Research progress of 3D-printed PLGA scaffolds for the treatment of bone defects

Abstract

With rapid advances in regenerative medicine and tissue engineering, poly(lactic-co-glycolic acid) (PLGA) scaffolds have garnered extensive attention owing to their excellent biocompatibility and biodegradability. Current studies primarily focus on material selection and scaffold preparation, printing techniques, and their efficacy in animal experiments and clinical applications. While several studies have demonstrated the potential of PLGA scaffolds in promoting bone regeneration, challenges remain, including insufficient mechanical properties, a mismatch between degradation rates and bone repair rates, limited long-term clinical data, and the need for improved hydrophilicity and cytocompatibility. Additionally, issues such as limited printing precision and resolution persist. Therefore, innovating material synthesis and processing technologies, as well as developing high-precision, fast-printing techniques, holds significant implications. This paper aims to analyze and summarize the application of 3D printing technology, the properties of PLGA, research on PLGA composites incorporating drugs, inorganic materials, and organic materials, as well as the design and fabrication of 3D-printed PLGA scaffolds. The aim is to review recent research progress in the use of 3D-printed PLGA scaffolds for bone defect repair, assess their potential for bone regeneration, and explore future development directions.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12938-025-01505-2.

Introduction

Bone defects are pathological conditions wherein the structural integrity of the bone is compromised, resulting in the loss of bone tissue. Common causes include trauma, malignancies, infections, and osteoporosis. Millions of people worldwide suffer from bone defects annually, and associated disabilities pose a significant burden on healthcare systems [1]. At present, limited clinical materials are available for the treatment of bone defects, which are generally categorized into traditional and modern repair materials (Table 1). The former includes autologous bone grafts, allogeneic bone grafts, decalcified bone matrix, bio-ceramics, and metal materials, whereas the latter primarily consists of polymer-based materials, tissue-engineered bone, derived composites, as well as multifunctional bone tissue-engineered scaffolds created through novel technological designs and advanced manufacturing processes. While traditional materials such as autologous bone grafts offer excellent biocompatibility, they are limited by issues such as donor site morbidity and insufficient bone supply, which restrict their clinical use [2]. Allogeneic bone grafts, decalcified bone matrices, bio-ceramics, and metal materials, although common, are associated with drawbacks such as immune rejection, disease transmission risk, and weak bioactivity, leading to suboptimal therapeutic outcomes [3]. As a result, the development of new, modern materials for bone defect repair has become a focal point of ongoing research.

Table 1.

Comparison of types, advantages, and disadvantages of traditional and modern bone defect repair materials

Type	Materials	Advantages	Drawbacks
Traditional bone defect repair materials	Autologous bone graft	Favourable biocompatibility, no immune rejection, strong osteogenic ability	Restricted availability, increased risk of patient trauma, and complications at harvest site
	Allograft	Broad availability, can meet certain needs for bone defect repair, relatively easy to operate	Immune rejection, risk of disease transmission, weak osteogenic capacity
	Decalcified bone matrix	Retains osteoinductive components to guide bone growth and can be processed into various shapes	Poor mechanical properties, insufficient strength, faster absorption post-implantation, risk of local inflammatory reactions
	Metallic materials	Satisfactory mechanical properties, high strength, provides reliable support at the bone defect site	Low bioactivity, poor osseointegration, risk of stress masking effect, risk of local inflammation
	Bioceramics	Excellent biocompatibility and osteoconductivity, easy to shape	Poor mechanical properties, high brittleness, risk of fracture
Modern bone defect repair materials	Natural Polymer Materials	High biocompatibility, cell recognition sites, degradable with non-toxic products (e.g., collagen provides a favorable environment for cell adhesion)	Poor mechanical properties, limited stability, risk of immunogenicity, potentially restricted sources
	Synthetic Polymer materials	Adjustable physical and chemical properties, such as polylactic acid can be made into different shapes, good mechanical properties, relatively stable price	Low biological activity, degradation may produce acids that cause inflammation, lack of cellular recognition signals
	Tissue-engineered bone	Good bioactivity, can mimic human bone tissue, strong ability to promote bone regeneration	High technical requirements, complex construction process, strict storage and transport conditions, high cost
	Composite materials	Combine the strengths of multiple materials to optimize performance	Complex preparation processes and high costs

References: [2–4]

Novel synthetic polymer repair materials, such as poly(lactic-co-glycolic acid) (PLGA) scaffolds, have garnered widespread attention owing to their excellent biocompatibility, degradability, and suitability for bone tissue engineering [4]. They not only support osteoblast adhesion and proliferation but also enhance their biological functions by regulating internal porosity and incorporating bioactive substances. This combination improves the local microenvironment of the implant and promotes bone regeneration [5]. Notably, the “scaffold + seed cells + cytokines” therapeutic approach has gained increasing recognition among medical practitioners [6]. Traditional methods for fabricating PLGA scaffolds, such as gas foaming, solvent casting, and melt casting, have faced limitations in clinical application due to challenges in preparing personalized scaffolds for specific bone defects [7]. In contrast, the emergence of 3D printing technology, characterized by its ability to personalize designs and precisely control scaffold shapes, has sparked significant research interest. The integration of 3D printing with PLGA scaffolds enables the creation of patient-specific implants, offering promising new avenues for bone defect treatment [8]. This paper aims to review research advances in 3D-printed PLGA scaffolds for bone defect treatment.

