Exploring the frontier of Polylactic Acid/Hydroxyapatite composites in bone regeneration and their revolutionary biomedical applications

Abstract

This review research investigates the potential of Polylactic Acid (PLA)/Hydroxyapatite (HA) composites in bone regeneration, focusing on the composites’ synthesis methods, mechanical properties, and biocompatibility. Through an extensive examination of various preparation techniques, such as solvent evaporation, phase separation, electrospinning, and lyophilisation, the study assesses how these methods influence the physical and biological properties of PLA/HA composites. Significant findings from the review highlight that PLA/HA composites enhance osteoblast activity and proliferation, demonstrating an increase in cell adhesion by up to 25% compared to PLA alone. These composites substantially improve mechanical properties, increasing compressive strength and fracture toughness by approximately 30% and 50%, respectively. These enhancements are pivotal for applications requiring robust, load-bearing materials supporting bone tissue integration and regeneration. In conclusion, due to their optimised mechanical strength, biodegradability, and bioactivity, PLA/HA composites are promising biomaterials for orthopaedic and dental applications. The review suggests future research directions focused on long-term clinical outcomes and further material refinement to maximise clinical efficacy and patient compatibility.

Keywords

Additive manufacturing biocompatibility bone regeneration potential of polylactic acid-hydroxyapatite composites scaffold fabrication tissue engineering

Introduction

Fused Deposition Modelling (FDM) represents a transformative advancement in additive manufacturing, particularly notable for its role in biomedical engineering.^1–3 This technology involves the layer-by-layer deposition of thermoplastic materials to create complex three-dimensional structures tailored to specific medical applications.^4,5 The precision and versatility of FDM allow for the fabrication of custom implants, prosthetics, and scaffolds tailored to individual patient anatomies, thus enhancing the effectiveness and integration of medical devices.^6,7 The significance of FDM in biomedical applications is profound. It offers a rapid, cost-effective method to produce devices that are otherwise challenging to manufacture using traditional methods.^8–10 For instance, FDM can produce geometrically complex structures like porous scaffolds that facilitate tissue integration and vascularisation, essential for tissue engineering.^11–13 Additionally, the ability of FDM to utilise biocompatible materials underscores its utility in creating implants that can be directly used in treatment scenarios without adverse reactions, thereby speeding up the recovery process and reducing overall healthcare costs.^14,15

Polylactic Acid (PLA) and ceramic composites are pivotal in biomedical materials, primarily due to their favourable properties such as biocompatibility, biodegradability, and mechanical robustness.^16–18 PLA, a thermoplastic aliphatic polyester derived from renewable resources like corn starch, is especially valued for its degradation properties. It occurs through hydrolysis within the human body, leaving no toxic residue.^19–21 This makes PLA an excellent candidate for temporary implants and scaffolds that support tissue growth and then safely degrade as the native tissue regenerates.^22,23 On the other hand, ceramic composites are employed for their osteoconductivity – their ability to support bone cell attachment and growth – which is crucial for bone tissue engineering.^24–26 When combined with PLA, the ceramic particles enhance the mechanical strength and stiffness of the composite, making it more suitable for load-bearing applications in orthopaedics.^27–29 Moreover, these composites can be finely tuned to match the mechanical properties of bone, reducing stress-shielding effects and promoting better integration with the host tissue.^30,31

The versatility of FDM and the advantageous properties of PLA and ceramic composites are setting new benchmarks in the design and functionality of biomedical devices.^32,33 Their integration into additive manufacturing heralds a new era of personalised medicine, where patient-specific solutions are not just a possibility but a practical and increasingly accessible reality.^33,34 This convergence of technology and material science is poised to drive significant advancements in healthcare, improving patient outcomes and the efficacy of medical treatments.^35–37 The integration of FDM, PLA, and ceramic composites has been the focus of extensive research, aiming to harness their synergistic benefits for biomedical applications.^38–40 Notably, studies have highlighted the adaptability of FDM in processing PLA-ceramic blends, which are pivotal for creating biodegradable scaffolds that support tissue regeneration and integration.^41–43

One significant study by Refs. 44 and 45 explored the mechanical properties of PLA-hydroxyapatite (HA) composites fabricated via FDM, demonstrating enhanced osteoconductivity and improved mechanical strength suitable for bone implants.⁴⁷ This study underscored the potential of combining PLA with ceramics to mimic natural bone’s mechanical and biological properties, thus facilitating more effective bone integration and healing. Further research by Refs. 46 to 48 examined the degradation behaviour of PLA-ceramic scaffolds under physiological conditions, revealing that ceramic particles like HA improve the mechanical integrity and bioactivity of the scaffolds, enhancing their utility in bone regeneration.

The findings from these studies are highly relevant to ongoing research in biomedical engineering, particularly in developing next-generation implantable devices.^49–51 The ability of FDM to accurately and efficiently create complex structures from PLA-ceramic composites opens up new avenues for the design of patient-specific implants that can be tailored to the unique anatomical and biomechanical requirements of individual patients.^52–54 Moreover, the research into the mechanical properties and biocompatibility of PLA-ceramic composites provides crucial insights into selecting material formulations that optimise structural and biological performance.^55–57 This is particularly relevant for the design of scaffolds that need to bear mechanical loads immediately upon implantation and gradually transfer these loads to regenerating tissues.

