Polyhydroxyalkanoate (PHA) Scaffolds in Biomedical Engineering: Fabrication, Properties and Applications

2.1 Structural classification of PHAs

PHAs are broadly categorized into three groups based on the number of carbon atoms in their monomer units:

Short-chain-length PHAs (scl-PHAs) contain 3–5 carbon atoms, as found in poly(3-hydroxybutyrate) (PHB) and its copolymer with hydroxyvalerate (PHBV) [10]. These semicrystalline polymers feature high melting points, stiffness, and brittleness (Figure 1B).

mcl-PHAs possess 6–14 carbon atoms, exemplified by polymers such as poly(3-hydroxyoctanoate) (PHO) and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) [11]. mcl-PHAs are characterized by lower crystallinity, reduced melting temperatures (typically 39–65°C), and elastomeric properties, making them suitable for flexible applications like nerve regeneration and soft tissue engineering (Figure 1B).

Long-chain-length PHAs, with 15 or more carbon atoms, are less common but provide distinct material properties [8].

Commonly used PHA types in biomedical applications include P3HB, PHBV, PHBHHx, P(3HB-co-4HB), and terpolymers such as PHBVHHx, each offering distinct mechanical and degradation profiles tailored to specific tissue engineering needs [12].

2.2 Biosynthesis pathways and microbial production

PHA biosynthesis occurs through diverse microbial metabolic pathways, influenced by carbon source, enzymatic activity, and genetic regulation. For instance, Wei et al. demonstrated that enzymatic regulation, particularly the deficiency of short-chain thioesterases in Escherichia coli, significantly affects the copolymer composition and yield of P(3HB-co–LA) [6]. Cai et al. showed that Cupriavidus necator can efficiently synthesize PHBV using volatile fatty acids (VFAs) as the sole carbon source, highlighting the role of metabolic adaptability in PHA production [7].

Recent research has expanded the range of microbial producers to include extremophiles and genetically engineered strains. For example, Halomonas halophila 18 H has been identified as an efficient producer of PHB, offering advantages for low-cost production under nonsterile conditions [14].

Thermophilic genera, including Caldimonas and Schlegelella, have been genomically characterized to elucidate the genetic determinants of PHA synthesis, facilitating strain optimization via metabolic engineering [15].

2.3 Sustainable substrates and production strategies

The use of renewable and waste-derived carbon sources – such as plant biomass, food waste, and animal by-products – further enhances the sustainability of PHA production. Lactic acid bacteria (LAB) and other microbial systems have been employed to convert these substrates into PHAs, emphasizing the ecological and economic benefits of integrated bioprocessing [16].

Advances in synthetic biology and fermentation technology continue to improve the scalability and cost-effectiveness of PHA production. Strategies such as constructing artificial microbial consortia and implementing high-density fermentation processes have shown promise for enhancing the yield of mcl-PHAs and other valuable copolymers [8].

2.4 Functionalization and tailored properties

Beyond their native production, PHAs can be functionalized to introduce additional properties such as antibacterial activity, enhanced biocompatibility, or targeted biodegradability. For instance, Cruz-Romero et al. functionalized PHAs with silver nanoparticles to impart antimicrobial functionality, expanding their applicability in medical devices and wound dressings [17].

The incorporation of different monomer units enables precise modulation of mechanical properties, crystallinity, and degradation rates, making PHAs highly versatile for applications ranging from bone scaffolds to elastic nerve conduits (Table 1).

3.1 Biocompatibility

PHAs demonstrate outstanding biocompatibility, evidenced by minimal inflammatory response and high tissue tolerance upon implantation. Their natural origin and metabolic resorbability promote excellent cellular acceptance, supporting their use in long-term in vivo applications [25]. The lack of cytotoxic leachates further validates their safety in sensitive physiological environments.

Surface morphology is a key factor affecting cellular responses to these biopolymers. For instance, Yu et al. showed that tailored surface properties significantly improve biocompatibility by enhancing interactions with human mesenchymal stem cells (MSCs) [26]. Beyond intrinsic properties, incorporating bioactive additives can further enhance PHA performance. Hsu et al. reported that incorporating hyaluronic acid (HA) into PHAs improved cytocompatibility with human foreskin fibroblasts, suggesting that composites with natural polymers positively influence cellular behavior [27]. Similarly, Chan et al. found that blending PHAs with low-molecular-weight polyethylene glycol (PEG) enhanced both biocompatibility and degradability, underscoring how physicochemical modifications can fine-tune biological properties [28].