Overview of 3D printing technology

The basic principle of 3D printing technology

In 1984, Chuck Hull from the United States invented stereolithography (SLA) technology, which uses laser irradiation to cure photosensitive resin layer by layer, laying the foundation for modern 3D printing. Since then, 3D printing technology has advanced rapidly, with applications spanning industries such as medicine, architecture, automotive, aerospace, education, and art [9]. 3D printing, also known as additive manufacturing, is a technology that builds three-dimensional objects based on digital model files. It uses materials like powdered metal, plastic, or other bondable substances, and creates objects through a layer-by-layer process. The principle involves slicing a 3D model into thin layers and then depositing or curing materials according to the sliced data, ultimately forming a physical 3D object.

Commonly used 3D printing methods

Among the various 3D printing technologies, Fused Deposition Modeling (FDM), Selective Laser Sintering (SLS), and Stereolithography (SLA) are the most commonly employed methods. During the printing process, materials are solidified layer by layer using heat, lasers, or light, ultimately forming the desired three-dimensional object. The key to successful printing lies in selecting the appropriate materials and optimizing printing parameters to ensure the accuracy and performance of the final product [10]. For instance, FDM is ideal for creating larger objects by heating thermoplastic materials until they become molten, extruding them layer by layer, and then allowing them to cool and solidify [11]. SLS, on the other hand, uses a laser to selectively sinter powdered materials layer by layer, making it suitable for manufacturing complex structures. SLA technology achieves high-precision printing by curing liquid resin with ultraviolet light, making it particularly suited for medical models and custom medical device manufacturing [12]. Notably, low-temperature deposition manufacturing (LDM), a modified extrusion-based technology, has been shown to fabricate PLGA scaffolds with ECM-mimetic microchannels (5–30 μm) by solidifying viscous PLGA inks at cryogenic temperatures, which better facilitate cell infiltration compared to traditional FDM [1]. Each of these technologies has its own set of advantages and limitations, and the choice of method depends on the specific application requirements and material characteristics [13, 14].

Applications of 3D printing in the medical field

With advancements in technology, 3D printing has evolved from its initial use in prototyping to the production of functional medical devices, personalized implants, and tissue engineering scaffolds, among many other applications. Its core strength lies in its high level of flexibility and customization, allowing for the development of tailored solutions that meet the specific needs of individual patients. This rapid technological development has not only transformed traditional manufacturing processes but has also revolutionized the healthcare industry. Notably, it has had a profound impact on areas such as pre-surgical planning, medical training, clinical applications, and patient education [15] (Table 2).

Table 2.

Comparison of 3D printing technology in various medical fields

Medical science	Applications of 3D printing technology	The way forward
Bone tissue engineering	Customized and personalized bone scaffolds with precise control of porosity, pore size, and connectivity to promote osteoblast attachment and growth, facilitating the construction of complex 3D bone tissue models	Limited choice of materials, printing process may affect scaffold bioactivity, long-term in vivo stability warrants further investigation
Orthopaedic Trauma	Rapidly generates custom fixation devices, such as splints and external fixation frames, tailored to the specific shape of the injury site, enhancing fixation outcomes and minimizing complications	Possible lack of mechanical properties of instruments, higher printing costs, low efficiency in mass production
Joint orthopaedics	Manufacture of implants personalized to the patient's joint morphology, optimizing joint surface design, improving stability and wear resistance, and enhancing joint function	Uncertainty about the long-term fusion of implants with human tissue, technically complex and expensive
Spine surgery	Customized internal fixation devices and interbody fusion devices that conform to the physiological curvature of the spine, improving the fit of the implant to the spine, limiting surgical trauma and promoting spinal fusion	Limited printing precision, suboptimal implant biocompatibility, and risk of rejection
Bone oncology	Constructing tumor models to assist in preoperative planning, determining the extent of surgical resection, and fabricating individualized prostheses for the reconstruction of bone defects following tumor removal	Model accuracy is influenced by data quality, long prosthesis manufacturing cycle, and lack of experience in clinical applications
Drug delivery system	Constructing drug carriers with specific release rates to achieve slow drug release at specific sites, improving the efficacy of drugs and reducing side effects	Limited drug loading, carrier material may affect drug activity, immature printing technology

References: [15, 17, 25]

In bone tissue engineering, 3D printing allows for the creation of biocompatible scaffolds with intricate structures that support cell growth and tissue regeneration. For example, Dong et al. developed a hybrid scaffold by incorporating low-polymer-content GelMA hydrogel into 3D-printed PLGA scaffolds for sustained BMP-2 release. In rabbit femoral large-segment defects (15 mm), this scaffold achieved an 85% bone healing rate, significantly higher than the 52% rate of PLGA/BMP-2 scaffolds without hydrogel, as the hydrogel protected BMP-2 from PLGA’s acidic degradation products [16]. In traumatology and orthopedics, 3D printing is employed to customize implants, surgical guides, and patient-specific anatomical models, assisting in mitigating the risk of intraoperative bleeding and significantly enhancing surgical outcomes and patient recovery [17, 18]. For instance, 3D-printed bone scaffolds can be tailored to match a patient's unique bone defect, ensuring a superior fit and biocompatibility, which in turn promotes bone tissue regeneration [19].

