Biomedical Processing of Polyhydroxyalkanoates
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bioengineering Review Biomedical Processing of Polyhydroxyalkanoates Dario Puppi * , Gianni Pecorini and Federica Chiellini * Department of Chemistry and Industrial Chemistry, University of Pisa, UdR INSTM – Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy; [email protected] * Correspondence: [email protected] (D.P.); [email protected] (F.C.) Received: 30 October 2019; Accepted: 25 November 2019; Published: 29 November 2019 Abstract: The rapidly growing interest on polyhydroxyalkanoates (PHA) processing for biomedical purposes is justified by the unique combinations of characteristics of this class of polymers in terms of biocompatibility, biodegradability, processing properties, and mechanical behavior, as well as by their great potential for sustainable production. This article aims at overviewing the most exploited processing approaches employed in the biomedical area to fabricate devices and other medical products based on PHA for experimental and commercial applications. For this purpose, physical and processing properties of PHA are discussed in relationship to the requirements of conventionally-employed processing techniques (e.g., solvent casting and melt-spinning), as well as more advanced fabrication approaches (i.e., electrospinning and additive manufacturing). Key scientific investigations published in literature regarding different aspects involved in the processing of PHA homo- and copolymers, such as poly(3-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate), are critically reviewed. Keywords: polyhydroxyalkanoates processing; electrospinning; additive manufacturing; selective laser sintering; fused deposition modeling; computer-aided wet-spinning 1. Introduction The always increasing interest on polyhydroxyalkanoates (PHA) for biomedical applications stems from their well-ascertained biocompatibility and biodegradability in physiological environments [1]. In addition, their microbial synthesis by means of sustainable processes with potential for large-scale industrial production [2], together with a better processing versatility and superior mechanical properties in comparison with other polymers from natural resources, make PHA unique polymer candidates for advanced research and development approaches. From a chemical point of view, PHA are aliphatic polyesters with a variable number of carbon atoms in the monomeric unit (Figure1). They are generally classified as short-chain length (SCL)-PHA when they consist of monomers C3-C5 in length, and medium-chain length (MCL)-PHA when they consist of monomers C6–C14 in length [3]. SCL-PHA consist of monomeric units of 3-hydroxybutyrate (3HB), 4-hydroxybutyrate (4HB), or 3-hydroxyvalerate (HV). MCL-PHA consist of monomeric units of 3-hydroxyhexanoate (HHx), 3-hydroxyoctanoate (HO), 3-hydroxydecanoate (HD), 3-hydroxydodecanoate (HDD), 3-hydroxytetradecanoate (HTD), or even longer-chain comonomer units [4]. In general, SCL-PHA have high crystallinity degree and behave as a stiff and brittle material, while MCL-PHA have reduced crystallinity and increased flexibility showing elastomeric properties. The length of the pendant groups of the monomer units plays a key role in the resulting polymer physical properties, so that SCL-PHA copolymers with ethyl side groups can show elongation at break values varying in the range 5–50% depending in comonomers units ratio [5]. In addition, copolymers consisting of both SCL- and MCL-subunits can have properties between those of the two states. While Bioengineering 2019, 6, 108; doi:10.3390/bioengineering6040108 www.mdpi.com/journal/bioengineering Bioengineering 2019, 6, 108 2 of 20 Bioengineering 2019, 6, x FOR PEER REVIEW 2 of 19 most bacteria accumulate PHA granules of only one type, i.e., SCL or MCL, bacteria accumulating SCL-MCL-PHAthose of the two copolymersstates. While were most also bacteria isolated accumulate [6]. PHA granules of only one type, i.e., SCL or MCL, bacteria accumulating SCL-MCL-PHA copolymers were also isolated [6]. Figure 1. (a(a) )General General chemical chemical structure structure of ofpolyhydroxy polyhydroxyalkanoatesalkanoates (PHA); (PHA); chemical chemical structure structure of ( ofb) (poly(3b) poly(3-hydroxybutyrate)-hydroxybutyrate) (PHB), (PHB), (c) ( c)poly(3 poly(3-hydroxybutyrate--hydroxybutyrate-coco--3-3-hydroxyvalerate)hydroxyvalerate) (PHBV), (PHBV), ( d) poly(4-hydroxybutyrate)poly(4-hydroxybutyrate) (P4HB),(P4HB), andand ((ee)) poly(3-hydroxybuyrate-poly(3-hydroxybuyrate-co-co-3-hydroxyexanoate)3-hydroxyexanoate) (PHBHHx).