Designing composite materials represents another effective strategy for improving biocompatibility. Wu et al. developed PHA composites reinforced with chestnut shell fibers, which exhibited good biocompatibility along with enhanced mechanical and degradation properties [29]. In another study, Aguilar-Rabiela et al. integrated mesoporous bioactive glass nanoparticles into PHBV microspheres, creating drug delivery systems that combine improved biocompatibility with functional performance [30].

Advances in processing techniques have further broadened the biomedical applications of PHAs. Lukasiewicz et al. created binary PHA systems with oligomeric plasticizers, yielding flexible biomaterials for soft tissue engineering that overcome brittleness while maintaining biocompatibility [31]. Additionally, Wu et al. produced functional PHA microspheres loaded with growth factors; these spheres exhibited antibacterial activity without compromising biocompatibility, highlighting the potential of multifunctional PHA platforms [32].

In summary, the biocompatibility of PHAs can be effectively enhanced through surface engineering, forming composites with natural polymers and bioactive fillers, and employing advanced processing methods. These strategies collectively widen the scope of PHA applications in tissue engineering, drug delivery, and regenerative medicine.

3.2 Biodegradability

A defining characteristic of PHAs is their predictable and controllable biodegradation, which occurs mainly through surface erosion driven by hydrolysis and enzymatic activity. As microbial biopolyesters, PHAs are inherently biodegradable, a property that distinguishes them from conventional plastics and aligns with sustainability objectives [33]. Degradation kinetics can be finely modulated by varying monomer composition, copolymer ratios, and crystallinity. For instance, scl-PHAs, such as PHB, typically degrade more slowly than mcl-PHAs or copolymers containing 4-hydroxybutyrate (4HB) [20]. Crucially, the degradation products – primarily hydroxy acid monomers – are nontoxic and can be metabolized via endogenous biochemical pathways, eliminating the need for surgical removal [34].

The biodegradation behavior of PHAs is strongly influenced by environmental conditions. Anunciado et al. demonstrated that ambient soil exposure and composting conditions significantly affect the degradation of biodegradable plastic mulches, underscoring the importance of context-specific assessments in evaluating biodegradation performance [35]. In marine environments, the biodegradation of PHAs, such as poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), follows standardized protocols (e.g., ASTM D7991-15), with studies showing that the incorporation of natural fillers, like Miscanthus fibers or distillers’ dried grains with solubles (DDGS), can modulate degradation rates [36].

Chemical modification offers another avenue for tuning PHA biodegradability. Qie et al. reported that oxidizing copolymer films containing 2-hydroxy-4-methylthiobutyrate enhanced their breakdown in seawater, suggesting that targeted molecular alterations can accelerate environmental degradation [37].

In biomedical contexts, the controlled biodegradation of PHAs is essential for applications such as resorbable implants and tissue engineering scaffolds. For example, Miu et al. developed polyhydroxyoctanoate-hydroxyapatite composites that exhibit tailored biodegradability alongside biocompatibility and bioresorbability, highlighting the functional integration of degradation properties in advanced biomedical materials [38].

In summary, the biodegradability of PHAs is governed by a complex interplay of material factors – including chemical structure, composite formulation, and surface modification – and environmental conditions. This tunable degradation profile supports their use across ecological and medical applications, where controlled breakdown and environmental compatibility are required.

3.3 Mechanical properties

PHA-based materials exhibit a broad range of mechanical behaviors – from rigid and brittle to soft and elastomeric – making them suitable for diverse biomedical and industrial applications. scl-PHAs, such as poly PHB, exhibit high tensile strength and stiffness comparable to polypropylene, rendering them suitable for bone tissue engineering and load-bearing applications. In contrast, mcl-PHAs, including PHO and PHBHHx, display a reduced Young’s modulus, high elongation at break, and rubber-like elasticity, making them ideal for soft tissue engineering, cardiovascular implants, and neural guides. This intrinsic tunability is further enhanced through copolymerization, blending, and advanced material processing.