Integrating these findings into current research projects can lead to more sophisticated designs of scaffolds and implants that are structurally robust and promote desirable cellular responses, such as osteointegration in bone tissue engineering.^58–60 Additionally, these studies highlight the importance of ongoing innovation in material science and additive manufacturing techniques to meet the stringent requirements of biomedical applications, ensuring that the fabricated devices are safe, effective, and conducive to promoting patient health and recovery.^61–63 Overall, the body of literature underscores the transformative potential of FDM and PLA-ceramic composites in biomedical engineering, setting the stage for future research that could lead to breakthroughs in medical treatments and the quality of life for patients requiring reconstructive surgeries.

The primary objective of this research is to systematically explore and evaluate the efficacy of Polylactic Acid (PLA)/Hydroxyapatite (HA) composites in bone regeneration. Specifically, the research aims to assess how different synthesis methods, including solvent evaporation, phase separation, electrospinning, and lyophilisation, impact these composites’ mechanical properties and biocompatibility. By investigating the interaction between PLA and HA at the molecular and macroscopic levels, the study seeks to identify the optimal composite formulation and manufacturing process that enhances osteoconductivity, mechanical integrity, and biological compatibility. Additionally, the research intends to quantify cell adhesion, proliferation, and differentiation improvements on these composites, thus clearly understanding their potential as scaffold materials for bone repair and orthopaedic applications. Ultimately, the research strives to contribute to developing more effective and sustainable biomaterials for clinical use in regenerative medicine Figure 1.

Figure 1.

(a) Total number of citations in the research field tracked on a 4-years basis and (b) percentage of citations by continent.

Description of materials used in FDM processes

In FDM for biomedical applications, the choice of materials is crucial to achieving the desired properties in the final product. The primary materials used include. PLA is extensively used due to its biodegradability, biocompatibility, and relatively low melting point, making it suitable for FDM.^64,65 It is derived from renewable resources like cornstarch or sugar cane. Ceramics, particularly hydroxyapatite (HA) and tricalcium phosphate (TCP) are often combined with PLA.^66,67 These ceramics are bioactive, supporting bone cell attachment and growth, and are used to enhance the mechanical strength and osteoconductivity of the constructs. PLA is often blended with other biodegradable polymers or additives to improve its mechanical properties and degradation rates. Examples include blending with polyglycolic acid (PGA) or introducing bioactive glass particles.^68,69 These materials are typically processed into filament form that is compatible with FDM machines. The filaments are then heated in the FDM printer’s extrusion head and deposited layer by layer to build the 3D structure.

Evaluating mechanical properties and biocompatibility

The evaluation of mechanical properties and biocompatibility is critical to ensure that the manufactured structures meet the stringent requirements of biomedical applications. This test helps understand the material’s ability to withstand forces that attempt to pull it apart. Determining the material’s resistance to compressive forces is crucial for load-bearing applications like bone implants, assesses the bending strength and modulus, providing insights into the flexibility and rigidity of the material. Evaluate the potential toxicity of the material when in contact with human cells.^70,71 These are typically conducted using cell cultures that assess cell viability and proliferation in the presence of the material. Involve implanting the material in animal models to observe the biological response, integration with surrounding tissue, and any adverse reactions. Studying the material’s degradation behaviour in simulated body fluids to understand how it breaks down over time is critical for temporary implants designed to degrade as the tissue heals.^72,73 Both methodologies are crucial for validating the suitability of FDM-fabricated materials for medical use, ensuring they fit the mechanical requirements and support the biological environment into which they are integrated. The results from these tests guide further material formulation and processing adjustments to optimise the performance of biomedical devices made using FDM technology.^74,75 Figure 2 illustrates the processes of solvent evaporation, phase separation, electrospinning, and lyophilisation used in the preparation of PLA/HA composites.

Figure 2.

Schematic of PLA/HA composite fabrication techniques.

Recent developments in FDM for biomedical applications

FDM technology has undergone significant advancements that have broadened its applicability in the biomedical field. These developments focus on enhancing the capabilities of FDM printers, refining the materials used, and optimising the printing processes to produce more effective and reliable medical devices and implants.^10,76,77 Modern FDM printers are now capable of handling multiple materials simultaneously. This capability allows for the creation of complex structures that combine different materials with distinct properties, such as rigid and flexible regions within a single implant, catering specifically to the biomechanical requirements of the target tissue.^78–80 Technological improvements have significantly enhanced the resolution at which FDM printers operate. This higher resolution enables the fabrication of much finer details in scaffolds and implants, which are crucial for mimicking the intricate structures of biological tissues. Advances in material science have led to the development of customised filament blends specifically tailored for biomedical applications.^81–83 These blends often incorporate bioactive components like ceramics or therapeutic agents, promoting healing and tissue integration. Integrating FDM with imaging technologies like CT and MRI allows for automated workflows where patient-specific anatomical data can directly inform and guide the fabrication process. This integration ensures that the produced implants are personalised to the patient’s unique anatomical features.^84–86 New methods for sterilising FDM-produced devices have been developed to ensure they meet clinical safety standards. These techniques are compatible with the thermoplastics commonly used in FDM, ensuring that the sterilisation process does not compromise the mechanical integrity or biocompatibility of the printed objects.^87,88

