plasmatic enzymes originate from tissues (for example, amylases, ph osphatases, and lipases), inflammatory cells, or intracellular metabolism (5).

Biological half-lives of enzymes in plasma (Table 2) are short and the enzymes themselves are eliminated quickly. However, this can change in case of onset of some diseases or on internal injury, when levels of these enzymes in blood, lymph, or urine can be increased. On the other hand, during inflammatory reaction mediated by the interaction between tissues and the surface of biomaterial, plasmatic proteins are adsorbed, the complement is activated, the area is infiltrated by neutrophils and macrophages, and free radicals and proteolytic enzymes are released (33).

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Table 2: Plasmatic concentrations and half-lives of selected human plasmatic enzymes (5)

Enzymes mentioned above can participate on the biodegradation of polymer material implanted in the human body if the matrix contains polymers degradable by these enzymes (5).

Biodegradable polymer materials are primarily intended for the manufacture of implant systems, therefore the impact of gastrointestinal system enzymes and other body surfaces can disregarded. However, enzymes contained in tears, i.e. lysozyme and alkaline phosphatase can influence polymer biodegradation. Inside the eye, aqueous humour plays important role in the degradation of implanted polymer material. Humour is formed from plasma and has similar range of enzymes (35) (36).

B) Intracellular enzymatic biodegradation

In the course of cellular enzymatic degradation of polymers, there are two key steps. The first step is depolymerization and cleavage of polymer chain. The second step is mineralization. The first step is running outside the cell because polymeric chain is too large and often poorly soluble. Extracellular enzymes either cleave the bonds in polymer chains randomly (endo cleavage), or cleave away the terminate monomer units from the main chain (exo cleavage). As soon as sufficiently small oligomer or monomer fragments are formed, they are transported into the cells where they are degraded. This phase, also called mineralization, provides the cell with energy, mostly in the form of ATP. Terminal metabolism products include carbon dioxide, water, methane, and nitrogen compounds. The general view of biodegradation process has several variants, dependent both on the polymer and the organism. However, enzymes participate always in the first and/or the second phase of the process (20).

A) Enzymatic hydrolysis

Hydrolysis is the key reaction in cleavage of glycoside, peptide and most ester bonds (for instance, in proteins, nucleic acids, polysaccharides, poly(hydroxy alkane acid)s). Enzymes involved are classified with respect to the bond they cleave – proteases, esterases, glycosidases, and phosphatases (20). Hydrolytic enzymes are present in plasma, interstices, villi of small intestine, lumen of gastrointestinal tract, and renal tubular epithelium (5). An overview of the most important enzymes participating on inflammatory reaction and biodegradation of polymer materials with examples is listed in Table 3.

1) Proteases

Proteases are proteolytic enzymes that catalyse the hydrolysis of peptide (amide) bond and sometimes also corresponding ester bond. There are four elementary groups according to the mechanism of action: serine proteases, cysteine proteases, aspartic proteases, and metalloproteases (5) (37).

a) Human serine endoproteases include chymotrypsin family, trypsin, elastase, thrombin, and proteinkinase K. Substrate specificity of particular enzymes from this group is various probably because of variety in the structure of their binding places (20). Proteinkinase K is the main enzyme to degrade keratin (5).

b) Cysteine endoproteases (sometimes called sulfhydrylproteases or thiolproteases) include plant enzymes – papain and ficin, which are often used in modelling the degradation conditions in vitro. These enzymes recognize specifically hydrophobic substituents at the second place from preferentially cleft bond (20). Other enzymes in this group are cathepsin B, C , and H (5).

c) Almost all metalloproteases act as exoproteases. Their structure contains bivalent cation (Zn[2]+ or Mn[2]+); however the function of the metallic ion was not clarified in all the enzymes (20).

d) The most important member of aspartic endoproteases is pepsin, which cleaves the bonds preferentially after the N-terminal of aromatic amino acids (20).

2) Esterases

Esterases are the most common enzymes in most tissues. They cleave ester bonds in polymer chains with the help of water as second substrate. Carboxylic group hydrolases are of much importance – lipases and cholesterolesterases. These enzymes are able to catalyse the hydrolysis of triglycerides to diglycerides, monoglycerides, glycerol, and fatty acids. Some lipases are able to hydrolyse polyesters to monomer or oligomer products that can be encapsulated by cells (for example, phagosomes) and further metabolised by other types of esterases (38).