Recent advances in modifying the mechanical properties of PHAs focus on surface and interfacial engineering. Jo et al. demonstrated that the silanization of cellulose nanocrystals (CNCs) significantly influences the morphology and mechanical behavior of PHA composites processed via melt extrusion, underscoring the role of nanofiller surface chemistry in enhancing composite performance [39]. Molecular dynamics simulations by Bejagam et al. provided atomistic insights into structure-property relationships, offering a predictive framework for tailoring mechanical characteristics through rational molecular design [40].

Processing techniques critically affect the mechanical performance of PHAs. Mustafa et al. optimized fused filament fabrication (FFF) parameters for polylactic acid (PLA)/PHA blends, achieving superior mechanical properties through precise control of printing conditions [41]. Similarly, Aziz et al. employed gray relational analysis to enhance the mechanical performance of 3D-printed PLA/PHBV/polycaprolactone (PCL) blends for orthopedic applications [42].

The development of PHA-based composites and nanocomposites represents a prominent strategy for mechanical enhancement. Najah et al. reported that calcium phosphate (CaP) reinforcement tunes the mechanical properties of PHA biocomposites for bone scaffold applications [43]. Champa-Bujaico et al. utilized machine learning to predict the mechanical behavior of PHA nanocomposites reinforced with graphene oxide and nanoclay, highlighting the growing role of computational tools in materials design [44]. Buntinx et al. further reviewed how ZnO nanofillers and processing advancements improve the mechanical integrity of PHA nanocomposites in packaging contexts [45].

Blending PHAs with other biodegradable polymers – such as PLA, poly(butylene succinate-co-adipate) (PBSA), and PCL – enables the fabrication of materials with balanced and application-specific mechanical profiles. Sabalina et al. illustrated that binary and ternary blends allow fine-tuning of thermomechanical properties [46], supporting their use in diverse biomedical and environmental applications.

In summary, the mechanical properties of PHAs are highly customizable through molecular design, surface modification, processing optimization, composite formation, and blending. These strategies, supported by emerging computational and machine learning approaches, facilitate the rational design of PHA-based materials with tailored mechanical performance for use in tissue engineering, medical devices, sustainable packaging, and beyond.

3.4 Processability

The processability of PHAs is crucial for their use in tissue engineering and regenerative medicine, building on their inherent biodegradability and biocompatibility. These biopolymers can be shaped into various structures using both conventional and advanced techniques, allowing the creation of scaffolds tailored to specific biomedical needs [47]. Common methods include electrospinning for nanofibrous scaffolds that mimic the extracellular matrix, salt leaching for interconnected porous 3D constructs, solvent casting for thin films, melt extrusion for filaments and fibers, and additive manufacturing (AM) (e.g., 3D printing) for patient-specific implants [48, 49].

Electrospinning is particularly valuable for creating PHA nanofibrous scaffolds with high surface-area-to-volume ratios and adjustable porosity, which promote cell adhesion, proliferation, and tissue integration [50, 51]. However, electrospinning microbial PHAs requires careful control of parameters such as solution concentration, viscosity, and temperature due to their narrow thermal processing window [51]. Recent improvements in nozzle design and solvent systems have facilitated the production of defect-free PHA nanofibers.

Beyond fibers, PHAs can also be processed into hydrogels for bioprinting and mold-based fabrication. Li et al. developed printable hydrogel inks from PHA composites, including blends with polyvinyl alcohol (PVA), which offer improved printability and mechanical stability while maintaining biodegradability [50, 52]. Such hydrogel systems show promise for building complex, cell-laden constructs for soft tissue engineering.

Downstream processing steps – including purification, blending, and functionalization – significantly affect the final properties of PHA scaffolds [53]. For example, incorporating bioactive fillers or other polymers can enhance melt strength, thermal stability, and interfacial properties, thereby widening the processing window and enabling the fabrication of more complex shapes [52]. Techniques like particulate leaching, gas foaming, and phase separation have also been employed to create porous PHA scaffolds with controlled pore size and connectivity, which are vital for nutrient diffusion and vascularization in tissue engineering [48, 52].

