Enhancing the Potential of PHAs in Tissue Engineering Applications: A Review of Chemical Modification Methods

Abstract

Polyhydroxyalkanoates (PHAs) are a family of polyesters produced by many microbial species. These naturally occurring polymers are widely used in tissue engineering because of their in vivo degradability and excellent biocompatibility. The best studied among them is poly(3-hydroxybutyrate) (PHB) and its copolymer with 3-hydroxyvaleric acid (PHBV). Despite their superior properties, PHB and PHBV suffer from high crystallinity, poor mechanical properties, a slow resorption rate, and inherent hydrophobicity. Not only are PHB and PHBV hydrophobic, but almost all members of the PHA family struggle because of this characteristic. One can overcome the limitations of microbial polyesters by modifying their bulk or surface chemical composition. Therefore, researchers have put much effort into developing methods for the chemical modification of PHAs. This paper explores a rarely addressed topic in review articles-chemical methods for modifying the structure of PHB and PHBV to enhance their suitability as biomaterials for tissue engineering applications. Different chemical strategies for improving the wettability and mechanical properties of PHA scaffolds are discussed in this review. The properties of PHAs that are important for their applications in tissue engineering are also discussed.

Keywords: chemical modifications; functionalized oligomers; polyhydroxyalkanoates (PHAs); polymer grafting; surface modifications; tissue engineering.

Figure 1

(a) General chemical structure of PHAs; * = chiral center, x = 1–4, R = hydrogen atom or an alkyl group. (b) The chemical structure of mers that make up scl-PHAs and mcl-PHAs; 3HB: (R)-3-hydroxybutyric acid (C₄), 3HV: (R)-3-hydroxyvaleric acid (C₅), 3HHx: (R)-3-hydroxyhexanoic acid (C₆), 3HO: (R)-3-hydroxyoctanoic acid (C₈), 3HD: (R)-3-hydroxydecanoic acid (C₁₀), 3HDD: (R)-3-hydroxydodecanoic acid (C₁₂).

Figure 2

Bar chart illustrating the proportion of review articles on PHA production relative to the total number of review articles on these polyesters.

Figure 3

Applications of microbial polyesters in various areas of tissue engineering. The authors were inspired by Ref. [21] in the preparation of this figure.

Figure 4

Two approaches are used for altering the chemical structure of microbial polyesters. (a) One utilizes polymerization of the PHB oligomers to obtain its multiblock copolymers, and (b) the second focuses on modifying the surface chemistry of the scaffold.

Figure 5

Scheme illustrating the stages of initiation, propagation, and termination of radical reactions involving PHB, which are induced by ionizing radiation. For simplicity, only one of the possible termination reactions is presented in the diagram.

Figure 6

Chemical structures of the monomers used for grafting the surfaces of PHB and PHBV products, and the structure of the PHB-g-PHEMA copolymer.

Figure 7

Simplified scheme for chemical surface modification using UV light and 3,4-dicarboxybenzenediazonium tosylate.

Figure 8

Schematic overview of the degradation reactions to which biopolyesters are subjected in order to obtain their oligomers. For simplicity, only those oligomers that are the main products of the specified reactions are shown; R = hydrogen atom or an alkyl group.

Figure 9

Mechanism of biopolyester reduction using LiAlH₄ (the counterion has been omitted for clarity); R = hydrogen atom or an alkyl group.

Figure 10

Schematic of the synthesis of thermoresponsive PNIPAAm-PHB-PNIPAAm triblock copolymer via ATRP.

Figure 11

Schematic of the synthesis of poly(ester urethane) from PHB oligoester diols, oligomeric PEG, and HDI [287].

Figure 12

Chemical structure of oligoester diols used in the synthesis of DegraPol polyurethanes.