Polycaprolactone

This page looks at the properties, processes, applications and impact of the biopolymer Polycaprolactone and it’s monomer, Caprolactone.

Introduction

Polycaprolactone (PCL) is a biodegradable polymer classified as a thermoplastic polyester^[1]. A Thermoplastic polyester is defined as a plastic polymer that becomes soft and formable when heated, yet hardens and becomes stable when cool^[2]. This makes it a very popular material for prototyping, since it can be easily shaped without the need for specialist equipment. PCL melts at 60 degrees Celsius, and consequently can be soft at room temperature. Although PCL is most commonly added to resins to improve their properties^[3], its biodegradability, non-toxicity and biocompatibility allows it to be used in the medical industry in tissue engineering. This is a very exciting field, and Polycaprolactone shows lots of promise in this regard. The polymer’s mechanical properties can be synthesized to mimic those of various biological compounds, while its degradable nature allows it to be implanted without the need of a future operation to remove it.

Chemical

The monomer Caprolactone consists of a ring of 6 carbons and 1 oxygen atom, where the first carbon is double bonded to a second oxygen^[4]. The polymer is fabricated by means of what is known as “ring opening polymerization”, where the carbon-oxygen ring of the original hydrocarbon is broken using a stannous (II) octoate (tin) catalyst and an alcohol initiator^[5]. Depending on the application the process can be performed making use of various atomic mechanisms or introducing different compounds. This results in a large selection of mechanical properties such as solubility, stiffness, elasticity, melting and glass-transition values^[6].

Synthesis of PCL begins with hydrogenation of benzene into cyclohexane using a catalyst of nickel or platinum. Once cyclohexane has been produced it is oxidized in air, typically with a cobalt catalyst, to form Cyclohexanone. Cyclohexanone is a colourless oil similar to acetone. Millions of tonnes of it are produced each year, albeit by a slightly different process, as a step in the production of nylon^[7]. Cyclohexanone is oxidized by means of Baeyer-Villiger oxidation, a process that oxidizes a ketone into a lactone, to form epsilon-Caprolactone^[8]. Caprolactone is then polymerised into PCL.

Biodegradability

Polycaprolactone is fully biodegradable. Composting is an ideal way to achieve this since composting temperatures easily surpass the 60 degree melting point of PCL. It is capable of degrading by means of biotic (due to biological organisms) and abiotic (in absence of biological organisms) mechanisms, with the most common being biotic. Biotic breakdown occurs in most environments including compost, sewage, soil and natural water sources. Abiotic degradation occurs in a phosphate buffer solution. PCL breaks down by means of hydrolysis of backbone ester bonds, when the polymer chain is split at a carbon double bond oxygen link and a water molecule is introduced to the loose ends. This process usually produces an acid, and in the case of PCL the acid produced in this step is 6-hydroxycaproic acid. Another mechanism of degradation is enzyme attack, or enzymatic hydrolysis. In seawater the latter plays the dominant role in the degradation of the polymer^[9].

It has also been shown that although PCL is not an acid itself it is capable of acting as a “reserve acid”, whereby the acid intermediary compounds released by decomposition behave as if an acid was present. Ammonia is a nuisance gas given off by composting material, but the presence of this polymer acting as a reserve acid in the degrading material measurably reduced the ammonia given off^[10]. This characteristic implies that the polymer can be used as an additive to control emissions of decomposing material, without negatively impacting the environment.

Mechanical

PCL can be formed into 3D structures which can be used to support tissue in tissue engineering. It is has a relatively high stiffness and slow biodegradability compared to other biopolymers, which allow it to be used to support hard tissue. The tensile modulus of a specimen produced by Selective Laser Sintering (SLS) was found to be approximately 350 MPa. Due to the additive nature of SLS, however, the build direction of the part influences the mechanical properties in that direction; more ductile properties arise when tension is applied perpendicular to the build direction. The elasticity modulus, 0.2% offset yield strength and ultimate tensile strength for parallel and perpendicular build directions^[11] are shown in table 1, with mean values of ABS plasic as a comparison^[12]. A Melt Extrusion PCL is reported to have a modulus of 264 MPa^[13].

