18.3.1.3 Ploylactide-co-caprolactone (PLCL)

PLCL Copolymers have both the potential strength of PLA and the elasticity of PCL. Changing PLA and/or PCL composition ratios allow optimization of TEVG mechanical properties and degradation periods. A PLCL (PLA/PCL 70/30) nanofiber TEVG was surface-coated with collagen and fabricated using a rotating mandrel. Mechanical testing revealed that in comparison to conventional Gore-Tex, the PLCL TEVG more closely resembled a native artery. In a rat model, the PLCL TEVG presented no evidence of graft thrombosis over 7 weeks, but lacked luminal ECs layer development [60]. Another group created a heparin coated PLCL (PLA/PCL 50/50) nanofiber TEVG, then seeded the scaffold with harvested autologous ECs, and implanted it as a femoral artery graft in a dog model [61–63]. During a 6-month follow-up, the heparin coated and endothelialized PLCL TEVG provided graft patency rates greater than 85%, but did not exhibit complete degradation. Although TEVG patency improves with ECs seeding [63], the process significantly diminishes the TEVG’s off-the-shelf usefulness and overall clinical value.   

2.2.1 Poly(ɛ-caprolactone)   

PCL is a fully biodegradable aliphatic polyester polymer coming from the polymerization of nonrenewable raw materials such as crude oil [78]. PCL can be prepared either by ring-opening polymerization of ɛ-caprolactone using a variety of anionic, cationic, and coordination catalysts or via free radical ring-opening polymerization of 2-methylene-1,3-dioxepane [78]. This polymer is a hydrophobic, semicrystalline polymer that could easily be thermally formed. The chemical structure of PCL is shown in Fig. 4.11. To improve the thermal, mechanical, and barrier properties while preserving the good biodegradability, various nanoparticles have been incorporated in the PCL matrix. The important nanoparticles are clays, CNTs, graphene, and silica [79–81]. However, only the preparation techniques and the resulting composites obtained with the use of clays and CNTs will be discussed in the subsequent section.

19.3.2 PCL and copolymers   

PCL and copolymers nanofibers are commonly used for TE applications [135–138]. PCL and PLA polymers have different biodegradability and were used in different tissue applications [25,139–142]. In recent years, the copolymer of them, PLCL, has been investigated as biomaterial for vascular TE [5,143–145]. For example, Ramakrishna and coworkers developed nanofiber scaffolds from copolymer PLCL (75:25) where SMCs and ECs can adhere, grow, and proliferate well [83,124,125].

PCL can be combined with elastomeric polymers like PU. For example, Williamson et al. fabricated PCL-PU scaffolds for vascular tissue applications [126]. The luminal surface had orientated PCL fibers and the outer layer was composed with PU fibers. The novel scaffold enhances HUVECs attachment and cells proliferated to form stable and functional monolayers. PCL can also be coated with CNT [146] and is used in vascular applications [147,148].   

Zhang et al. prepared bi-layered scaffolds of PCL, PGC, gelatin, and elastin for vascular TE applications [33,34]. PGC is a copolymer of glycolide (75%) and caprolactone (25%) widely used in sutures. The novel scaffold (PGC/PCL) was evaluated and the authors observed that grafts with a composition ratio of 3:1 enhance HUVECs and human aortic ECs attachment and proliferation in in vitro conditions. In addition, the scaffold had good mechanical properties, was biocompatible, and had antithrombotic properties, which makes this new scaffold a powerful tool for vascular regeneration applications.   

More recently, researchers are focused on exploring the effect of conductive polymers on small diameter PCL blood vessel grafts [149,150]. For example, Xiong et al. combined PCL nanofibers with a conductive polymer such as polypyrrole (PPy) to study the effects of electrically stimulating a material on its thrombogenic and inflammatory properties for blood-contacting devices [150]. Results showed that fibers coated with heparin-doped PPy (PPy-HEP) demonstrated better electroactivity, lower surface resistivity and better anticoagulation response as compared to fibers coated with pristine PPy. Red blood cell compatibility was greatly improved on PPy-HEP-coated PCL fibers in comparison to uncoated PCL. It was also observed that the application of a low alternating current led to a 4-fold reduction of platelet activation for the PPy-HEP-coated fibers as compared to nonstimulated conditions. In parallel, a reduction in the leukocyte adhesion to both pristine PPy-coated and PPy-HEP-coated fibers was observable with AC stimulation.   

13.2.1.2.3 PCL-b-PEG   

Though the copolymers of PCL/PEG were explored in 1980, their association properties in aqueous solution especially gelation were explored by Martini et al. in the year 1994. Fig. 13.5 shows an example of synthesis of PCL–PEG–PCL triblock copolymer, where caprolactone monomer was initially ring opened by hydroxyl group of PEG (Liu et al., 2008). In the recent years, Qian group extensively studying the properties of PCL/PEG hydrogels and their biomedical applications (Ni et al., 2014; Gong et al., 2009).   

