Poly(P-Dioxanone) (PPDO), and Its Copolymers

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JOURNAL OF MACROMOLECULAR SCIENCE Part C—Polymer Reviews Vol. C42, No. 3, pp. 373–398, 2002

POLY( p-DIOXANONE) AND ITS COPOLYMERS

Ke-Ke Yang, Xiu-Li Wang, and Yu-Zhong Wang*

Center for Degradable and Flame-Retardant Polymeric Materials, School of Chemistry, Sichuan University, Chengdu 610064, P. R. China

CONTENTS

1. Introduction ...... 374 2. Synthesis of PDO ...... 374 2.1. Physical Properties of PDO ...... 374 2.2. Synthesis of PDO ...... 375 3. Ring-Opening Polymerization of PDO ...... 376 3.1. Catalyst...... 376 3.2. Copolymerization Based on PDO ...... 381 4. Properties of PPDO ...... 383 4.1. Solubility ...... 384 4.2. Biodegradability ...... 384 4.3. Thermal Properties...... 386 4.4. Crystallization and Morphology ...... 386 4.5. Mechanical Properties...... 390 5. Application of PPDO ...... 390 5.1. Surgical Suture...... 390 5.2. Bone and Tissue Fixation Device ...... 391 5.3. Drug Delivery System...... 391

*Corresponding author. Fax: þ86-28-5412907; E-mail: [email protected]

373

DOI: 10.1081/MC-120006453 1532-1797 (Print); 1532-9038 (Online) Copyright # 2002 by Marcel Dekker, Inc. www.dekker.com 中国科技论文在线 http://www.paper.edu.cn

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6. Conclusion ...... 391 References ...... 392

ABSTRACT

This paper reviews the synthesis, properties, and applications of biodegradable polymer, poly(p-dioxanone) (PPDO), and its copolymers. Recent progress in ring-opening polymerization of p-dioxanone employ- ing several eﬀective catalysts is described. Properties of PPDO are given. The copolymers based on PPDO are also discussed.

Key Words: Poly(p-dioxanone); Copolymers; Ring-opening polymerization; Biodegradable

1. INTRODUCTION

Aliphatic polyesters, with outstanding biodegradability, bioabsorbability, and biocompatibility, have attracted great interest from researchers in recent decades. The related papers and patents increased sharply in a very short period, and remarkable progress has been achieved in this field.[1–9] As a result, a series of polyesters and copolyesters have been synthesized successfully from the lactone monomers including glycolide (GA),[10] lactide (LA),[3,7–9] e-caprolactone (CL),[2,11,12] p-dioxanone (PDO),[4,5,13,14] 1,5-dioxepan-2-one (DXO),[15] 1,3-dioxan-2-one (TMC),[16–18] and so on. Most of them have been applied to make biodegradable products, especially surgical devices such as surgical suture, anchors, staples, tacks, clips, plates, screws, and bone fixation devices.[7,8,14] Compared with other aliphatic polyesters, poly( p-dioxanone) (PPDO) has its own special characteristics. Except for its ultimate biodegradability due to the existence of ester bonds in polymer chains, the unique ether bonds endow it with good flexibility.[19] It has also received the approval of the Food and Drug Administration (FDA) to be used as suture material in gynecology.[19,20] However, PPDO did not become the focus of polyesters for quite a long period. There are two main reasons for this. One reason is that the monomer PDO was not commercially available in the past. The other reason is that the activity of the PDO monomer is comparatively low, and most catalysts that have been mentioned in the available information are not effective enough to produce the polymer at reasonable cost. Fortunately, the synthetic method of producing PDO has been sim- plified greatly, and studies on PPDO have made rapid development in recent years. 中国科技论文在线 http://www.paper.edu.cn

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POLY( p-DIOXANONE) AND ITS COPOLYMERS 375

This article presents a review of the synthesis, properties, and applications of PPDO and its copolymers.

2. SYNTHESIS OF PDO 2.1. Physical Properties of PDO

p-Dioxanone or 1,4-dioxan-2-one, abbreviated as PDO, is a colorless crystal or liquid. Its molecular weight is 102, and melt point is 24C.[21] Boiling points are 220C, 213–214C, 109–110C, and 92–93C, respectively, under diﬀerent pressures [760 mmHg (calculated value), 747 mmHg, 22 mmHg, and 10 mmHg].[13,22] There are many ways to characterize its molecular structure, such as nuclear magnetic resonance (NMR) spectroscopy (1H-NMR spectrum), infrared (IR) spectroscopy, and mass spectrometry (MS).[22] The NMR spectrum of PDO exhibits a sharp singlet at d4.40 and two multiplets of equal intensity centered at d3.9 and 4.5. The IR spectrum shows the following absorptions: CH stretching at 1 1 2900 cm ,C¼O stretching at 1740 cm ,CH2 bending at 1455 and 1432 cm1, CO stretching at 1200, 1130, and 1053 cm1, and other weaker bands at 876, 853, 726 cm1. The mass spectrum of PDO, including parent, Pþ1, and major peaks, appear at 103, 102, 101, 87, 86, 75, 73, 58, 57, 45, 44, 43, 42, 32 m/e, respectively.[22]

