In Vitro Tests of FDM 3D-Printed Diclofenac Sodium-Containing Implants
Abstract
:1. Introduction
2. Results
2.1. Design of the Drug Reservoirs and Printing of the Samples
2.2. Content Uniformity and Weight Variation
2.3. PLA Degradation
2.4. Characterization
2.4.1. Thermogravimetric (TG) and Heatflow (Differential Scanning Analyis, DSC) Analysis
2.4.2. Contact Angle Measurement
2.4.3. Scanning Electron Microscopy
2.4.4. Microcomputed Tomography (MicroCT)
2.4.5. Raman Spectroscopy
2.5. In Vitro Dissolution Test
2.6. MTT Assay
3. Discussion
4. Materials and Methods
4.1. Materials
4.1.1. Used Polymer Filaments
4.1.2. Diclofenac Sodium as a Model API
4.2. Methods
4.2.1. Design of the Drug Reservoirs and Printing of the Samples
4.2.2. Content Uniformity and Weight Variation
4.2.3. PLA Degradation
4.2.4. Characterization
Thermogravimetric (TG) and Heatflow (Differential Scanning Analyis, DSC) Analysis
Contact Angle
Scanning Electron Microscopy (SEM)
Microcomputed Tomography (MicroCT)
Raman Spectroscopy
4.2.5. In Vitro Dissolution Test
4.2.6. Cytotoxicity Experiments
Sterilization
Cell Culture
MTT Cell Viability Assay
4.2.7. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Appendix A
Sample | PLA_16_0 | PLA_19_0 | PLA_22_0 | PLA_22_5 | PLA_22_10 | PLA_22_15 | Anti_16_0 | Anti_19_0 | Anti_22_0 | PETG_16_0 | PETG_19_0 | PETG_22_0 | PMMA_16_0 | PMMA_19_0 | PMMA_22_0 | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Sampling time (h) | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD |
0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
0.083 | 0.55 | 0.34 | 3.46 | 1.24 | 20.23 | 6.07 | 3.59 | 1.02 | 0.13 | 0.12 | 0.59 | 0.13 | 5.7 | 3.37 | 17.97 | 2.27 | 36.5 | 4.78 | 5.79 | 3.19 | 20.91 | 4.97 | 1.72 | 0.5 | 7.67 | 1.17 | 3.54 | 0.71 | 14.1 | 1.84 |
0.25 | 2.59 | 0.4 | 11.55 | 0.89 | 24.45 | 3.81 | 11.97 | 1.3 | 0.46 | 0.3 | 6.94 | 1.54 | 8.02 | 4.23 | 30.03 | 1.82 | 46.67 | 3.21 | 8.51 | 1.31 | 53.48 | 2.79 | 3.57 | 1.11 | 14.54 | 1.31 | 9.86 | 1.03 | 26.57 | 1.47 |
0.5 | 2.55 | 0.34 | 19.68 | 3.95 | 35.44 | 3.07 | 17.12 | 1.22 | 1.72 | 0.71 | 14.74 | 2.98 | 13.01 | 2.94 | 42.96 | 1.34 | 62.22 | 3.26 | 12.83 | 2.06 | 76.07 | 1.86 | 7.69 | 0.84 | 22.51 | 2 | 18.54 | 3.25 | 32.76 | 2.02 |