10.4.4 Poly(є-caprolactone) (PCL)   

Poly(є-caprolactone) (PCL) is a semicrystalline polymer produced by a catalyzed ring opening of є-caprolactone. The resulting polymer consists of five methylene groups separating a polar ester group. PCL is biocompatible and is currently used as a material for degradable sutures. PCL has a tensile modulus of 0.19–0.38kNm/g (van de Velde and Kiekens, 2002). PCL has a degradation time of approximately two years, but PCL can be copolymerized with PLGA for a more rapidly degrading polymer (Yang et al., 2001).

Poly(ɛ-caprolactone)

Poly(ɛ-caprolactone) (PCL) (Structure 23.5) is an aliphatic polyester that has been intensively investigated as a biomaterial. The discovery that PCL can be degraded by microorganisms led to evaluation of PCL as a biodegradable packaging material; later, it was discovered that PCL can also be degraded by a hydrolytic mechanism under physiological conditions [148–150]. Under certain circumstances, crosslinked PCL can be degraded enzymatically, leading to what can be called enzymatic surface erosion [148,149]. Low molecular weight fragments of PCL are reportedly taken up by macrophages and degraded intracellularly, with a tissue reaction similar to that of the other poly(hydroxy acids) [150]. Compared with PGA or PLA, the degradation of PCL is significantly slower. PCL is therefore most suitable for the design of long-term, implantable systems such as Capronor, a one-year implantable contraceptive device [151].    

Poly(ɛ-caprolactone) exhibits several unusual properties not found among the other aliphatic polyesters. Most noteworthy are its exceptionally low glass transition temperature of about −60°C and its low melting temperature of 57°C. Another unusual property is its high thermal stability. Whereas other tested aliphatic polyesters had decomposition temperatures (Td) between 235 and 255°C, poly(ɛ-caprolactone) has a Td of 350°C, which is more typical of poly(ortho esters) than aliphatic polyesters [152].

A useful property of PCL is its propensity to form compatible blends with a wide range of other polymers [153]. In addition, ɛ-caprolactone can be copolymerized with numerous other monomers (e.g., ethylene oxide, chloroprene, THF, δ-valerolactone, 4-vinylanisole, styrene, methyl methacrylate, vinylacetate). Particularly noteworthy are copolymers of ɛ-caprolactone and lactic acid, which have been studied extensively [149,154]. PCL and copolymers with PLA have been electronspun to create nanofibrous tissue-engineered scaffolds that show promise for vascular applicaions [155,20–22]. The toxicology of PCL has been extensively studied as part of the evaluation of Capronor. Based on a large number of tests, the monomer ɛ-caprolactone, and the polymer PCL, are currently regarded as non-toxic and tissue compatible materials. Early clinical studies [156] of the Capronor system were started around the year 2000 and resulted in a commercial implant used in Europe, but not in the USA.

Poly(ε-caprolactone)

Poly(ε-caprolactone) (PCL) (Structure 23.4) is an aliphatic polyester that has been intensively investigated as a biomaterial (Pitt, 1990). The discovery that PCL can be degraded by microorganisms led to evaluation of PCL as a biodegradable packaging material (Pitt, 1990). Later, it was discovered that PCL can also be degraded by a hydrolytic mechanism under physiological conditions (Pitt et al., 1981). Under certain circumstances, cross-linked PCL can be degraded enzymatically, leading to “enzymatic surface erosion” (Pitt et al., 1981). Low-molecular-weight fragments of PCL are reportedly taken up by macrophages and degraded intracellularly, with a tissue reaction similar to that of other poly(hydroxy acids) (Pitt et al., 1984). Compared with PGA or PLA, the degradation of PCL is significantly slower. PCL is therefore most suitable for the design of long-term, implantable systems such as Capronor, a one-year implantable contraceptive device (Pitt, 1990).

Poly(ε-caprolactone) exhibits several unusual properties not found among the other aliphatic polyesters. Most noteworthy are its exceptionally low glass transition temperature of −62°C and its low melting temperature of 57°C. Another unusual property of poly(ε-caprolactone) is its high thermal stability. Whereas other tested aliphatic polyesters had decomposition temperatures (T_d) between 235 and 255°C, poly(ε-caprolactone) has a T_d of 350°C, which is more typical of poly(ortho esters) than of aliphatic polyesters (Engelberg and Kohn, 1991). PCL is a semicrystalline polymer with a low glass transition temperature of about -60°C. Thus, PCL is always in a rubbery state at room temperature. Among the more common aliphatic polyesters,this is an unusual property, which undoubtedly contributes to the very high permeability of PCL for many therapeutic drugs (Pitt et al., 1987).