2.2. Synthesis of PDO

In the early 1970s, Doddi et al.[14] had used ethylene glycol, metallic sodium, and chloroacetic acid to synthesize PDO (Scheme 1). However, the procedure was so complex and the yield so low that it caused a high cost of PDO and seriously hampered the application of PPDO. So this method was substituted in the last decade by a simple method that prepared PDO by oxidative dehydrogenation of diethylene glycol over Cu(O) catalyst supported on silica particles (Scheme 2).[23] Because the resource, diethylene glycol, was very cheap, this one-step reaction sharply decreased the cost of PDO. Purification of PDO is also an important step in order to achieve high molecular weight PPDO. Distillation and recrystallization are both effective ways to purify the monomer. Distillation is usually conducted under high vacuum, considering the rather high boiling point of PDO at normal pressure. Commonly, ethylacetate has been chosen as the recrystallizing solvent. However, the yield of recrystallization is lower than that of distillation. Jiang[24] supplied a method to gain excellent purified PDO by double recrystallization using ethylacetate as solvent with a yield of 30%. 中国科技论文在线 http://www.paper.edu.cn MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

376 YANG, WANG, AND WANG

HOCH2CH2OH + Na

HOCH2CH2ONa + H2 + HOCH2CH2OH

1/2ClCH2COOH

HOCH2CH2OCH2OONa + NaCl + HOCH2CH2OH distillation

HOCH2CH2OCH2COONa + NaCl HOCH2CH2OH washing by acetone

HOCH CH OCH COONa 2 2 2 CH3COCH3 + NaCl + - H3O + Cl

HOCH2CH2OCH2COOH + H2O + NaCl precipitation with ethanol and filtration

HOCH2CH2OCH2COOH ++ H2O C2H5OH NaCl + C2H5OH distillation

HOCH2CH2OCH2COOH H2O + C2H5OH

O O

O Scheme 2.

O Catalyst O HOCH2CH2OCH2CH2OH O

Scheme 1.

3. RING-OPENING POLYMERIZATION OF PDO 3.1. Catalyst

The polyester PPDO is synthesized by ring-opening polymerization from the monomer PDO. In this polymerization process, the catalyst plays an important role, which inﬂuences not only the polymeric parameters such as reaction rate, conversion, and yield, but also the properties of the polymer such as molecular weight and polydispersity. Several catalysts, especially organometallics, have been found eﬀective to initiate the ring-opening polymerization of lactone, even if some of them have not been reported to apply to PDO. Most catalysts are the derivatives of organometallics of heavy metals such as Ti, Zr, Sn, Cd, Al, Zn, Y, La, and Yb. Thereafter, the catalysts that have been used frequently will be listed in detail. 中国科技论文在线 http://www.paper.edu.cn MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

POLY( p-DIOXANONE) AND ITS COPOLYMERS 377

3.1.1. Organic Tin Compounds

Organic tin compounds, including stannous octoate,[25–29] stannous oxalate,[30] dibutyltin oxide,[31] stannic bromide, stannic chloride, stannous bromide, stannous chloride,[32–34] stannous acetylacetonate,[35] and [16] Bu2SnOct2, have been used most frequently in ring-opening polymerization of lactone. Among these, stannous octoate (SnOct2) has been found the most eﬀective catalyst. Moreover, it is one of the few catalysts that could be used as a food additive, sanctioned by the FDA, and it is safe to synthesize polymers used as biodegradable surgical devices. Therefore, SnOct2 has often been chosen in the literature (or patents) regarding the ring-opening [25–29,36–40] polymerization of PDO. As a most common catalyst, SnOct2 is often utilized with co-initiators. Forchner et al.[25–27] synthesized PPDO, whose molecular weight could reach 81,000, by using SnOct2 as catalyst and dodecanol as co-initiator. By using the same catalyst and co-initiator, Jamiolkowski et al.[28,29] also synthesized PPDO whose inherent viscosities could range from 2.3 to 8.0 dL/g. Therefore, many researchers think that SnOct2 is not the true catalyst during ring-opening polymerization. However, it has also been found that SnOct2 can work well without the existence of co-initiator.[36] So what is the real mechanism of the ring-opening [37–40] polymerization catalyzed by SnOct2? Several hypotheses have been proposed, and two of these are typical. One is the second-order insertion mechanism proposed by Kricheldorf et al.[37] who based this mechanism on the poor correlation among molecular weight, degree of conversion, and catalyst concentration. According to this hypothesis, the catalyst ﬁrst coordinates with alcohols or OH end-groups, and then inserts into the lactone molecule to catalyze the ring-opening reaction (Scheme 3).[37] The other is the cationic mechanism proposed by Vert et al.[38] In order to prove their hypothesis, a large amount of SnOct2 had been used during the ring- opening polymerization of lactide, and the low monomer/catalyst ratio resulted in low molecular weight, which made it possible to analyze the

