Review on Hydrolytic Degradation Behavior of Biodegradable - medIND

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molecular weight is reached at the beginning of third stage, and oligomers start to diffuse out from the polymer. Water molecules diffuse into the void created by ...
Trends Biomater. Artif. Organs, 25(2), 79-85 (2011)

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Review on Hydrolytic Degradation Behavior of Biodegradable Polymers from Controlled Drug Delivery System Chhaya Engineer1, Jigisha Parikh1 and Ankur Raval2 Department of Chemical Engineering, Sardar Vallabhbhai National Institute of Technology, Surat, India Sahajanand Medical Technologies Pvt. Ltd., Surat, India Corresponding author: Jigisha Parikh, e-mail: [email protected]

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Received 31 July 2010; Accepted 3 August 2010; Available online 4 May 2011 Biodegradable polymers are extensively used in medical device industry for the controlled delivery of pharmaceutical agent to the targeted region. Successful performance of any controlled drug delivery system (DDS) relies on the drug elution kinetics which further depends on the degradation behavior of the biodegradable polymers. Thus, fundamental understanding of the polymer degradation phenomena is the important aspect in the design and development of controlled drug delivery system. Polymer degradation is the complex phenomena known to be affected by the various inter-related factors such as polymer physico-chemical properties, drug-polymer interaction, preparation technique, degradation environment, etc. This article intends to provide the overview of the degradation mechanisms of biodegradable polymers, factors influencing the degradation, advanced characterization techniques of polymer degradation, various modeling approach to study polymer degradation and influence of polymer degradation on biocompatibility.

Introduction Controlled drug delivery technology represents one of the frontier areas of science, which involves multidisciplinary scientific approach, contributing to the human welfare. Controlled drug delivery is concerned with the systematic release of a pharmaceutical agent to maintain a therapeutic level of the drug in the body for a sustained period of time [1, 2]. Biodegradable polymers have been used in controlled drug delivery for many years as a means of prolonging the action of therapeutic agent in the body, without the need to remove the device after treatment [3, 4]. Biodegradable polymers are an interesting class of material that can degrade to non-toxic products and find interesting medical and pharmaceutical applications [5] such as matrices for drug delivery [6], scaffold for tissue engineering [7], degradable implants in orthopedic surgery [8, 9], etc. The most extensively investigated and advanced polymers in regard to available toxicological and chemical data are the aliphatic polyesters based on lactic and glycolic acids [10]. Homo and copolymers of Lactide and Glycolide have been focused in the search for appropriate polymer for drug delivery system because of its biocompatibility and hydrolytic degradation in to lactic and glycolic acids which are subsequently eliminated as carbon dioxide and water via the Krebs cycle [10-12]. The popularity of PLA and PLGA is further explained by the fact that FDA has approved them for a number of clinical applications [13].

Despite the growing use of biodegradable polymers, there are still many unsolved problem that hinder to take full advantage of this materials. One example is lack of understanding the mechanism of polymer degradation which controls the essential processes; like the release of drug from the DDS and mechanical stability of polymeric implants. For successful development of any DDS, it is essential to understand the degradation behavior of biodegradable polymers used as drug delivery vehicle. There are different types of polymer degradation such as photo, thermal, mechanical and chemical degradation [14, 15]. For in-vivo application; thermal degradation is not of much significance. Mechanical degradation affects those polymers which are subjected to mechanical stress; e.g. for medical implants, sutures, etc [16, 17]. All biodegradable polymers contain hydrolysable bonds making them more prone to chemical degradation via hydrolysis or enzyme-catalyzed hydrolysis. Enzymatic degradation does not play significant role in polymers belonging to lactide/glycolide family [18, 19]. Therefore, study of hydrolytic degradation is utmost important while considering performance of polymeric implants or polymeric drug delivery system. The objective of this article is to outline the hydrolytic degradation phenomena of biodegradable polymers when incorporated in controlled drug delivery systems and to