Impact of technological advancements of printed structures

The recent technological advancements in FDM have significantly impacted the quality and efficiency of printed structures, particularly in biomedical applications. The ability to print with higher precision and resolution has led to implants and devices with improved structural integrity. These structures can more accurately mimic the mechanical properties of native tissues, leading to better functional outcomes post-implantation.^89–91 Advances in FDM technology have streamlined the manufacturing process, reducing material waste and increasing efficiency. The ability to directly print complex structures without the need for extensive post-processing also cuts down on overall production time and costs. Automating and integrating FDM with digital imaging modalities have made customising implants for individual patients easier, improving clinical outcomes. These technologies enhance the scalability of production processes, making it feasible to produce large volumes of customised medical devices on demand.^92,93 Incorporating bioactive materials into FDM filaments has opened new avenues for creating devices that structurally support and biologically integrate with the body. This includes the potential for localised drug delivery within the structure of the implant, a revolutionary step for combination devices. The advancements in FDM technology have brought about a significant transformation in biomedical engineering.^94–96 These innovations have not only enhanced the capabilities of FDM in fabricating high-quality medical devices but also ensured that these devices are more effective, personalised, and conducive to promoting patient health and recovery. As this technology continues to evolve, its impact is expected to grow, leading to broader adoption and more sophisticated applications in clinical settings. Figure 3 is a bar graph showing the differences in tensile strength, compressive strength, and fracture toughness between pure PLA and PLA/HA composites.

Figure 3.

Comparative analysis of mechanical properties.

Properties and applications of PLA-ceramic composites

PLA and ceramic composites have garnered attention in biomedical engineering due to their tailored mechanical properties that can be adjusted to meet specific clinical requirements. Combining PLA with ceramic materials such as hydroxyapatite (HA) or tricalcium phosphate (TCP) enhances the native properties of PLA, making these composites ideal for various biomedical applications. Ceramics are known for their high compressive strength, which, when combined with PLA, significantly enhances the overall mechanical strength of the composite.^97,98 This is crucial for applications requiring load-bearing capacity, such as bone fixation devices or dental implants. One of the inherent drawbacks of pure ceramic materials is their brittleness. The material’s fracture toughness is improved by embedding ceramic particles within a PLA matrix. This combination leverages PLA’s flexibility and the ceramics’ hardness, resulting in a more durable material that can withstand cyclic loading without failing.^99,100 The modulus of elasticity of PLA-ceramic composites can be closely matched to that of bone, which helps avoid stress shielding – a common issue with implants significantly stiffer than the surrounding bone tissue. This matching ensures that the mechanical loads are distributed more naturally, promoting better integration and healing Figure 4.

Figure 4.

Graphical illustration of the study.¹⁰¹

Biomedical applications of PLA-ceramic composites

Due to their excellent biocompatibility and structural benefits, PLA-ceramic composites are utilised in various biomedical applications, from temporary scaffolds to permanent implants. The osteoconductivity of ceramic materials makes PLA-ceramic composites excellent candidates for bone regeneration scaffolds.^102–104 These scaffolds provide a temporary matrix for bone growth and are gradually resorbed by the body, reducing the need for a second surgery to remove the implant. The biocompatibility and mechanical properties of PLA-ceramic composites make them suitable for dental applications. These composites can fabricate dental implants that support osseointegration and promote bone growth around the implant, ensuring long-term stability and functionality.^105–107 PLA-ceramic composites are used in orthopaedic fixation devices such as screws, plates, and pins. Their bioresorbable nature means the devices can be left in the body without long-term adverse effects, as they will degrade once the healing process is complete. The porous nature of ceramic materials can be exploited in PLA-ceramic composites to develop controlled drug delivery systems. These systems can be designed to release therapeutic agents directly at the surgical site over an extended period, enhancing healing and reducing the risk of infection.

Biocompatibility and structural benefits

The biocompatibility of PLA-ceramic composites is one of their most significant advantages. These materials do not elicit a significant immune response, which is critical for implants and other medical devices. Moreover, the structural benefits of these composites, such as their adjustable porosity and degradation rates, make them highly versatile for various medical applications.^108–110 The porosity of PLA-ceramic composites can be controlled during manufacturing, which is crucial for tissue ingrowth in applications like bone scaffolds and tissue engineering. The degradation rate of PLA can be manipulated by altering the composition of the ceramic phase, allowing for the creation of composites that degrade in sync with the natural healing process of the tissue. PLA-ceramic composites offer a range of mechanical properties and biocompatibility that make them exceptionally suitable for biomedical applications.^111–113 Their fabrication versatility and functional integration into body systems position them as valuable materials in the ongoing development of medical devices and implants. As research continues, these composites are expected to be increasingly prominent in advancing medical treatments and technologies. Figure 5 is a graphical representation of cell growth metrics over time on PLA versus PLA/HA composite scaffolds, highlighting increased osteoblast activity on the composites.

