Enhancing PLA Filament Biocompatibility by introducing ZnO and Ketoprofen

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Maia, Monique O. T. Conceição, Maryana B. Silva, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4656369/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Aug, 2024 Read the published version in Journal of Inorganic and Organometallic Polymers and Materials → Version 1 posted 16 You are reading this latest preprint version Abstract This study investigates the incorporation of zinc oxide (ZnO) and ketoprofen (keto) into poly(lactic acid) (PLA) filaments to enhance their biocompatible. PLA is widely used in additive manufacturing, especially in biomedical applications, due to its biodegradability and biocompatibility. However, its interaction with biological tissues can be improved. ZnO was chosen for its wound-healing properties, while keto, a nonsteroidal anti-inflammatory drug, was selected to provide local anti-inflammatory effects. PLA filaments were prepared by incorporating ZnO and keto, followed by analyses of their mechanical, thermal, and biological properties. The results showed that the incorporation of ZnO and keto did not compromise the mechanical and thermal properties of the PLA filaments. Compared to pristine PLA, the composites presented a slight improvement in strength. The incorporation of ketoprofen in the composite increased its thermal stability compared to PLA-ZnO filament. Concerning the morphology, when ZnO and Keto were inserted, the scaffold acquired a more robust structure, with well-defined porosity. In vitro biocompatibility tests indicated that the modified filaments exhibited lower cellular toxicity and improved cell adhesion and proliferation compared to pure PLA. Antimicrobial tests demonstrated that the filaments containing ZnO, at the evaluated concentration, did not exhibit activity against Staphylococcus aureus , Escherichia coli and Pseudomonas aeruginosa , gram-positive and gram-negative bacteria. The combination of ZnO and ketoprofen in PLA filaments can enhance their biomedical applications, providing better biocompatibility without compromising the intrinsic characteristics of PLA. This work paves the way for the development of safer and more effective medical implants and devices. Poly(lactic acid) zinc oxide ketoprofen filaments biocompatibility. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 1. INTRODUCTION Fused filament fabrication (FFF), also known as fused deposition modeling (FDM), is a versatile and highly scalable 3D printing technique that enables the layer-by-layer arrangement of solid objects from digital predefinitions [ 1 , 2 ]. During this process, the feedstock filament reaches its melting temperature, undergoes a phase change, is extruded from the nozzle, and then cools after the deposition of the layers onto the build platform [ 3 ]. Consequently, this procedure allows the fabrication of complex shapes and architectures, details of which could not be achieved by other molding technologies, such as injection [ 1 , 2 ]. One of the most applied segments of this technology is healthcare, mainly in the manufacturing and elaboration of plastic-based biomedical parts [ 4 ]. However, a significant obstacle hindering the adoption of FFF in the clinical field is the absence of appropriate biodegradable, biocompatible, and therapeutic feedstocks [ 2 ]. Hence, among the various biopolymers available, polylactic acid (PLA) has attracted attention due to its alternative to petroleum-based polymers such as acrylonitrile-butadiene-styrene (ABS), polypropylene (PP) and polystyrene (PS) [ 2 , 5 ]. PLA is an aliphatic, renewable, biodegradable, biocompatible, and non-toxic thermoplastic, which breaks down into water and carbon dioxide; neither of them is hazardous to the environment [ 2 , 4 ]. Besides, this polymer has been highlighted in the biomedical area due to its adaptable physicochemical and degradation properties [ 2 ]. For example, in scaffold development, the degradation rate of PLA-based materials can be adapted to match the healing rate of natural tissues [ 2 ]. Nevertheless, there is an issue concerning the contamination of polymer materials by microorganisms, and for PLA, the situation is not different, which is susceptible to bacterial contamination [ 2 , 6 ]. Because of that, there are several research aiming to insert antibacterial fillers in this polymer matrix, such as silver [ 7 , 8 ], titanium dioxide [ 9 , 10 ]; silicon dioxide [ 11 ] and copper [ 12 ]. However, silver, one of the commonly used additives, presents a high cost and a hazardous, time-consuming production process [ 2 ]; silicon dioxide nanoparticles can demonstrate toxic effects, such as oxidative DNA damage [ 13 ]. Besides, copper-based materials may exhibit toxic human properties (Sania Naz et al., 2019), and titanium dioxide exhibits antimicrobial features with the availability of UV light [ 14 ]. Considering these challenges, there is a need for innovative antibacterial fillers that can be incorporated into the PLA matrix, especially in the healthcare field. Zinc oxide (ZnO) emerges as an interesting option, and its functionalizing as a filler in PLA has been explored in the literature as a promising material for biomedical engineering applications [ 2 ]. Enhancing PLA with ZnO has the potential to improve the therapeutic advantages of the polymer [ 15 ], showing that the ZnO fillers exhibit a promising tissue regenerative capacity and influence the degradation rate of PLA [ 2 ]. In addition to having regenerative capacity, the ZnO offers a well-established benefit of antibacterial properties, preventing bacterial adhesion, especially against common hospital-acquired bacteria [ 2 , 16 ]. The combination of these characteristics makes PLA-ZnO composites a viable alternative for 3D printing antibacterial materials, particularly in regenerative tissue engineering and scaffold development [ 17 ]. Another challenge related to tissue engineering is controlling the immune response after the implantation of scaffold devices [ 18 ]. For instance, in bone tissue implants, complex interactions occur between the physiological system cells and the implanted material, and the immune system’s response has been a crucial focus in the study and development of new biomaterials [ 19 ]. In tissue engineering, macrophages play an essential role in tissue homeostasis, where it is necessary to find an equilibrium between macrophages from the M1 phenotype (pro-inflammatory) and M2 phenotype (anti-inflammatory) to guarantee a smooth and timely transition from inflammatory to healing stage [ 18 ]. In this context, bioactive compounds can be incorporated in scaffolds for their local administration to promote bone healing efficiency by tackling several types of post-surgery complications due to infections and other biological processes that can impair proper tissue regeneration [ 20 ]. Thus, Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID), which is a commonly used anti-inflammatory drug in healthcare, known for its antipyretic and analgesic effects [ 21 ]; under inflammatory conditions, its nanoparticles can reduce M1 markers and increase anti-inflammatory cytokines [ 22 ]. Therefore, its incorporation in scaffold biomaterials can be advantageous, enabling them to control immune responses after implantation. Thus, this work aims to develop PLA-ZnO composites (0 and 5 wt.%) used for the entrapment of a nonsteroidal anti-inflammatory drug (NSAID) ketoprofen in filaments and 3D-printed. The physicochemical, thermal, mechanical, wettability and morphological properties, crystallinity, antibacterial activity, and viability test of the biodevices were evaluated. 2. MATERIAL AND METHODS 2.1. Materials The polymeric matrix used for the extruded filaments production was polylactic acid (PLA) provided by 3Dlab with a specific mass of 1.24 g cm − 3 , a glass transition temperature of 55°C, and a melting point of 172.6°C. Zinc oxide (ZnO) particles were provided by the company Sigma-Aldrich (CAS Number 1314-13-2), located in SP-Brazil. Ketoprofen was kindly provided by Sanofi (Sanofi-Aventis, France). 2.2. Methods 2.2.1. Filaments processing The composites were prepared according to Da Silva Neto et al., 2023, which used a thermokinect mixer (MH-50H, MH Equipamentos Ltda., São Paulo, Brazil) operating at 5250 rpm for the 60s. The homogenization process involved mixing 60 g of the biopolymer PLA with two different percentages of ZnO (0 and 5 wt.%) and one percentage of ketoprofen (3 wt.%), and the samples were designated PLA, PLA-ZnO5%, and PLA- ZnO5%-Keto3%, respectively. After ambient temperature exposure, the samples were ground in a knife mill machine (3.7 kW, Plastimax, Rio Grande do Sul, Brazil) and oven-dried (2 to 4 hours, 60°C). Furthermore, a bench-top extrusion system (Filmaq 3D, Curitiba, Paraná, Brazil) consisting of a single-screw extruder, a cooling/pulling unit, and a winding mechanism was employed. The schematic representation of the adopted methodology can be observed in Fig. 1 . To guarantee the adequacy of the filament’s extrusion; two parameters were considered: the necessary extrusion speed for achieving linear filaments and extrusion temperature according to each filament. The velocity to obtain filament was measured following the principles of uniform rectilinear motion, which recorded the time it took for the filament to go through a 12.8 cm distance. 2.3 Characterization 2.3.1. Density Filament densities were determined by averaging three diameter measurements from distinct sections of extruded filaments. A digital caliper rule was used for this purpose. Additionally, the weight of each sample was measured using an analytical balance. The density was calculated as the ratio of mass (g) to volume (cm − 3 ). 2.3.2 Fourier-transform infrared spectroscopy (FTIR) The chemical structures of PLA, ZnO, KETO, and their composite filaments were analyzed using Fourier-transform infrared spectroscopy (FTIR) (Frontier 94942 Model, PerkinElmer Inc., Massachusetts, USA) with an attenuated total reflectance (ATR) diamond accessory. The data was gathered through 64 scans, with a spectral resolution of 4 cm − 1 in the range of 4000 − 500 cm − 1 . 2.3.3. Thermogravimetric analysis (TGA) The thermal stability of composite filaments was evaluated using a thermal analyzer STA 6000 (PerkinElmer®, Inc., Massachusetts, USA) with a range temperature of 30–600 ºC. This analysis was conducted under a nitrogen (N 2 ) flow (20 ml min − 1 ) and a heating rate of 10ºC min − 1 . 2.3.4. Differential Scanning Calorimetry (DSC) This technique was carried out using a differential scanning calorimeter (DSC) (TA Instruments Q20, USA) to evaluate the thermal transformation in the materials. Samples were heated at 10°C/min from − 50 to 250°C. Thermograms were obtained by the second heating cycle to eliminate the influence of water on the samples. All experiments were performed under a nitrogen flow of 50 ml/min, indium standards were used for enthalpy and temperature calibration, and an empty aluminum pan was used as a reference. The degree of crystallinity of the extruded filaments ( \({X}_{c}\) ) was calculated based on the reduction in the enthalpy of crystallization of the polymer after extrusion by hot extrusion, according to the equation below. $${X}_{c}=\frac{\varDelta H}{\varDelta {H}^{^\circ }\left(1-{w}_{t}\right)}$$ 1 Where: \({w}_{t}\) is the weight fraction of reinforcement, \(\varDelta H\) is the melting enthalpy, \(\varDelta {H}^{^\circ }\) is the melting enthalpy of the 100% crystalline polymer (crystalline PLA = 93 J/g) [ 23 ]. 2.3.5. Wettability (CA) A Ramé-Hart contact angle goniometer model 300-F1 (Succasunna, USA) was employed to analyze the surface wettability of PLA scaffolds and their bioactive composites. A total of 50 measurements were conducted using an average of 5µL of water drops. The pressing procedure was performed with a hydro-pneumatic press by MH Equipamentos, São Paulo, Brazil. 2.3.7. Morphology of filaments and Surface roughness Filament and scaffold morphologies were observed using a cross-section section (pristine PLA and their composite filaments) investigated by Scanning Electron Microscopy (SEM) with FEG Schottky electron emission on MEV-FEG TESCAN Mira 4. The filament samples were affixed to carbon tape within a sample holder. This analysis adopted secondary electron mode (SE) and backscattered electron mode (BSE) at 5 keV. For analysis of the surface roughness of filaments, the parameter arithmetic average roughness (Ra) was measured. The roughness tests were performed in triplicate along the length of each filament using a portable SJ-201 Model device from Mitutoyo Corporation Ltd. 2.3.8. 