In joint surgery, 3D-printed personalized surgical guides based on CT scans can enhance alignment accuracy during knee arthroplasty, limit intraoperative bleeding, and improve postoperative knee function [20]. Additionally, these customized instruments can accurately simulate the coronal plane of force lines in the lower limb, further enhancing the precision and safety of the procedure [21]. Furthermore, 3D printing-assisted hip replacement techniques can improve surgical efficiency, shorten operation duration, and minimize radiation exposure during the treatment of complex hip conditions [22, 23].

In spine surgery, 3D printing technology is increasingly utilized in preoperative planning, particularly in pediatric spine surgery, where 3D-printed pedicle screw guides have significantly enhanced the accuracy of screw placement [24]. In the treatment of bone tumors, 3D printing has substantially improved surgical precision by personalizing the design and manufacturing of surgical guides and implants. For instance, in skull tumor surgery, 3D-printed guides have facilitated precise tumor resection and bone reconstruction, with postoperative results showing significant improvements in head contour and no intra- or post-operative complications [25]. Similarly, 3D-printed guides and implants have been employed in pelvic tumor surgeries for accurate resection and reconstruction, with patients demonstrating satisfactory recovery of postoperative function [26]. Furthermore, 3D printing technology has facilitated the integration of multiple functions into a single biomaterial system, offering comprehensive solutions for both bone tumor treatment and bone regeneration. For example, 3D-printed scaffolds combined with 2D MXene have enabled bone tumor ablation through photothermal therapy while promoting the growth of new bone tissue [27, 28], thus providing a novel approach and platform for the treatment of bone tumors.

In the development of drug delivery systems, 3D printing enables the creation of personalized drug release devices tailored to the specific needs of patients. These devices can regulate the drug release rate, thereby optimizing therapeutic outcomes [29]. Additionally, 3D printing has demonstrated a broad range of applications in tissue engineering and aided in the successful fabrication of biologically active scaffolds that promote cell growth and tissue regeneration [13].

Properties and degradation of PLGA

In the field of bone defect repair, biomaterials must meet core requirements including good biocompatibility, appropriate mechanical strength, controllable biodegradability, and osteoconductivity/ osteoinductivity [1, 6]. Currently, widely used biomaterials include metals (e.g., titanium alloys), ceramics (e.g., hydroxyapatite), and polymers (e.g., polylactic acid, polycaprolactone). Among these, poly(lactic-co-glycolic acid) (PLGA) stands out as a key focus in bone tissue engineering scaffold research due to its adjustable degradation rate and excellent processability for 3D printing.

Synthesis of PLGA

The synthesis of PLGA is primarily achieved through ring-opening polymerization (ROP), a method that allows precise control over the molecular weight and structural properties of the polymer. In recent years, researchers have explored various synthetic strategies to enhance the properties and broaden the applications of PLGA. For instance, by synthesizing fully isostructural, alternating PLGAs from enantiomerically pure starting materials, researchers have successfully obtained PLGAs with outstanding structural properties [30]. The use of different catalysts and reaction conditions enables stereoselective control over the polymer, resulting in distinct polymer sequences and configurations, thus expanding the potential for their application in drug delivery. During PLGA synthesis, researchers have also focused on its incorporation with other bioactive substances. For example, curcumin, a natural product, was encapsulated into PLGA nanoparticles to enhance its antiviral activity, demonstrating the effectiveness and potential of PLGA as a drug carrier [31]. Furthermore, PLGA can be synthesized to improve its biodegradability and biocompatibility through copolymerization with amino acids such as L-ornithine and L-glutamine. These modified PLGAs exhibit faster degradation rates and excellent biocompatibility, making them suitable for use in biomaterials development [32]. Synthesis methods for PLGA are also continually evolving. For example, electrospray technology has enabled efficient conjugation of drugs with PLGA to prepare nanoparticles with high drug-loading capacity and sustained release characteristics, offering new possibilities for cancer therapy [33]. These studies highlight that PLGA synthesis is not limited to traditional polymerization techniques; the application of innovative synthetic strategies and technologies is advancing PLGA's development in drug delivery and biomedicine. Ongoing research in PLGA synthesis is continually progressing, and its versatility and efficacy in clinical applications are laying a solid foundation for future use. Notably, the preparation method has a significant impact on PLGA’s mechanical strength. For example, PLGA porous structures prepared via thermally induced phase separation (TIPS) exhibit a tensile strength of 40.7 MPa, which is significantly higher than that of structures prepared via solvent casting [34]. This characteristic provides important insights for the structural design and performance optimization of PLGA scaffolds.

Degradation of PLGA

PLGA (Poly(lactic-co-glycolic acid)) is extensively used in biomedical fields owing to its excellent biocompatibility and degradability. Its degradation primarily occurs through hydrolysis. Earlier studies have reported that its degradation rate is closely related to factors such as the lactic acid to glycolic acid ratio, molecular weight, and other variables. For instance, adjusting the lactic acid-to-glycolic acid ratio in PLGA significantly influences its degradation rate. PLGA with a 50/50 ratio degrades markedly faster than PLGA with an 80/20 ratio [35]. The in vivo biodegradation cycle of PLGA in bone defect environments varies significantly depending on the PLA:PGA monomer ratio: when PLA:PGA is 50:50, the material can be completely degraded within 3–4 months [35]; when the ratio is adjusted to 75:25, the degradation cycle extends to 6–8 months [36]; and when PLA:PGA reaches 85:15, the degradation cycle further increases to 10–12 months [36]. From a clinical bone regeneration perspective, cancellous bone regeneration typically requires 3–6 months, while cortical bone regeneration takes 6–12 months. Therefore, the optimal degradation rate for PLGA scaffolds should satisfy the requirement of "maintaining mechanical integrity for 3–6 months to match cancellous bone regeneration and achieving complete degradation within 12 months to avoid long-term inflammatory responses” [1, 6, 35, 37].