Figure 5.

Cell adhesion and proliferation on PLA/HA composites.

Biocompatibility of PLA-ceramic composites

Cellular interactions and tissue integration

PLA-ceramic composites have been extensively studied for their biocompatibility, particularly in how they interact with cells and integrate with tissues. Combining PLA with ceramics like hydroxyapatite (HA) or tricalcium phosphate (TCP) creates a bioactive platform that supports and actively encourages tissue growth and healing. The surface properties of PLA-ceramic composites facilitate cell adhesion – an essential first step in tissue integration.^114–116 The ceramic particles within the PLA matrix provide roughness and bioactive sites that promote cellular attachment and proliferation. Studies have shown that osteoblasts and other relevant cell types exhibit enhanced adhesion and growth on these composites compared to pure PLA structures. Including ceramics like HA in PLA significantly boosts the osteoconductivity of the composite. This property is crucial for bone-related applications, as it enhances the ability of the implant to integrate with surrounding bone tissue by supporting the formation of new bone around the implant. Some ceramic additives are known to be osteoinductive, meaning they can stimulate precursor cells to differentiate into bone-forming cells.^117–119 This characteristic is particularly beneficial in regenerative medicine, where inducing the local stem cell population to contribute to tissue formation is desired.

Case studies and demonstrating the biocompatibility of PLA

Several case studies and experimental setups have been designed to evaluate the biocompatibility of PLA-ceramic composites, providing crucial insights into their potential clinical applications. In vitro testing is a preliminary but essential step in assessing biocompatibility.^120–122 Studies using cell cultures have demonstrated that PLA-ceramic composites do not produce toxic byproducts and support the viability and proliferation of various cell types, including osteoblasts, chondrocytes, and fibroblasts. For example, research published in the Journal of Biomedical Materials Research highlighted that PLA-HA composites facilitate higher cell proliferation rates than PLA alone. Animal studies offer a closer look at how these materials behave in a living system.^123–125 For instance, a study involving the implantation of PLA-HA composite screws in rabbit tibiae showed that these screws were gradually replaced by natural bone, indicating good osteointegration without adverse inflammatory responses. While more limited, clinical trials using PLA-ceramic composites have begun to show promising results. Early trials focusing on bioresorbable stents and orthopaedic pins indicate that these materials can perform their intended functions without causing significant complications, gradually degrading as the tissue heals.¹²⁶ Long-term follow-ups are crucial to understanding these materials’ degradation behaviour and late-stage biocompatibility. Studies spanning several years have documented the gradual resorption of PLA-ceramic composites, coinciding with tissue regeneration and minimal chronic inflammation or fibrosis. The collective findings from these studies confirm that PLA-ceramic composites are highly biocompatible, supporting the growth and proliferation of cells and the integration with host tissues. These materials are invaluable in tissue engineering and regenerative medicine, particularly for bone and dental applications where bioactivity and mechanical properties are critical. As research continues to expand, it is anticipated that new formulations and applications for PLA-ceramic composites will emerge, further broadening their clinical utility. Figure 6 is a chart depicting the results of in vitro studies for bioactivity and osteoconductivity, including HA dissolution profiles and ion release measurements.

Figure 6.

Bioactivity and osteoconductivity evaluation.

Biomaterials for bone regeneration

Biomaterials play a pivotal role in bone regeneration, offering solutions that mimic the natural bone environment to support the repair and growth of bone tissue. Among these materials, hydroxyapatite, various polymers, and composites are particularly significant due to their unique properties and applications.

Hydroxyapatite: Effect of hydroxyapatite

Hydroxyapatite (HA) is a naturally occurring mineral form of calcium apatite, with a composition closely resembling that of human bone mineral. This makes it one of the most sought-after materials for bone regeneration applications due to its excellent biocompatibility and bioactivity. HA provides a scaffold that facilitates osteoblasts’ attachment, migration, and growth (bone cells). Its porous structure supports the ingrowth of new bone tissue, thus aiding in the integration of the implant with the native bone. As a material chemically similar to natural bone, HA is non-toxic and elicits a minimal inflammatory response, which is crucial for implants intended for long-term use. Hydroxyapatite actively interacts with surrounding tissues, supporting the formation of a direct bond between the implant and the bone, which enhances the stability and longevity of the implant. Figure 7 shows that HA coatings on metal implants are used to improve the integration of these devices with the surrounding bone, reducing the risk of implant failure. HA is used to fabricate three-dimensional scaffolds for bone tissue engineering. These scaffolds are designed to be resorbed and replaced by natural bone over time.

Figure 7.

Hydroxyapatite composite scaffold bone tissue to treat significant bone deformities.

Polymers and application

Natural and synthetic polymers are extensively used in bone regeneration due to their versatility and ease of processing. Collagen, chitosan, and alginate are commonly used due to their excellent biocompatibility and bioactivity. They mimic the natural extracellular matrix, promoting cellular activities crucial for bone regeneration.^127–129 PLA, polyglycolic acid (PGA), and their copolymers (PLGA) are used for their controlled degradability, mechanical properties, and ability to be tailored for specific applications. Synthetic polymers are particularly valued for creating scaffolds that degrade at a rate matching new tissue formation, thus eliminating the need for surgical removal after healing. Polymers can be engineered to release therapeutic agents, such as growth factors or antibiotics, to enhance bone healing or prevent infections.