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review the various factors influencing the polymer degradation. The most important features of the degradation and erosion of degradable polymers are discussed here. Advanced analytical techniques utilized to characterize polymer degradation as well approaches for polymer degradation and erosion modeling are reviewed. Efforts are also made to correlate the polymer degradation with the biocompatibility aspects. A better comprehension of polymer degradation mechanism would help in predicting the drug release rate and will aid in future development of polymeric drug delivery systems. Biodegradable Polymers in Controlled Drug Delivery Biodegradable polymers are gaining exponential interest in the field of controlled drug delivery. A promising way to achieve controlled drug delivery is by incorporating the therapeutic agent into the biodegradable polymeric vehicle, releasing the agent continuously as the polymer degrades [13, 20]. The release kinetics of drug from controlled drug delivery systems is controlled by diffusion and/or erosion mechanisms [21, 22]. For non-erodible polymers, diffusion mechanism governs the drug elution kinetics, which provides burst release of drug which should be unavoidable in some cases. For biodegradable polymers, diffusion and degradation, both phenomena contributes to the drug elution response. Therefore, drug release kinetics can be tailored precisely by use of biodegradable polymers [23]. For biodegradable polymeric DDS; drug is released in three phases [21, 24]: (i) an initial burst due to dissolution or diffusion of drug followed by (ii) a lag phase and finally (iii) controlled release of drug governed by polymer degradation. For continuous drug release to occur from these systems the diffusion- and degradation-controlled phases must overlap and therefore the degradation profile

of the polymer is important for a controlled release formulation. In order to elucidate the mechanism governing drug release, it appears essential to enumerate the degradation profile of the polymers. Mechanism of Polymer Degradation and Erosion The difference between polymer “degradation“ and “erosion“ is not clear in many cases. Biodegradable polymers undergo hydrolytic bond cleavage to form watersoluble degradation products that can dissolve in an aqueous environment, resulting in polymer erosion [25, 26]. In this context, degradation is a chemical phenomenon and erosion encompasses physical phenomena, such as dissolution and diffusion. Polymer degradation is the key route of erosion [27]. Polymer erosion is so far more complex than degradation, because it depends on many other processes, such as degradation, swelling, dissolution and diffusion of oligomers and monomers, and morphological changes. The erosion of a polymer matrix can proceed through two alternative physical mechanisms: (a) surface erosion and (b) bulk erosion as shown in Figure 1. For ideal surface erosion, erosion rate is constant and proportional to external surface area [28]. For bulk eroding polymers such as PLA and PLGA, things are more complicated as they have no constant erosion rate [27, 29]. Hydrolytic degradation of members of the polylactide/ glycolide family proceeds through four stages as represented in Figure 2: First stage of water diffusion followed by second stage, in which oligomers with acidic end-groups autocatalyze the hydrolysis reaction. A critical molecular weight is reached at the beginning of third stage, and oligomers start to diffuse out from the polymer. Water molecules diffuse into the void created by the removal of

Table 1: Effect of Various Factors on Polymer Degradation Factor Type of Polymer Effect Increase in glycolide content accelerate Copolymer Composition PLGA polymer degradation Faster degradation in amorphous than Morphology Lactic and glycolic acids crystalline polymer Spray−dried particles degrade faster than Preparation Technique PDLA and PLGA particles prepared by solvent evaporation. Accelerate degradation. Autocatalysis PDLA Faster degradation in center compare to surface PDLA+Caffeine Accelerate degradation 75/25 PLGA+Ganciclovir Decrease in degradation rate due to basic drug PLGA+Lidocaine Type of drug doesn’t significantly affect Presence of drug PLGA+Ibuprofene polymer degradation kinetics.

Molecular weight

PDLA and PLGA+diazepam 50/50 PLGA

Polymer end−group

50/50 PLGA

Temperature

PDLA

pH

PLA

Size and geometry

PDLA

Reference 40, 41 34 42 35, 36 37 43 44

Presence of drug increase degradation rate

42

Faster degradation with low Mw polymers Uncapped polymer degrade faster than capped Rapid degradation due to increase in temperature Low pH accelerate polymer degradation Large size plates degrade faster and heterogeneous than thinner films.

45 45 46, 47 27, 35, 48, 49 47, 50

Review on Hydrolytic Degradation Behavior of Biodegradable Polymers the oligomers, which in turn encourages oligomers diffusion. Marked decrease in polymer mass and a sharp increase in the drug release rate occur during third stage as the drug diffuses from the porous regions. In fourth stage, polymeric matrix become highly porous and degradation proceeds homogeneously and more slowly [10, 30-32]. Factors Influencing Polymer Degradation In recent years a number of parameters have been identified that influence the polymer degradation. Among them are the copolymer composition [33], morphology [34], autocatalysis by acidic degradation products inside a matrix [35, 36], presence of drugs [37] or other excipients [38] and preparation technique [39]. However, the impacts of these parameters that increase or decrease the degradation rate are not exactly clear. Review on effect of various factors on polymer degradation is presented in Table 1. The physico-chemical properties of the incorporated drug as well interaction between polymeric matrix and drug is critical parameter which has a strong effect on polymer degradation and the drug release [51]. For example, hydrophilic drugs facilitate water penetration in the system and lead to the creation of highly porous polymer networks upon drug leaching; thus accelerate polymer degradation. In contrast, lipophilic drugs hinder water diffusion into the matrix and retard polymer degradation [44]. For acidic