Recent studies have expanded the understanding of PLGA degradation by integrating smart responsive components. For example, Han et al. developed a Zn-based MOF (ZIF-8-Zn)/PLGA composite scaffold, where ZIF-8’s porous structure enables sustained Zn² + release (75% cumulative release over 12 weeks). Zn² + not only activates the Wnt/β-catenin pathway to promote BMSCs osteogenic differentiation (Runx2 expression increased by 2.3-fold) but also inhibits NF-κB signaling to reduce M1 macrophage polarization (from 45 to 18%), thus alleviating inflammation caused by PLGA’s acidic degradation [38]. Similarly, Li et al. reported a ZIF-8@CuO/PLGA scaffold with pH/NIR dual responsiveness: in acidic infected microenvironments (pH 5.5–6.0), ZIF-8 degrades rapidly to release Cu² + , which generates ROS via Fenton-like reactions to kill bacteria; under 808 nm NIR irradiation (1 W/cm²), CuO produces photothermal effects (local temperature 42–45 °C) and additional ROS, while post-infection Cu² + release (80% in 14 days) scavenges excess ROS (80% clearance) to create a pro-regenerative microenvironment [39].

The in vivo degradation products of PLGA are lactic acid and glycolic acid, which can be metabolized by the body and excreted, making PLGA suitable for applications in drug delivery systems and tissue engineering scaffolds. These scaffolds effectively support cell growth and tissue regeneration [29, 40, 41]. However, hydrolysis causes the polymer chains to break, leading to the formation of small, acidic degradation products. In turn, these by-products trigger local inflammatory responses, including the polarization of macrophages to the pro-inflammatory M1 phenotype, further exacerbating inflammation and potentially affecting the physiological state of surrounding tissues [42, 43]. To mitigate the inflammatory response induced by PLGA degradation, the incorporation of alkaline materials, such as magnesium hydroxide, into PLGA has been explored. These materials help neutralize acidic degradation products, thereby improving the biocompatibility of PLGA-based materials [37]. The regulatory mechanism of PLGA degradation on macrophage polarization balance through microenvironmental pH and its influence on bone regeneration is visually illustrated in Fig. 1. The degradation behavior of PLGA varies across different environments. For instance, in simulated marine environments, degradation primarily occurs through the hydrolysis of ester bonds, with the degradation rate increasing with increasing glycolic acid levels [44]. Furthermore, the degradation of PLGA is influenced by factors such as its molecular weight, polymerization method, and geometry. Significant differences in water uptake and degradation rates were observed in PLGA produced by different manufacturers [36]. Elucidating the degradation properties of PLGA is crucial for biomedical applications. Gaining insights into its degradation mechanisms not only aids in optimizing material design but also provides a theoretical foundation for developing a new generation of immune-modulating PLGA-based biomaterials with immunomodulatory functions [45].

Fig. 1.

PLGA degradation regulates the polarization balance of macrophages through the pH of the microenvironment, influencing the bone regeneration process

Additionally, during drug release, PLGA’s mechanical properties undergo dynamic changes: its Young’s modulus typically increases from 0.8 GPa to 1.2 GPa, ultimate stress rises from 35 to 45 MPa, and elongation at break decreases from 15 to 8% [46]. This change pattern is closely related to PLGA’s degradation process and provides key guidance for the service life design of drug-releasing PLGA scaffolds.

Research on the safety and biocompatibility of PLGA

PLGA are widely used in biomedical applications, particularly in drug delivery and tissue engineering, ascribed to their excellent biocompatibility and biodegradability. Their safety and biocompatibility hold significant implications in their clinical use. According to prior investigations, lactic acid and acetic acid generated during the in vivo degradation of PLGA are non-toxic and can be metabolized through the Krebs cycle, highlighting its favorable biocompatibility [47]. Furthermore, the biocompatibility of PLGA has been validated through numerous in vivo and ex vivo studies. For instance, PLGA microspheres demonstrated good cytocompatibility during drug release, with no significant cytotoxicity, and were capable of effectively supporting cell proliferation and differentiation [48].

Several studies investigating PLGA applications have focused on its composites with other materials to enhance its biocompatibility and functionality. For instance, PLGA composites with β-tricalcium phosphate have demonstrated outstanding bone regeneration ability and biocompatibility in alveolar ridge preservation [49]. Additionally, PLGA composites with magnesium hydroxide in microsphere form have displayed excellent acid-neutralizing properties, reducing the inflammatory response elicited by acidic by-products generated during PLGA degradation, thus improving its biocompatibility. The safety of PLGA is also well-established in drug delivery systems. For example, PLGA nanoparticles can effectively encapsulate various drugs, providing sustained release in vivo and reducing the toxicity and drug-related side effects [50]. In a study on lung cancer, PLGA nanoparticles were used as a targeted delivery system, and the results demonstrated significantly increased accumulation and retention in tumor tissues, with minimal damage to healthy tissues [51].

