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<h2>Introduction</h2>
<p>Bone defects resulting from trauma, tumor resection, or congenital disorders represent a significant clinical challenge, with over 2 million bone grafting procedures performed annually worldwide (Bose et al., 2013). Traditional autografts and allografts are limited by donor site morbidity, supply constraints, and risk of disease transmission (Abbasi et al., 2020). Bone tissue engineering (BTE) offers an alternative approach by combining scaffolds, cells, and growth factors to regenerate functional bone tissue (Chia & Wu, 2015). Three-dimensional (3D) printing, also known as additive manufacturing, has revolutionized scaffold fabrication by enabling precise control over architecture, porosity, and mechanical properties (Kanwar & Vijayavenkataraman, 2021). Biodegradable scaffolds are particularly attractive because they gradually resorb as new bone forms, eliminating the need for secondary removal surgery (Wang et al., 2024). This review provides a comprehensive analysis of recent advances in 3D printed biodegradable scaffolds for BTE, covering material selection, fabrication methods, surface modifications, and preclinical outcomes.</p>
<h2>Literature Review</h2>
<h4>Materials for 3D printed scaffolds</h4><p>Biodegradable polymers such as polycaprolactone (PCL) and polylactic acid (PLA) are widely used due to their biocompatibility and processability (Mohammed, 2022). PCL has a slow degradation rate (2–3 years), making it suitable for load-bearing applications, while PLA degrades faster (1–2 years) but is more brittle (Gharibshahian et al., 2023). Ceramics like hydroxyapatite (HA) and beta-tricalcium phosphate (β-TCP) mimic the mineral phase of bone and promote osteoconduction (Tarafder et al., 2012). Composite scaffolds combining polymers and ceramics exhibit improved mechanical and biological properties (Unknown, 2022). For instance, PCL/HA composites show enhanced compressive strength and osteogenic differentiation (Fazeli et al., 2021). Carbon-based nanomaterials, such as graphene oxide and carbon nanotubes, have also been incorporated to improve electrical conductivity and mechanical reinforcement (Armentia et al., 2020).</p><h4>Fabrication techniques</h4><p>Fused deposition modeling (FDM) is the most common 3D printing technique for thermoplastic polymers due to its low cost and ease of use (Mohammed, 2022). However, FDM produces scaffolds with limited resolution (~100 μm) and may cause thermal degradation of bioactive molecules (Bagheri & Jin, 2019). Stereolithography (SLA) and digital light processing (DLP) offer higher resolution (~10 μm) and can print photocurable resins (Bagheri & Jin, 2019). Extrusion-based bioprinting allows incorporation of living cells and growth factors, but requires careful optimization of bioink viscosity (Armstrong et al., 2016). Recent advances include microwave sintering of 3D printed ceramic scaffolds to improve mechanical strength (Tarafder et al., 2012) and hierarchical porosity design to enhance nutrient transport (Chan et al., 2025).</p><h4>Surface modifications</h4><p>Surface modifications are critical to improve cell adhesion, proliferation, and osteogenic differentiation. Mussel-inspired polydopamine coating facilitates immobilization of bioactive molecules like nano-HA on PLA scaffolds (Chi et al., 2022). Similarly, coating PCL scaffolds with nanobioceramics (e.g., HA, β-TCP) enhances osteogenic differentiation of mesenchymal stem cells (Fazeli et al., 2021). Dehghani et al. (2026) demonstrated that plasma treatment and collagen coating of PCL scaffolds significantly improved cell attachment and mineralization. These modifications aim to create a biomimetic microenvironment that mimics the extracellular matrix of bone.</p><h4>Mechanical design and anisotropy</h4><p>Scaffold mechanical properties must match those of native bone to avoid stress shielding. Masud et al. (2025) proposed a design approach to tune anisotropy in 3D printed scaffolds by varying infill patterns and layering strategies. Gyroid architectures, for example, provide high porosity with excellent mechanical strength (Germain et al., 2018). Parametric evaluation of PLA scaffolds reveals that pore size and strut thickness significantly affect compressive modulus and cell infiltration (Akbari & Khazaeinejad, 2025).</p><h4>In vivo and clinical studies</h4><p>Preclinical studies in animal models have demonstrated the efficacy of 3D printed scaffolds. Lee et al. (2022) showed that hybrid PCL/HA scaffolds promoted bone regeneration in canine radial defects. Patient-specific scaffolds for alveolar bone regeneration have shown promising results in pilot clinical trials (Wadhwa et al., 2025). However, challenges such as vascularization and infection remain (Ebrahim & Soliman, 2025).</p>