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drugs, faster hydrolysis of ester bonds because of acid catalysis can be observed which accelerates polymer degradation [37, 52]. In contrast, in the case of basic drugs two effects can be observed: base catalysis of ester bond cleavage and neutralization of carboxyl end groups of polymer chains which minimizes or eliminates the autocatalytic effect of acidic chain ends. Thus the degradation can be accelerated or slowed down depending on the relative importance of the two effects [37, 53-55]. These examples illustrate an important principle in the design of controlled drug delivery systems: The degradation rate of a given polymer is not an unchangeable property, but depends to a very large degree on readily controllable factors as discussed above. Physicochemical Characterization Techniques for Polymer Degradation Due to complexity of the physical and chemical phenomena involved in polymer degradation, each polymeric DDS should precisely characterize for polymer degradation analysis. Several investigation techniques have been used to correlate degradation parameters sensitive to the degradation process. In most cases the parameter used for monitoring degradation are changes in molecular weight [56]. However, other parameters such as changes in crystallinity [57], thermal changes [58], pH changes in the degradation medium or inside the pores

Table 2: Characterization Techniques Used to Study Polymer Degradation

haracterization Technique GPC

Molecular weight

DSC

Thermal changes

PDLA PLGA PDLA

TGA

Thermal changes

PDLA

Changes in concentration of terminal group

poly(ethylene naphth alene−2,6−dicarboxyl ate) Polyesters

IR

Degradation Parameter

FT−IR

Absorbance of peak

SEM

Surface characterization

NMR

Molar fraction of monomer and degree of degradation

HPLC Raman Spectroscopy TOF−SIMS

Type of Polymer

Copolymers of sebacic acid and car boxyphenoxy propane PDLA

Outcome

Reference

Molecular weight decrease as the degradation proceeds. Tg decrease as degradation proceeds. Above Tg, polymer degradation is faster. Hydrolytic degradation rate constant was determined by acidcatalysis reac tion. Hydrolysis of ester bonds proceeds li nearly with time. Degradation rate inc rease with increasing polydispersity. Crystalline region is more resistant to erosion than amorphous. Matrix erodes in highly porous device.

30, 45−47

42

46 58 61 66

59

Variation of molecular weight

Cross−linked Polyethyleneimine

Determination of monomer release Chemical composition, molecular weight, morphology Surface molecular weight and end−group

PDLA and PLGA

Base catalyzed hydrolysis of PDLA w as by a random scission mechanism, while acid catalyzed is f aster chain−end scission. Degradation mechanism and degradation half−life was established. GA degrade faster than LA

Copolymer of lactide /caprolactone

Hydrolytic degradation was monitore d. Crystallinity increase with time.

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PLLA

Good linearity obtained in the kinetics study of PLLA degradation at the surface.

51, 69

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Bulk Erosion

Time

Figure 1: Schematic Representation of Surface Erosion and Bulk Erosion

of the eroding polymeric matrix [59], formation of functional groups in degrading products [60] or changes in the concentration of terminal groups [61] have been used. To monitor these parameters as a function of reaction time, numerous methods have been reported in the literature. A simple but rather effective technique to characterize the degradation of a polymeric matrix is recording of mass loss during the degradation period. As it is linear for surface eroding devices only, mass loss profiles allow assessing the type of erosion that a polymer matrix is undergoing [28, 29]. Qualitative evaluation of polymer degradation can be performed by Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) which provide insight into the external and internal