(PHBHHx). Poly(3-hydroxybutyrate)Poly(3-hydroxybutyrate) (PHB), (PHB), which which was was the the first first discovered discovered PHA PHA in the in 1920sthe 1920s [7], together [7], together with itswith copolymers its copolymers poly(3-hydroxybutyrate- poly(3-hydroxybutyrateco-3-hydroxyvalerate)-co-3-hydroxyvalerate (PHBV),) represent(PHBV), therepresent most investigated the most microbialinvestigated polyesters microbial in the polyesters biomedical in areathe thanksbiomedical to the thermoplasticarea thanks to behavior, the thermoplastic mechanical propertiesbehavior, suitablemechanical for load-bearingproperties suitable applications, for load and-bearing versatile applications, synthesis methods and versatile [8,9]. Novel synthesis microbial methods synthesis [8,9]. proceduresNovel microbial have synthesis allowed procedures the biomedical have allowed investigation the biomedical of PHA withinvestigation a wide rangeof PHA of with molecular a wide structures,range of molecular in terms ofstructures molecular, in weight, terms of length molecular of alkyl weight, side group, length and of ratioalkyl ofside comonomer group, and units, ratio as of a meanscomonomer to develop units, materials as a means with to physical develop properties materials tailored with tophysical specific properties applications tailored [10,11 ].to A specific widely investigatedapplications example[10,11]. inA thiswidely context investigated is represented example by poly(3-hydroxybuyrate- in this context is representedco-3-hydroxyexanoate) by poly(3- (PHBHHx),hydroxybuyrate which-co- shows3-hydroxyexanoate) tunable elasticity (PHBHHx) by varying, which HHx shows percentage, tunable elasticity exploitable by varying for diff erentHHx applications,percentage, exploitable such as engineering for different tissues applications, with much such different as engineering stiffness (e.g., tissues bone, with cartilage, much nerve, different and bloodstiffness vessel) (e.g., [ 12bone,]. Thanks cartilage, to its nerve low crystallinity,, and blood poly(4-hydroxybutyrate)vessel) [12]. Thanks to its (P4HB) low crystallinity, has higher flexibility, poly(4- ductility,hydroxybutyrate) and processing (P4HB) propertieshas higher inflexibility, comparison ductility to PHB,, and whichprocessing have properties been exploited in comparison to develop to biomedicalPHB, which devices have been for soft exploited tissue repair to develop [13]. P4HB biomedical products devices currently for onsoft the tissue clinical repair market [13] include,. P4HB amongproducts others, currently GalaFLEX on the® clinical, a surgical market mesh include of knitted, among fibers others, [14 ],GalaFLEX® TephaFLEX , a® surgicalsutures, mesh meshes, of tubes,knitted and fibers thin [14 films], TephaFLEX® [15], MonoMax sutures,®sutures meshes, [16 ],tubes, Phantom and thin Fiber films™ sutures [15], MonoMax® and BioFiber sutures®Surgical [16], MeshPhantom [17]. Fiber™ sutures and BioFiber® Surgical Mesh [17]. PHA versatility in terms of processing approaches and conditions has allowed the investigation and applicationapplication of of a widea wide range range of fabrication of fabrication techniques techniques relevant relevant to biomedical to biomedical research andresearch industrial and application.industrial application. As it will beAs discussedit will be discussed in detail in in the detail following in the following sections, techniquessections, techniques based on based different on workingdifferent principlesworking principles have been have successfully been successfully employed employed to process to PHA, process either PHA, in the either form in of the a melt form or of a solution,a melt or a and solution, shape and them shape at di themfferent at scaledifferent length scale levels. length Techniques levels. Techniques with an oldwith industrial an old industrial history, suchhistory, as meltsuch spinningas melt spinning and blow and extrusion, blow extrusion, are currently are currently employed employed to produce to produce implantable implantable medical devicesmedical madedevices from made PHA from that PHA are available that are onavailable the market. on the Other market. approaches Other approaches industrially industrially employed inemployed the case in of the commodity case of commodity use polymers, use polymers, such as solventsuch as castingsolvent andcasting injection and injection molding, molding, or under or developmentunder development for porous for polymerporous polymer structures structure fabrication,s fabrication, such as freeze such dryingas freeze and drying phase and separation phase methods,separation have methods, been alsohave optimized been also foroptimized PHA processing. for PHA processing. In this context, In this this context, review this article review is aimed article at summarizingis aimed at summarizing PHA processing PHA properties processing in relationship properties to in the relationship requirements