0.75 | 5.4 | 0.46 | 35.66 | 10.96 | 49.04 | 3.14 | 26.21 | 2.26 | 6.31 | 1.47 | 29.32 | 2.37 | 16.39 | 2.54 | 56.85 | 1.6 | 77.44 | 3.42 | 18.58 | 4.42 | 90.47 | 1.35 | 18.17 | 1.62 | 37.04 | 12.42 | 38.28 | 6.32 | 57.01 | 3.08 |
1 | 9.6 | 0.88 | 49.66 | 3.37 | 67.22 | 1.73 | 37.27 | 1.66 | 18.75 | 2.75 | 42.43 | 1.4 | 18.91 | 1.26 | 60.96 | 1.73 | 84.59 | 3.1 | 30.12 | 9.25 | 91.29 | 0.83 | 29.23 | 1.1 | 71.8 | 0.83 | 74.17 | 4.62 | 75.32 | 2.99 |
2 | 16.65 | 0.92 | 80.04 | 6.51 | 82.95 | 1.24 | 55.67 | 0.43 | 31.61 | 2.83 | 66.73 | 1.72 | 48.61 | 1.41 | 60.71 | 1.09 | 86.47 | 1.17 | 55.65 | 5.32 | 94.22 | 0.43 | 57.7 | 0.88 | 81.38 | 0.43 | 97.23 | 1.1 | 92.95 | 3.41 |
4 | 22.9 | 1.02 | 84.5 | 2.48 | 91.53 | 2.8 | 62.3 | 2.05 | 42.65 | 2.28 | 73.99 | 1.38 | 74.9 | 2.25 | 59.66 | 1.69 | 87.6 | 0.96 | 61.55 | 0.95 | 96.33 | 1.69 | 73.75 | 1.55 | 82.85 | 0.56 | 98.83 | 0.61 | 90.6 | 2.15 |
6 | 30.49 | 1.55 | 88.14 | 2.4 | 94.45 | 5.32 | 63.94 | 2.89 | 42.22 | 1.66 | 82.99 | 3.48 | 87.33 | 1.82 | 61.34 | 1.73 | 88.51 | 0.37 | 61.97 | 1.42 | 97.94 | 1.52 | 75.29 | 1.06 | 85.44 | 0.88 | 98.87 | 0.87 | 99.96 | 1.49 |
8 | 33.85 | 1.19 | 88.06 | 3.52 | 94.37 | 4.67 | 65.89 | 1.45 | 45.08 | 0.76 | 83.33 | 2.94 | 83.09 | 0.33 | 63.76 | 0.84 | 90.3 | 1.2 | 62.23 | 2.63 | 97.86 | 0.52 | 76.96 | 1.01 | 89.45 | 0.81 | 99.07 | 0.99 | 99.19 | 2.42 |
12 | 43.6 | 1.96 | 90.3 | 4.52 | 93.9 | 3.43 | 68.79 | 0.35 | 46.6 | 1.64 | 84.91 | 1.4 | 86.11 | 0.85 | 64.64 | 2.05 | 85.56 | 3.86 | 63.41 | 4.29 | 98.48 | 0.99 | 75.59 | 1.66 | 91.09 | 1.99 | 98.63 | 1.21 | 99.3 | 0.38 |
14 | 47.82 | 2.2 | 92.98 | 2.72 | 94.42 | 2.09 | 68.44 | 0.42 | 48.95 | 1.61 | 86.87 | 1.6 | 92.63 | 3.3 | 66.55 | 1.56 | 87.23 | 2.01 | 61.24 | 1.22 | 97.64 | 2.43 | 78.3 | 1.71 | 89.89 | 1.58 | 99.53 | 0.57 | 98.05 | 1.78 |
16 | 54.09 | 1.09 | 92.26 | 2.91 | 96.53 | 0.62 | 68.61 | 0.46 | 49.14 | 1.2 | 86.94 | 2.78 | 93.28 | 1.3 | 68.03 | 1.65 | 88.35 | 1.35 | 59.89 | 1.63 | 98.03 | 1.7 | 80.25 | 1.26 | 92.07 | 1.46 | 98.64 | 0.41 | 98.85 | 0.24 |
18 | 61.1 | 1.55 | 90.35 | 3.26 | 94.54 | 2.06 | 68.79 | 1.33 | 49.95 | 1.91 | 86.08 | 1.09 | 94.37 | 0.78 | 68.35 | 0.77 | 93.47 | 2.73 | 60.96 | 2.7 | 97.82 | 2.3 | 78.16 | 1.25 | 93.36 | 1.17 | 98.68 | 1.66 | 97.67 | 0.5 |