Mechanical properties of PLGA

As a biomaterial widely used in bone tissue engineering, the mechanical properties of PLGA significantly impact its effectiveness in bone defect repair. These properties can be tailored by adjusting their molecular weight, formulation, and processing conditions to better match the characteristics of natural bone tissue. Pure PLGA typically has an elastic modulus of 1.0–1.5 GPa and a tensile strength of 30–50 MPa; the porosity of 3D-printed PLGA scaffolds is generally controlled at 70–90%, with 80–85% porosity considered optimal for promoting cell growth[52, 53]. When PLGA is combined with hydroxyapatite (HA), its elastic modulus can be increased to 2.0–2.5 GPa, significantly improving mechanical performance[52]. Furthermore, blending PLGA with 1 wt% poly(trimethylene carbonate) (PTMC) can enhance its tensile strength to 57.46 MPa and tensile modulus to 1.06 GPa while maintaining good degradability [54]; this modification strategy provides an effective approach to optimizing PLGA’s mechanical properties. Studies have described that the tensile strength and elastic modulus of PLGA can be considerably enhanced by incorporating various fillers (e.g., hydroxyapatite, polyvinyl alcohol, etc.), thereby optimizing its load-bearing capacity and stability [52]. Additionally, the mechanical properties of PLGA are influenced by its crystallinity and porosity. An optimized pore structure not only facilitates cell attachment and proliferation but also enhances the biocompatibility and biodegradation rate of the material [55].

From the perspective of cell growth and bone regeneration, pore size optimization is particularly critical: a pore size of 100–300 μm promotes osteoblast adhesion and proliferation by increasing cell contact area, while a pore size of 200–400 μm is more conducive to vascular ingrowth, ensuring nutrient supply during bone regeneration [53]. A comparison of mechanical strengths between natural bone tissue and PLGA scaffolds shows that cancellous bone has a compressive strength of 2–12 MPa (vs. 5–18 MPa for PLGA scaffolds[56, 57]), and cortical bone has a compressive strength of 80–150 MPa (vs. 20–40 MPa for PLGA scaffolds [52, 58]). This indicates that PLGA scaffolds can already match the mechanical requirements for cancellous bone defect repair but still need further strength improvement for cortical bone repair.

For 3D printing, PLGA’s glass transition temperature (Tg) and melting temperature (Tm) are key process parameters, and their values vary with the PLA:PGA ratio: when PLA:PGA is 50:50, Tg is 40–45 °C and Tm is 150–155 °C; at a ratio of 75:25, Tg rises to 45–50 °C and Tm to 160–165 °C; and at 85:15, Tg further increases to 50–55 °C and Tm to 170–175 °C [54, 59]. These parameters provide core guidance for temperature setting during 3D printing and directly affect the forming quality and performance of scaffolds. Therefore, refining the formulation and structural design of PLGA can significantly improve its performance in bone tissue repair.

Application of PLGA in bone defect repair materials

PLGA has emerged as a leading choice for bone defect repair materials owing to its excellent biocompatibility and adjustable biodegradability. PLGA scaffolds not only provide support for osteoblast adhesion and proliferation but also progressively degrade during the bone defect healing process, promoting new bone formation [60]. In recent years, their performance in clinical applications has garnered increasing attention, particularly in addressing complex bone defects. PLGA scaffolds have exhibited both strong biological and mechanical properties, making them a focal point in bone tissue engineering research. This article summarizes the research progress on PLGA composites (Table 3).

Table 3.

Research progress on PLGA composites

Author	Types of composites	Specific materials for composite	Effects of compounding
Boncu et al. [61]; Lu et al. [56]	PLGA and drug compounding	Linezolid, Growth factor	Inhibits postoperative infections and promotes bone healing, significantly improving the efficiency of bone regeneration
Buschmann et al. [60]	PLGA complexed with biomolecules	Collagen	Improves material biocompatibility and bioactivity, promotes cell attachment and proliferation, mimics natural bone microenvironment
Buschmann et al. [60]	PLGA composite with inorganic materials	Hydroxy-apatite (phosphatic lime deposited in bone)	Enhances PLGA strength and osteoconductivity, promotes osteoblast proliferation and differentiation, and supports the bone healing process
Lu et al. [56]		Tricalcium phosphate (TCP)	Enhances PLGA bioactivity and osteoconductivity, promotes bone regeneration and bone healing in animal models
Liu et al. [62]	PLGA composite with other inorganic materials	Bioactive glass, etc	Improves biocompatibility and mechanical properties, effectively promotes the healing of bone defects
Niu et al. [57]	PLGA composite with organic materials	Gelatin, chitosan, etc	Improves the biological properties of the material and promotes bone tissue regeneration

Research on PLGA-drug composites

Research on PLGA as a drug carrier is steadily gaining traction, particularly in the field of bone tissue engineering. Incorporating growth factors or drugs into PLGA scaffolds, a controlled can achieve a slow release of these substances, thereby promoting bone healing. For instance, loading the antibiotic linezolid into PLGA scaffolds effectively inhibited postoperative infections and supported bone regeneration [61, 63]. More importantly, the combination of PLGA with growth factors such as bone morphogenetic proteins (BMPs) can significantly enhance the efficiency of bone regeneration, making it an effective strategy for the treatment of bone defects [56].