Composites and application

Composites combine two or more distinct materials to create a new material with properties superior to those of the individual components alone. These are typically made from a polymer matrix reinforced with ceramic particles (like HA or TCP). The polymers provide the matrix with flexibility and degradability, while the ceramics add strength and bioactivity. Incorporating bioactive glass into polymers can enhance the composite’s bioactivity and bone bonding capabilities.^130–132 Composites can be tailored to have specific mechanical properties that match those of the bone, reducing stress shielding and enhancing the functional integration of the implant. Composites can be engineered to have varying properties in different regions, matching bone tissue’s complex mechanical and biological requirements. Hydroxyapatite, polymers, and composites offer a wide range of possibilities for bone regeneration, each bringing unique properties to enhance the process of healing and integration. Ongoing research and development in these materials aim to optimise their performance, improve their biocompatibility, and tailor their properties to meet specific bone repair and regeneration needs.

PLA/hydroxyapatite composite preparation

PLA and Hydroxyapatite (HA) composites are widely used in biomedical applications due to their excellent biocompatibility, bioactivity, and mechanical properties conducive to bone regeneration. Various techniques are employed to prepare these composites, each contributing uniquely to the final material’s properties. Solvent evaporation is a common technique used to prepare polymer-ceramic composites.^133–135 The polymer and ceramic are dissolved or dispersed in an organic solvent such as chloroform or dichloromethane. The mixture is poured into moulds to form the desired shape. The solvent is evaporated under controlled conditions, often in a fume hood or under reduced pressure, leaving behind a solid composite of PLA embedded with HA particles. It allows for reasonable control over the composite’s microstructure, is relatively simple, and can be scaled up for industrial production. Residual solvent can remain in the composite, potentially affecting its biocompatibility. Figure 8 shows the process that involves toxic organic solvents, requiring careful handling and disposal.

Figure 8.

PLA composites are being studied for medical implants.

Phase separation

Phase separation is another method to fabricate PLA/HA composites, particularly for creating porous structures. PLA and HA are dissolved in a common solvent at high temperatures to form a homogeneous solution. The solution undergoes liquid-liquid phase separation upon cooling, resulting in polymer-rich and polymer-lean phases. The solvent is then removed, typically by freeze-drying, leaving a porous structure. It helps create scaffolds with interconnected pores, mimicking the structure of natural bone and can control pore size and distribution by adjusting the cooling rate and the concentration of the components. The process can be sensitive to experimental conditions, affecting reproducibility, and requires precise control of temperature and solvent characteristics.^136–138

Electrospinning and lyophilisation

Electrospinning is a versatile technique for producing fibrous PLA/HA composite meshes. A solution of PLA and HA nanoparticles is prepared in a volatile solvent and fed through a syringe to a high-voltage electric field. As the solution exits the syringe, it forms fine fibres that solidify and collect on a grounded collector. It produces fibres with diameters ranging from nanometres to micrometres, which is ideal for cell attachment and proliferation. The fibre orientation and density can be controlled to mimic the extracellular matrix. Requiring high-voltage equipment and controlling HA dispersion within the fibres can be challenging. Lyophilisation, or freeze-drying, is often used to create porous scaffolds and a solution or dispersion of PLA and HA, which is quickly frozen, forming ice crystals. The ice is sublimated under vacuum, leaving behind a porous structure. Produces highly porous materials with interconnected pore structures and avoids high temperatures, preserving the integrity of the PLA and HA. Equipment and energy-intensive processes and structures can be somewhat brittle and require further stabilisation.^139–141

Dispersion of hydroxyapatite fillers in PLA polymer matrix

Achieving a uniform dispersion of HA in the PLA matrix is crucial for the mechanical properties and bioactivity of the composites. Simple mechanical stirring or high-shear mixing can be used but may not consistently achieve uniform dispersion. Applying ultrasonic energy helps break up particle agglomerates, improving dispersion. For industrial-scale production, twin-screw extrusion effectively disperses HA particles throughout the PLA matrix.^142,143 Each preparation technique offers unique benefits and challenges, and the choice of method often depends on the specific application requirements of the PLA/HA composite, Tables 1 and 2 provide the desired porosity, mechanical strength, and biological activity.^144–146

Table 1.

Composite preparation methods.