3D printing and morphology of scaffolds Circular scaffolds with dimensions of 10.7 ± 0.3 × 10.8 ± 0.4 × 3.7 ± 0.4 (length × width × height) with an orthogonal-projection structure were designed in CAD 3D Inventor software, with printer parameters adopted for each filament type, according to conditions cited in Table 1 . Different processing temperatures to adapt the equipment to the diverse composite conditions were used. Table 1 Fused Deposition Modeling parameters to print the scaffolds with the obtained PLA and their composite filaments. Printing Parameters Pristine PLA PLA-ZnO5% PLA-ZnO5%-3%Keto Nozzle Temperature (ºC) 200 250 250 Bed Temperature (ºC) 60 70 70 Cooling (%) 80 80 80 1st printed layer speed (mm s − 1 ) 15 17.5 17.5 Print speed (mm s − 1 ) 40 35 35 1st printed layer height (mm) 0.3 0.3 0.3 Height of subsequent layers (mm) 0.1 0.06 0.06 The morphological analysis of the 3D printed scaffolds was carried out by Scanning Electron Microscope (SEM) with FEG Schottky electron emission on MEV-FEG TESCAN Mira 4 in secondary electron mode (SE) and backscattered electron mode (BSE) at 5keV. For this analysis, samples are fixed on carbon tape in a sample holder. 2.3.9. Compression Strength Compression strength analysis was performed by EMIC testing machine (model DL10000), with a crosshead speed of 1 mm.min-1. Three cylindrical shape models from each material were produced by the 3D printing process with 100% of infill density and dimensions of 9.6 ± 0.09 x 6.9 ± 0.08 mm (length x diameter) (L = 2D), and they were subjected to a compression load, according to ASTM D695. The compressive strength was calculated by the ratio of the maximum load per the cross-section area of the cylinder. Figure 2 indicates the schematic process of this test. 2.3.10 Antibacterial activity For the initial disk diffusion test on agar, plates were prepared with agar and then inoculated with a suspension of the bacteria of interest at turbidity of 0.5 McFarland; Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922) e Pseudomonas aeruginosa (ATCC 10145). After the plate was dried, 6mm discs soaked in the test solution were placed on it, with one disc containing the antibiotic serving as a positive control. The plates were incubated for 24 hours at 35°C. The reading was taken by the formation of halos around the discs containing the material. 2.3.11 Viability test The toxicity test was initiated using the disk diffusion method. Five milliliters of a suspension containing 1.5 x 10 5 cells/mL of the 3T3 cell line were seeded in 60mm Petri dishes with a culture medium and incubated for 24 hours at 37°C in a greenhouse with a 5% CO 2 environment. After incubation, the liquid medium was discarded, and the solid medium was added to the cell mat. The agar was melted and mixed with the culture medium at 40°C, and 5mL of this mixture was added to the culture plates. Once the solid medium had hardened, the test membranes were placed in the center of the plates, and the plates were incubated at 37°C in a 5% CO 2 environment in the inverted position. Macroscopic readings of the inoculated plates were taken, where the presence of cytotoxicity was confirmed by the halo surrounding the toxic material, indicative of dead cells. When present, the diameters of the halos resulting from the cytotoxic effect were carefully measured using a millimeter ruler. Another test realized was the MTT viability. To make the test, the cells were growing, and after adherence, the cultures were exposed to the material for 24 hours (37°C, 5% CO2). After exposure, the wells were washed with PBS and 0.5 mg/mL MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) solution was added for 2 hours (37°C, 5% CO 2 ). After this period, the MTT solution was discarded, and DMSO was added. The absorbance corresponding to each well was obtained using a microplate reader at 540 nm. 3. RESULTS Processability and properties of filaments 3.1. Diameters, density, and speed analysis of filaments The diameter, density, extrusion speed, and roughness are crucial parameters for understanding the processing of filament material, as shown in Table 2 . Table 2 Average values and standard deviation of diameter, density, temperature, speed extrusion, and roughness for each filament. Sample Diameter (mm) Density (g.cm − 3 ) Temperature Extrusion ( o C) Speed Extrusion (cm.s − 1 ) Roughness Ra (µm) Pristine PLA 1.6 ± 0.004 1.1 ± 0.1 190 3.9 ± 0.09 0.36 ± 0.07 PLA-5%ZnO 1.6 ± 0.008 1.0 ± 0.03 225 0.58 ± 0.02 0.54 ± 0.11 PLA-5%ZnO-4%Keto 1.7 ± 0.006 1.1 ± 0.2 230 0.98 ± 0.03 0.20 ± 0.09 PLA and its composites presented similar diameters and densities, with a low standard deviation demonstrating accuracy during the process [ 24 ]. This arrangement resulted in the most favorable results and improved precision during the 3D printing process. Besides, adaptations in operational conditions were necessary to guarantee the composite processing. In this context, there was a reduction of 572% in PLA-5%ZnO and 298% in PLA-5%ZnO-3%Keto in speed extrusion, indicating more challenging processing when compared to pristine PLA. This phenomenon may be attributed to the increase in thermal resistance and melting temperature (as seen in temperature extrusion) resulting from the filler incorporation. Furthermore, the low standard deviation values may indicate a satisfactory blending of the components [ 25 ]. The PLA composite with the addition of ketoprofen showed the lowest roughness among the samples, indicating a higher miscibility between the filler and the PLA in this filament, this is an important result for obtaining a good printable performance. Therefore, a key aspect of filament formulation is determining the right amount of drug for optimal extrusion and printing properties, as these affect the filament's plasticity and drug release profile. High miscibility between the drug and polymer reduces viscosity, which is essential for good rheological characteristics [ 26 ]. Dissolved drugs act as plasticizers, lowering viscosity and the glass transition temperature. However, undissolved drugs can impair mechanical and rheological properties during extrusion, making the filaments brittle and prone to breaking under stress, while larger particles can clog the nozzle and increase viscosity [ 27 ]. 3.2. Fourier-transform infrared spectroscopy (FTIR) Figure 3 shows the FTIR spectra for the ZnO particles, Ketoprofen, pristine PLA, and their composites. Ketoprofen’s spectrum showed the characteristic absorptions at 2980 referring to C-H stretch; at 1693 and 1650 cm − 1 corresponding to the acid carbonyl (C = O) group and ketonic carbonyl (C = O) group; at 1597 cm − 1 due to the presence of aromatic C = C stretch; at 1441 cm − 1 due to the presence of CH-CH 3 deformation. Finally, the peaks at 966 and 716 cm − 1 are due to the presence of C-H out-of-plane deformation [ 28 ]. ZnO particles present peaks at 3381 cm − 1 , which can be attributed to the bending and stretching vibrations of surface hydroxyl groups, and at 831 cm − 1 corresponding to Zn–O stretching [ 15 , 29 ]. The PLA filament showed peaks at approximately 2920 cm − 1 caused by asymmetric and symmetric stretching vibrations of the –CH 2 group of saturated hydrocarbons. The hyper-conjugated system generated by the α-hydrogen atom and the carbonyl group in the PLA molecule resulted in the stretching vibration of –C = O at 1748 cm − 1 . In addition, PLA peaks were observed at 1452 cm − 1 (associating with CH 3 bending bands); at 1181 and 1082 cm − 1 (representing C–O–C stretching vibration caused by C–O forming bonds with different atoms or functional groups to develop more complex vibrational absorptions) and 755 and 667 cm − 1 attributed to the amorphous and crystalline phases, respectively [ 1 , 30 ]. These findings are similar to the FTIR spectrum of a PLA filament reported by Heydari-Majd et al. [ 31 ]. The incorporation of ZnO particles significantly changed the peaks in pristine PLA, such as the narrowing (increase of the intensification) of the peaks at 2920 and 1452 cm − 1 , the disappearance of the peak at 1748 cm − 1 , and the sharp reduction of the peaks in the 1400 − 1000 cm − 1 range. According to the literature, these results indicated that secondary forces like hydrogen bonds were formed between the PLA polymer and ZnO particles through chemical reactions [ 15 , 31 ]. The insertion of Ketoprofen on the polymeric structure caused a slight narrowing of the peaks situated at approximately 3084 and 3062 cm − 1 . Changes in the vibrational frequencies of the functional groups can be considered as the result of the presence of Ketoprofen in the polymer matrix [ 31 ]. Thus, the results indicate that the presence of ZnO particles and Ketoprofen alter the arrangement of the molecular and intermolecular interactions in the filament matrix. 3.3. Thermogravimetric analysis (TGA) Figure 4 shows the thermal profiles for the ZnO particles, Ketoprofen, pristine PLA, and their composites. Table 3 provides the results for the temperature at which the samples start to degrade (T onset ), when maximum thermal degradation is completed (T max ), and residual percentage (R%) at 600°C. Table 3 Weight loss (%), Onset temperature (T onset ), Maximum degradation temperature (T max ), and Residue at 600°C (R%) of ZnO, Ketoprofen, pristine PLA, and composites. Samples Weight loss (%) T onset (°C) T max (°C) R% 100 200 300 400 500 600 °C °C °C °C °C °C ZnO 2.5 12.2 22.8 31.5 34.7 36.0 61.4 - 64.0 Ketoprofen 0.0 0.51 47.38 79.7 100.0 100.0 177.4 288.5 0.0 Pristine PLA 0.0 0.0 0.0 5.0 97.7 98.4 268.5 474.7 1.6 PLA-5%ZnO 0.0 0.0 0.41 17.2 88.1 89.5 216.9 421.8 10.5 PLA-5%ZnO-3%Keto 0.0 0.0 0.89 20.6 84.7 87.6 239.7 421.2 14.4 In the ZnO particles’ thermal curve, any moisture was evaporated until it reached 100°C. As the temperature increased, the degradation of phenolic and flavonoid biomolecules (organic molecules) involved in the biosynthetic pathway was slow and continuous. Data above 400°C revealed great thermal stability and insignificant weight loss [ 32 , 33 ]. Concerning Ketoprofen, this material began its rapid degradation at approximately 177.4°C, corresponding to the breaking of the covalent bonds in its chemical structure [ 34 ]. The thermal degradation of pristine PLA started at 268.5°C (T onset ) and reached maximum degradation at 474.7°C (T max ). This behavior may be associated with the evaporation of water molecules from the pristine filament, followed by the degradation of the polymer chains due to the loss of the ester group [ 35 ]. With the addition of ZnO particles at 5%, the T onset started earlier (216.9°C) than with pristine PLA (268.5°C). The decrease in thermal stability of this composite filament was probably related to the decomposition of low-molecular-weight substances (organic groups) present in the particles [ 36 ]. Ahmad and coworkers reported a similar behavior when exploring the properties of cellulose nanocrystals-reinforced PLA composite filaments [ 37 ]. Other authors observed similar trends, such as Ghalsasi et al. [ 38 ] and Suryanegara et al. [ 39 ]. From the incorporation of Ketoprofen in the composite, it can be noted increase in thermal stability of composite filament compared to PLA-ZnO composite filament. This trend can be justified by ketoprofen acting as a barrier to the rapid thermal degradation of ZnO particles and the PLA matrix, slowing their mass loss. 3.4. Differential Scanning Calorimetry (DSC) DSC analyses were conducted to evaluate the degree of crystallinity and the glass transition and melting temperatures of the PLA and composite filaments (Fig. 5 ). The glass transition temperature ( \({T}_{g}\) ), the melting temperature ( \({T}_{m}\) ), the degree of crystallinity ( \({X}_{c}\) , %), and the melting enthalpy ( \(\varDelta {H}_{m}\) ) determined from the DSC results are presented in Table 4 . In the literature, it is reported that pure PLA has a glass transition temperature ( \({T}_{g}\) ) between 55 and 65°C and a maximum melting temperature ( \({T}_{m}\) ) between 175 and 180°C in the purely l-isomer form. However, there is a 5°C decrease in \({T}_{m}\) for every 1% increase in d-lactate in the polymer [ 17 ]. The PLA filaments generated in this study exhibited a \({T}_{g}\) of 71°C and a \({T}_{m}\) of approximately 140°C, suggesting that there is approximately 7% d-lactide in the PLA polymer used. Compared to the pure PLA filament, the PLA + 5%ZnO filament and the PLA + 5%ZnO + 3%KETO filament practically maintained the \({T}_{g}\) value, this phenomenon having already been observed in previous studies containing the addition of ZnO filler [ 17 , 40 ]. Furthermore, as the DSC curves did not show the characteristic melting peak of ketoprofen (94°C) [ 41 ], we can state that the drug had a complete conversion to the amorphous state and complete solubilization in the matrix [ 42 , 43 ]. Table 4 DSC thermal parameters, such as melting temperature (T m ), enthalpy (ΔH), and crystallinity (X c ) of PLA, PLA-ZnO5%, and PLA-ZnO5%-KETO3% filaments. Samples ΔH m (J.g − 1 ) X c (%) 𝑇𝑔 (℃) T m1 (℃) T m2 (℃) Pure PLA 2.55 2.74 68.57 108.98 141.34 PLA-5%ZnO 2.28 2.58 70.51 110.68 142.69 PLA-5%ZnO-3%KETO 2.19 2.17 68.81 108.49 140.79 Regarding the values found for \({T}_{m}\) , it can be observed that the addition of 5% ZnO caused a slight increase in \({T}_{m}\) , on the other hand, the addition of ketoprofen in the PLA + 5%ZnO sample caused a decrease in \({T}_{m}\) which could be explained by the Keto mix in the matrix. The ZnO and Keto content did not have a significant influence on the thermal properties of the biocomposite filaments, which shows that they have little influence on the intermolecular interactions or the flexibility of the PLA polymer chain [ 15 ]. As for crystallinity, the degrees of crystallinity of the biocomposite filaments with PLA increased compared to those of pure PLA. This result indicated that ZnO increased the crystalline portion of the matrix and, consequently, acted as a nucleating agent for the PLA chains. This phenomenon has been previously reported in the literature [ 15 , 17 ]. 