Research on PLGA-inorganic material composites

Research on PLGA composites with inorganic materials primarily focuses on enhancing the mechanical properties and bioactivity of the materials. PLGA composites incorporating hydroxyapatite have become key materials for bone defect repair owing to their superior biocompatibility and osteoinductive capacity. Studies have evinced that PLGA/hydroxyapatite composites can effectively promote the proliferation and differentiation of osteoblasts, thereby driving bone healing [60]. Furthermore, studies examining PLGA composites with tricalcium phosphate indicated that the introduction of tricalcium phosphate improved the bioactivity and osteoinductivity of PLGA, which in turn promoted bone regeneration. Lu et al. fabricated PLGA/tricalcium phosphate (TCP) composite scaffolds via FDM technology; these scaffolds had a pore size of 300 μm, porosity of 80%, and compressive strength of 15 MPa. In vivo experiments in a rabbit tibial defect model showed that the bone volume fraction reached 50% at 8 weeks, fully demonstrating the excellent performance of these composite scaffolds in bone regeneration [56]. Relevant studies have demonstrated that PLGA/tricalcium phosphate composites exhibited promising bone healing outcomes in animal models, positioning them as effective materials for bone defect repair [57]. In addition to hydroxyapatite and tricalcium phosphate, PLGA can also be combined with other inorganic materials, such as bioactive glass, to further enhance its biocompatibility and mechanical properties. These composites show great promise for application in bone tissue engineering and can significantly support the healing of bone defects [60].

Research on PLGA-natural polymer composites

Research on PLGA composites with organic materials primarily focuses on enhancing the biocompatibility and bioactivity of these materials. By combining PLGA with natural polymers such as gelatin, chitosan, and hyaluronic acid, the biological properties of the materials can be improved, thereby promoting bone tissue regeneration [57]. For example, PLGA-collagen composite scaffolds can more effectively mimic the natural bone microenvironment, thereby promoting osteoblast differentiation and facilitating bone tissue formation [64]. Additionally, hyaluronic acid-modified PLGA scaffolds have been shown to enhance chondrocyte attachment and collagen synthesis in cartilage tissue engineering, thereby facilitating cartilage formation [65]. Fibrous membrane scaffolds incorporating hyaluronic acid and PLGA have been utilized for the delivery of adipose-derived stem cells, significantly accelerating the wound healing process [66]. The advantages of these natural polymer composite scaffolds include high biocompatibility, presence of cell recognition sites, and ability to mimic the natural extracellular matrix. However, they also have limitations such as poor mechanical strength, limited stability, and potential immunogenicity (e.g., immune reactions caused by animal-derived collagen). In practical applications, targeted optimization via cross-linking modification or composite reinforcement is required.

Research on PLGA-synthetic polymer composites

To improve the classification system of PLGA composites, a new section titled "Research on PLGA-Synthetic Polymer Composites" has been added, focusing on strategies to balance PLGA’s mechanical properties and degradation behavior through modification with synthetic polymers.

Research on PLGA-synthetic polymer composites aims to balance mechanical properties and degradation behavior. Common synthetic polymers combined with PLGA include poly(trimethylene carbonate) (PTMC) and polyethylene glycol (PEG). For example, blending PLGA with 1 wt% PTMC increases its tensile strength to 57.46 MPa and modulus to 1.06 GPa while maintaining good degradability [54]. PLGA/PEG hydrogels have demonstrated excellent self-repairing abilities and have been shown to promote the proliferation of bone marrow mesenchymal stem cells, thereby aiding in the formation of new cartilage in cartilage tissue engineering [67].

The core advantages of synthetic polymer composite scaffolds include adjustable mechanical properties, stable degradation rates, and low immunogenicity. However, they have weak bioactivity (lack of cell recognition signals), and degradation products of some synthetic polymers (e.g., PEG) may pose acidic irritation risks. Therefore, further improvements in biocompatibility and osteoinductivity are needed via surface functionalization (e.g., peptide grafting) or incorporation of bioactive factors.

Design and preparation of 3D printed PLGA scaffolds

Design principles of 3D printed bone scaffolds

Traditional stent manufacturing methods are generally constrained by material limitations and design complexities, which pose challenges to meet specific individual requirements. 3D printing technology offers new possibilities for the design and preparation of PLGA stents. The design principles for 3D printed stents include factors such as porosity, pore size, surface morphology, and structural optimization. Through 3D printing, complex scaffold structures can be created, allowing for the optimization of porosity and pore size, which in turn enhances both their biocompatibility and mechanical properties [58, 60].

In orthopedics, 3D-printed scaffolds not only offer structural support but also promote bone tissue regeneration and improve the biocompatibility of implants [68]. Furthermore, with advancements in material science, 3D printing is gradually overcoming the biological inertness of traditional scaffold materials by incorporating more biocompatible materials [69]. It is worthwhile emphasizing that cells on the scaffolds must be able to efficiently exchange oxygen and nutrients and concomitantly remove metabolic waste. At the same time, the bone defect area requires vascularization and tissue reconstruction, which necessitates scaffolds to have an interconnected, longitudinal network structure [70].

The porosity of 3D scaffolds is positively correlated with the cell contact surface area, with higher porosity further enhancing cell adhesion. Previous studies observed that optimal cell growth occurs in scaffolds with a porosity of 80–90%. In addition to porosity, pore size is another critical factor. Of note, the ideal pore diameter for promoting cell growth ranges from 10 to 400 µm [53]. Therefore, when designing 3D printed scaffolds, it is essential to optimize appropriate porosity, pore diameter, and material selection [53].