20 | 69.49 | 3.05 | 91.29 | 1.82 | 95.15 | 1.76 | 70.17 | 1.59 | 48.95 | 0.94 | 86.74 | 2.94 | 95.09 | 1.67 | 69.98 | 1.43 | 93.34 | 1.74 | 59.4 | 1.18 | 98.49 | 1.16 | 77.59 | 2.78 | 93.8 | 1.22 | 96.59 | 3.74 | 99.28 | 0.55 |
24 | 90.12 | 2.42 | 93.33 | 0.7 | 97.31 | 2.72 | 70.85 | 1.46 | 51.26 | 1.5 | 87.53 | 1.56 | 97.48 | 1.7 | 71.34 | 1.57 | 95.73 | 0.89 | 59.96 | 2.81 | 99.49 | 0.57 | 79.77 | 1.36 | 96.39 | 1.14 | 97.14 | 1.37 | 99.49 | 0.38 |
Pairwise Comparison of Dissolution Profiles | |||
---|---|---|---|
Sample 1 vs. | Sample 2 | f1 | f2 (%) |
PLA_16_0 | PLA_19_0 | 51.47 | 17.47 |
PLA_16_0 | PLA_22_0 | 56.63 | 14.22 |
PLA_19_0 | PLA_22_0 | 10.63 | 48.21 |
PLA_22_0 | PLA_22_5 | 32.87 | 27.41 |
PLA_22_0 | PLA_22_10 | 57.25 | 15.32 |
PLA_22_0 | PLA_22_15 | 18.68 | 38.61 |
PLA_22_5 | PLA_22_10 | 36.31 | 33.58 |
PLA_22_5 | PLA_22_15 | 23.87 | 40.79 |
PLA_22_10 | PLA_22_15 | 90.20 | 22.55 |
Anti_16_0 | Anti_19_0 | 42.81 | 26.82 |
Anti_16_0 | Anti_22_0 | 26.55 | 22.85 |
Anti_19_0 | Anti_22_0 | 28.31 | 29.51 |
PETG_16_0 | PETG_19_0 | 47.87 | 15.46 |
PETG_16_0 | PETG_22_0 | 19.98 | 42.03 |
PETG_19_0 | PETG_22_0 | 60.80 | 18.49 |
PMMA_16_0 | PMMA_19_0 | 9.21 | 51.12 |
PMMA_16_0 | PMMA_22_0 | 11.16 | 47.93 |
PMMA_19_0 | PMMA_22_0 | 7.07 | 51.33 |
PLA_16_0 | Anti_16_0 | 46.36 | 21.26 |
PLA_16_0 | PETG_16_0 | 39.89 | 30.54 |
PLA_16_0 | PMMA_16_0 | 53.23 | 16.39 |
Anti_16_0 | PETG_16_0 | 40.30 | 29.59 |
Anti_16_0 | PMMA_16_0 | 14.56 | 35.43 |
PETG_16_0 | PMMA_16_0 | 34.99 | 26.13 |
PLA_19_0 | Anti_19_0 | 37.73 | 30.33 |
PLA_19_0 | PETG_19_0 | 22.72 | 26.15 |
PLA_19_0 | PMMA_19_0 | 10.82 | 46.70 |
Anti_19_0 | PETG_19_0 | 34.04 | 23.19 |
Anti_19_0 | PMMA_19_0 | 37.22 | 24.35 |
PETG_19_0 | PMMA_19_0 | 18.02 | 28.65 |
PLA_22_0 | Anti_22_0 | 13.01 | 40.53 |
PLA_22_0 | PETG_22_0 | 39.05 | 30.36 |
PLA_22_0 | PMMA_22_0 | 5.85 | 61.29 |
Anti_22_0 | PETG_22_0 | 47.96 | 22.59 |
Anti_22_0 | PMMA_22_0 | 15.28 | 39.93 |
PETG_22_0 | PMMA_22_0 | 31.10 | 26.85 |
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Sample | Weight | Content Uniformity | ||
---|---|---|---|---|
Average (mg) | ±SD | Average (mg) | ±SD | |