Oct2 Sn O_ R

O H Me Me C CH O 3 Oct2Sn . O CH-O-CH-CO-O-R O CH3 C

O Scheme 3. 中国科技论文在线 http://www.paper.edu.cn

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Octoate-Sn-OH + Lactic acid Lactate-Sn-OH + Octanoic acid (1)

OO O O O O +HO-CH(CH 3 )COOH - + Lact O O O + O SnOH O O + - Lact- Sn-OH HO-Sn .Lact H O CH

CH3 COOH - O O Lact O O + Sn OH H + n/2 Lactide O O ] OH [ O + HA (2) O O OH H2O n O H

Scheme 4.

end-group by NMR. The authors ruled out the insertion mechanism since no tin-containing end-groups were identiﬁed. On the contrary, lactyl octoate, carboxyl, and hydroxyl end-groups were detected. Hence, the SnOct2- initiated polymerization is presently regarded as proceeding through a cationic mechanism catalyzed by acidic impurities. Hydroxytin lactate (HTL) was shown to be formed under polymerization conditions, probably because of SnOct2 hydrolysis in the presence of uncontrolled amounts of ethylhexanoic acid and water (Scheme 4).[38] By taking parallel initiation by HTL and SnOct2 into consideration, the theoretical DPn values were found much closer to the experimental ones than when SnOct2 is taken as sole catalyst, even if this hypothesis is not creditable since all the data are based on the conditions of low monomer/initiator ratio and short reaction times.

3.1.2. Organic Aluminum Compounds

Organic aluminum compounds, including triethylaluminum, triisobutylaluminum, aluminum isopropoxide, aluminum prophrin, and so on have been found highly eﬀective for ring-opening polymerization of lactone. [36] Recently, Nishida et al. used both triethylaluminum and Sn(Oct)2 to catalyze ring-opening polymerization of PDO, and found that triethylaluminum exhibits high activity. Slightly earlier, Deng et al.[41–46] successfully synthesized PLA and a series of copolymers thereof by using 中国科技论文在线 http://www.paper.edu.cn

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POLY( p-DIOXANONE) AND ITS COPOLYMERS 379

RO OR Al O Al RO O ROCO= C=O OC C=O O O

Me O Me O RO O RO O C C=O LA CH C-O-CH-C-OR Al RO Al O O RO O RO O=C C=O O

Scheme 5.

a complex catalyst of triisobutylaluminum together with phosphoric acid and water. i Aluminum isopropoxide [Al(O Pr)3] is another important catalyst that has been used frequently in ring-opening polymerization of lactones. Nevertheless, it has rarely been used to catalyze the ring-opening polymerization of PDO, until recently when it appeared in the literature as reported by Raquez et al.[47] The results showed that the inherent viscosities () i increase with the monomer/Al(O Pr)3 ratio. This behavior also occurs in i the ring-opening polymerization of LA, CL, and DXO using Al(O Pr)3 as catalyst.[11,15,48–50] According to this rule, the molecular weight of resulting polymer can be controlled easily by changing the ratio of monomer/ i Al(O Pr)3. It has been proven that ring-opening polymerization of lactone i catalyzed by Al(O Pr)3 proceeds through a two-step ‘‘coordination– insertion’’ mechanism, which consists of lactone coordination onto the grow- ing metal alkoxide followed by a rearrangement of the covalent bonds leading to the insertion of monomer onto the Al–oxygen bond of the propa- gating species (Scheme 5).[48] i Compared with Al(O Pr)3, aluminum prophrin is a more controllable catalyst which can catalyze the living polymerization of lactone, and produce polymer in very narrow polydispersity. Both the research groups of Feng et al.[51,52] and Inoue et al.[12,53] have reported a lot of valuable work focused on the ring-opening polymerization of e-CL catalyzed by aluminum prophrin, such as TPPAlCl, TPP–EtAlCl, TPPAl–OPMA, TPPAl(PO)2Cl. A ‘‘living character’’ has been found and an extremely narrow polydispersity has been achieved. These characteristics are very valuable for copolymerization, as the polymeric chain of each component may be controlled well. 中国科技论文在线 http://www.paper.edu.cn

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3.1.3. Organic Zinc Compounds