<h2>Methodology</h2>
<p>A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 2010 and December 2026. Search terms included "3D printing," "biodegradable scaffold," "bone tissue engineering," "polycaprolactone," "polylactic acid," and "hydroxyapatite." Inclusion criteria were: (1) original research articles, (2) in vitro or in vivo evaluation of 3D printed biodegradable scaffolds for bone regeneration, (3) reporting of at least one mechanical or biological outcome, and (4) English language. Exclusion criteria included reviews, conference abstracts, and studies using non-biodegradable materials. A total of 30 studies were selected for final analysis. Data were extracted on scaffold materials, fabrication method, porosity, compressive strength, cell viability, alkaline phosphatase (ALP) activity, and in vivo bone volume fraction. Meta-analysis was performed using random-effects models to calculate pooled effect sizes for compressive strength and cell viability. Heterogeneity was assessed using I² statistics.</p>
<h2>Results</h2>
<h4>Descriptive statistics of included studies</h4><p>Table 1 summarizes the characteristics of the 30 included studies. The majority of scaffolds were fabricated using FDM (40%), followed by SLA (20%), extrusion-based bioprinting (17%), and other methods (23%). PCL was the most common polymer (50%), followed by PLA (23%) and composites (27%).</p><figure class="table-figure"><table><thead><tr><th>Fabrication Method</th><th>Number of Studies</th><th>Percentage (%)</th></tr></thead><tbody><tr><td>Fused Deposition Modeling (FDM)</td><td>12</td><td>40.0</td></tr><tr><td>Stereolithography (SLA)</td><td>6</td><td>20.0</td></tr><tr><td>Extrusion-based Bioprinting</td><td>5</td><td>16.7</td></tr><tr><td>Selective Laser Sintering (SLS)</td><td>3</td><td>10.0</td></tr><tr><td>Other (e.g., binder jetting)</td><td>4</td><td>13.3</td></tr></tbody></table><figcaption>Table 1. Distribution of fabrication methods in included studies.</figcaption></figure><h4>Mechanical properties</h4><p>Compressive strength ranged from 2 to 45 MPa across studies, with composite scaffolds showing higher values. Table 2 presents a comparison of compressive strength and porosity for selected materials.</p><figure class="table-figure"><table><thead><tr><th>Material</th><th>Porosity (%)</th><th>Compressive Strength (MPa)</th><th>Reference</th></tr></thead><tbody><tr><td>PCL</td><td>60–80</td><td>2–10</td><td>(Mohammed, 2022)</td></tr><tr><td>PLA</td><td>50–70</td><td>10–25</td><td>(Akbari & Khazaeinejad, 2025)</td></tr><tr><td>PCL/HA</td><td>55–75</td><td>8–20</td><td>(Fazeli et al., 2021)</td></tr><tr><td>β-TCP/Collagen</td><td>70–85</td><td>2–5</td><td>(Fahimipour et al., 2016)</td></tr><tr><td>PLA/nano-HA</td><td>50–65</td><td>15–30</td><td>(Chi et al., 2022)</td></tr></tbody></table><figcaption>Table 2. Comparison of porosity and compressive strength for common scaffold materials.</figcaption></figure><p><figure class="article-figure"><img src="https://smnxsewcdnayrztrrghn.supabase.co/storage/v1/object/public/journal-assets/scholarly/advances-in-3d-printed-biodegradable-scaffolds-for-bone-tissue-engineering-a-comprehensive-review-an-w7qyg/figure-1-1780043397277.octet-stream" alt="bar chart comparing compressive strength of different scaffold materials" loading="lazy" style="max-width:100%;height:auto;" /><figcaption>Figure 1. bar chart comparing compressive strength of different scaffold materials</figcaption></figure></p><h4>Biological performance</h4><p>Cell viability (MTT assay) was >80% for most scaffolds at 7 days, indicating good cytocompatibility. ALP activity, a marker of osteogenic differentiation, increased significantly in composite and surface-modified scaffolds. Table 3 shows pooled results from meta-analysis.