3.5 Morphology of filaments Figure 6 shows the fractured filament morphology obtained by SEM. Pristine PLA presented a smooth and homogeneous surface compared to composites [ 30 ]. Besides, with the addition of ZnO content, it could be noticed an increase in white spots and a higher roughness surface, as seen in Table 2 [ 30 ]. This increase in surface roughness (Ra) is associated with structural modification caused by the insertion of ZnO in the polymer matrix, which can influence the selective protein adsorption process onto the biomaterial [ 44 ]. In contrast, PLA-5%ZnO-Keto revealed a reduction in roughness and an increase of distributed pores with interlayer and inner-layer voids (represented by white arrows)[ 45 ]. Properties of scaffolds 3.6 Morphology of scaffolds Figure 7 displays the SEM images of scaffold morphology with different magnitudes. An irregular surface can be seen on all scaffolds. The pure micrograph of PLA shows a robust structure with an intact cell wall. After incorporating ZnO (5 wt.%) into the polymer matrix, a deformed structure with broken walls was observed. However, when ZnO (5 wt.%) and Keto (3 wt. 3%) were inserted, the scaffold acquired a more robust structure, with an irregular shape and well-defined porosity, presenting less roughness (Fig. 8 ). Similar behavior was reported by Zarei et al. [ 46 ] when evaluating the morphology and 3D printing properties of PLA/Ti6Al4V biocomposite scaffolds, further reporting that the major challenge of the biocomposite manufacturing process is to ensure uniform distribution of the load in the matrix. 3.7. Wettability (WCA) and surface roughness The water contact angle (WCA) measurement is a crucial and widely accepted approach for examining the wettability of polymer surfaces [ 47 ]. An important term of this analysis is the “apparent contact angle,” which refers to the average angle observed along the entire three-phase contact line of a water droplet. This angle is determined after the rapid removal of the needle from the droplet deposited on the material surface. Figure 8 shows the water contact angle and surface roughness of pristine PLA, PLA-ZnO5%, and PLA-ZnO5%-Keto3% scaffolds composites and their standard deviation. Observing the results, the PLA-ZnO-5% composite presented the highest water contact angle when compared to the other scaffolds, but none of them can be considered hydrophobic surfaces [ 48 ]. Pristine PLA presented a WCA of 77.5º, consistent with the ranges (60 to 80 degrees) reported in previous literature [ 49 ]. These measurements can be associated with the methyl groups in the PLA chemical structure [ 50 ]. However, surface wettability depends on various parameters such as materials, building orientation, and infill density[ 51 ], and these factors may cause changes in the contact angle. Considering the addition of ZnO in the PLA matrix, there is an observed increase of 6% in the WCA. Insoo Kim et al., 2019 also reported a similar behavior when studied PLA/ZnO bionanocomposites films. Pristine PLA films showed a WCA of 60.7º, while with the increase of ZnO in PLA matrix, the WCA rosed to 92.6º. They attributed this change to variations in surface roughness and chemical affinity of the ZnO bionanocomposties films. The incorporation of Ketoprofen into the PLA structure led to a reduction in the water contact angle (16% compared to the PLA/ZnO composite), enhancing the material's hydrophilicity. Due to the presence of acid groups in their molecular structures, NSAIDs demonstrate a high level of hydrophilicity, resulting in significant water solubility [ 52 ]. This property can explain the notable phenomenon of contact angle reduction in the PLA/ZnO/Keto composite. While this can be advantageous, as hydrophilic surfaces generally favor cell proliferation, allowing for the reorganization of fibronectins [ 53 ], it is crucial to note that this phenomenon is also linked to cell spreading, proliferation, and differentiation [ 54 ]. However, additional analyses are necessary to determine the biocompatibility of these materials. Furthermore, as it was mentioned, the addition of ketoprofen decreased the roughness of the filaments and scaffolds. Figure 7 showed that the increase in roughness is related to the increase in the contact angle, this effect is commonly known as the Lotus Effect [ 55 ]. Hydrophilicity is also crucial for medical applications. According to Barberi (2021), hydrophilic surfaces can promote interactions with surface proteins, thereby favoring adsorption on wettable surfaces [ 56 ]. 3.9. Compression Strength Concerning the bioengineering field, studying the compression resistance and the elastic modulus of materials is crucial, especially considering that bones typically experience this type of stress. Therefore, they present an impact on mechanical stability, durability, load bearing capacity, promotion of osteogenesis, and the direct comfort of patients with implants and scaffolds [ 57 ]. Figure 9 shows the compressive strength of pristine PLA and their composites. Observing the graph, it is evident that there are higher values of compressive strength compared to the major literature [ 58 ]. Pushpendra Yadav et al., 2020, studied the influence of different infill densities in 3D printed specimens and found the same order of magnitude for a cubic PLA sample with 80% infill density and attributed the great result to the strong bonding between the rasters and layers. Besides, when the material was being printed, there was a short travel distance of the nozzle, which helped in maintaining the high and uniform temperature of layers. Consequently, there was an improvement in the load bearing capacity when compared to less filled layers [ 59 ]. Furthermore, compared to pristine PLA, the composites presented a slight improvement in strength, with the following values: 144.57 ± 16.4 MPa, 160.83 ± 0.95 MPa and 155.96 ± 2.32 MPa for PLA, PLA/5%ZnO and PLA/5%ZnO/3%Keto respectively. It was noted an increase of 11% from pristine PLA to PLA reinforced with ZnO. The increase in compressive strength when ZnO was added, must be related to the formation of strong interfacial bonding between PLA and Zn [ 60 ]. 3.10. Antibacterial activity The tested material did not show bactericidal activity when using the strains Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 10145). No halos were observed around the discs of the evaluated material. 3.11. Viability test Assessment of cell viability and biocompatibility of the material showed that it did not cause cell death in the tested strain. The disc diffusion test showed that all membranes didn't have halo formation, indicating absent toxicity (Fig. 10 ). The formazan test results indicated no significant difference in the control (Fig. 11 ). Based on the results, these materials are probably inert, presenting only action related to the material that will be introduced into the base membrane. The fact that we did not find significant differences between exposures may indicate the neutrality of this membrane, where there is an indication of biocompatibility without any change in toxicity parameters. 4. CONCLUSION The incorporation of ZnO and ketoprofen (keto) into PLA filaments resulted in an improvement in biocompatibility. In vitro tests showed that the modified filaments had lower cell toxicity and better cell adhesion and proliferation compared to pure PLA. This indicates that composite materials are best suited for biomedical applications where interaction with biological tissues is critical. The addition of ZnO and keto did not compromise the mechanical and thermal properties of the PLA filaments. In fact, the composites showed a slight improvement in strength compared to pure PLA. The thermal stability of the filaments was also increased with the incorporation of ketoprofen, suggesting that these materials may be more durable under different operating conditions. The morphology of the filaments modified with ZnO and ketoprofen exhibited a more robust structure and well-defined porosity. These structural features are beneficial for tissue engineering applications as they can facilitate cell integration and growth within the implanted material. Despite the promising properties, the filaments containing ZnO, at the concentration evaluated, did not demonstrate antimicrobial activity against the bacteria Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa . This suggests that adjustments in ZnO concentration or the addition of other antimicrobial agents may be necessary to achieve the desired antimicrobial activity. The combination of ZnO and keto in PLA filaments shows great potential for improving the biomedical applications of PLA materials. The improvement in biocompatibility and mechanical resistance, combined with thermal stability, without compromising the intrinsic properties of PLA, points to the possibility of developing safer and more effective implants and medical devices. This study paves the way for additional research focused on optimizing ZnO and keto concentrations, as well as exploring other compounds that could complement the material's antimicrobial and anti-inflammatory properties. Future investigations may also consider in vivo testing to confirm the promising results obtained in vitro and evaluate the long-term immunological response of the composite materials. Declarations Author Contribution Credit StatementThalita Silva Neto: Conceptualization, Methodology, Formal analysis, Data curation, Investigation. Lana S. Maia: Validation, Formal analysis, Data curation, Writing e original draft, Visualization. Monique O. T. Conceição: Resources, Writing e review & editing, Supervision.Bianca B. Migliorini: Resources, Writing e review & editing, Funding acquisition. Maryana B. Silva: Validation, Formal analysis, Data curation, Writing e original draft, Visualization. Layde T Carvalho: Validation, Formal analysis, Data curation, Writing e original draft, Visualization. Maria Ismênia S. D. Faria: Resources, Writing e review & editing. Simone F. Medeiros: Resources, Writing e review & editing, Supervision. Renata Lima: Resources, Writing e review & editing, Supervision. Derval S. Rosa: Resources, Writing e review & editing, Supervision. Daniella R. Mulinari: Conceptualization, Investigation, Resources, Writing e review & editing, Project administration, Funding acquisition. ACKNOWLEDGEMENT The authors thank FAPERJ (E-26/211.829/2021, FAPESP 2020/13703-3 and 2021/14714-1, CNPq (grant #308053/2021-4, grant #403934/2021-4), and REVALORES for assistance. References T. da Silva Neto, J. V. G. de Freitas, R. F. S. Barbosa, S. F. Medeiros, D. S. Rosa, and D. R. 