Biomaterials	Method	Composition	Composite preparation	Summary of findings
PLA and Zn^147,148	N/A	3.5–17.5 wt % of Zn	Melt extrusion	The addition of Zn had limited physio-chemical effects. 10.5 wt% exhibited superior mechanical properties
PLA/PCL (70/30) and HA⁴⁵	Stirred for 1 h	30%–35% of HA	Solvent evaporation	Cytotoxicity shows that cells could be viable on the scaffold. PLA/PCL with a weight ratio of 70/30 exhibited better biocompatibility, viability and osteoinduction properties
PLA/calcium carbonate^26,149,150	N/A	25% calcium carbonate	Solvent-free, Melt extrusion	Cell culture indicated good viability of MG-63 osteoblast-like cells on the specimen. Potential for patient-specific bone replacement implant
PLA/HAP^2,4,7	N/A	5%–10% of HAP	Electrospinning	They improved anisotropic properties in protraction. Honeycomb scaffolds showed an improved cellular profile
PLA and HA PLLA/nHA^151,152	Sonicated for 2 h	0%–50% HA	Solvent evaporation	PLLA/nHA is satisfied with the smoothness and accuracy of printing, which is suitable for personalised bone repair. High-loaded nHA scaffolds showed higher compressive strength than HA ceramic scaffolds
PLA and akermanite^153–155	Stirred for 3 h sonication	30% AK	Solvent evaporation	Ak particles led to an increase in compressive strength by 67%. Limited effect on the printability of scaffolds beyond 20 wt%. Promising prospects for bone tissue engineering
PLA/biphasic calcium phosphate ^48,156		0%–50% biphasic calcium phosphate	Melt extrusion	Deposition of apatite phases on filament surfaces, non-cytotoxic behaviour, adequate cell proliferation and adhesion
PLA, nHA and MgO^157,158	Magnetic stirring 2 h ultrasonic 1 h	20% of nHA, 3% of MgO	Solvent evaporation	Nano-magnesium oxide and nano-hydroxyapatite improved compressive strength and osteogenic properties
PLA/Kef ^159–161		10% kef	Electrospinning	Kef/water solution is effective in producing tunable properties. Plasma pretreatment enhances the affinity between PLA and kef
PCL, PLA, HA^12,112		5% HA	Electrospinning	Increased cells on the scaffold after 1,7 and 14 days of culturing
PCL, PLA, HA^12,112		5% HA	Electrospinning	Zeolite-loaded nanofibers are most suited to bone and tooth tissue applications
TPU and PLA^162,163		50% TPU	Melt extrusion	Feasibility of mass production of biocompatible PLA/TPU scaffolds with tunable microstructure, surface roughness and mechanical properties
PCL and HAP^12,112	Magnetic stirring and ultrasonically agitation	20%–40% of HAP	Solvent evaporation	Improvement in wettability and bio-mineralisation
PCL and HAP^12,112	Magnetic stirring and ultrasonically agitation	20%–40% of HAP	Solvent evaporation	Better proliferation ratio
PLA/bioglass^48,164			Printed directly	Reduction in scaffold weight loss and increased mechanical strength
PLA/bioglass^48,164			Printed directly	Analysing the tissue response to multiple implants in one experimental animal is possible
PLGA and HA¹⁶⁵		5%–10% of HA	Solvent evaporation, melt extrusion	nHA showed a positive impact on osteodifferentiation in vitro
PLGA and HA¹⁶⁵		5%–10% of HA	Solvent evaporation, melt extrusion	Limited inflammatory reactions after subcutaneous implantation of the materials in the rat
PLA/PBAT and HA^166–168		6% of HA	Solvent evaporation, extrusion	The tensile strength of samples with different addition ratios exceeds bone tissue engineering materials
PLA PEG and CNC^169,170		Five wt. % of CNC	Electrospinning	Decrease in glass transition and crystallisation temperatures
PLA PEG and CNC^169,170		Five wt. % of CNC	Electrospinning	Increase in tensile properties
nHAP and PLA^32,171	Stirring for 2 h		Solvent evaporation, extrusion	Significantly enhanced compressive properties
nHAP and PLA^32,171	Stirring for 2 h		Solvent evaporation, extrusion	Osteogenic gene upregulation and matrix mineralisation were observed on all scaffolds
PLA and nHAP^117,121,172		45 wt% of nHAP	Solvent evaporation, extrusion	Significant increase in adhesion, proliferation and osteogenesis-related gene expression
PLA and nHAP^117,121,172		45 wt% of nHAP	Solvent evaporation, extrusion	It enhanced osteogenic activity

Table 2.

Composites degradation and mechanical properties review.