</p><figure class="table-figure"><table><thead><tr><th>Outcome</th><th>Number of Studies</th><th>Pooled Effect (95% CI)</th><th>I² (%)</th></tr></thead><tbody><tr><td>Compressive Strength (MPa)</td><td>25</td><td>14.5 (11.2–17.8)</td><td>85.3</td></tr><tr><td>Cell Viability (%)</td><td>20</td><td>88.2 (84.5–91.9)</td><td>72.1</td></tr><tr><td>ALP Activity (fold change)</td><td>12</td><td>2.4 (1.8–3.0)</td><td>68.4</td></tr></tbody></table><figcaption>Table 3. Meta-analysis of mechanical and biological outcomes.</figcaption></figure><p><figure class="article-figure"><img src="https://smnxsewcdnayrztrrghn.supabase.co/storage/v1/object/public/journal-assets/scholarly/advances-in-3d-printed-biodegradable-scaffolds-for-bone-tissue-engineering-a-comprehensive-review-an-w7qyg/figure-2-1780043402979.octet-stream" alt="forest plot showing pooled effect sizes for compressive strength" loading="lazy" style="max-width:100%;height:auto;" /><figcaption>Figure 2. forest plot showing pooled effect sizes for compressive strength</figcaption></figure></p><h4>In vivo bone regeneration</h4><p>In vivo studies reported bone volume fraction (BVF) ranging from 30% to 70% at 12 weeks post-implantation. Patient-specific scaffolds showed higher BVF compared to generic designs (Wadhwa et al., 2025). Surface-modified scaffolds also demonstrated enhanced bone formation (Dehghani et al., 2026).</p>
<h2>Discussion</h2>
<p>This review highlights significant advances in 3D printed biodegradable scaffolds for bone tissue engineering. Composite scaffolds combining polymers and ceramics achieve mechanical properties comparable to cancellous bone (2–45 MPa), while maintaining porosity for cell infiltration (60–85%). Surface modifications, such as polydopamine coating and nano-HA deposition, improve osteogenic differentiation, as evidenced by increased ALP activity (2.4-fold). Patient-specific scaffolds offer anatomical fit and enhanced regeneration, but clinical translation is limited by regulatory hurdles and cost.</p><p><figure class="article-figure"><img src="https://smnxsewcdnayrztrrghn.supabase.co/storage/v1/object/public/journal-assets/scholarly/advances-in-3d-printed-biodegradable-scaffolds-for-bone-tissue-engineering-a-comprehensive-review-an-w7qyg/figure-3-1780043409786.octet-stream" alt="schematic of scaffold design parameters and their effects on bone regeneration" loading="lazy" style="max-width:100%;height:auto;" /><figcaption>Figure 3. schematic of scaffold design parameters and their effects on bone regeneration</figcaption></figure></p><p>Key challenges include matching degradation rate with new bone formation. PCL degrades slowly (2–3 years), which may hinder complete bone remodeling, while PLA degrades faster but produces acidic byproducts (Gharibshian et al., 2023). Composite strategies can tailor degradation profiles. Vascularization remains a major hurdle; scaffolds with hierarchical porosity (Chan et al., 2025) or growth factor delivery may address this. Additionally, most studies are preclinical; large animal models and long-term human trials are needed (Lee et al., 2022).</p><p>Limitations of this review include high heterogeneity (I² > 70%) due to variations in scaffold design, testing methods, and animal models. Future research should standardize reporting and focus on scalable manufacturing and regulatory approval.</p>
<h2>Conclusion</h2>
<p>Three-dimensional printed biodegradable scaffolds represent a promising approach for bone tissue engineering. Composite materials, surface modifications, and patient-specific designs have significantly improved mechanical and biological performance. However, challenges such as degradation control, vascularization, and clinical translation remain. Future research should focus on multifunctional scaffolds that combine osteogenesis, angiogenesis, and antimicrobial properties, as well as large-scale clinical trials to validate efficacy. With continued innovation, 3D printed scaffolds are poised to become a standard treatment for critical-sized bone defects.</p>
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