morphology of degradable polymer systems [42]. A standard technique to characterize polymer degradation is to determine the molecular weight reduction of the polymer by means of gel permeation chromatography (GPC) or by intrinsic viscosity [62]. Such information is of vital importance for quantifying polymer degradation because many theories link the drug diffusion coefficient inside degradable polymers to the polymer molecular weight as small chain molecule offer less restriction for drug diffusion than long chains [63]. For the changes that degradable polymers undergo during degradation, thermal analysis such as Differential Scanning Calorimetry (DSC) and Thermo gravimetric Analysis (TGA) are rather useful [58]. Some of the advanced techniques useful for study of polymer degradation are: determination of the molar fraction of the monomer by nuclear magnetic resonance (1H NMR) [51, 52], changes in crystallinity by Wide angle X-ray diffraction [9, 64, 65], determination of monomer release by HPLC [42], end-group analysis by FT-IR [66] and study of polymer structure and degradation by Raman scattering [67]. Review of various analytical techniques used to characterize polymer degradation is presented in Table 2. These techniques are only a brief collection of frequently used tools that have been applied to characterize polymer matrix during degradation and is far not complete. Polymer Degradation and Erosion Models Computational models can be useful tools for increasing the understanding of polymer degradation and drug release processes from the controlled drug delivery systems. Modeling of polymer degradation is very complex as degradation is influenced by various factors including kinetics of water uptake, chemical reaction involved in hydrolytic cleavage, etc. Models have been developed which take into account many of the factors influencing polymer (PLGA) degradation and subsequent drug release

Figure 2: Schematic Representation of Hydrolytic Degradation of Polymer

Review on Hydrolytic Degradation Behavior of Biodegradable Polymers such as drug diffusivity and dissolution, pore structure development, polymer composition, and device geometry [70, 71]. However, few models have fully considered the autocatalytic PLGA hydrolysis kinetic mechanism which is believed to be a key factor leading to particle sizedependent heterogeneous polymer degradation [50, 72]. Despite the size dependence of autocatalytic PLGA degradation, still it is not studied in any previous model; which tracks hydrogen ion concentration as a function of space and time in addition to modeling degradation kinetics, molecular weight distribution, and drug transport with varying diffusivity. Often polymer degradation is assumed to follow wellmixed pseudo-first-order kinetics in models that aim to include autocatalytic effects [70, 73, 74]. Researchers have shown that for poly(lactic acid), pseudo-first-order kinetics are a good approximation for hydrolysis catalyzed by an external strong acid but are insufficient for modeling autocatalysis [75]. They proposed two alternative kinetic expressions. The first considers quadratic autocatalysis. This model had limitations because it did not capture the effects of partial dissociation of the carboxylic acid end groups. The second kinetic expression did consider partial dissociation effects and had half-order dependence on carboxylic acid. This model fits the data very well except near the extrema of the data set. Erosion modeling is even more complex than degradation modeling because of the multitude of involved processes. There are only few approaches to erosion modeling but none of them covers all processes that are involved in erosion. Mathematical models reported in literature can be classified into two categories: (i) empirical models that only describe the resulting erosion rate without considering it as the result of mass transport and chemical reaction phenomena [70]; and (ii) models considering physicochemical phenomena such as diffusional mass transfer or chemical reaction processes using direct Monte Carlo techniques [27, 29]. In early approaches, only heterogeneous erosion was modeled. Diffusion theory was introduced to describe the diffusion of low-molecular weight compounds from eroding polymers [76]. Later, moving erosion fronts as well as dissolution fronts for crystalline matter were introduced [77, 78]. A substantial improvement was made when combining the diffusion equation with a reaction term accounting for the degradation of the polymer [79]. The degradation of polymer was included into the models under the premise of first-order kinetics for the chain scission [80]. Recently, the formation and release of oligomers and molecular weight changes were taken into account, also using a diffusion/reaction equation [81, 82]. All these approaches relied on differential equations for describing erosion.

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apply these approaches to the polymer degradation. In addition, such models are unique to a specific system and can not be generalized. Polymer Degradation and Biocompatibility Successful biodegradable polymeric system should not cause any significant systemic or local reactions. When biocompatibility of a polymeric system or implants is under question, not only the polymer itself but its degradation rate is also important. The changes that occur in the physiochemical properties of the polymer during degradation may alter their functionality and the associated biological response. In addition, the nature of the degradation products will, in part, define the ultimate biocompatibility of the polymer since it may also induce alteration to cellular function [83-85]. Degradation rate of polymeric system or implants play an important role in the engineering process of a new tissue. Polymer degradation rate affects cell vitality, cell growth and even host response [86]. Ideal in-vivo degradation rate of polymeric implants should be similar or slightly less than the rate of tissue formation so that the space occupied by polymeric devices can be replaced by newly formed tissue [87]. Effect of polymer degradation on biocompatibility of system is not thoroughly investigated till date. Understanding the degradation mechanism of polymers (degradation kinetics, identification of degradation products) is, therefore, of crucial importance when selecting and designing polymer for specific applications.