Parameter optimization during the 3D printing process

Parameter optimization during the 3D printing process plays a crucial role in determining the structure and performance of scaffolds. Factors such as printing speed, temperature, layer thickness, and print path must be carefully adjusted to achieve optimal scaffold performance and structure [56, 57]. Printing speed: Typically ranges from 5 to 50 mm/s. The optimal 3D printing rate for PLGA scaffolds is a complex, multi-factorially determined parameter requiring systematic optimization based on specific material formulations, printer characteristics, and biomedical application goals [71–73]. Temperature: For FDM printing, nozzle temperatures are usually set between 180 and 200 °C to ensure PLGA melts sufficiently without thermal degradation; the build plate temperature is maintained at 25–30 °C to prevent warping [72]. Guo et al. provided quantitative insights into temperature effects: nozzle temperatures below 185 °C caused incomplete melting, leading to 20% lower compressive strength, while temperatures above 205 °C induced PLGA thermal degradation (molecular weight reduced by 15%), decreasing scaffold stability. They also found that a build plate temperature of 30 °C reduced layer warping by 30% compared to 25 °C [71]. Layer thickness: Commonly 50–300 μm. Thinner layers (50–100 μm) improve structural precision but increase printing time, while 100–200 μm balances precision and efficiency for bone scaffolds [73–75]. Hidden parameters: Cooling rate and interlayer delay time also affect scaffold properties. A moderate cooling rate (5–10 °C/s) reduces internal stress, while an interlayer delay of 2–5 s ensures adequate layer adhesion[73, 76]. The interplay between these parameters directly impacts scaffold porosity, compressive strength, and cell viability. For example, a combination of 20 mm/s speed, 190 °C nozzle temperature, and 150 μm layer thickness has been shown to produce PLGA scaffolds with ~ 85% porosity and compressive strength of 12–15 MPa, suitable for cancellous bone repair[77]. Additionally, Cubo-Mateo et al. identified interlayer delay time as a critical "hidden parameter": a 3-s delay improved layer adhesion by 25% (compressive strength increased from 12 to 15 MPa) without significantly extending printing time, compared to a 1-s delay [76]. The complete workflow of 3D-printed PLGA scaffold design and preparation, including design principles, parameter optimization, and material processing steps, is summarized in Fig. 2.

Fig. 2.

Flowchart of design and preparation of PLGA for 3D printing

Application of 3D printed PLGA scaffolds in bone defect repair

Types of bone defects and treatment challenges

The use of 3D-printed PLGA scaffolds for bone defect repair is becoming increasingly common, showing promising results in preclinical studies and animal experiments. By optimizing scaffold design and material combinations, bone tissue regeneration can be significantly enhanced [56, 58]. Bone defects can be classified into fractures, post-resection defects following bone tumor removal, and congenital bone defects. The treatment of these defects presents several challenges, particularly in selecting the appropriate materials and techniques to effectively promote bone healing [56, 57].

Preclinical and clinical progress of 3D-printed PLGA scaffolds

Preclinical animal experiments

PLGA scaffolds have been extensively used in animal studies on bone regeneration, demonstrating excellent biocompatibility, biodegradability, and bone healing effects, thus providing a solid foundation for their clinical application. Research has shown that PLGA scaffolds can effectively support the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.

The PLGA/gelatin microsphere composite scaffolds constructed by Xia et al. had a strut size of 400 μm and pore size of 350 μm compared with pure PLGA scaffolds, their tensile strength increased from 12 to 18 MPa, and elastic modulus from 1.0 GPa to 1.4 GPa. By sustaining the release of recombinant human bone morphogenetic protein-2 (rhBMP-2), these scaffolds achieved complete bone union at 8 weeks in a rabbit radial defect model [78]. The PLGA/bioactive glass composite scaffolds developed by Yang et al. had a pore size of 250 μm and porosity of 78%, exhibiting excellent bone regeneration effects in a rat calvarial defect model with 45% new bone area at 12 weeks [79]. Recent studies have further expanded the functionality of PLGA scaffolds: for example, the PLGA/Mg composite scaffolds designed by Long et al. had a compressive strength of 22 MPa, and in a rabbit osteosarcoma post-surgery model, they not only inhibited tumor recurrence but also achieved 55% bone defect filling at 10 weeks [80]; the 3D-printed PLGA/HA microsphere scaffolds by Wei et al. had a pore size of 200–300 μm, porosity of 75–80%, and compressive strength of 18–22 MPa, with 60% new bone formation at 12 weeks in a rabbit femoral defect model [81]; Song et al. modified PLGA with duck foot-derived collagen, and the resulting PLGA/collagen/HA scaffolds (300 μm pore size, 80% porosity) achieved 58% new bone volume fraction at 8 weeks in a rat tibial defect model [82].

Yan & Xia further validated PLGA’s potential with adipose-derived stem cells (ADSCs): they loaded ADSCs onto 3D-printed PLGA/n-HA scaffolds (porosity 80%, pore size 300 μm). ADSCs showed 90% viability at 7 days, with ALP activity reaching 85% of BMSCs. In rat tibial defects, this scaffold achieved 52% new bone volume fraction at 8 weeks, compared to 38% for PLGA/n-HA scaffolds without ADSCs, highlighting ADSCs’ advantages in sourcing and biocompatibility [83]. Ghorbani et al. also reported a multi-phasic PLGA scaffold in rabbit osteochondral defects: the scaffold’s cartilage layer (PLGA-gelatin fibers) increased SOX9 expression by 2.8-fold, while the bone layer (PLGA-PDA-simvastatin) increased OCN expression by 3.1-fold, resulting in 80% cartilage thickness recovery at 12 weeks [84].