Table 1
	Parallel	Perpendicular	ABS Plastic
Tensile Elastic Modulus	360 MPa	340 MPa	1825 MPa
0.2% Yield Strength	8.2 MPa	10 MPa	39 MPa
Ultimate Tensile strength	10 MPa	16 MPa	35.5 MPa

Electrospinning

PCL is commonly electrically spun to create nanofibers used in biological engineering. The electrospinning technique creates an extremely fine thread of the polymer which is collected into sheets or onto a roll. This is achieved by means of a high voltage, usually in tens of kV, being applied to a drop of liquid polymer. A short distance away the opposite charge is applied to the collection surface. When the voltage reaches a critical point the drop of polymer forms a Taylor cone, from the point of which a thread with a thickness in the order of nanometres emerges. This thread is captured by the collection surface, typically a rotating drum. A polymer is either melted or dissolved, before entering an injection system that forces it to one or more small nozzles (capillary tubes) and applying a high voltage. When the polymer fluid erupts from the tip of the Taylor cone any solvents that might have been used to dissolve the polymer immediately evaporate, leaving only the polymer^[14].

Electro-spun PCL can be mechanically tested in two ways, namely macroscopically and micro/nanoscopically. Macroscopic testing can easily be performed on a specimen consisting of thousands of fibers running parallel, but the microscopic testing of single threads becomes problematic. A process allowing such analysis has recently been developed, involving the bending of a single stand of polymer suspended over a narrow channel^[15].

Macroscale tensile testing of PCL fibre scaffolds found a mean Young’s modulus of 3.8 MPa, a value which does not reflect individual fibres very well. By means of the three point bending test the mean Young’s modulus of individual electro-spun PCL fibers was found to be 3.7 GPa. The significant difference in elastic moduli can be explained by the highly porous nature and random orientation of electro-spun PCL fiber mats^[16].

Medical

Polycaprolactone can also be used as a drug delivery mechanism in the medical field, where the biodegradation of PCL is taken advantage of in order to effect delivery of encapsulated therapeutics within cells. The polymer can be manipulated in several ways to cause it to bond with the drug and deliver it to the correct location, although it is often not necessary to implement specific targeting. The difficulty lies in ensuring the polymer detaches from the drug at the correct time for effective delivery. In order to do so, the carrier must pass through the lipid membrane, a double row of fatty, hydrophobic molecules surrounding cells. The most common method for achieving penetration of the lipid membrane and detachment of the therapeutic is by means of the hydrolysis of PCL. As the chain hydrolysis, the hydrophobic properties of the lipid membrane change the molecular shape of the PCL molecule until it is able to pass through the membrane. Once through, the PCL continues to break down, leaving only the therapeutic drug. This gives PCL an advantage over other, more slowly degrading polymers. When these are used the partially broken down products are typically secreted by cells and filtered out by the kidneys, but PCL achieves full hydrolysis within the target cells^[17].

PCL used in tissue engineering degrades in about 2 years. The resorption takes place in two steps, beginning immediately upon contact with water. The first step is gradual hydrolysing of the ester bonds as the polymer takes up water, a process during which the mechanical properties of the polymer reduce linearly with molecular weight. Resorption speed, and consequently the rate of reduction of mechanical properties, is slower for higher molecular weights. The total implant mass, however, does not significantly change during this process. The second stage of resorption occurs when the polymer has degraded to the point where the products of degradation are small enough to be water-soluble, or absorbed by macrophages – white blood cells responsible for absorbing cellular detritus, foreign substances or anything else not useful for a healthy body^[18].