Lipases are active on the lipid-water divide and are almost inactive on water-soluble substrates. Extracellular lipase is active on the o/w boundary only on condition that hydrophobic part of lipase molecule binds with hydrophobic interaction with the oil surface while the active area present in hydrophilic part of enzyme breaks down the substrate molecule. Similar mechanism is present in case lipase breaks down polyester surface (20) (37).

3) Glycosidases

Glycosidases hydrolyse glycosidic bond in polysaccharides (for example, starch, inulin, cellulose, and their derivatives). The most important types are amylases and cellulases (20).

a) Amylases act on starch and derived polysaccharides, cleaving α-1,4 and/or β-1,6 glycosidic bonds. α - Amylase hydrolyses α-1,4 glycosidic bonds in starch, while maintaining the configuration of the C(1) atom of the glycone, i.e. sugar component of heteroglycoside. It is also able to disregard branching points and degrades starch to branched oligosaccharides of varying length. Βeta-amylase, an exo -enzyme, works from the non-reducing end and catalyses the hydrolysis of the second α-1,4 glycosidic bond, cleaving off two glucose units at once. It causes the inversion of configuration in C(1) from α to β, releasing one molecule of maltose (20).

b) Cellulases hydrolyse β-1,4 glycosidic bonds in cellulose and derived polymers. They do not act on crystalline cellulose (constituent of cotton or Avicel), hydrolysing only amorphous forms of cellulose (including amorphous parts of crystalline cellulose) and soluble derivatives (carboxyethylcellulose and hydroxyethylcellulose). Its endoglucanase activity is characterised by random cleavage of β - glycosidic bonds. Examples include cellobiohydrolases (that degrade amorphous cellulose by ongoing cleaving off of cellobiose units from the non-reducing end) , exoglucohydrolases (that cleave off glucose units from the non-reducing end), and β-glucosidases (that are inactive on polymer materials) (20).

4) Phosphatases

These hydrolytic enzymes catalyse the cleavage of phosphoester bonds in polymer chain. Examples include acidic phosphatase, that is present in plasma, and alkaline phosphatase, that is present in cell membranes (5).

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Table 3: Short overview of enzymes participating on biodegradation of polymer materials and on inflammatory reaction caused by the implantation (5)

B) Enzymatic oxidation

Enzymatic oxidation in biological systems is catalysed by large group of enzymes – oxidoreductases. Oxidation or reduction of substrate can be achieved by many ways, depending on chemical mechanism and the nature of resulting product. Most oxidoreductases operate on principle (a). In this type of reaction, an enzyme catalyses the oxidation of substrate by removing hydrogen atom and/or electrons with the help of an acceptor – B (NAD+, NADP+, cytochrome, etc.); substrate A acts as electron donor (20).

(a) AH2 + B → A + BH2

Reactions (b) and (c) require the presence of oxygen molecule and therefore they can run under aerobic conditions only. The mechanism of catalysis requires a cofactor. In reaction (a), the cofactor is regenerated by another enzymatic system after the reaction. In reactions (b) and (c), the cofactor is regenerated at the end of cycle (20).

(b) AH2 + O2 → A + H2O2

(c) AH2 + ½ O2 → A + H2O

Reactions (d) to (g) represent the oxidation of substrate by including one or more oxygen atoms in its molecule. These reactions differ with respect to the source of oxygen atom: water, hydrogen peroxide, or oxygen molecule. Enzymes that introduce oxygen are called oxygenases. Oxygenases can be divided in two classes: monooxygenases catalyse the inclusion of one oxygen atom in the substrate in the form of hydroxy group, which requires the presence of NADH or NADPH as the complementary reduced substrate. On the other hand, dioxygenases catalyse the inclusion of the whole oxygen molecule in the substrate. Resulting product of the reaction can be a dihydroxy derivative, however, oxygen atoms are usually included in the form of carboxylic or hydroperoxide group (20).

(d) A + H2O + B → AO + BH2

(e) A + H2O2 → AO + H2O

(f) A + O2 + BH2 → AO + B +H2O (monooxygenase)

(g) A + O2 → AO2 (dioxygenase)

Oxidative degradation of polymers can be exemplified with the biodegradation of water-soluble poly(ethylene glycol) (PEG). PEG-dehydrogenase acts both as enzyme oxidizing aldehyde group and cleaving ether bonds. The terminal group R-O-CH2-CH2OH is oxidised sequentially to R-O-CHOH-COOH. The length of PEG chain is shortened in each step by two CH2 units with release of one molecule of 2-hydroxyacetic acid (20).



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Title: Biodegradable Polymers in Pharmacy and Medicine. Classification, Chemical Structure, Principles of Biodegradation and Use