Looking ahead, emerging processing technologies – such as melt electrowriting, microfluidic spinning, and multimaterial 3D printing – are expected to further enhance the architectural and functional quality of PHA-based scaffolds [8]. These advances, coupled with a better understanding of process-structure-property relationships, will continue to establish PHAs as versatile, sustainable, and clinically useful biomaterials.

3.5 Surface modifiability

The surface characteristics of PHAs – including their chemistry and topography – critically influence biological performance and integration with host tissues. Surface modification methods can significantly enhance the biofunctionality of PHA materials, enabling customized cellular responses such as improved adhesion, differentiation, and tissue-specific regeneration [54, 55]. Standard approaches include plasma treatment, chemical grafting, physical adsorption, and biomolecular conjugation, which allow the immobilization of bioactive elements such as RGD peptides, collagen, heparin, and growth factors to promote targeted biological interactions.

Plasma surface modification offers an efficient, solvent-free method to introduce functional groups and improve surface energy without affecting bulk material properties. Mohammadalipour et al. demonstrated that plasma treatment improves the surface properties of electrospun PHB nanofibers, enhancing their potential for bone tissue engineering by increasing hydrophilicity and cell attachment [18].

The incorporation of inorganic phases and nanoparticles further expands the possibilities for functionalization. For example, CaP-reinforced PHA biocomposites exhibit enhanced surface bioactivity and osteoconductivity, supporting mineral deposition and improving integration in bone regeneration [29]. Similarly, incorporating silver nanoparticles imparts antibacterial properties to PHAs, broadening their use in infection prevention for wound dressings and implant coatings [56].

Micro- and nano-scale topological modifications also help guide cellular behavior. Wu et al. created functional PHA microspheres with controlled surface features – such as rough microporous or smooth granular structures – to regulate the release of bioactive molecules like BMP-2 and enhance antimicrobial and osteogenic effects [32]. Chen et al. used phase-separation methods to adjust the surface architecture of PHA microspheres, improving their bone regeneration performance through enhanced cell-material interactions and controlled growth factor delivery [57].

Furthermore, advanced surface engineering methods utilizing nanoscale patterning and dynamic bio-interfaces can better mimic the natural extracellular matrix. Du et al. emphasized that rationally designed surface nanostructures and chemical functionalities can significantly improve the biocompatibility and bioactivity of synthetic biomaterials, indicating strong potential for applying these strategies to PHAs [58].

In summary, the ability to modify PHA surfaces through physical, chemical, and biological methods provides a powerful means to customize their interactions with biological environments. These modifications are crucial for developing advanced PHA-based scaffolds and delivery systems with improved integration capacity, therapeutic function, and clinical relevance in regenerative medicine.

3.6 Composite and functional enhancements

PHAs serve as versatile matrix materials for advanced composites in biomedical engineering, helping overcome inherent limitations such as brittleness, limited bioactivity, and lack of electrical conductivity. By integrating functional fillers, nanoscale modifiers, and other polymers, the performance of PHA-based materials can be substantially improved while maintaining essential biodegradability and biocompatibility [59, 60].

One important approach involves reinforcing PHAs with bioactive inorganic phases to enhance mechanical and osteogenic properties. Ye et al. showed that adding β-tricalcium phosphate (β-TCP) to PHA matrices increases compressive strength and osteoconductivity, making these composites well-suited for bone tissue engineering scaffolds [61]. Similarly, hydroxyapatite (HA) and related nanocomposites like HAp/CoFe₂O₄ have been used to promote biomineralization and bone regeneration. Hossain et al. reported that such nanocomposites possess favorable functional group profiles and bandgap properties (3.51–5.47 eV), supporting their use in functionalized bone grafts [62].

The incorporation of conductive components extends PHA functionality to electrically responsive tissues. Combining PHAs with conductive polymers (e.g., polyaniline, polypyrrole) or carbon-based nanomaterials (e.g., graphene oxide, carbon nanotubes) provides adjustable electrical conductivity, enabling applications in neural interfaces, cardiac patches, and biosensing platforms [63].

Advanced manufacturing techniques, including 3D printing and microfluidics, enable the fabrication of complex composite architectures with spatially controlled properties [47, 64]. Combining PHAs with other biodegradable polymers – such as PLA or PCL – allows the design of multimaterial systems with graded mechanical properties and degradation rates that closely match natural tissue heterogeneity [65].