Biocompatibility is a very important part of tissue engineering, and in the case of electrospun implants it is influenced by several factors including thickness of fibers and density of the weave. The best results have been achieved by blending polymers, either by spinning two different polymers simultaneously or by mixing multiple polymers into solution before spinning. Doing so also allows finer control of degradation rates, such that the implant breaks down at a rate similar to new tissue growth. For example, α‐MHC is the major protein comprising thick cardiac muscle filaments, used in contraction of the heart^[19]. A blend of 4%PEG–86%PCL–10%CPCL polymers, when seeded with ESCs (Embryonic Stem Cells) demonstrated an extremely high α‐MHC expression as a result of ideal mechanical and elastic properties^[20].

Sustainability

Benzene is typically refined from natural fossil fuels, and consequently the majority of PCL produced does not stem from a sustainable source. Artificial manipulation of hydrocarbons is, however, a very prominent part of sustainability. Most hydrocarbon fuels, including benzene, can be produced from other more renewable sources^[21], something which will certainly become more widespread in the future. The Polymer PCL is completely biodegradable, and offers no concerns as far as the environmental impact of waste. The Baeyer-Villiger process, which originally produced wasteful carboxylic acids has since been re-engineered into an environmentally friendly process with water as the only by-product^[22].

References

[1] Malikmammadov, E., Tanir, T.E., Kiziltay, A., Hasirci, V. & Hasirci, N. 2017. “PCL and PCL-based materials in biomedical applications”, Journal of Biomaterials Science, Polymer Edition, Volume 29, issue 7-9. [Online]. Available: https://www.tandfonline.com/doi/full/10.1080/09205063.2017.1394711?scroll=top&needAccess=true&. [2018, October 05]

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[5] Sawdon, A.J. & Peng, C. 2015.”Ring-Opening Polymerization of ε-Caprolactone Initiated by Ganciclovir (GCV) for the Preparation of GCV-Tagged Polymeric Micelles”, Molecules, 20, 2857-2867. [Online]. PDF. Available: http://www.mdpi.com/1420-3049/20/2/2857/pdf. [2018, October 06]

[6] Malikmammadov, E., Tanir, T.E., Kiziltay, A., Hasirci, V. & Hasirci, N. 2017. “PCL and PCL-based materials in biomedical applications”, Journal of Biomaterials Science, Polymer Edition, Volume 29, issue 7-9. [Online]. Available: https://www.tandfonline.com/doi/full/10.1080/09205063.2017.1394711?scroll=top&needAccess=true&. [2018, October 06]

[7] Organic Chemistry Lab Report—Synthesis of Cyclohexanone: Chapman-Stevens Oxidation, 2018 [S.a.]. Available: https://owlcation.com/stem/Organic-Chemistry-Lab-Report-Synthesis-of-Cyclohexanone-Chapman-Stevens-Oxidation. [2018, October 06]

[8] Baeyer-Villiger Oxidation. [S.a.]. Avaliable: https://www.organic-chemistry.org/namedreactions/baeyer-villiger-oxidation.shtm. [2018, October 06]

[9] Ebnesajjad, S. 2013. Handbook of biopolymers and biodegradable plastics properties, processing and applications. Plastics Design Library, Elsevier.

[10] Ebnesajjad, S. 2013. Handbook of biopolymers and biodegradable plastics properties, processing and applications. Plastics Design Library, Elsevier.

[11] Eshraghi ,S. & Das, S. 2010. Mechanical and Microstructural Properties of Polycaprolactone Scaffolds with 1-D, 2-D, and 3-D Orthogonally Oriented Porous Architectures Produced by Selective Laser Sintering. [Online]. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874084/. [2018, October 06]

[12] Overview of materials for Acrylonitrile Butadiene Styrene (ABS), Extruded. [S.a.]. [Online]. Available: http://www.matweb.com/search/DataSheet.aspx?MatGUID=3a8afcddac864d4b8f58d40570d2e5aa&ckck=1. [2018, October 06]