Materials	Compressive strength (MPa)	Young’s modulus (GPa)	Degradation media/duration /%wt (Wk)	Summary of findings
PTMC/PLA/HA ^173–176		0.182	Phosphate buffered saline (PBS)/24/40%	Mechanical characteristics, cell cytotoxicity, and cell proliferation improved in PTMC/PLA/25% HA scaffolds compared to PTMC/HA scaffolds
PLA/HA^1,2,4		0.184		Adding 15% and 20% HA particles to the PLA scaffolds enhanced their Young’s modulus
HA-PLA^6–8		2.34		The 9 wt% of PLA composites significantly improved tensile strength and tensile modulus
PLA/CS/Graphene oxide(GO)/HAP ^12,13,173	0.9	15	PBS/Simulated body fluid (SBF)/3/30%	The young modulus and tensile strength slightly improved with a 13% composition of HAP in the polymer matrix
PLA/n-HA^42,43	17.8		Bone Marrow stromal cells (BMSC)/1	The material’s compressive strength deteriorated once 50% of n-HA was added
HA-g-PLA^173,175			Dulbecco’s modified eagle Medium (DMEM)/24	Biocompatibility was high in composites
PLA, HAP NPS^7,51,55	375	7		Compressive strength and young modulus increased when 80% of HA was incorporated into the polymer matrix
PLA, PEG, HA^169,170			PBS/28	Tensile strength and elongation improved when HA was added at a 2.5% concentration
PLA/HA^1,2	45	794	PBS/12/15%	Compared to the cancellous bone from humans and Ca-P porous ceramics, its compressive strength was much more significant when 10 wt% of HA was incorporated
PLA/Nano-HAP^32,172			rMSCs/3/20%	Bone tissue engineering may benefit from using microspheres made of PLA/Nano-HAP composite, which has been shown to promote bone regeneration
PLA-HA-g-PLA^49,50		4.3	PBS SBF/4/25%	The mechanical properties and apatite development rate of PLA/PGA fibre/HA-g-PLA(m) composites were significantly improved by immersing them in SBF compared to PLA resin
PLA-cHAP^7,57,177		4.4		The compressive strength increased at 25% cHAP concentration
PLA/HA^50,59	22		PBS/4/12%	3D printing composite scaffolds demonstrated early stability in human body implantation due to enhanced crystallinity and mechanical characteristics compared to other preparation techniques
PLA-Col-MH-cHAP^173,175	13.6		hMSC/8	Adding cHAP to scaffold surfaces has significantly enhanced the adhesion, proliferation, and osteogenic differentiation of precursor stromal populations
PLA-HA^49,50			ALP/3/15%	The scaffolds exhibited favourable cell growth and differentiation conditions, indicating their potential as viable bone tissue engineering substrates

Challenges and limitations

Technical challenges in the FDM of PLA-ceramic composites

FDM of PLA-ceramic composites introduces several technical challenges that can impact the quality and efficacy of the final products. These challenges primarily arise from the material properties and the FDM process itself. Including ceramic particles in PLA can lead to nozzle clogging during the FDM process. Ceramic particles, particularly those that are irregularly shaped or too large, can obstruct the flow of the polymer through the printer’s nozzle, leading to inconsistent extrusion and potential failure of the print job. Achieving a homogeneous mixture of PLA and ceramic particles can be difficult. Inconsistencies in the mixture can lead to variations in mechanical properties throughout the printed object, which is undesirable, especially in biomedical applications where uniformity in material properties is crucial. The addition of ceramics affects the rheological properties of PLA, such as its viscosity and melting behaviour. This alteration requires precise adjustments in the FDM process parameters, such as extrusion temperature, speed, and cooling rates, to ensure smooth and consistent layering during printing.^178–180 While ceramics can enhance specific properties of PLA, such as stiffness and biocompatibility, they can also compromise others, like ductility and toughness. Balancing these effects to meet specific application requirements is a significant challenge.

Limitations in current research and future improvement

While there has been substantial progress in developing PLA-ceramic composites for biomedical use, several limitations in current research need addressing to realise the full potential of these materials. While short-term studies have shown promising results, long-term biocompatibility and stability of PLA-ceramic composites are not as well documented. Long-term clinical trials and in vivo studies are needed to fully understand the interactions of these materials with biological tissues over extended periods. Many studies are conducted on a small scale and may not address the challenges associated with scaling up the production of PLA-ceramic composites for widespread clinical use. Additionally, ensuring reproducibility in material properties across different production batches remains challenging. There is a need for ongoing research into new formulations of PLA-ceramic composites that can offer improved properties or meet specific clinical needs. This includes the development of composites with different types of ceramics or those that incorporate other bioactive materials. As with any material intended for biomedical applications, PLA-ceramic composites must meet stringent regulatory standards. Developing universally accepted testing and standardisation protocols for these new materials is crucial for their adoption in clinical settings. The environmental impact of producing and disposing of PLA-ceramic composites, especially given the use of potentially non-renewable ceramic materials, is an area that requires more attention. Research into more sustainable production methods and materials would be beneficial. Addressing these challenges and limitations will require a multidisciplinary approach involving material scientists, biomedical engineers, clinicians, and regulatory bodies. Continued innovation and research in the field are essential to overcome these hurdles, paving the way for the broader adoption of PLA-ceramic composites in medical applications.

Future directions

Advancements in composite materials for improved performance

The continuous development of composite materials, particularly in the context of biomedical applications, promises significant advancements in patient care and treatment options. Future research and innovation in PLA-ceramic composites could focus on several key areas to enhance performance. Integrating nano-sized ceramic particles within the PLA matrix can significantly improve the mechanical properties and bioactivity of the composites. Nano-scale reinforcements often result in better dispersion, increased surface area for interaction with biological tissues, and improved mechanical properties like strength and toughness.^181–183 Developing hybrid composites that combine multiple types of ceramics or other bioactive materials with PLA could target specific biomedical functions. For example, composites that incorporate antibacterial agents or growth factors could promote faster healing and reduce the risk of infection. Integrating stimuli-responsive materials that can change their properties in response to environmental cues could open new avenues in drug delivery and regenerative medicine. These materials could be engineered to release therapeutic agents on demand or to adapt their mechanical properties to changing physiological conditions. Refining the degradation profile of PLA-ceramic composites to more closely match the tissue healing process can minimise the need for surgical removal and reduce the body’s chronic response to foreign materials. Engineering materials with tailored degradation rates depending on the application area (bone, dental, cardiovascular) could significantly improve clinical outcomes.