Another interesting property of PCL is its propensity to form compatible blends with a wide range of other polymers (Koleske, 1978). In addition, ε-caprolactone can be copolymerized with numerous other monomers (e.g., ethylene oxide, chloroprene, THF, δ-valerolactone, 4-vinylanisole, styrene, methyl methacrylate, vinylacetate). Particularly noteworthy are copolymers of ε-caprolactone and lactic acid that have been studied extensively (Pitt et al., 1981; Feng et al., 1983). PCL and copolymers with PLA have been electronspun to create nanofibrous tissue-engineered scaffolds that show promise for vascular applications (Venugopal et al., 2005; He et al., 2005a, 2005b; Xu et al., 2004). The toxicology of PCL has been extensively studied as part of the evaluation of Capronor. Based on a large number of tests, the monomer, ε-caprolactone, and the polymer, PCL, are currently regarded as nontoxic and tissue-compatible materials. Consequently, clinical studies of the Capronor system are currently in progress (Kovalevsky and Barnhart, 2001).

It is interesting to note that in spite of its versatility, PCL has so far been predominantly considered for controlled-release drug delivery applications. In Europe, PCL is being used as a biodegradable staple, and it stands to reason that PCL (or blends and copolymers with PCL) will find additional medical applications in the future. The most recent, comprehensive review of the status of PCL has been by Pitt (1990).

5.3.2 Poly(ɛ-caprolactone)

Poly(ɛ-caprolactone) PCL is a semicrystalline, biodegradable polymer with melting temperature (T_m) of ~60°C and a glass transition temperature (T_g) of ~−60°C. The structure and properties of PCL are shown in Fig. 5.27 [100].

PCL is synthesized by the ring opening polymerization of the cyclic monomer ɛ-caprolactone as shown in Fig. 5.28 [101]. Molecular weight of the polymer is controlled by low-molecular-weight alcohols while catalysts such as stannous octoate are used to catalyze the polymerization reaction. Polymerization of PCL can be affected by various mechanisms such as anionic, cationic, coordination, and radical mechanism. Each mechanism will have an effect on molecular weight, molecular weight distribution, end-group composition, and chemical structure of the copolymers [102].

Poly(ε-caprolactone) (PCL) is soluble in different solvents such as chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, cyclohexanone, and 2-nitropropane at room temperature. However, it is least soluble in acetone, 2-butanone, ethyl acetate, dimethylformamide, and acetonitrile and is insoluble in alcohol, petroleum ether, and diethyl ether [104]. In order to improve stress crack resistance, dyeability, and adhesion, PCL are blended with other polymers. Some of these polymers include cellulose propionate, CAB, PLA, and Polylactic acid-co-glycolic acid [54].

Poly(ε-caprolactone) (PCL) undergoes biodegradation by outdoor living organisms such as bacteria and fungi; however, they do not degrade in animal and human bodies because they lack suitable enzymes [105]. Fig. 5.29a, b, and c shows degree of degradation of Poly(ε-caprolactone) (PCL) when it is exposed to three different mechanisms [106]. In the first mechanism, PCL undergoes degradation by surface erosion as shown in Fig. 5.29a. The surface erosion involves the hydrolytic cleavage of the polymer backbone only at the surface [106,107]. This happens only when the rate of hydrolytic chain scission and the production of oligomers and monomers are faster than the rate of water intrusion into the polymer bulk, leading to thinning of polymer overtime without affecting the molecular weight [106].

Fig. 5.29b studies degradation timeline of PCL when it undergoes bulk degradation [106]. Bulk degradation happens when water penetrates into the entire polymer bulk, resulting in hydrolysis throughout the entire polymer matrix. This starts random hydrolytic chain scission which causes an overall reduction in molecular weight. If water diffuses into the polymer bulk and hydrolyzes the chains enabling the monomers or oligomers to diffuse out; thus leading to gradual erosion of polymer chain [106].

Fig. 5.29c shows degradation timeline of PCL when it undergoes bulk degradation using auto catalysis [106]. In this mechanism, the internal concentration of autocatalysis products produces an acidic gradient as the newly generated carboxyl end group formed during ester bond cleavage accumulates. This in turn accelerates the internal degradation compared to the surface, leaving an outer layer of higher molecular weight skin with a lower molecular weight, degraded, interior [106].   

Due to high permeability, excellent biocompatibility toward many drugs, and its ability to be fully excreted from the body once bio-resorbed, Poly(ε-caprolactone) (PCL) is suitable for controlled drug delivery applications. In comparison to other polymers, biodegradation of Poly(ε-caprolactone) (PCL) is slow which makes it most suitable for long-term delivery [108–110]. PCL are also used in sutures, wound dressings, contraceptive devices, fixation devices, and dentistry as shown in Fig. 5.30 [111,112].