Additionally, encapsulating and controlling the release of bioactive molecules – such as growth factors, antibiotics, or genetic material – from PHA composite microspheres or hydrogels improves their therapeutic function. Guo et al. developed growth factor-loaded PHA microspheres with customized release profiles, supporting long-term bioactivity in regenerative applications [66].

In summary, composite and functionalization strategies significantly broaden the applications of PHAs in biomedical engineering. By combining PHAs with ceramics, conductive polymers, nanomaterials, and bioactive agents, researchers can create materials with improved mechanical, electrical, antibacterial, and regenerative properties. These advances highlight PHAs as highly adaptable, multifunctional platforms for next-generation medical devices, tissue scaffolds, and drug delivery systems [67, 68].

4.1 Additive manufacturing techniques

AM, particularly fused deposition modeling (FDM), has emerged as a highly promising approach for fabricating PHA scaffolds with precise geometric control and complex pore structures. Pryadko et al. emphasized FDM’s capability to create customized structures for specific tissue defects, enhancing integration and function [68]. Recent studies have demonstrated the feasibility of 3D printing biosynthetic mcl-PHA produced through fed-batch fermentation using carbon sources such as glycerol and sodium octanoate [69]. These elastomeric scaffolds possess mechanical properties suitable for soft tissue engineering, including tendon regeneration [69, 70]. Furthermore, FDM has been employed to create porous antibacterial PHA scaffolds, such as those based on PAP34HB, which show promise for oral soft tissue regeneration [4].

4.2 Thermally induced phase separation

Thermally induced phase separation (TIPS) represents another effective method for creating highly porous PHA-based scaffolds, often used in combination with other biodegradable polymers. Lopresti et al. fabricated blends of PLLA and PHA, demonstrating that incorporating up to 30 wt% PHA significantly influences morphology, porosity, and mechanical behavior [71]. This technique enables precise control over microstructural features, facilitating the design of scaffolds that mimic the natural extracellular matrix.

4.3 Conventional fabrication methods

Traditional methods such as solvent casting, particulate leaching, and electrospinning remain widely used for PHA scaffold production, particularly in early-stage research and specific biomedical applications. These approaches offer simplicity and cost-effectiveness, enabling the creation of films, fibrous mats, and porous membranes with good biocompatibility [72]. However, they typically lack the architectural precision and reproducibility achievable with advanced AM technologies.

4.4 Functionalization and composite strategies

Recent developments have integrated functionalization steps during or after scaffold fabrication to enhance bioactivity and performance. For instance, mineral coatings on FDM-printed PHA scaffolds improve osteoconductivity and bone-mimicking properties [73]. Similarly, incorporating antibacterial agents or bioactive molecules through blending, coating, or encapsulation supports applications in infected wound healing and controlled drug delivery [4].

4.5 Emerging approaches and future outlook

Novel methods such as microfluidic spinning, melt electrowriting, and hybrid manufacturing are expanding opportunities to create high-resolution, multimaterial PHA scaffolds. These technologies enable the replication of hierarchical and heterogeneous tissue structures – such as osteochondral or neurovascular interfaces – with region-specific mechanical and chemical cues.

In summary, PHA scaffold fabrication encompasses a diverse range of techniques, each offering distinct advantages in resolution, scalability, and functional customization. The continued integration of advanced manufacturing, biomaterial science, and biofunctionalization strategies is essential for fully realizing the potential of PHA-based scaffolds in regenerative medicine and personalized healthcare.

5.1 Bone tissue engineering

PHA scaffolds have been extensively investigated for bone regeneration, with their mechanical properties and osteoconductivity adjustable through composite design and surface modification. Ye et al. demonstrated that incorporating β-TCP into PHA matrices using FDM significantly enhanced compressive strength and bioactivity, promoting osteogenic differentiation and bone formation [61]. Similarly, the addition of HA or other calcium phosphates improves mineral deposition and scaffold integration in bone defects [74]. The ability to create patient-specific porous structures through 3D printing enables anatomical matching and vascular infiltration, which are crucial for repairing large bone defects.