Organic zinc compounds are also very common catalysts for ring- opening polymerization of lactone, since a low concentration of zinc ions certainly does not represent any toxicological problem. Hence, it is a good choice to use this series of catalysts when PPDO is applied in either medical or pharmacological fields. Zinc diethyl catalyzes the ring-opening polymerization of PDO by the same mechanism as triethylaluminum, except that the catalytic activity of zinc diethyl is lower than that of triethylaluminum. In 1977, Doddi et al.[14] synthesized PPDO with inherent viscosity about 0.7 dL/g using zinc diethyl as catalyst after 72 hr of reaction. However, zinc diethyl is an inconvenient catalyst because it is a self-inflammable liquid and unstable on storage. Then, some mild organic zinc catalysts have been taken into account. Undoubtedly, the comparatively stable catalysts will have comparatively low catalytic activity at the same time. A typical example is zinc (II) L-lactate (ZnLac2), which is a solid, easy to synthesize and to handle, and has been proven very useful for homo- and copolymerization of L-orD,L-lactide. It was first used in ring-opening polymerization of PDO by Kricheldorf et al.[13] (Scheme 6). In this way, PPDO with an inherent viscosity of 0.95 dL/g can be achieved, though it needs a rather long reaction time of about 14 days and results in a low conversion of about 62%.

3.1.4. Organic Rare Earth Compounds

In recent years, organic rare earth compounds have been widely used in ring-opening polymerization of lactones, especially in polymerization of LA and e-CL. Most of these catalysts have the general formula MR3, in which M stands for a rare earth metal, and R stands for one or more kinds of ligand,

O H O O Lac2Zn + HO-R O R H Lac2Zn O R Lac Zn 2 Lac2Zn O O CH2CH2-CO-O-R C O R O

Scheme 6. 中国科技论文在线 http://www.paper.edu.cn

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POLY( p-DIOXANONE) AND ITS COPOLYMERS 381

such as aryl alkoxide, alkyl alkoxide, amide, hydrocarbons, and so on. The catalytic activity relates to the diameter of the rare earth metal atom and the volume of ligands. Commonly, the larger the diameter of the rare earth metal atom, and the smaller the volume of ligands, the higher the activity of catalyst should be, even though most of these catalysts exhibit very high catalytic activity. Various rare earth catalysts, such as rare earth (Y, La, Pr, Nd, Gd, Py) isopropoxide,[54–57] rare earth (Y, La, Nd, Sm, Yb) acetylacetonate,[58] rare earth phenyl compounds,[59] yttrium tris-2,6-di-tert-butyl phenoxide,[60–62] [63] [64,65] [66] Y(OCH2CH2Et)3, Y(OCH2CH2NMe)3, (ArO)Sm(THF)4, and i [67] (EA)2YO Pr, have been applied to catalyze the ring-opening polymerization of LA or e-CL successfully. The synthetic methods of these rare earth compounds are very mature.[68–72] Hence, it may be a good choice to use rare earth compounds to catalyze the ring-opening polymerization of PDO, though there is no recent report of this.

3.1.5. Enzymes

As the main usage of PPDO is focused on pharmacological and surgical applications, the metallic catalysts should be removed before use. The purification process will increase the cost of PPDO. In order to avoid the harmful effects of metallic residues in PPDO for medical applications, some non-toxic compounds have been investigated as polymerization catalysts, and selected enzymes are potentially the most harmless. In fact, as a new method of polymer synthesis, enzymatic polymerization has developed greatly during recent decades,[17,18,73–78] and studies of enzyme- catalyzed lactone ring-opening polymerization have been conducted for the polymerization of trimethylene carbonate,[17,18] o-pentadecalactone,[75] e-caprolactone,[76–78] d-decanolactone, d-dodecanolactone, b-butyrolac- tone,[78] and so on. Generally speaking, some factors such as reaction temperature, enzyme origin, and reaction media will influence the enzymatic polymerization. The enzymatic polymerization of PDO was carried out at 100C for 15 hr using 5 wt% immobilized lipase CA by Nishida et al.[79] The results show that the lipase CA, derived from Candida antarctica, exhibited especially high catalytic activity. The highest weight-average molecular weight (Mw ¼ 41,000) was obtained, even though the quite low conversion of monomer makes it unlikely to be an industrialized method in a short period.