[13] Pitt, C.G., Chasalow, F.I., Hibionada, Y.M., Klimas, D.M. & Schindler, A. 1981. “Aliphatic polyesters. I. The degradation of poly (ε-caprolactone) in vivo”, Applied Polymer Science. 1981; 26, 3779–3787. [Online]. Available: https://onlinelibrary.wiley.com/doi/abs/10.1002/app.1981.070261124. [2018, October 06]

[14] Bhardwaj, N. & Kundu, S.C. 2010. Electrospinning: A fascinating fiber fabrication technique. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0734975010000066. [2018, October 06]

[15] Croisier, F., Duwez, A.S., Jérôme, C., Léonard, A.F., van der Werf, K.O., Dijkstra, P.J. & Bennink, M.L. 2011. Mechanical testing of electrospun PCL fibers. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S1742706111003680. [2018, October 06]

[16] Croisier, F., Duwez, A.S., Jérôme, C., Léonard, A.F., van der Werf, K.O., Dijkstra, P.J. & Bennink, M.L. 2011. Mechanical testing of electrospun PCL fibers. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S1742706111003680. [2018, October 06]

[17] Broz, P., 2010. Polymer-based Nanostructures: Medical Applications. Chapter 9.2 RSC Publishing

[18] Sastri, V.R. 2010. Plastics in medical devices: properties, requirements and applications. Plastics Design Library, Elsevier.

[19] Molkentin, J.D., Jobe, S.M. & Markham, B.E. 1996. Alpha-myosin heavy chain gene regulation: delineation and characterization of the cardiac muscle-specific enhancer and muscle-specific promoter. [Online]. Available: https://www.ncbi.nlm.nih.gov/pubmed/8782063. [2018, October 07]

[20]  Zhao, G., Zhang, X., Lu, T. J. & Xu, F. 2015. Recent Advances in Electrospun Nanofibrous Scaffolds for Cardiac Tissue Engineering. [Online]. Available: https://onlinelibrary.wiley.com/doi/full/10.1002/adfm.201502142. [2018, October 07]

[21] Tamers, MA. 1976. Total synthesis benzene and its derivatives as major gasoline extenders. [Online]. Available: https://www.ncbi.nlm.nih.gov/pubmed/17796154. [2018, October 07]

[22] Sasakura, N., Nakano, K., Ichikawa, Y. & Kotsuki , H. 2012. A new environmentally friendly method for the Baeyer–Villiger oxidation of cyclobutanones catalyzed bythioureas using H₂O₂ as an oxidant. [Online]. Available: https://pubs.rsc.org/en/content/articlehtml/2012/ra/c2ra20898a. [2018, October 05]

[23] Vincent, J. 2016 3D-printed ‘hyperelastic bone’ could be the future of reconstructive surgery,[Online]. Available: https://www.theverge.com/2016/9/28/13094642/hyperelastic-bone-graft-substance-unveiled. [2018, October 07]

Figure 1. “Caprolactone-from-xtal-2007-3D-balls” By Mills. B. [Public domain]. Availible from Wikimedia Commons. [2018, October 06]

Figure 2. “Benzene-aromatic-3D-balls”, By Mills, B. [Public domain]. Availible from Wikimedia Commons. [2018, October 06]

Figure 3. “Cyclohexane-chair-3D-balls”, By Mills. B. [Public domain]. Availible from Wikimedia Commons. [2018, October 06]

Figure 4. “Cyclohexanone-3D-balls”, By Mills. B. [Public domain]. Availible from Wikimedia Commons. [2018, October 06]

Figure 5. “Caprolactone-from-xtal-2007-3D-balls” By Mills. B. [Public domain]. Availible from Wikimedia Commons. [2018, October 06]

Figure 6. “Taylor_cone_photo” By Lambarts, R. [Public domain]. Availible from Wikimedia Commons. [2018, October 06]

Figure 7. “SEM images of electrospun chitosan-based nanofibers”. Zahng, M. University of Washington. [Online]. Available: https://www.nanowerk.com/spotlight/spotid=569.php. [2018, October 07]