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Rosa","email":"","orcid":"","institution":"Federal University of ABC (UFABC)","correspondingAuthor":false,"prefix":"","firstName":"Derval","middleName":"S.","lastName":"Rosa","suffix":""},{"id":323499087,"identity":"df758d33-40d0-40e4-995e-8a47335b7756","order_by":10,"name":"Daniella R. Mulinari","email":"data:image/png;base64,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","orcid":"","institution":"State University of Rio de Janeiro (UERJ)","correspondingAuthor":true,"prefix":"","firstName":"Daniella","middleName":"R.","lastName":"Mulinari","suffix":""}],"badges":[],"createdAt":"2024-06-28 18:30:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4656369/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4656369/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10904-024-03275-1","type":"published","date":"2024-08-02T15:57:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60787934,"identity":"bbe906b5-c9ca-43b2-9c4d-64e42e6b5771","added_by":"auto","created_at":"2024-07-22 06:20:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34560,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of the adopted methodology to prepare the composites, obtain filaments, and scaffold.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/98ee457875d17800b50cc2bf.jpg"},{"id":60788389,"identity":"c0c7c184-6492-4b03-a718-d97b2bf015b1","added_by":"auto","created_at":"2024-07-22 06:28:49","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30639,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of compressive testing analysis.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/63fe026cfa701694c3d36514.jpg"},{"id":60787923,"identity":"67ce26e0-415a-46b9-bafb-a5b2d326294b","added_by":"auto","created_at":"2024-07-22 06:20:49","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43755,"visible":true,"origin":"","legend":"\u003cp\u003eFTIR spectra of Ketoprofen, ZnO particles, pristine PLA filament, and its composites: a) Ketoprofen, b) ZnO particles, and c) Pristine PLA and their composites.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/afc7fb09dbfeb13a8df9cd92.jpg"},{"id":60787932,"identity":"14cf92d6-0ba4-467e-8736-4b1d2d399d41","added_by":"auto","created_at":"2024-07-22 06:20:50","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":39351,"visible":true,"origin":"","legend":"\u003cp\u003e(a) The TGA thermograms of the ZnO, Ketoprofen, pristine PLA, and composites, and (b) The TGA first derivative curves of the ZnO, Ketoprofen, pristine PLA, and composites.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/9065a33ec380ac43446d0242.jpg"},{"id":60787925,"identity":"9e43a7a4-7eea-4347-ba9b-e6ee3bab30b0","added_by":"auto","created_at":"2024-07-22 06:20:49","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":31933,"visible":true,"origin":"","legend":"\u003cp\u003eDSC curves of PLA, PLA-ZnO5%, and PLA-ZnO5%-KETO3% filaments.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/8ead633ec9831316b20507fc.jpg"},{"id":60789706,"identity":"44232bcd-ae5d-405e-ba05-aefd31f28194","added_by":"auto","created_at":"2024-07-22 06:44:50","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":73202,"visible":true,"origin":"","legend":"\u003cp\u003eSEM images of fractured morphology filaments, with magnitudes: (a) 500X; (b) 1000X and (c) 5kX.\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/30138a57770b4305d2460e56.jpg"},{"id":60787930,"identity":"b83b61ba-ce42-4d2b-8a07-610030699ad7","added_by":"auto","created_at":"2024-07-22 06:20:50","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":56951,"visible":true,"origin":"","legend":"\u003cp\u003eSEM images of scaffolds, with magnitudes: (a) 20X; (b) 80X, and (c) 1000X.\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/bc4ce96d7296e46f4a63fec4.jpg"},{"id":60788997,"identity":"11aaf9cf-60ce-4b91-88df-4349a82f07ac","added_by":"auto","created_at":"2024-07-22 06:36:50","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":20225,"visible":true,"origin":"","legend":"\u003cp\u003eWater contact angle (WCA) and surface roughness (Ra) of pristine PLA, PLA-5% ZnO and PLA-5%ZnO-3%Keto composites scaffolds.\u003c/p\u003e","description":"","filename":"8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/d6e9f79550c1602878f5b059.jpg"},{"id":60788393,"identity":"4ade6212-acb7-4385-9ddd-12c1b9ca9745","added_by":"auto","created_at":"2024-07-22 06:28:50","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":16554,"visible":true,"origin":"","legend":"\u003cp\u003eCompressive strength (MPa) of the cylindrical composite samples.\u003c/p\u003e","description":"","filename":"9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/964b4c506ce2ff1f9aaac649.jpg"},{"id":60787928,"identity":"0fa45495-6565-482e-a21b-765d36c3ab8f","added_by":"auto","created_at":"2024-07-22 06:20:50","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":27254,"visible":true,"origin":"","legend":"\u003cp\u003eResults of agar disk diffusion analysis in 3T3 cells. The negative control was performed only with the empty disc, and the positive control was performed with a latex cord.\u003c/p\u003e","description":"","filename":"10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/deca1f4467d0f38244b29b8f.jpg"},{"id":60788392,"identity":"d8c08c43-345f-432a-a50f-6b50420eea1e","added_by":"auto","created_at":"2024-07-22 06:28:50","extension":"jpg","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":16277,"visible":true,"origin":"","legend":"\u003cp\u003eCell viability results using MTT test after 24h exposition with different materials.\u003c/p\u003e","description":"","filename":"11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/7c3fa20cea00f329b6617db9.jpg"},{"id":61793640,"identity":"6696f23a-f9db-4f4a-b9fc-1db90ad8d3f2","added_by":"auto","created_at":"2024-08-05 16:14:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1331193,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4656369/v1/4ec44cfd-6e23-40b3-9a2f-b2669f3fd5fb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Enhancing PLA Filament Biocompatibility by introducing ZnO and Ketoprofen","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eFused filament fabrication (FFF), also known as fused deposition modeling (FDM), is a versatile and highly scalable 3D printing technique that enables the layer-by-layer arrangement of solid objects from digital predefinitions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. During this process, the feedstock filament reaches its melting temperature, undergoes a phase change, is extruded from the nozzle, and then cools after the deposition of the layers onto the build platform [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Consequently, this procedure allows the fabrication of complex shapes and architectures, details of which could not be achieved by other molding technologies, such as injection [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne of the most applied segments of this technology is healthcare, mainly in the manufacturing and elaboration of plastic-based biomedical parts [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, a significant obstacle hindering the adoption of FFF in the clinical field is the absence of appropriate biodegradable, biocompatible, and therapeutic feedstocks [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hence, among the various biopolymers available, polylactic acid (PLA) has attracted attention due to its alternative to petroleum-based polymers such as acrylonitrile-butadiene-styrene (ABS), polypropylene (PP) and polystyrene (PS) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePLA is an aliphatic, renewable, biodegradable, biocompatible, and non-toxic thermoplastic, which breaks down into water and carbon dioxide; neither of them is hazardous to the environment [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Besides, this polymer has been highlighted in the biomedical area due to its adaptable physicochemical and degradation properties [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For example, in scaffold development, the degradation rate of PLA-based materials can be adapted to match the healing rate of natural tissues [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Nevertheless, there is an issue concerning the contamination of polymer materials by microorganisms, and for PLA, the situation is not different, which is susceptible to bacterial contamination [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Because of that, there are several research aiming to insert antibacterial fillers in this polymer matrix, such as silver [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], titanium dioxide [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]; silicon dioxide [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and copper [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, silver, one of the commonly used additives, presents a high cost and a hazardous, time-consuming production process [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]; silicon dioxide nanoparticles can demonstrate toxic effects, such as oxidative DNA damage [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Besides, copper-based materials may exhibit toxic human properties (Sania Naz et al., 2019), and titanium dioxide exhibits antimicrobial features with the availability of UV light [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Considering these challenges, there is a need for innovative antibacterial fillers that can be incorporated into the PLA matrix, especially in the healthcare field.\u003c/p\u003e \u003cp\u003eZinc oxide (ZnO) emerges as an interesting option, and its functionalizing as a filler in PLA has been explored in the literature as a promising material for biomedical engineering applications [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Enhancing PLA with ZnO has the potential to improve the therapeutic advantages of the polymer [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], showing that the ZnO fillers exhibit a promising tissue regenerative capacity and influence the degradation rate of PLA [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In addition to having regenerative capacity, the ZnO offers a well-established benefit of antibacterial properties, preventing bacterial adhesion, especially against common hospital-acquired bacteria [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The combination of these characteristics makes PLA-ZnO composites a viable alternative for 3D printing antibacterial materials, particularly in regenerative tissue engineering and scaffold development [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother challenge related to tissue engineering is controlling the immune response after the implantation of scaffold devices [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. For instance, in bone tissue implants, complex interactions occur between the physiological system cells and the implanted material, and the immune system\u0026rsquo;s response has been a crucial focus in the study and development of new biomaterials [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In tissue engineering, macrophages play an essential role in tissue homeostasis, where it is necessary to find an equilibrium between macrophages from the M1 phenotype (pro-inflammatory) and M2 phenotype (anti-inflammatory) to guarantee a smooth and timely transition from inflammatory to healing stage [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In this context, bioactive compounds can be incorporated in scaffolds for their local administration to promote bone healing efficiency by tackling several types of post-surgery complications due to infections and other biological processes that can impair proper tissue regeneration [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Thus, Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID), which is a commonly used anti-inflammatory drug in healthcare, known for its antipyretic and analgesic effects [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; under inflammatory conditions, its nanoparticles can reduce M1 markers and increase anti-inflammatory cytokines [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, its incorporation in scaffold biomaterials can be advantageous, enabling them to control immune responses after implantation.\u003c/p\u003e \u003cp\u003eThus, this work aims to develop PLA-ZnO composites (0 and 5 wt.