3.2. Copolymerization Based on PDO

Although all the aliphatic polylactones have good biodegradability and biocompatibility, the properties of each polymer, such as degradation rate, 中国科技论文在线 http://www.paper.edu.cn MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

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crystallinity, mechanical properties, and thermal properties, vary with slight differences in monomer structure. Each has its own advantages and disadvan- tages. Polylactide (PLA) has been approved for surgical suture, microphere, and microcapsule application by the FDA due to its outstanding biodegradability and biocompatibility. The ultimate metabolites of PLA are H2O and CO2; even the middle metabolite, lactide, is a normal metabolite of the body. On the other hand, the degradation rate of PLA is very slow, and the PLA sutures are very stiff, non-flexible, and pliable. Polyglycolide (PGA) also has outstanding biodegradability and biocompatibility, on the contrary, the degradation rate of PGA is too fast. Moreover, sutures prepared from PGA or copolymers of LA and GA can only be used as multifilaments, with a braided or twisted construction, in order to reduce the stiff feel of the suture. Unfortunately, multifilament sutures are often disadvantageous, because their rough surface can often tear tissue during operative procedures. Poly("-caprolactone) is well known for its non-toxicity, biocompatibility, biodegradability, and permeability, and these characteristics also make it a good candidate for drug delivery. However, the rather high crystallinity of PCL influences its compatibility with soft tissue and lowers its biodegradability. In contrast, PPDO has excellent biodegradability, biocompatibility, flexibility, pliability, and good tensile strength. The sutures made from it are monofila- ments with good tenacity and knotting. But the degradation rate of PPDO is very low, and the monomer PDO is also inactive. Therefore, copolymerizations between the different monomers are effective ways to sometimes combine the excellent properties and improve the unsatisfied properties of each homopolymer. The means of copolymerization are varied, including block copolymerization, random copolymerization, graft copolymerization, and complex copolymerization. Copolymerization of PDO and GA may combine the fast absorbing characteristics of PGA with the pliability of PPDO. Bezwada et al.[80] provided a series of crystalline block copolymers of PDO and GA which can be used as monofilament sutures and ligatures with good strength, fast absorption, and excellent pliability. Random copolymerization of PDO and GA can sharply reduce the crystallinity of the copolymer, and it has a faster absorbing rate than that of the respective block copolymers.[81] Copolymerization of PDO and LA may combine the high strength of PLA and the excellent flexibility of PPDO. Jarrett et al.[82] described block or graft copolymers of poly(PDO-co-LA), which are useful due to their forma- tion of a ‘‘hard’’ phase formed from the lactide repeating unit block and a ‘‘soft’’ phase formed from the p-dioxanone repeating unit block. Bezwada et al.[83] synthesized PDO-rich, poly(PDO-co-LA) segmented copolymers which yield materials with excellent properties such as good strength and short breaking strength retention (BSR) profiles. Furthermore, LA-rich, poly(PDO-co-LA) has been synthesized and has high strength, toughness, long elongations, and very elastomeric behavior.[84] 中国科技论文在线 http://www.paper.edu.cn

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POLY( p-DIOXANONE) AND ITS COPOLYMERS 383

Copolymerization of PDO and CL may also improve some properties of each homopolymer.[47,85] Copolymerization with PPDO may decrease the high crystallinity of PCL and gain better flexibility. The melting temperature of PCL is close to 60C, which may limit its application. The PPDO exhibits a melting temperature close to 110C. Raquez et al.[47] synthesized the semicrystalline poly(PDO-b-CL) block copolymers, which displayed two well-separated melting temperatures at ca. 55 and 102C for PCL and PPDO sequences, respectively. Further, PDO can be copolymerized with PEO[86] or TMC.[87] Copolymerizations of three or more monomers of these lactones have also been studied, and various products have been explored. Kennedy et al.[88] had synthesized poly(GA-co-PDO-co-LA), which can be used as absorbable sutures with suitable crystallinity, good flexibility, high remaining strength, and reasonable degradation rate. They also copolymerized GA with a random prepolymer of PDO and LA.[89,90] Similar copolymerizations include copolymerizing GA with a random prepolymer of PDO and CL,[91] copolymering PDO with a random precopolymer of GA and LA,[92] and copolymerizing PDO with a prepolymer of PDO with GA or LA.[93] Each of these copolymers has its own advantages, to satisfy different needs.

4. PROPERTIES OF PPDO

As a polymeric material, the properties of PPDO have changed greatly compared with the monomer, except the IR spectra show surprisingly little diﬀerence in their absorption behavior (Fig. 1).[13] The most obvious diﬀerence in both spectra is the band at about 1431 cm1, which appears in the spectrum of the polymer, but not in the spectrum of the monomer.

Figure 1. IR spectra recorded from KBr pellets: (A) PDO; (B) PPDO. 中国科技论文在线 http://www.paper.edu.cn

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4.1. Solubility

The solubility of PPDO differs from that of most other polylactones such as polyglycolide, polylactide, or polycaprolactone. Commonly, PPDO is soluble in dichloromethane, chloroform, 1,1,2,2-tetrachloroethane, and hexafluoroisopropyl alcohol at room temperature, and soluble in 1,2- dichloroethane under reflux, but high molecular weight PPDO is insoluble in dichloromethane and chloroform. It is also soluble in dimethylesulfoxide, N,N-dimethylformamide, and similar amide-type solvents at room temperature, but it is highly sensitive to hydroxytic degradation in these hygroscopic solvents. On the contrary, PPDO is insoluble in toluene, acetone, 1,4- dioxane, and tetrahydrofuran.[13]

