Systematic Evaluation of Structure–Property–Biocompatibility Relationships of Polyhydroxyalkanoate Copolymers for Advanced Veterinary Applications

Polyhydroxyalkanoates (PHAs) are a family of microbial polyesters distinguished by their excellent biocompatibility and tunable degradation profiles. However, systematic evaluation of the interaction effect between their chemical structure, material properties, and biological performance remains limited, particularly in veterinary medicine applications. In this study, we conducted comprehensive in vitro and in vivo evaluations of five commercially available PHA (co)polymers: poly(3-hydroxybutyrate) (PHB); poly(3-hydroxybutyrate-co-4-hydroxybutyrate) containing 5 mol% or 15 mol% 4-hydroxybutyrate monomer (P34HB 5%, P34HB 15%); and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) containing 5 mol% or 15 mol% 3-hydroxyvalerate monomer (PHBV 5%, PHBV 15%). Material characterization confirmed that the introduction of proper comonomers effectively reduced crystallinity and accelerated the degradation process. Biological assays demonstrated quite excellent cytocompatibility and hemocompatibility among all tested PHA materials. Notably, P34HB 5% nanoparticles promoted human umbilical vein endothelial cell (HUVEC) migration. In a 12-week murine subcutaneous implantation model, the PHBV 15% group exhibited the thinnest fibrous capsule formation and the mildest inflammatory response. Furthermore, intramuscular injection of nanoparticles revealed favorable muscle tissue compatibility in all groups. These results provided a co-polymer ratio-based justification for PHA selection, thus providing support for the application of these biomaterials in veterinary drug delivery platforms, wound dressings, and biodegradable implants.