Conclusion Study of polymer degradation behavior is pre-requisite for successful performance of any biodegradable polymeric drug delivery systems. Polymer degradation has proven to be a difficult phenomenon to describe analytically, numerically or empirically. Drug diffusion and drug-interaction with polymer make it more complicated. Though various research studies are carried out till date; still many aspects need to be considered to thoroughly investigate the polymer degradation behavior. Due to the fundamental differences in the physicochemical properties of drugs and polymers used for controlled drug delivery, the dominating chemical reaction and/or physical mass transfer processes can significantly differ from system to system. In-vivo polymer degradation behavior may also differ from in-vitro degradation response; which is still not investigated sufficiently. This review suggests that careful consideration of the degradation profiles of various polymers will be helpful in elucidating the degradation behavior of, and possibly designing, future drug delivery systems for a potentially wide variety of medical applications.

Despite some progress in the area of modeling, much more data and more sophisticated models are needed to

References 1. O. Pillai, A. Dhanikula and R. Panchagnula, R, Curr. Opin. Chem. Biol, 5, 439-446 (2001). 2. R. S. Langer and D. L. Wise, Medical Applications of Controlled Release, Applications and Evaluation, CRC Press: Florida, Vol. I and II (1984). 3. R. S. Langer, Science, 249, 1527-1533 (1990). 4. J. Heller, Drug Delivery Systems, in: Biomaterials Science: An Introduction to Materials in Medicine, (Ed) D. Ratner, A. S. Hoffman, F. J. Schoen and J. E. Lemons, Academic Press: New York, 347-356 (1996). 5. N. A. Peppas and R. S. Langer, Science, 264, 1065-1067 (1994).