PLA_16_0 | 346.93 | 5.39 | 29.45 | 0.89 |
PLA_19_0 | 476.44 | 2.74 | 29.87 | 0.75 |
PLA_22_0 | 608.79 | 1.45 | 29.60 | 0.83 |
PLA_22_5 | 635.87 | 1.65 | 29.94 | 0.47 |
PLA_22_10 | 646.04 | 4.81 | 29.75 | 0.73 |
PLA_22_15 | 690.85 | 5.34 | 29.86 | 0.86 |
Anti_16_0 | 344.08 | 4.00 | 29.53 | 0.92 |
Anti_19_0 | 468.19 | 3.48 | 29.78 | 1.0 |
Anti_22_0 | 617.77 | 3.74 | 29.56 | 0.82 |
PETG_16_0 | 354.17 | 2.40 | 29.72 | 0.45 |
PETG_19_0 | 513.55 | 0.54 | 29.99 | 0.67 |
PETG_22_0 | 648.54 | 1.86 | 29.68 | 0.81 |
PMMA_16_0 | 366.49 | 3.61 | 29.66 | 0.36 |
PMMA_19_0 | 527.96 | 2.57 | 29.53 | 0.63 |
PMMA_22_0 | 615.87 | 2.84 | 29.91 | 0.78 |
Sample | Measured Weight (mg) ± SD | |||||
---|---|---|---|---|---|---|
After Printing | 1st Week | 2nd Week | 4th Week | 6th Week | 8th Week | |
PLA_16_0 | 315.44 ± 0.57 | 315.32 ± 0.42 | 314.82 ± 0.22 | 314.59 ± 0.84 | 315.93 ± 1.34 | 314.75 ± 0.56 |
PLA_19_0 | 446.87 ± 0.98 | 446.47 ± 0.88 | 446.53 ± 1.18 | 446.43 ± 0.58 | 445.86 ± 0.18 | 445.42 ± 0.76 |
PLA_22_0 | 576.96 ± 1.45 | 577.05 ± 0.72 | 576.37 ± 0.48 | 577.04 ± 0.33 | 577.04 ± 0.33 | 576.53 ± 0.18 |
PLA_22_5 | 603.65 ± 0.12 | 602.72 ± 0.27 | 602.27 ± 0.34 | 603.74 ± 0.37 | 602.72 ± 1.05 | 603.52 ± 1.05 |
PLA_22_10 | 615.98 ± 2.41 | 615.49 ± 0.38 | 615.92 ± 1.58 | 615.63 ± 0.81 | 615.07 ± 0.23 | 615.07 ± 0.45 |
PLA_22_15 | 660.57 ± 1.34 | 659.59 ± 1.14 | 660.39 ± 0.56 | 659.79 ± 0.34 | 660.82 ± 1.54 | 660.03 ± 0.72 |
Anti_16_0 | 313.82 ± 1.21 | 312.28 ± 0.51 | 313.03 ± 0.93 | 313.75 ± 0.63 | 312.34 ± 0.25 | 312.06 ± 0.57 |
Anti_19_0 | 437.19 ± 0.97 | 436.97 ± 0.84 | 437.03 ± 0.14 | 436.13 ± 0.59 | 436.94 ± 0.37 | 437.42 ± 0.70 |
Anti_22_0 | 586.82 ± 0.75 | 586.42 ± 0.55 | 585.97 ± 1.25 | 585.36 ± 0.74 | 586.22 ± 1.16 | 586.34 ± 0.04 |
Sample | Weight of the Measured Diclofenac (mg) in the Cavity | Total Weight (mg) of Diclofenac | |||||
---|---|---|---|---|---|---|---|
1st Cavity | 2nd Cavity | 3rd Cavity | 4th Cavity | 5th Cavity | 6th Cavity | ||
PLA_16_0 | 28.04 ± 0.15 | - | - | - | - | - | 28.04 ± 0.15 |
PLA_16_5 | 4.73 ± 0.04 | 7.87 ± 0.18 | 11.32 ± 0.71 | 2.61 ± 0.31 | 0.19 ± 0.005 | 1.34 ± 0.09 | 28.06 ± 0.22 |
PLA_16_10 | 10.89 ± 0.22 | 5.58 ± 0.16 | 11.76 ± 0.29 | 2.32 ± 0.17 | 1.87 ± 0.04 | 0.29 ± 0.13 | 32.71 ± 0.17 |