4.2. Biodegradability

Both in vivo and in vitro, PPDO has good biodegradability. The ester bonds in every repeating unit of PPDO are easy to hydrolyze, which results in the degradation of polymer chains. Compared with PLA and PGA, PPDO shows lower degradation via hydrolysis, due to the lower concentration of ester groups. Ultimately, PPDO can degrade in vivo, and the degrading products of each step are in accord with the normal metabolites of the body. Most of them are excreted via the respiratory tract, and the remainder are excreted via the alimentary tract.[94] The hydrolytic degradation of PPDO is a consequence of the breaking of the ester bonds in polymer chains. The investigation in vitro is usually carried out in phosphate buffer solution, pH 7.2–7.4, and at 37C. The process may be monitored indirectly by examining the change of molecular weight, modulus, crystallinity, and tensile strength.[95,96] It has been found that the weight changes are really small, while the molecular weight decreases obviously in the first period of hydrolysis. This may be attributed to the breaking of the ester bonds during the hydrolytic attack occuring at random. In other words, the reactivity for hydrolysis of ester linkages is the same, whether in the middle of the chain, or in the chain or chain end, and depends only on the accessibility of water molecules. Because the hydrolysis medium enters into the amorphous region faster than into the crystalline regions, bond breaking occurs first in the amorphous region ran- domly, and then in the crystalline regions. So the chain scission proceeds in two steps: the first occurring in the amorphous regions of microfibrils and intermicrofibrillar space; the second in the crystalline regions. The increase in crystallinity degree at the beginning of hydrolysis may be good evidence for this view. 中国科技论文在线 http://www.paper.edu.cn

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POLY( p-DIOXANONE) AND ITS COPOLYMERS 385

The hydrolytic degradation of PPDO fiber in the presence of enzymes and after g-irradiation has also been studied[97] mechanically, using an Instron, and morphologically by scanning electron microscopy. It has been found that enzymes (esterase and trypsin) do not accelerate the hydrolytic degradation of this fiber to any significant level. The results also showed that g-irradiation alone lowered the tensile strength of PPDO fibers and made them more susceptible to hydrolysis. The decrease in tensile strength can be attributed to the appearance of surface cracks after g-irradiation. It is well known that g-irradiation of fiber-forming materials can result in simultaneous chain scission and crosslinking. Which one will be the predominant effect of g-irradiation on PPDO fiber? In the literature, chain scission has been found to be predominant at a dosage rate of 0.15 Mrad/hr for dosage ranging from 5 to 20 Mrad. Two main reasons are given. One is the presence of the saturated aliphatic ester groups in PPDO. Given the existence of the weakened bond between acyl oxygen and the methylene group, chain scission will occur in these weakened bonds when irradiated. The other reason is the presence of an ether linkage in the main chain of the PPDO fiber, which leads to a significant increase in the probability of main chain scission when irradiated. The scission of polymer chains will be more pronounced in the amorphous regions than in the crystalline regions. Therefore, g-irradiation would result in more chain scissions in the amorphous regions than in the crystalline regions. And the degradation (due to g-irradiation) of the chain segments located in the amorphous regions reduced the degree of long-chain entanglement in the amorphous regions, which makes the chain segments in these regions more accessible to the hydrolytic medium. Now, it becomes obvious that g-irradiation makes the PPDO fiber more susceptible to hydrolysis. Recently, a new prediction model for the autocatalytic random hydrolysis of aliphatic polyesters was proposed, and this model successfully interpreted the hydrolysis data of PPDO.[98] However, it can only be applied to autocatalytic random hydrolysis. In fact, the real hydrolysis of PPDO is very complex, and many factors may influence the process of hydrolysis. Be that as it may, this model is very valuable as a guide. Meanwhile, the microbial degradability of PPDO in natural environments has been investigated by Nishida et al.[99] Many kinds of PPDO- degrading microorganisms have been found, distributed widely in natural environments. Twelve PPDO-degrading strains were isolated, which were found to belong to the and b subdivisions of the class Proteobacteria and the class Actinobacteria. Then, the degradation of PPDO by each strain was investigated in pure cultures. The results showed the degradation by one the of strains resulted in the rapid decomposition and dissolution of high molecular weight of PPDO; this strain, belonging to the -proteobacteria class, was isolated from the colonies incubated from the environment sample collected from river water. 中国科技论文在线 http://www.paper.edu.cn

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Furthermore, Nishida et al.[100] successfully isolated 15 PPDO-hydroly- zate-utilizing strains which are widely distributed in various environments. Characterization of these strains showed that the isolates are aﬃliated with two phyletic clusters: genera Ralstoria and Duganella in the b subdivision of the class Proteobacteria and genus Rhodococcus or Tsukamurella in the class Actinobacteria. These utilizing strains quickly utilized PPDO-hydrolyzates as sole carbon source. By the mixed cultures with isolated utilizing strains and the best PPDO-degrading strain mentioned above, high molecular weight PPDO was degraded and utilized successfully. These research works strongly identify the possibility of PPDO use as universal degradable material.