84

C. Engineer, J. Parikh and A. Raval

6. S. J. Holland, B. J. Tighe, and P. L. Gould, J. Controlled Release, 4, 155-180 (1986). 7. L. E. Freed, J. C. Marquis and A. Nohria, J. Emmanual, A. G. Mikos and R. S. Langer, J. Biomed. Mater. Res, 27, 11-23 (1993). 8. A. M. Reed and D. K. Gilding, Polymer, 22, 494-498 (1981). 9. J. W. Leenslang, A. J. Pennings, R. M. Ruud, F. R. Rozema and G. Boering, Biomaterials, 8, 70-73 (1987). 10. D. H. Lewis, Biodegradable polymers as drug delivery systems, Controlled release of bioactive agents from Lactide/Glycolide polymers, in Biodegradable polymers as drug delivery systems. (Ed) M. Chasin, and R. Langer, Marcel Dekker: New York, 1-43 (1990). 11. R. L. Kronenthal, Biodegradable polymers in medicine and surgery, in Polymers in medicine and surgery, (Ed) R. L. Kronenthal, Z. Oser, E. Martin, Plentum Press: New York, 119 (1975). 12. A. M. Reed and D. K. Gilding, Polymer, 22, 494-498 (1981). 13. U. Edlund and A. Albertsson, Adv. Polym. Sci, 157, 67-112 (2002). 14. C. H. Banford and C. Tipper, Comprehensive Chemical Kinetics, Elsevier: New York, Vol. 14 (1972). 15. N. Grassie and G. Scott, Polymer Degradation and Stabilization, Cambridge University Press: New York, (1985). 16. A. Brandwood, K. R. Noble and K. Schindhelm, Adv. Biomater, 10, 413-420 (1992). 17. N. D. Miller and D. F. Williams, Biomaterials, 5, 365-368 (1984). 18. C. G. Pitt, F. I. Chasalow, Y. M. Hibionada, D. M. Klimas and A. Schindler, J. App. Poly. Sci, 26, 3779-3787 (1981). 19. M. Therin, P. Christel, S. M. Li, H. Garreau and M. Vert, Biomaterials, 13, 594-600 (1992). 20. J. Heller, in Medical Applications of Controlled Release, (Ed) R. S. Langer and D. L. Wise, CRC Press: Florida, Vol. I, 69-101 (1984). 21. Z. Ramtoola, O. I. Corrigan and C. Barrett, J. Microencapsulation, 9, 415-423 (1992). 22. B. V. Parikh, S. M. Upadrashta, S. H. Neau and N. O. Nuessle, J. Microencapsulation, 10, 141-153 (1993). 23. J. Swarbrick and J. C. Boylan, Biodegradable Polyester Polymers as Drug Carriers to Clinical Pharmacokinetics and Pharmacodynamics, Informa Health Care. 24. J. F. Fitzgerald and O. I. Corrigan, J. Controlled Release, 42, 125-132 (1996). 25. L. G. Griffith, Acta Mater, 48, 263-277 (2000). 26. A. Merkli, C. Tabatabay and R. Gruny and J. Heller Prog. Polym. Sci, 23, 563-580 (1998). 27. A. Gopferich, Biomaterials, 23, 103-114 (1996). 28. A. Gopferich and R. Langer, Macromolecules, 26, 4105-4112 (1993). 29. A. Gopferich, Macromolecules, 30, 205-269 (1998). 30. C. S. Proikakis and N. J. Mamouzelos, Polym. Degrad. Stab, 91, 614-619 (2006). 31. C. M. Agrawal, K. F. Haas D. A. Leopold and H. G. Clark, Biomaterials, 13, 176-182 (1992). 32. L. G. Cima, D. E. Ingber, J. P. Vacanti and R. Langer, Biotechnol. Bioeng, 38, 145-158 (1991). 33. M. Vert, P. Christel, F. Chabot and J. Leray, in Macromolecular Materials, (Ed) G. W. Hastings and P. Ducheyne, CRC Press: Florida, 119 (1984). 34. M. Vert, S. Li and H. Garreau, Clinical Materials, 10, 3-8 (1992). 35. S. M. Li, H. Garreau and M. Vert, J. Mater. Sci. Mater. Med, 1, 123-130 (1990). 36. S. M. Li, H. Garreau, and M. Vert, J. Mater. Sci. Mater. Med, 1, 198-206 (1990). 37. S. Li, S. Girod-Holland and M. Vert, J. Controlled Release, 40, 41-53 (1996). 38. J. Heller, Polym. Sci. Technol, 34, 357-368 (1986). 39. E. Mathiowitz, D. Kline and R. Langer, J. Scanning Microsc, 4(2), 329-340 (1990). 40. R. Miller, J. Brady and D. Cutright, J. Biomed. Mater. Res, 11, 711-719 (1977). 41. S. M. Li, H. Garreau and M. Vert, J. Mater. Sci. Mater. Med, 1, 131-139 (1990). 42. P. Giunchedi, B. Conti and S. Scalia, J. Controlled Release, 56, 53-62 (1998). 43. X. Chen and C. P. Ooi, J. Biomater. Appl, 20, 287-302 (2006). 44. D. Klose and F. Siepmann, Int. J. Pharm, 354, 95-103 (2008). 45. M. A. Tracy, K. L. Ward and L. Firouzabadian, Biomaterials, 20, 1057-1062 (1999). 46. S. Li and S. McCarthy, Biomaterials, 20, 35-44 (1999). 47. M. Dunne, O. I. Corrigan and Z. Ramtoola, Biomaterials, 21, 1659-1668 (2000). 48. J. Heller, J. Controlled Release, 2, 167-177 (1985). 49. J. Heller, Polymer Sci. Tech, 34, 357-368 (1986). 50. I. Grizzi, H. Garreau S. Li and M. Vert, Biomaterial, 16, 305-311 (1995). 51. J. Chen, J. Lee and N. L. Hernandez de Gatica, Macromolecules, 33, 4726-4732 (2000). 52. A. Frank, S. K. Rath and S. S. Venkatraman, J. Controlled Release, 102, 333-344 (2005). 53. T. Tarvainen, T. Karjalainen M. Malin, S. Pohjolainen, J. Tuominen and J. Seppala, J. Controlled Release, 81, 252-261 (2002). 54. H. V. Maulding, T. R. Tice, D. R. Cowsar, J. W. Fong, J. E. Pearson and J. P. Nazareno, J. Controlled Release, 3, 103-117 (1986). 55. R. Bodmeier and H. G. Chen, J. Pharm. Sci, 78, 819-822 (1989). 56. Gopferich, A. (1997). Handbook of Biodegradable Polymers, (Harwood Academic Publishers, Amsterdam), pp. 451“471. 56. A. Gopferich, Mechanism of polymer degradation and elimination, in Handbook of biodegradable polymers, (Ed) A. J. Domb, J. Kost and D. M. Wiseman, Harwood Academic Publishers: Amsterdam, 451“71 (1997). 57. S. Hurrell and R. E. Cameron, J. Mater. Sci. Mater. Med, 12, 811-816 (2001). 58. Y. Aso, S. Yoshioka, A. Li Wan Po and T. Terao, J. Controlled Release, 31(1), 33-39 (1994) 59. A. Gopferich and R. Langer, J. Polym. Sci. Part A: Polym. Chem, 31, 2445-2458 (1993). 60. Y. T. Yoo, B. J. Lee, S. S. Im and D. K. Kim, Polym. Degrad. Stab, 79 (2), 257-264 (2003). 61. H. Zang and I. M. Ward, Macromolecules, 28, 7622-7629 (1995). 62. L. G. Griffith, Acta Mater, 48(1), 263-277 (2000). 63. J. Siepmann and A. Gopferich, Adv, Drug Delivery Rev, 48, 229-247 (2001). 64. T. H. Nguyen, C. Shih and K. J. Himmelstein, J. Pharm. Sci, 73, 1563-1568 (1984). 65. C. Shih, T. Higuchi and K. J. Himmelstein, Biomaterials, 5, 237-240 (1984). 66. M. Partini and R. Pantani, Polym. Degrad. Stab, 92, 1491-1497 (2007). 67. G. Kister, G. Cassanas and M. Bergounhon, Polymer, 41, 925-932 (2000).