PLA_16_15 | 12.12 ± 0.10 | 6.41 ± 0.05 | 6.08 ± 0.004 | 3.10 ± 0.14 | 1.85 ± 0.20 | 0.29 ± 0.31 | 29.85 ± 0.13 |
Sample | Diffusion Rate (µg·mL−1·h−1) | Flux (µg·cm−2·h−1) | Dissolved API Amount (%) | t-Test Result | |||
---|---|---|---|---|---|---|---|
Average 0–2 h | Average 2–24 h | 0–2 h | 2–24 h | 2 h | 24 h | 2 h vs. 24 h | |
PLA_16_0 | 2.57 | 1.08 | 0.49 | 0.21 | 16.64 | 90.12 | **** |
PLA_19_0 | 13.00 | 0.21 | 1.83 | 0.03 | 80.04 | 93.33 | * |
PLA_22_0 | 21.70 | 0.25 | 2.33 | 0.03 | 82.95 | 97.31 | ** |
PLA_22_5 | 10.15 | 0.25 | 1.09 | 0.03 | 55.66 | 70.85 | **** |
PLA_22_10 | 4.26 | 0.33 | 0.46 | 0.04 | 31.61 | 51.26 | *** |
PLA_22_15 | 10.07 | 0.36 | 1.08 | 0.04 | 66.73 | 87.53 | *** |
Anti_16_0 | 7.42 | 0.85 | 1.42 | 0.16 | 48.61 | 97.48 | **** |
Anti_19_0 | 19.63 | 0.18 | 2.76 | 0.02 | 60.71 | 71.34 | *** |
Anti_22_0 | 31.15 | 0.19 | 3.35 | 0.02 | 86.47 | 95.73 | *** |
PETG_16_0 | 9.43 | 0.06 | 1.80 | 0.01 | 55.65 | 59.96 | ns |
PETG_19_0 | 28.62 | 0.08 | 4.03 | 0.01 | 94.22 | 99.49 | *** |
PETG_22_0 | 7.76 | 0.40 | 0.83 | 0.04 | 57.70 | 79.77 | **** |
PMMA_16_0 | 17.56 | 0.26 | 3.36 | 0.05 | 81.38 | 96.39 | **** |
PMMA_19_0 | 17.18 | 0.00 | 2.42 | 0.00 | 97.23 | 97.14 | ns |
PMMA_22_0 | 21.77 | 0.12 | 2.34 | 0.01 | 92.95 | 99.48 | * |
Sample | Zero-Order Kinetics | First-Order Kinetics | Zero-Order Kinetics | First-Order Kinetics | * Zero-Order Kinetics | * First-Order Kinetics |
---|---|---|---|---|---|---|
0–24 h | 0–24 h | 0–2 h | 0–2 h | 0–X h | 0–X h | |
PLA_16_0 | 0.98 | 0.85 | 0.98 | 0.97 | - | - |
PLA_19_0 | 0.56 | 0.71 | 0.98 | 0.99 | - | - |
PLA_22_0 | 0.52 | 0.72 | 0.89 | 0.98 | - | - |
PLA_22_5 | 0.60 | 0.68 | 0.97 | 0.99 | - | - |
PLA_22_10 | 0.68 | 0.71 | 0.93 | 0.94 | - | - |
PLA_22_15 | 0.61 | 0.73 | 0.98 | 0.99 | - | - |
Anti_16_0 | 0.73 | 0.93 | 0.97 | 0.94 | - | - |
* Anti_19_0 | 0.43 | 0.60 | 0.65 | 0.68 | 0.91 | 1.00 |
* Anti_22_0 | 0.36 | 0.65 | 0.64 | 0.80 | 0.85 | 0.98 |
PETG_16_0 | 0.51 | 0.49 | 0.99 | 0.97 | - | - |
* PETG_19_0 | 0.29 | 0.67 | 0.60 | 0.77 | 0.95 | 1.00 |
PETG_22_0 | 0.61 | 0.67 | 0.98 | 0.97 | - | - |
PMMA_16_0 | 0.54 | 0.80 | 0.88 | 0.90 | - | - |