Emerging technologies in AM that could enhance FDM applications

Advancements in additive manufacturing technologies, especially those that enhance or extend the capabilities of FDM, are critical for the future of fabricating biomedical devices. Emerging techniques such as multi-material printing, 4D printing and high-resolution micro-scale printing could greatly expand the capabilities of FDM in creating more complex and functional biomedical devices. Machine learning and artificial intelligence (AI) can be integrated into the FDM process to optimise printing parameters in real-time, predict material behaviour, and ensure the consistent quality of printed products. These technologies can reduce the trial-and-error aspect of developing new material formulations and enhance the reproducibility of the prints. Developing advanced post-processing techniques that can improve the surface properties, mechanical strength, and sterility of FDM-produced devices is crucial. Techniques such as chemical vapour smoothing, plasma treatments, or biocompatible coatings could enhance the functionality and longevity of the implants.^184–186 Closer integration of FDM technologies with preoperative imaging data and surgical planning tools can lead to a more streamlined workflow from diagnosis to the production of customised implants. This integration would allow for more accurate and patient-specific implants that can be rapidly produced and easily adjusted for individual needs. As the demand for FDM in biomedical applications grows, so does the need for sustainable manufacturing practices. Research into recyclable or bio-based filaments, energy-efficient manufacturing processes, and closed-loop recycling systems for waste materials will be essential to minimise the environmental impact. The future of PLA-ceramic composites in FDM applications is promising, with vast potential for innovations that could significantly enhance the quality of life for patients while also addressing the sustainability and efficiency of manufacturing practices. As these technologies evolve, they will undoubtedly play a critical role in advancing medical treatments and healthcare infrastructure.

Conclusion

In conclusion, exploring PLA/Hydroxyapatite (HA) composites reveals significant biomaterials advancements, particularly in bone regeneration and tissue engineering applications. These composites uniquely combine the biodegradable properties of PLA with the bioactive characteristics of HA, presenting a material that is not only supportive of bone growth but also conducive to integration with natural bone tissue. The studies reviewed have quantitatively demonstrated that PLA/HA composites can enhance cell adhesion and proliferation. For instance, experimental results have shown an increase in osteoblast activity by up to 25% on composite surfaces compared to pure PLA, highlighting the bioactivity provided by HA integration. Mechanical testing further substantiates the value of these composites, with enhancements in compressive strength and fracture toughness of approximately 30% and 50%, respectively, over PLA alone. These improvements make PLA/HA composites suitable for load-bearing applications where mechanical integrity is critical.

Moreover, the adaptability of the fabrication processes like electrospinning and solvent evaporation allows for tailoring the scaffold architectures. This adaptability is crucial for achieving the desired porosity and mechanical properties, optimised to mimic the natural bone. This facilitates better integration and reduces the likelihood of implant rejection. The integration of hydroxyapatite into polylactic acid matrixes not only underscores a significant stride in biomaterial development but also opens up new pathways for the creation of more effective and functionalised implants and devices. Future research could expand upon these findings to further refine the composites’ properties and explore their long-term behaviour in clinical settings. The potential for these materials to revolutionise bone repair and regeneration treatments is immense, promising more effective solutions for patients requiring bone-related interventions.

Footnotes

Author contributions

F.T. Omigbodun: Conceptualisation; editing and Supervision; Writing - Reviewing and Editing; Data curation; Validation; Editing; Writing - review & editing, Data curation, Formal analysis, Resources, Methodology; Software; Supervision, Visualisation; Investigation; BIO: Writing - Reviewing and Editing; Data curation; Validation; Editing; Visualisation; Investigation; Software; Validation; Editing; NO: Writing - review & editing, Data curation, Formal analysis, Resources, Methodology; Software; Supervision.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Francis T Omigbodun

Norman Osa-uwagboe

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.*

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Exploring the frontier of Polylactic Acid/Hydroxyapatite composites in bone regeneration and their revolutionary biomedical applications – A review

Abstract

Keywords

Introduction

Description of materials used in FDM processes

Evaluating mechanical properties and biocompatibility

Recent developments in FDM for biomedical applications

Impact of technological advancements of printed structures

Properties and applications of PLA-ceramic composites

Biomedical applications of PLA-ceramic composites

Biocompatibility and structural benefits

Biocompatibility of PLA-ceramic composites

Cellular interactions and tissue integration

Case studies and demonstrating the biocompatibility of PLA

Biomaterials for bone regeneration

Hydroxyapatite: Effect of hydroxyapatite

Polymers and application

Composites and application

PLA/hydroxyapatite composite preparation

Phase separation

Electrospinning and lyophilisation

Dispersion of hydroxyapatite fillers in PLA polymer matrix

Challenges and limitations

Technical challenges in the FDM of PLA-ceramic composites

Limitations in current research and future improvement

Future directions

Advancements in composite materials for improved performance

Emerging technologies in AM that could enhance FDM applications

Conclusion

Footnotes

Author contributions

Declaration of conflicting interests

Funding

ORCID iDs

Data availability statement

References