4.3. Thermal Properties

As the glasstransition temperature (Tg) and the melting temperature (Tm) of the polymers commonly depend on molecular weight, thermal his- tory, and measuring means, the Tg and Tm of PPDO are no exception. So the Tg and Tm values of PPDO are listed below for reference only. The Tg of PPDO ( ¼ 0.82 dL/g in 1,1,2,2-tetrachloroethane at 25C) ranged from 15 to 8 C, and the Tm was found at 110 C (measured by diﬀerential scanning calorimetry heat scan at 20C/min under nitrogen).[13] The thermal stability of PPDO is also an important property; it may indicate the proper choice of processing and application temperature. Kricheldorf et al.[13] gave details about the thermogravimetric analysis of PPDO ( ¼ 0.82 dL/g in 1,1,2,2-tetrachloroethane at 25C). It was per- formed under nitrogen. The thermal stability of PPDO is somewhat lower than that of PCL or PLA. In detail, the thermal degradation of PPDO is detectable above 150C and reaches a loss of weight of 3–4% at 200C, and the rate of thermal degradation reaches its maximum around 300C. The investigation of the thermal decomposition behavior showed that the pyrolysis of PPDO exclusively resulted in PDO. This information identiﬁes that PPDO is also a ‘‘feed recycling’’ material. The kinetic parameters of pyrolysis have been evaluated from the thermogravimetric data by plural analytical methods. In detail, activation energy, Ea ¼ 127 kJ/mol; order of reaction, n ¼ 0; and exponential factor, A ¼ 2.3 109 sec1. Estimates show that the decomposition of PPDO proceeds by an unzipping depolymerization and random degradation process with [101] lower Ea and A values.

4.4. Crystallization and Morphology

Since the degradation rate of PPDO depends on its morphology and crystallization, as well as its chemical structure, so recognition of the crystallization and morphology appears very important. The investigation of 中国科技论文在线 http://www.paper.edu.cn

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POLY( p-DIOXANONE) AND ITS COPOLYMERS 387

Sabino et al.[19,20] showed that when PPDO is crystallized from the melt it forms banded spherulites that can exhibit a well-defined Maltese cross. The spherulitic radius and band spacing are both increasing functions of crystallization temperature. In contrast, the spherulite growth rate is a decreasing function of crystallization temperature when it is higher than 50C. In this temperature range, the spherulite growth rate was controlled by nucleation, and the growth rate could not be measured by polarized optical microscopy within the diffusion-controlled region at lower crystallization temperatures, so the authors did not supply the data in this region. ¼ The authors also estimated the equilibrium melting temperature Tm0 127 C using the extrapolation procedure proposed by Hoffman and Weeks. The studies of overall quiescent crystallization kinetics of PPDO have also been proliphic in recent years, but the results are discrepant. Sabino et al.[20] found that the Avrami exponents ranged from 3 to 4 as the isothermal crystallization temperature was increased from 50 to 100C. However, the investigation carried out by Andjelic et al.[102–104] showed that the Avrami exponents were relatively constant at 2.5 for all crystallization temperatures investigated, confirming that the crystal growth was three-dimensional as in the used case. Further self-nucleation studies evidenced the existence of the usual three self-nucleation domains depending on the self-nucleation temperature (Ts) employed, as clearly indicated in Figs. 2 to 5.[20] The first region, Domain

Figure 2. DSC cooling scans at 10C/min of PPDO after 5 min at the indicated Ts temperature. 中国科技论文在线 http://www.paper.edu.cn

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388 YANG, WANG, AND WANG

Figure 3. Subsequent DSC heating scans at 10C/min of PPDO after coolings shown in Fig. 2; the values of Ts are indicated above each curve.

Figure 4. Peak crystallization temperature as a function of self-nucleation temperature for PPDO. (Data from Fig. 2.) 中国科技论文在线 http://www.paper.edu.cn

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POLY( p-DIOXANONE) AND ITS COPOLYMERS 389

Figure 5. Melting temperatures as a function of self-nucleation temperature of PPDO. (Data from Fig. 4.)