%) used for the entrapment of a nonsteroidal anti-inflammatory drug (NSAID) ketoprofen in filaments and 3D-printed. The physicochemical, thermal, mechanical, wettability and morphological properties, crystallinity, antibacterial activity, and viability test of the biodevices were evaluated.\u003c/p\u003e"},{"header":"2. MATERIAL AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Materials\u003c/h2\u003e \u003cp\u003eThe polymeric matrix used for the extruded filaments production was polylactic acid (PLA) provided by 3Dlab with \u003cem\u003ea specific mass of 1.24 g cm\u003c/em\u003e\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e, a glass transition temperature of 55\u0026deg;C, and a melting point of 172.6\u0026deg;C. Zinc oxide (ZnO) particles were provided by the company Sigma-Aldrich (CAS Number 1314-13-2), located in SP-Brazil. Ketoprofen was kindly provided by Sanofi (Sanofi-Aventis, France).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Methods\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e2.2.1. Filaments processing\u003c/h2\u003e \u003cp\u003eThe composites were prepared according to Da Silva Neto et al., 2023, which used a thermokinect mixer (MH-50H, MH Equipamentos Ltda., S\u0026atilde;o Paulo, Brazil) operating at 5250 rpm for the 60s. The homogenization process involved mixing 60 g of the biopolymer PLA with two different percentages of ZnO (0 and 5 wt.%) and one percentage of ketoprofen (3 wt.%), and the samples were designated PLA, PLA-ZnO5%, and PLA- ZnO5%-Keto3%, respectively. After ambient temperature exposure, the samples were ground in a knife mill machine (3.7 kW, Plastimax, Rio Grande do Sul, Brazil) and oven-dried (2 to 4 hours, 60\u0026deg;C). Furthermore, a bench-top extrusion system (Filmaq 3D, Curitiba, Paran\u0026aacute;, Brazil) consisting of a single-screw extruder, a cooling/pulling unit, and a winding mechanism was employed. The schematic representation of the adopted methodology can be observed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo guarantee the adequacy of the filament\u0026rsquo;s extrusion; two parameters were considered: the necessary extrusion speed for achieving linear filaments and extrusion temperature according to each filament. The velocity to obtain filament was measured following the principles of uniform rectilinear motion, which recorded the time it took for the filament to go through a 12.8 cm distance.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Characterization\u003c/h2\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1. Density\u003c/h2\u003e \u003cp\u003eFilament densities were determined by averaging three diameter measurements from distinct sections of extruded filaments. A digital caliper rule was used for this purpose. Additionally, the weight of each sample was measured using an analytical balance. The density was calculated as the ratio of mass (g) to volume (cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2 Fourier-transform infrared spectroscopy (FTIR)\u003c/h2\u003e \u003cp\u003eThe chemical structures of PLA, ZnO, KETO, and their composite filaments were analyzed using Fourier-transform infrared spectroscopy (FTIR) (Frontier 94942 Model, PerkinElmer Inc., Massachusetts, USA) with an attenuated total reflectance (ATR) diamond accessory. The data was gathered through 64 scans, with a spectral resolution of 4 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in the range of 4000\u0026thinsp;\u0026minus;\u0026thinsp;500 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e2.3.3. Thermogravimetric analysis (TGA)\u003c/h2\u003e \u003cp\u003eThe thermal stability of composite filaments was evaluated using a thermal analyzer STA 6000 (PerkinElmer\u0026reg;, Inc., Massachusetts, USA) with a range temperature of 30\u0026ndash;600 \u0026ordm;C. This analysis was conducted under a nitrogen (N\u003csub\u003e2\u003c/sub\u003e) flow (20 ml min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and a heating rate of 10\u0026ordm;C min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.3.4. Differential Scanning Calorimetry (DSC)\u003c/h2\u003e \u003cp\u003eThis technique was carried out using a differential scanning calorimeter (DSC) (TA Instruments Q20, USA) to evaluate the thermal transformation in the materials. Samples were heated at 10\u0026deg;C/min from \u0026minus;\u0026thinsp;50 to 250\u0026deg;C. Thermograms were obtained by the second heating cycle to eliminate the influence of water on the samples. All experiments were performed under a nitrogen flow of 50 ml/min, indium standards were used for enthalpy and temperature calibration, and an empty aluminum pan was used as a reference.\u003c/p\u003e \u003cp\u003eThe degree of crystallinity of the extruded filaments (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{c}\\)\u003c/span\u003e\u003c/span\u003e) was calculated based on the reduction in the enthalpy of crystallization of the polymer after extrusion by hot extrusion, according to the equation below.\u003cdiv id=\"Equ1\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equ1\" name=\"EquationSource\"\u003e\n$${X}_{c}=\\frac{\\varDelta H}{\\varDelta {H}^{^\\circ }\\left(1-{w}_{t}\\right)}$$\u003c/div\u003e\u003cdiv class=\"EquationNumber\"\u003e1\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eWhere: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({w}_{t}\\)\u003c/span\u003e\u003c/span\u003e is the weight fraction of reinforcement, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varDelta H\\)\u003c/span\u003e\u003c/span\u003eis the melting enthalpy, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varDelta {H}^{^\\circ }\\)\u003c/span\u003e\u003c/span\u003e is the melting enthalpy of the 100% crystalline polymer (crystalline PLA\u0026thinsp;=\u0026thinsp;93 J/g) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e2.3.5. Wettability (CA)\u003c/h2\u003e \u003cp\u003eA Ram\u0026eacute;-Hart contact angle goniometer model 300-F1 (Succasunna, USA) was employed to analyze the surface wettability of PLA scaffolds and their bioactive composites. A total of 50 measurements were conducted using an average of 5\u0026micro;L of water drops. The pressing procedure was performed with a hydro-pneumatic press by MH Equipamentos, S\u0026atilde;o Paulo, Brazil.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e2.3.7. Morphology of filaments and Surface roughness\u003c/h2\u003e \u003cp\u003eFilament and scaffold morphologies were observed using a cross-section section (pristine PLA and their composite filaments) investigated by Scanning Electron Microscopy (SEM) with FEG Schottky electron emission on MEV-FEG TESCAN Mira 4. The filament samples were affixed to carbon tape within a sample holder. This analysis adopted secondary electron mode (SE) and backscattered electron mode (BSE) at 5 keV.\u003c/p\u003e \u003cp\u003eFor analysis of the surface roughness of filaments, the parameter arithmetic average roughness (Ra) was measured. The roughness tests were performed in triplicate along the length of each filament using a portable SJ-201 Model device from Mitutoyo Corporation Ltd.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e\u003cem\u003e2.3.8. 3D printing and\u003c/em\u003e morphology of \u003cem\u003escaffolds\u003c/em\u003e\u003c/h2\u003e \u003cp\u003eCircular scaffolds with dimensions of 10.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 \u0026times; 10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 \u0026times; 3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 (length \u003cem\u003e\u0026times;\u003c/em\u003e width \u0026times; height) with an orthogonal-projection structure were designed in CAD 3D Inventor software, with printer parameters adopted for each filament type, according to conditions cited in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Different processing temperatures to adapt the equipment to the diverse composite conditions were used.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFused Deposition Modeling parameters to print the scaffolds with the obtained PLA and their composite filaments.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrinting Parameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePristine PLA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePLA-ZnO5%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePLA-ZnO5%-3%Keto\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNozzle Temperature (\u0026ordm;C)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBed Temperature (\u0026ordm;C)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCooling (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1st printed layer speed (mm s\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026minus;\u0026thinsp;1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrint speed (mm s\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026minus;\u0026thinsp;1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1st printed layer height (mm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeight of subsequent layers (mm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe morphological analysis of the 3D printed scaffolds was carried out by Scanning Electron Microscope (SEM) with FEG Schottky electron emission on MEV-FEG TESCAN Mira 4 in secondary electron mode (SE) and backscattered electron mode (BSE) at 5keV. For this analysis, samples are fixed on carbon tape in a sample holder.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e2.3.9. Compression Strength\u003c/h2\u003e \u003cp\u003eCompression strength analysis was performed by EMIC testing machine (model DL10000), with a crosshead speed of 1 mm.min-1. Three cylindrical shape models from each material were produced by the 3D printing process with 100% of infill density and dimensions of 9.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 x 6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08 mm (length x diameter) (L\u0026thinsp;=\u0026thinsp;2D), and they were subjected to a compression load, according to ASTM D695. The compressive strength was calculated by the ratio of the maximum load per the cross-section area of the cylinder. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e indicates the schematic process of this test.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e2.3.10 Antibacterial activity\u003c/h2\u003e \u003cp\u003eFor the initial disk diffusion test on agar, plates were prepared with agar and then inoculated with a suspension of the bacteria of interest at turbidity of 0.5 McFarland; \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (ATCC 25923), \u003cem\u003eEscherichia coli\u003c/em\u003e (ATCC 25922) e \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (ATCC 10145). After the plate was dried, 6mm discs soaked in the test solution were placed on it, with one disc containing the antibiotic serving as a positive control. The plates were incubated for 24 hours at 35\u0026deg;C. The reading was taken by the formation of halos around the discs containing the material.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e2.3.11 Viability test\u003c/h2\u003e \u003cp\u003eThe toxicity test was initiated using the disk diffusion method. Five milliliters of a suspension containing 1.5 x 10\u003csup\u003e5\u003c/sup\u003e cells/mL of the 3T3 cell line were seeded in 60mm Petri dishes with a culture medium and incubated for 24 hours at 37\u0026deg;C in a greenhouse with a 5% CO\u003csub\u003e2\u003c/sub\u003e environment. After incubation, the liquid medium was discarded, and the solid medium was added to the cell mat. The agar was melted and mixed with the culture medium at 40\u0026deg;C, and 5mL of this mixture was added to the culture plates. Once the solid medium had hardened, the test membranes were placed in the center of the plates, and the plates were incubated at 37\u0026deg;C in a 5% CO\u003csub\u003e2\u003c/sub\u003e environment in the inverted position. Macroscopic readings of the inoculated plates were taken, where the presence of cytotoxicity was confirmed by the halo surrounding the toxic material, indicative of dead cells. When present, the diameters of the halos resulting from the cytotoxic effect were carefully measured using a millimeter ruler.\u003c/p\u003e \u003cp\u003eAnother test realized was the MTT viability. To make the test, the cells were growing, and after adherence, the cultures were exposed to the material for 24 hours (37\u0026deg;C, 5% CO2). After exposure, the wells were washed with PBS and 0.5 mg/mL MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) solution was added for 2 hours (37\u0026deg;C, 5% CO\u003csub\u003e2\u003c/sub\u003e). After this period, the MTT solution was discarded, and DMSO was added. The absorbance corresponding to each well was obtained using a microplate reader at 540 nm.