5.2 Soft tissue regeneration

mcl-PHAs, such as PHO and PHBHHx, exhibit elastomeric characteristics suitable for soft tissue applications. Panaksri et al. developed biosynthetic mcl-PHA scaffolds with tailored elasticity and degradation behavior, ideal for engineering tendons, ligaments, and blood vessels [69]. Their inherent flexibility and resilience withstand cyclic mechanical loading, mimicking native tissue conditions. Moreover, surface topographic features – such as microgrooves or aligned nanofibers – can guide MSC differentiation and tissue-specific development [75].

5.3 Neural tissue engineering

PHA-based conduits and scaffolds support peripheral nerve regeneration by providing physical guidance and biochemical signals. Combining electrical conductivity – achieved through the incorporation of graphene or polypyrrole – with controlled delivery of neurotrophic factors enhances axonal growth and functional recovery [76]. Microfluidic-generated fibers and 3D-printed channels made from PHAs enable precise architectural control, replicating endoneurial tube structures and promoting Schwann cell alignment [77].

5.4 Cartilage tissue engineering

The viscoelastic and lubricating properties of specific PHA copolymers, such as PHBHHx and P(3HB-co-4HB), make them suitable for cartilage repair. Scaffolds with controlled porosity and surface modifications (e.g., chitosan or HA coatings) enhance chondrocyte adhesion and glycosaminoglycan production [78]. Researchers have developed bilayered osteochondral scaffolds that combine mineralized PHA for the bone layer and elastomeric PHA for the cartilage zone to address joint interface regeneration.

5.5 Cardiovascular applications

PHA scaffolds find application in vascular graft engineering due to their compliance, suturability, and blood compatibility. Small-diameter tubular scaffolds, fabricated through electrospinning or 3D printing, exhibit antithrombogenic properties when modified with heparin or nitric oxide donors [79]. Additionally, cardiac patches created from conductive PHA composites facilitate cardiomyocyte synchronization and electrical signal propagation in the infarcted heart.

5.6 Skin and wound healing

PHA-based nanofibrous mats and hydrogels accelerate wound healing by maintaining a moist environment, providing antibacterial protection (e.g., via silver nanoparticles), and enabling sustained release of growth factors [76]. Their tunable degradation rate ensures proper tissue integration and reduces the need for frequent dressing changes.

5.7 Emerging trends and functional enhancements

Recent advancements include immunomodulatory PHAs that actively control macrophage polarization and reduce fibrotic responses [78]. Delivering bioactive molecules – such as VEGF for angiogenesis or BMP-2 for bone formation – from PHA microspheres or coatings further enhances regenerative outcomes [61]. Furthermore, four-dimensional (4D) printing of PHAs enables the creation of shape-changing scaffolds that adapt to dynamic physiological conditions.

In summary, PHA scaffolds provide a versatile platform for tissue engineering across various organ systems. Through strategic material design, advanced fabrication, and biofunctionalization, PHAs can be customized to meet specific mechanical, biological, and practical requirements of different clinical applications, opening pathways for next-generation regenerative therapies.

6.1 Versatile carrier systems

PHAs, particularly medium-chain-length types (mcl-PHAs), exhibit excellent film-forming capability, compatibility with both hydrophobic and hydrophilic drugs, and adjustable degradation rates – making them suitable for various delivery platforms, including microspheres, nanoparticles, hydrogels, and electrospun fibers [80, 81]. Their production from renewable resources further supports sustainable and scalable biomedical applications [80].

6.2 Electrospun fiber-based delivery

Electrospun PHA fibers, especially those derived from PHBV, offer high surface-area-to-volume ratios and programmable drug release profiles. Kaniuk et al. demonstrated that these fibrous mats enable sustained release of antibiotics or antiinflammatory drugs, supporting applications in wound dressings and postsurgical implants where localized, prolonged drug delivery is essential [52].

6.3 Nanoparticulate and microparticulate systems

PHA-based micro- and nanoparticles serve as promising carriers for encapsulating small molecules, proteins, and nucleic acids. Their surfaces can be modified with targeting ligands (e.g., peptides or antibodies) to achieve tissue- or cell-specific delivery [82, 83]. Reddy et al. emphasized that the tunable thermal and mechanical properties of mcl-PHAs facilitate the design of nanoparticles with enhanced drug-loading capacity and controlled-release behavior [81].