Review on Hydrolytic Degradation Behavior of Biodegradable Polymers 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80.

85

M. Peng, W. Liu and G. Yang, Polym. Degrad. Stab, 93, 476-482 (2008). J. W. Lee and J. A. Gardell, Anal. Chem, 75, 2950-2958 (2003). R. P. Batycky, J. Hanes and R. Langer, J. Pharm. Sci, 86, 1464-1470 (1997). D. Y. Arifin, L. Y. Lee and C. H. Wang, Adv. Drug Delivery Rev, 58, 1274-1325 (2006). A. C. Grayson, M. J. Cima and R. Langer, Biomaterials, 26, 2137-2145 (2005). C. Raman, C. Berkland, K. K. Kim and D. W. Pack, J. Controlled Release, 103, 149-158 (2005). J. Siepmann, K. Elksarraz, F. Siepmann and D. Klose, Biomacromolecules, 6, 2312-2319 (2005). G. L. Siparsky, K. J. Vorhees and F. Miao, J. Environ. Polym. Degrad, 6, 31-41 (1998). R. W. Baker and H. K. Lonsdale, Am. Chem. Soc. Div. Org. Coat. Plast. Chem. Prepr. 3, 229 (1976). P. I. Lee, J. Membr. Sci, 7, 255-275 (1980). A. G. Thombre and K. J. Himmelstein, Biomaterials, 5, 250-254 (1984). A. G. Thombre, Biodegrad. Polym. Plastics, 109, 214-225 (1992). J. Heller and R. W. Baker, Theory and practice of controlled drug delivery from bioerodible polymers, in Controlled Release of Bioactive Materials, (Ed) R. W. Baker, Academic Press: New York (1980). 81. K. J. Himmelstein and J. George, Proc. Int. Symp. Control. Rel. Bioact. Mater. 20, 53-54 (1993). 82. K. J. Himmelstein, Polym. Prepr. Am. Chem. Soc., Div. Polym. Chem. 33, 4849 (1992). 83. C. Agrawal, Polymer Based Systems on Tissue Engineering, Replacement and Regeneration, Kluwer Academic Publisher: Netherland, 25-54 (2002). 84. A. Gabriela, A. Marques and E. Manuela, Biodegradable Systems in Tissue Engineering and Regenerative Medicine, CRC Press: Florida, 339-354 (2004). 85. A. Tezcaner and V. Hasirci, Tissue Engineering and Novel Delivery Systems, CRC Press: Florida, 173-196 (2004). 86. J. E. Babensee, J. M. Anderson, L. V. Melntire and A. G. Mikos, Adv. Drug Delivery Rev, 33, 111-139 (1998). 87. C. E. Holy, S. M. Dang, J. E. Davies and M. S. Shoichet, Biomaterials, 20, 1177-1185 (1999).