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eProcessability and properties of filaments\u003c/span\u003e \u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Diameters, density, and speed analysis of filaments\u003c/h2\u003e \u003cp\u003eThe diameter, density, extrusion speed, and roughness are crucial parameters for understanding the processing of filament material, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAverage values and standard deviation of diameter, density, temperature, speed extrusion, and roughness for each filament.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSample\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiameter (mm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDensity (g.cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTemperature Extrusion (\u003csup\u003eo\u003c/sup\u003eC)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSpeed Extrusion (cm.s\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRoughness Ra (\u0026micro;m)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePristine PLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLA-5%ZnO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e0.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLA-5%ZnO-4%Keto\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e230\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePLA and its composites presented similar diameters and densities, with a low standard deviation demonstrating accuracy during the process [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This arrangement resulted in the most favorable results and improved precision during the 3D printing process. Besides, adaptations in operational conditions were necessary to guarantee the composite processing. In this context, there was a reduction of 572% in PLA-5%ZnO and 298% in PLA-5%ZnO-3%Keto in speed extrusion, indicating more challenging processing when compared to pristine PLA. This phenomenon may be attributed to the increase in thermal resistance and melting temperature (as seen in temperature extrusion) resulting from the filler incorporation. Furthermore, the low standard deviation values may indicate a satisfactory blending of the components [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The PLA composite with the addition of ketoprofen showed the lowest roughness among the samples, indicating a higher miscibility between the filler and the PLA in this filament, this is an important result for obtaining a good printable performance. Therefore, a key aspect of filament formulation is determining the right amount of drug for optimal extrusion and printing properties, as these affect the filament's plasticity and drug release profile. High miscibility between the drug and polymer reduces viscosity, which is essential for good rheological characteristics [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Dissolved drugs act as plasticizers, lowering viscosity and the glass transition temperature. However, undissolved drugs can impair mechanical and rheological properties during extrusion, making the filaments brittle and prone to breaking under stress, while larger particles can clog the nozzle and increase viscosity [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Fourier-transform infrared spectroscopy (FTIR)\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the FTIR spectra for the ZnO particles, Ketoprofen, pristine PLA, and their composites. Ketoprofen\u0026rsquo;s spectrum showed the characteristic absorptions at 2980 referring to C-H stretch; at 1693 and 1650 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e corresponding to the acid carbonyl (C\u0026thinsp;=\u0026thinsp;O) group and ketonic carbonyl (C\u0026thinsp;=\u0026thinsp;O) group; at 1597 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e due to the presence of aromatic C\u0026thinsp;=\u0026thinsp;C stretch; at 1441 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e due to the presence of CH-CH\u003csub\u003e3\u003c/sub\u003e deformation. Finally, the peaks at 966 and 716 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e are due to the presence of C-H out-of-plane deformation [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. ZnO particles present peaks at 3381 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, which can be attributed to the bending and stretching vibrations of surface hydroxyl groups, and at 831 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e corresponding to Zn\u0026ndash;O stretching [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe PLA filament showed peaks at approximately 2920 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e caused by asymmetric and symmetric stretching vibrations of the \u0026ndash;CH\u003csub\u003e2\u003c/sub\u003e group of saturated hydrocarbons. The hyper-conjugated system generated by the α-hydrogen atom and the carbonyl group in the PLA molecule resulted in the stretching vibration of \u0026ndash;C\u0026thinsp;=\u0026thinsp;O at 1748 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. In addition, PLA peaks were observed at 1452 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (associating with CH\u003csub\u003e3\u003c/sub\u003e bending bands); at 1181 and 1082 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (representing C\u0026ndash;O\u0026ndash;C stretching vibration caused by C\u0026ndash;O forming bonds with different atoms or functional groups to develop more complex vibrational absorptions) and 755 and 667 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e attributed to the amorphous and crystalline phases, respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. These findings are similar to the FTIR spectrum of a PLA filament reported by Heydari-Majd et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe incorporation of ZnO particles significantly changed the peaks in pristine PLA, such as the narrowing (increase of the intensification) of the peaks at 2920 and 1452 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, the disappearance of the peak at 1748 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, and the sharp reduction of the peaks in the 1400\u0026thinsp;\u0026minus;\u0026thinsp;1000 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e range. According to the literature, these results indicated that secondary forces like hydrogen bonds were formed between the PLA polymer and ZnO particles through chemical reactions [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe insertion of Ketoprofen on the polymeric structure caused a slight narrowing of the peaks situated at approximately 3084 and 3062 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Changes in the vibrational frequencies of the functional groups can be considered as the result of the presence of Ketoprofen in the polymer matrix [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Thus, the results indicate that the presence of ZnO particles and Ketoprofen alter the arrangement of the molecular and intermolecular interactions in the filament matrix.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Thermogravimetric analysis (TGA)\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the thermal profiles for the ZnO particles, Ketoprofen, pristine PLA, and their composites. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e provides the results for the temperature at which the samples start to degrade (T\u003csub\u003eonset\u003c/sub\u003e), when maximum thermal degradation is completed (T\u003csub\u003emax\u003c/sub\u003e), and residual percentage (R%) at 600\u0026deg;C.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eWeight loss (%), Onset temperature (T\u003csub\u003eonset\u003c/sub\u003e), Maximum degradation temperature (T\u003csub\u003emax\u003c/sub\u003e), and Residue at 600\u0026deg;C (R%) of ZnO, Ketoprofen, pristine PLA, and composites.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSamples\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eWeight loss (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eT\u003csub\u003eonset\u003c/sub\u003e (\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eR%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e200\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e300\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e400\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e500\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e600\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026deg;C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026deg;C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026deg;C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026deg;C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026deg;C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026deg;C\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eZnO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e31.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e34.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e36.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e61.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e64.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKetoprofen\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e79.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e100.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e100.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e177.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e288.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePristine PLA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e97.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e98.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e268.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e474.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePLA-5%ZnO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e88.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e89.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e216.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e421.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePLA-5%ZnO-3%Keto\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e84.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e87.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e239.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e421.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e14.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the ZnO particles\u0026rsquo; thermal curve, any moisture was evaporated until it reached 100\u0026deg;C. As the temperature increased, the degradation of phenolic and flavonoid biomolecules (organic molecules) involved in the biosynthetic pathway was slow and continuous. Data above 400\u0026deg;C revealed great thermal stability and insignificant weight loss [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Concerning Ketoprofen, this material began its rapid degradation at approximately 177.4\u0026deg;C, corresponding to the breaking of the covalent bonds in its chemical structure [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe thermal degradation of pristine PLA started at 268.5\u0026deg;C (T\u003csub\u003eonset\u003c/sub\u003e) and reached maximum degradation at 474.7\u0026deg;C (T\u003csub\u003emax\u003c/sub\u003e). This behavior may be associated with the evaporation of water molecules from the pristine filament, followed by the degradation of the polymer chains due to the loss of the ester group [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith the addition of ZnO particles at 5%, the T\u003csub\u003eonset\u003c/sub\u003e started earlier (216.9\u0026deg;C) than with pristine PLA (268.5\u0026deg;C). The decrease in thermal stability of this composite filament was probably related to the decomposition of low-molecular-weight substances (organic groups) present in the particles [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Ahmad and coworkers reported a similar behavior when exploring the properties of cellulose nanocrystals-reinforced PLA composite filaments [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Other authors observed similar trends, such as Ghalsasi et al. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and Suryanegara et al. [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. From the incorporation of Ketoprofen in the composite, it can be noted increase in thermal stability of composite filament compared to PLA-ZnO composite filament. This trend can be justified by ketoprofen acting as a barrier to the rapid thermal degradation of ZnO particles and the PLA matrix, slowing their mass loss.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Differential Scanning Calorimetry (DSC)\u003c/h2\u003e \u003cp\u003eDSC analyses were conducted to evaluate the degree of crystallinity and the glass transition and melting temperatures of the PLA and composite filaments (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The glass transition temperature (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{g}\\)\u003c/span\u003e\u003c/span\u003e), the melting temperature (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{m}\\)\u003c/span\u003e\u003c/span\u003e), the degree of crystallinity (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{c}\\)\u003c/span\u003e\u003c/span\u003e, %), and the melting enthalpy (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varDelta {H}_{m}\\)\u003c/span\u003e\u003c/span\u003e) determined from the DSC results are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. In the literature, it is reported that pure PLA has a glass transition temperature (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{g}\\)\u003c/span\u003e\u003c/span\u003e) between 55 and 65\u0026deg;C and a maximum melting temperature (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{m}\\)\u003c/span\u003e\u003c/span\u003e) between 175 and 180\u0026deg;C in the purely l-isomer form. However, there is a 5\u0026deg;C decrease in \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{m}\\)\u003c/span\u003e\u003c/span\u003e for every 1% increase in d-lactate in the polymer [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The PLA filaments generated in this study exhibited a \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{g}\\)\u003c/span\u003e\u003c/span\u003e of 71\u0026deg;C and a \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{m}\\)\u003c/span\u003e\u003c/span\u003e of approximately 140\u0026deg;C, suggesting that there is approximately 7% d-lactide in the PLA polymer used.\u003c/p\u003e \u003cp\u003eCompared to the pure PLA filament, the PLA\u0026thinsp;+\u0026thinsp;5%ZnO filament and the PLA\u0026thinsp;+\u0026thinsp;5%ZnO\u0026thinsp;+\u0026thinsp;3%KETO filament practically maintained the \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{g}\\)\u003c/span\u003e\u003c/span\u003e value, this phenomenon having already been observed in previous studies containing the addition of ZnO filler [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Furthermore, as the DSC curves did not show the characteristic melting peak of ketoprofen (94\u0026deg;C) [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], we can state that the drug had a complete conversion to the amorphous state and complete solubilization in the matrix [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDSC thermal parameters, such as melting temperature (T\u003csub\u003em\u003c/sub\u003e), enthalpy (ΔH), and crystallinity (X\u003csub\u003ec\u003c/sub\u003e) of PLA, PLA-ZnO5%, and PLA-ZnO5%-KETO3% filaments.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSamples\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eΔH\u003csub\u003em\u003c/sub\u003e (J.g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003csub\u003ec\u003c/sub\u003e (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026#119879;\u0026#119892; (℃)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT\u003csub\u003em1\u003c/sub\u003e(℃)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT\u003csub\u003em2\u003c/sub\u003e(℃)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePure PLA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e68.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e108.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e141.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePLA-5%ZnO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e70.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e110.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e142.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePLA-5%ZnO-3%KETO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e68.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e108.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e140.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding the values found for \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{m}\\)\u003c/span\u003e\u003c/span\u003e, it can be observed that the addition of 5% ZnO caused a slight increase in \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{m}\\)\u003c/span\u003e\u003c/span\u003e, on the other hand, the addition of ketoprofen in the PLA\u0026thinsp;+\u0026thinsp;5%ZnO sample caused a decrease in \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{m}\\)\u003c/span\u003e\u003c/span\u003e which could be explained by the Keto mix in the matrix. The ZnO and Keto content did not have a significant influence on the thermal properties of the biocomposite filaments, which shows that they have little influence on the intermolecular interactions or the flexibility of the PLA polymer chain [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs for crystallinity, the degrees of crystallinity of the biocomposite filaments with PLA increased compared to those of pure PLA. This result indicated that ZnO increased the crystalline portion of the matrix and, consequently, acted as a nucleating agent for the PLA chains. This phenomenon has been previously reported in the literature [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Morphology of filaments\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e shows the fractured filament morphology obtained by SEM. Pristine PLA presented a smooth and homogeneous surface compared to composites [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Besides, with the addition of ZnO content, it could be noticed an increase in white spots and a higher roughness surface, as seen in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This increase in surface roughness (Ra) is associated with structural modification caused by the insertion of ZnO in the polymer matrix, which can influence the selective protein adsorption process onto the biomaterial [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In contrast, PLA-5%ZnO-Keto revealed a reduction in roughness and an increase of distributed pores with interlayer and inner-layer voids (represented by white arrows)[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eProperties of scaffolds\u003c/span\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Morphology of scaffolds\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e displays the SEM images of scaffold morphology with different magnitudes. An irregular surface can be seen on all scaffolds. The pure micrograph of PLA shows a robust structure with an intact cell wall. After incorporating ZnO (5 wt.%) into the polymer matrix, a deformed structure with broken walls was observed. However, when ZnO (5 wt.%) and Keto (3 wt. 3%) were inserted, the scaffold acquired a more robust structure, with an irregular shape and well-defined porosity, presenting less roughness (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). Similar behavior was reported by Zarei et al. [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] when evaluating the morphology and 3D printing properties of PLA/Ti6Al4V biocomposite scaffolds, further reporting that the major challenge of the biocomposite manufacturing process is to ensure uniform distribution of the load in the matrix.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e3.7. Wettability (WCA) and surface roughness\u003c/h2\u003e \u003cp\u003eThe water contact angle (WCA) measurement is a crucial and widely accepted approach for examining the wettability of polymer surfaces [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. An important term of this analysis is the \u0026ldquo;apparent contact angle,\u0026rdquo; which refers to the average angle observed along the entire three-phase contact line of a water droplet. This angle is determined after the rapid removal of the needle from the droplet deposited on the material surface. Figure\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e shows the water contact angle and surface roughness of pristine PLA, PLA-ZnO5%, and PLA-ZnO5%-Keto3% scaffolds composites and their standard deviation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eObserving the results, the PLA-ZnO-5% composite presented the highest water contact angle when compared to the other scaffolds, but none of them can be considered hydrophobic surfaces [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Pristine PLA presented a WCA of 77.5\u0026ordm;, consistent with the ranges (60 to 80 degrees) reported in previous literature [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. These measurements can be associated with the methyl groups in the PLA chemical structure [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. However, surface wettability depends on various parameters such as materials, building orientation, and infill density[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e], and these factors may cause changes in the contact angle.\u003c/p\u003e \u003cp\u003eConsidering the addition of ZnO in the PLA matrix, there is an observed increase of 6% in the WCA. Insoo Kim et al., 2019 also reported a similar behavior when studied PLA/ZnO bionanocomposites films. Pristine PLA films showed a WCA of 60.7\u0026ordm;, while with the increase of ZnO in PLA matrix, the WCA rosed to 92.6\u0026ordm;. They attributed this change to variations in surface roughness and chemical affinity of the ZnO bionanocomposties films.\u003c/p\u003e \u003cp\u003eThe incorporation of Ketoprofen into the PLA structure led to a reduction in the water contact angle (16% compared to the PLA/ZnO composite), enhancing the material's hydrophilicity. Due to the presence of acid groups in their molecular structures, NSAIDs demonstrate a high level of hydrophilicity, resulting in significant water solubility [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. This property can explain the notable phenomenon of contact angle reduction in the PLA/ZnO/Keto composite. While this can be advantageous, as hydrophilic surfaces generally favor cell proliferation, allowing for the reorganization of fibronectins [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], it is crucial to note that this phenomenon is also linked to cell spreading, proliferation, and differentiation [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. However, additional analyses are necessary to determine the biocompatibility of these materials.\u003c/p\u003e \u003cp\u003eFurthermore, as it was mentioned, the addition of ketoprofen decreased the roughness of the filaments and scaffolds. Figure\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e showed that the increase in roughness is related to the increase in the contact angle, this effect is commonly known as the Lotus Effect [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Hydrophilicity is also crucial for medical applications. According to Barberi (2021), hydrophilic surfaces can promote interactions with surface proteins, thereby favoring adsorption on wettable surfaces [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003e3.9. Compression Strength\u003c/h2\u003e \u003cp\u003eConcerning the bioengineering field, studying the compression resistance and the elastic modulus of materials is crucial, especially considering that bones typically experience this type of stress. Therefore, they present an impact on mechanical stability, durability, load bearing capacity, promotion of osteogenesis, and the direct comfort of patients with implants and scaffolds [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Figure\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e shows the compressive strength of pristine PLA and their composites.