6.4 Combinational therapies and regenerative delivery

PHA scaffolds and particles are increasingly utilized for combination therapy, simultaneously delivering bioactive agents (e.g., growth factors, antibiotics) while supporting tissue regeneration. Pulingam et al. demonstrated that drug-loaded PHA systems significantly reduce microbial infections and accelerate healing in soft tissue models, highlighting their dual role as both degradable scaffolds and therapeutic carriers [83].

6.5 Functionalization and hybrid systems

To improve targeting and release precision, PHAs are often combined with other functional materials. For instance, blending with chitosan or incorporating them into metal-organic frameworks (MOFs) can enhance mucoadhesion, pH-responsive release, and cellular uptake efficiency [82, 84]. Such modifications broaden their applications in gastrointestinal, neurological, and cancer drug delivery.

6.6 Future perspectives

Continuing advances in synthetic biology and material engineering enable the biosynthesis of novel PHA copolymers with customized properties – such as improved hydrophilicity, stimuli-responsive degradation, or innate targeting abilities [85, 86]. Combined with innovations in nanotechnology and precision manufacturing, PHAs are poised to play an expanding role in personalized and programmable drug delivery systems.

The integration of drug delivery functionality into PHA scaffolds represents a convergence of material science and therapeutic design, creating opportunities for combination systems that support both structural regeneration and localized drug therapy. Looking forward, such multifunctional approaches will be crucial for addressing remaining challenges in scaling up and clinically adopting PHA-based technologies, as discussed in the next section.

7.1 Current challenges in PHA-based tissue engineering

Despite their significant potential in tissue engineering, several key challenges must be addressed to enable the widespread clinical adoption of PHAs.

High production costs: the economic viability of PHA production remains constrained by high fermentation and purification costs. Future efforts should focus on leveraging synthetic biology tools and waste-derived feedstocks to develop more sustainable and cost-effective production methods.

Limited mechanical performance for specific applications: although PHAs possess tunable mechanical properties, certain applications – such as load-bearing bone grafts or dynamic tendon repairs – require greater strength, fatigue resistance, and elastic recovery. Advanced composite strategies and copolymer blending are essential to meet these biomechanical demands.

Degradation rate mismatch: aligning PHA scaffold degradation rates with tissue regeneration timelines remains challenging. Variations in polymer composition, crystallinity, and in vivo conditions can lead to premature structural failure or delayed resorption, potentially compromising therapeutic outcomes.

Surface biofunctionalization: while PHAs are naturally biocompatible, their bioactivity often requires enhancement through surface modification. The development of scalable and reproducible functionalization methods – such as peptide conjugation, plasma treatment, or nanoparticle integration – remains an ongoing area of research.

Regulatory and standardization hurdles: the lack of standardized processing protocols and comprehensive long-term safety data impedes regulatory approval. Establishing robust quality control measures and conducting thorough biocompatibility testing are crucial for successful clinical translation.

7.2 Future directions and emerging opportunities

Looking forward, several innovative approaches show significant potential for advancing PHA-based scaffolds toward clinical applications and broader biomedical impact.

AI-guided material design: machine learning and computational modeling can accelerate the development of PHA copolymers with customized properties, predicting degradation behavior, mechanical performance, and biological interactions before synthesis.

4D printing of stimuli-responsive scaffolds: four-dimensional bioprinting enables the creation of dynamic PHA constructs that change shape or function in response to physiological signals (e.g., pH, temperature, or enzyme activity), facilitating personalized and adaptive tissue regeneration.

Integrated stem cell and immunomodulatory strategies: combining PHA scaffolds with stem cell therapies and immunomodulatory agents (e.g., cytokine-releasing microspheres) can enhance regenerative outcomes while minimizing fibrotic responses.

Harnessing piezoelectric properties: utilizing the inherent piezoelectricity of certain PHAs (e.g., PHB) offers opportunities for electrically stimulated tissue repair, particularly in neural and musculoskeletal applications.

Sustainable production and circular design: aligning PHA production with circular bioeconomy principles – utilizing agricultural waste, CO₂, or microbial consortia – supports both environmental sustainability and scalable manufacturing.

Clinical translation roadmap: establishing clear regulatory pathways and initiating pilot clinical studies will be essential for transitioning PHA scaffolds from laboratory research to practical medical applications.