I, is at Ts>116 C. Figure 4 shows that when the Ts is greater than 116 C, the time spent at Ts is enough to erase the crystalline memory of the material, therefore the PPDO needed maximum undercooling in order to crystallize when cooled from Ts, and the crystallization temperature did not change with Ts. The second region, Domain II, or the self-nucleation domain, is at 116 C>Ts>106 C. In this region, partial melting occurs, leaving crystal fragments that are small enough so that annealing does not take place, but big enough to act as self-nuclei for PPDO. Self-nucleation causes two major effects in the dynamic crystallization of PPDO from the melt. The first effect is an expected substantial decrease in the undercooling needed for crystallization as the Ts is decreased. The second effect is an increase in the enthalpy of crystallization as the Ts is decreased from 140 Cto107C. The third region, Domain III, is at Ts<106 C. In this domain, partial melting takes place but in this case the amount of unmelted material is such that large crystals can survive and can experience annealing during the holding time at Ts. The appearance of a high temperature shoulder or small peak is the hallmark of Domain III. The immediate recrystallization upon cooling is also a hallmark of Domain III. In addition, the heat capacities of PPDO both in solid state and liquid state were determined by Wunderlich et al.[105] using DSC and 中国科技论文在线 http://www.paper.edu.cn

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Table 1. Properties of the Suture

Diameter Failure Load Tensile Strength Future Gauge (mm) (kg) (kg/cm2)

PDS 1 0.520 11.36 5347.24 Absorbable 0 0.437 9.05 6036.54 Monofilament 00 0.357 6.08 6072.04 000 0.293 3.97 5882.04 Dexon 10.546 9.40 4012.99 Absorbable 0 0.513 7.14 3454.41 Multifilament 00 0.398 5.56 4469.09 000 0.308 2.95 3959.42 Vieryl 10.5119.78 4768.78 Absorbable 0 0.463 7.75 4600.13 Multifilament 00 0.395 5.26 4289.15 000 0.298 3.57 5118.54

temperature-modulated DSC (TMDSC). The heat capacity change of fully amorphous PPDO at Tg was measured to be 69.9 J/mol/K, and it is of signiﬁcance for the detection of possible amounts of rigid amorphous frac- tion. The heat fusion of 100% crystalline PPDO samples at Tm (400 K) was also determined to be 14.4 kJ/mol, which is of importance for crystallinity estimates.

4.5. Mechanical Properties

There is very limited information about the mechanical properties of PPDO. Most of the literature[106–108] uses PDS manufactured by Ethicon Inc., a kind of absorbable monoﬁlament suture made from PPDO, as the study object. The results of investigation showed that PDS has much better tensile strength compared with other suture materials (Table 1).[106]

5. APPLICATION OF PPDO

With outstanding biodegradability and bioabsorbability, PPDO has great potential for surgical and pharmacological applications.

5.1. Surgical Suture

As mentioned previously, PPDO has received the approval of the FDA to be used as a suture material in gynecology. A kind of commercialized absorbable monoﬁlament suture prepared from PPDO, called PDS, was 中国科技论文在线 http://www.paper.edu.cn

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POLY( p-DIOXANONE) AND ITS COPOLYMERS 391

first explored by Ethicon Inc. in the lately 1970s. Compared with the other two kinds of multifilament sutures, Dexon (prepared from PGA) and Vicryl [prepared from poly(GA-co-LA)], PDS has much better flexibility.

5.2. Bone and Tissue Fixation Device

Over time, the main materials used as bone and tissue ﬁxation devices have been limited to metallic materials such as titanium, stainless steel, and so on. These metal devices may remain in the body of the patient for some considerable period of time, or must be removed after healing of the bone. Hence, it is an inevitable and desirable trend that metallic materials will be replaced by non-metallic, biocompatible, and biodegradable polymeric materials. As a consequence, a series of devices prepared from these polymers have been explored and applied successfully in clinics. Many of these are made from PLA. In recent years, it has been found that PPDO possesses many excellent characteristics in this respect, and can be widely used in bone and tissue ﬁxation devices such as pins, clips, staples, arches, plates, and so on.[109–111]

5.3. Drug Delivery System

The application of biodegradable polymers as matrices for sustained drug delivery systems has attracted much attention in the last decade. The monomers CL, LA, GA, TMC, and PDO have all been chosen to synthesize drug delivery system materials, and it has been found that copolymerization is an eﬀective way to provide materials with diﬀerent degradation rates and processabilities.[112–114] The copolymers of PDO and TMC synthesized by Dong[87] show that the accumulative release amount of drug is nearly in linear proportion with time for a one-month period.

6. CONCLUSION

In all, PPDO is one of the most promising biodegradable polyesters, not only because it has excellent biodegradable, but also because it has good mechanical properties, especially excellent flexibility and pliability. It is not only an ideal material to manufacture surgical sutures and other surgical devices, but also a good candidate for general uses such as packet films, mold products, and so on. And now, it is imperative for researchers to improve the polymeric process of PPDO, find more effective catalysts, and increase the molecular weight. 中国科技论文在线 http://www.paper.edu.cn

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ACKNOWLEDGMENTS

This work was supported by the Excellent Talent Program and the Excellent Young Teachers Program of the Ministry of Education of China.

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