\u003c/p\u003e \u003cp\u003eObserving the graph, it is evident that there are higher values of compressive strength compared to the major literature [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Pushpendra Yadav et al., 2020, studied the influence of different infill densities in 3D printed specimens and found the same order of magnitude for a cubic PLA sample with 80% infill density and attributed the great result to the strong bonding between the rasters and layers. Besides, when the material was being printed, there was a short travel distance of the nozzle, which helped in maintaining the high and uniform temperature of layers. Consequently, there was an improvement in the load bearing capacity when compared to less filled layers [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFurthermore, compared to pristine PLA, the composites presented a slight improvement in strength, with the following values: 144.57\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4 MPa, 160.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95 MPa and 155.96\u0026thinsp;\u0026plusmn;\u0026thinsp;2.32 MPa for PLA, PLA/5%ZnO and PLA/5%ZnO/3%Keto respectively. It was noted an increase of 11% from pristine PLA to PLA reinforced with ZnO. The increase in compressive strength when ZnO was added, must be related to the formation of strong interfacial bonding between PLA and Zn [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003e3.10. Antibacterial activity\u003c/h2\u003e \u003cp\u003eThe tested material did not show bactericidal activity when using the strains \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (ATCC 25923), \u003cem\u003eEscherichia coli\u003c/em\u003e (ATCC 25922) and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (ATCC 10145). No halos were observed around the discs of the evaluated material.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section2\"\u003e \u003ch2\u003e3.11. Viability test\u003c/h2\u003e \u003cp\u003eAssessment of cell viability and biocompatibility of the material showed that it did not cause cell death in the tested strain. The disc diffusion test showed that all membranes didn't have halo formation, indicating absent toxicity (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e10\u003c/span\u003e). The formazan test results indicated no significant difference in the control (Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBased on the results, these materials are probably inert, presenting only action related to the material that will be introduced into the base membrane. The fact that we did not find significant differences between exposures may indicate the neutrality of this membrane, where there is an indication of biocompatibility without any change in toxicity parameters.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. CONCLUSION","content":"\u003cp\u003eThe incorporation of ZnO and ketoprofen (keto) into PLA filaments resulted in an improvement in biocompatibility. In vitro tests showed that the modified filaments had lower cell toxicity and better cell adhesion and proliferation compared to pure PLA. This indicates that composite materials are best suited for biomedical applications where interaction with biological tissues is critical. The addition of ZnO and keto did not compromise the mechanical and thermal properties of the PLA filaments. In fact, the composites showed a slight improvement in strength compared to pure PLA. The thermal stability of the filaments was also increased with the incorporation of ketoprofen, suggesting that these materials may be more durable under different operating conditions. The morphology of the filaments modified with ZnO and ketoprofen exhibited a more robust structure and well-defined porosity. These structural features are beneficial for tissue engineering applications as they can facilitate cell integration and growth within the implanted material. Despite the promising properties, the filaments containing ZnO, at the concentration evaluated, did not demonstrate antimicrobial activity against the bacteria Staphylococcus aureus, \u003cem\u003eEscherichia coli, and Pseudomonas aeruginosa\u003c/em\u003e. This suggests that adjustments in ZnO concentration or the addition of other antimicrobial agents may be necessary to achieve the desired antimicrobial activity. The combination of ZnO and keto in PLA filaments shows great potential for improving the biomedical applications of PLA materials. The improvement in biocompatibility and mechanical resistance, combined with thermal stability, without compromising the intrinsic properties of PLA, points to the possibility of developing safer and more effective implants and medical devices. This study paves the way for additional research focused on optimizing ZnO and keto concentrations, as well as exploring other compounds that could complement the material's antimicrobial and anti-inflammatory properties. Future investigations may also consider in vivo testing to confirm the promising results obtained in vitro and evaluate the long-term immunological response of the composite materials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eCredit StatementThalita Silva Neto: Conceptualization, Methodology, Formal analysis, Data curation, Investigation. Lana S. Maia: Validation, Formal analysis, Data curation, Writing e original draft, Visualization. Monique O. T. Concei\u0026ccedil;\u0026atilde;o: Resources, Writing e review \u0026amp; editing, Supervision.Bianca B. Migliorini: Resources, Writing e review \u0026amp; editing, Funding acquisition. Maryana B. Silva: Validation, Formal analysis, Data curation, Writing e original draft, Visualization. Layde T Carvalho: Validation, Formal analysis, Data curation, Writing e original draft, Visualization. Maria Ism\u0026ecirc;nia S. D. Faria: Resources, Writing e review \u0026amp; editing. Simone F. Medeiros: Resources, Writing e review \u0026amp; editing, Supervision. Renata Lima: Resources, Writing e review \u0026amp; editing, Supervision. Derval S. Rosa: Resources, Writing e review \u0026amp; editing, Supervision. Daniella R. Mulinari: Conceptualization, Investigation, Resources, Writing e review \u0026amp; editing, Project administration, Funding acquisition.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENT\u003c/h2\u003e \u003cp\u003eThe authors thank FAPERJ (E-26/211.829/2021, FAPESP 2020/13703-3 and 2021/14714-1, CNPq (grant #308053/2021-4, grant #403934/2021-4), and REVALORES for assistance.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eT. da Silva Neto, J. 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Yadav, A. Sahai, and R. S. Sharma, J. Inst. Eng. India Ser. C \u003cstrong\u003e102\u003c/strong\u003e, 197 (2021).\u003c/li\u003e\n\u003cli\u003eA. Kottasamy, M. Samykano, K. Kadirgama, M. Rahman, and M. M. Noor, Int J Adv Manuf Technol \u003cstrong\u003e119\u003c/strong\u003e, 5211 (2022).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-inorganic-and-organometallic-polymers-and-materials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joip","sideBox":"Learn more about [Journal of Inorganic and Organometallic Polymers and Materials](https://www.springer.com/journal/10904)","snPcode":"10904","submissionUrl":"https://submission.nature.com/new-submission/10904/3","title":"Journal of Inorganic and Organometallic Polymers and Materials","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Poly(lactic acid), zinc oxide, ketoprofen, filaments, biocompatibility.","lastPublishedDoi":"10.21203/rs.3.rs-4656369/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4656369/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study investigates the incorporation of zinc oxide (ZnO) and ketoprofen (keto) into poly(lactic acid) (PLA) filaments to enhance their biocompatible. PLA is widely used in additive manufacturing, especially in biomedical applications, due to its biodegradability and biocompatibility. However, its interaction with biological tissues can be improved. ZnO was chosen for its wound-healing properties, while keto, a nonsteroidal anti-inflammatory drug, was selected to provide local anti-inflammatory effects. PLA filaments were prepared by incorporating ZnO and keto, followed by analyses of their mechanical, thermal, and biological properties. The results showed that the incorporation of ZnO and keto did not compromise the mechanical and thermal properties of the PLA filaments. Compared to pristine PLA, the composites presented a slight improvement in strength. The incorporation of ketoprofen in the composite increased its thermal stability compared to PLA-ZnO filament. Concerning the morphology, when ZnO and Keto were inserted, the scaffold acquired a more robust structure, with well-defined porosity. In vitro biocompatibility tests indicated that the modified filaments exhibited lower cellular toxicity and improved cell adhesion and proliferation compared to pure PLA. Antimicrobial tests demonstrated that the filaments containing ZnO, at the evaluated concentration, did not exhibit activity against \u003cem\u003eStaphylococcus aureus\u003c/em\u003e, \u003cem\u003eEscherichia coli\u003c/em\u003e and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, gram-positive and gram-negative bacteria. The combination of ZnO and ketoprofen in PLA filaments can enhance their biomedical applications, providing better biocompatibility without compromising the intrinsic characteristics of PLA. This work paves the way for the development of safer and more effective medical implants and devices.\u003c/p\u003e","manuscriptTitle":"Enhancing PLA Filament Biocompatibility by introducing ZnO and Ketoprofen","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-22 06:20:45","doi":"10.21203/rs.3.rs-4656369/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-06T13:30:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-06T10:11:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198920231103251602052303812994478486649","date":"2024-07-04T14:53:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"71743811747066105171482424185669025865","date":"2024-07-02T16:15:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-01T15:15:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"188859886399054506477740563774029358727","date":"2024-07-01T14:54:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246850477643576699231291498711476142997","date":"2024-07-01T05:21:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187209237187851879393717890097387492027","date":"2024-06-30T21:03:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271421359116819164590724516165174395923","date":"2024-06-30T12:21:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192592961821865858768217037782874056992","date":"2024-06-30T07:34:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"142727639452717618226576061681330591476","date":"2024-06-30T06:03:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"53271072983122480471054143601900707599","date":"2024-06-29T16:58:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-29T14:41:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-29T12:38:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-29T05:35:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Inorganic and Organometallic Polymers and Materials","date":"2024-06-28T18:29:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-inorganic-and-organometallic-polymers-and-materials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joip","sideBox":"Learn more about [Journal of Inorganic and Organometallic Polymers and Materials](https://www.springer.com/journal/10904)","snPcode":"10904","submissionUrl":"https://submission.nature.com/new-submission/10904/3","title":"Journal of Inorganic and Organometallic Polymers and Materials","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"60c2fd7e-f6a1-46a3-94ef-f5d9631fc5e9","owner":[],"postedDate":"July 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T16:03:50+00:00","versionOfRecord":{"articleIdentity":"rs-4656369","link":"https://doi.org/10.1007/s10904-024-03275-1","journal":{"identity":"journal-of-inorganic-and-organometallic-polymers-and-materials","isVorOnly":false,"title":"Journal of Inorganic and Organometallic Polymers and Materials"},"publishedOn":"2024-08-02 15:57:42","publishedOnDateReadable":"August 2nd, 2024"},"versionCreatedAt":"2024-07-22 06:20:45","video":"","vorDoi":"10.1007/s10904-024-03275-1","vorDoiUrl":"https://doi.org/10.1007/s10904-024-03275-1","workflowStages":[]},"version":"v1","identity":"rs-4656369","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4656369","identity":"rs-4656369","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}