PMMA_19_0 | 0.45 | 0.40 | 0.93 | 0.95 | - | - |
PMMA_22_0 | 0.47 | 0.45 | 0.90 | 0.98 | - | - |
Properties | Method | PLA | Antibacterial PLA | PETG | PMMA |
---|---|---|---|---|---|
Specific gravity (g/cm3) | D792 | 1.24 | 1.24 | 1.29 | 1.17 |
Heat distortion temperature at 0.45 MPa (°C) | D790 | 55 | 80‒90 | 68 | 106 |
Glass Trans. temperature (°C) | D3418 | 55‒60 | 55‒60 | 80 | 105 |
Tensile strength (MPa) | ISO 527 | 60 | 66 | 53 | 90 |
Tensile elongation (%) | ISO 527 | 6.00 | 3.31 | 4.01 | 15.0 |
Tensile modulus (MPa) | ISO 527 | 3800 | 4400 | 2040 | 2900 |
Notched Izod impact (kJ/m2) | ISO 180 | 16 | 118 | 4.5 | 6.4 |
Properties | Method | PLA | Antibacterial PLA | PETG | PMMA |
---|---|---|---|---|---|
Tensile strength (MPa) | ISO 527 | 31.6 | 33.0 | 43.0 | 83.0 |
Tensile modulus (MPa) | ISO 527 | 1800 | 2300 | 2800 | 3200 |
Notched Izod impact (kJ/m2) | ISO 180 | 2.6 | 3.8 | 9.4 | 2.0 |
Filament Type | PLA | Antibacterial PLA | PETG | PMMA |
---|---|---|---|---|
Filament Diameter (mm) | 1.75 | 1.75 | 1.75 | 1.75 |
Extruder Nozzle Diameter (µm) | 400 | 400 | 400 | 400 |
Infill Percentage (%) | 0, 5, 10, 15 | 0, 5, 10, 15 | 0, 5, 10, 15 | 0, 5, 10, 15 |
Extrusion Temperature (℃) | 215 | 215 | 250 | 270 |
Bed Temperature (℃) | 60 | 60 | 90 | 110 |
Layer Thickness (µm) | 200 | 200 | 200 | 200 |
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Arany, P.; Papp, I.; Zichar, M.; Csontos, M.; Elek, J.; Regdon, G., Jr.; Budai, I.; Béres, M.; Gesztelyi, R.; Fehér, P.; et al. In Vitro Tests of FDM 3D-Printed Diclofenac Sodium-Containing Implants. Molecules 2020, 25, 5889. https://doi.org/10.3390/molecules25245889
Arany P, Papp I, Zichar M, Csontos M, Elek J, Regdon G Jr., Budai I, Béres M, Gesztelyi R, Fehér P, et al. In Vitro Tests of FDM 3D-Printed Diclofenac Sodium-Containing Implants. Molecules. 2020; 25(24):5889. https://doi.org/10.3390/molecules25245889
Chicago/Turabian StyleArany, Petra, Ildikó Papp, Marianna Zichar, Máté Csontos, János Elek, Géza Regdon, Jr., István Budai, Mónika Béres, Rudolf Gesztelyi, Pálma Fehér, and et al. 2020. "In Vitro Tests of FDM 3D-Printed Diclofenac Sodium-Containing Implants" Molecules 25, no. 24: 5889. https://doi.org/10.3390/molecules25245889