Progress in clinical research

The use of PLGA scaffolds in clinical studies has been steadily increasing, particularly in the repair of bone defects and the management of post-surgical bone tumors. These scaffolds have demonstrated excellent biological and mechanical properties. For example, a PLGA/Mg composite scaffold was designed for the comprehensive postoperative management of osteosarcoma, and the scaffold not only inhibited tumor recurrence but also promoted the healing of bone defects, highlighting its good biocompatibility and biodegradability [80]. Another study explored the combination of PLGA with duckfoot-derived collagen, revealing that the composite scaffold effectively alleviated the inflammatory response and concurrently enhanced bone regeneration, especially when used in conjunction with hydroxyapatite, which demonstrated superior osteogenic effects [82]. Importantly, several clinical cases have further highlighted the effectiveness of PLGA scaffolds in bone regeneration. For example, a study involving rabbit bone defects signaled that 3D-printed PLGA/HA composite scaffolds effectively promoted bone regeneration and the formation of mature bone tissue in animals [81]. The outcomes of these successful cases have established the efficacy and reliability of PLGA scaffolds in promoting bone regeneration, suggesting that their clinical application will continue to expand in the future.

Recent advances (2021–2025)

In 2021, Lu et al. fabricated PLGA/TCP composite scaffolds via FDM technology, achieving dual "tumor inhibition-bone repair" functions in a rabbit osteosarcoma model for the first time and providing a new strategy for post-tumor bone defect repair [56]; in 2022, Wei et al. incorporated HA microspheres into PLGA scaffolds, increasing the compressive strength by 30% compared with pure PLGA and significantly improving mechanical support performance [81]; in 2023, Song et al. modified PLGA with duck foot-derived collagen, reducing inflammatory responses by 25% in in vivo experiments and providing a new method for enhancing scaffold biocompatibility [82].

Conclusion

While 3D-printed PLGA scaffolds demonstrate significant potential in bone defect repair, they face several challenges that need to be overcome, including technological advancements, biodegradation rate control, safety validation, and cost management.

Technological challenges: Printing precision (especially for complex porous structures) and speed require improvement. Developing high-resolution printers (≤ 50 μm precision) and bio-inks with better flowability could enhance scaffold structural fidelity. Additionally, integrating real-time monitoring during printing (e.g., infrared spectroscopy for material degradation detection) may ensure batch consistency [10, 69].

Material optimization: The mechanical properties of PLGA can be enhanced by blending with PTMC or incorporating HA nanoparticles, but balancing strength and degradation remains critical. For example, PLGA/PTMC (99:1) scaffolds show tensile strength comparable to cancellous bone (~ 57 MPa) but require further testing for long-term stability [54]. Controlling degradation rates to match bone repair (typically 3–6 months for cortical bone) can be achieved by adjusting the lactic/glycolic acid ratio or surface coating with calcium phosphate [35, 37].

Clinical translation: Long-term safety data (5 + years) are lacking, particularly regarding the immunogenicity of degradation products. Large-scale multicenter trials are needed to validate efficacy in diverse patient populations (e.g., elderly vs. pediatric). Cost reduction is also essential; adopting open-source printing platforms and biodegradable raw materials could lower production costs by 30–50% [8, 69].

Current research still has three key limitations: first, most preclinical studies are based on small animal models (e.g., rats, rabbits), and the feasibility of translating results to large animals (e.g., dogs, sheep) and humans has not been verified; second, the interaction mechanism between PLGA degradation products and the immune system is not fully understood, and the immunomodulatory effects during long-term degradation require further investigation; third, data on the long-term mechanical stability of composite scaffolds (e.g., PLGA/HA) in vivo are insufficient, and the performance degradation pattern during their service life remains unclear.

Future directions: Multifunctional scaffolds integrating drug delivery (e.g., BMP-2 + chemotherapy agents) and diagnostic capabilities (e.g., pH-responsive nanoparticles for infection detection) are promising. AI-driven design, which optimizes porosity and structure based on patient-specific bone mechanics, could further improve therapeutic outcomes [58, 64].

In the future, continuous technological innovation and interdisciplinary collaboration (materials science, medicine, engineering) are anticipated to further enhance the clinical value of 3D-printed PLGA scaffolds, extending their benefits to a broader patient population.

Abbreviation

PLGA

Poly(lactic-co-glycolic acid)

CT

Computerised tomography

3D

Three dimensional

PTMC

Poly(trimethylene carbonate)

FDM

Fused Deposition Modeling

SLS

Selective Laser Sintering

SLA

Stereolithography

BMP

Bone morphogenetic protein

HA

Hydroxyapatite

TCP

Tricalcium phosphate

Mg

Magnesium (used as an abbreviation for magnesium-incorporated materials)

PEG

Polyethylene glycol

ADSC-EXO

Adipose stem cell-derived exosomes

Author contributions

HY and CL wrote the main manuscript text. BX and YL and XX and ZW is responsible for article checking and literature formatting. ZC and FY is responsible for guiding the writing work of the article. All authors read and approved the final manuscript.

Funding

This research was supported by the First-Class Discipline Team of Kunming Medical University (Grant No. 2024XKTDTS05), the Scientific Research Fund Project of Yunnan Provincial Department of Education (Grant No. 2025J0261), the Applied Basic Research Foundation of Yunnan Province and Kunming Medical University (Grant No. 202401AY070001-330) and the Yunnan Province College Student Innovation Training Program Project Fund (Grant No. 202510678050X).

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.