Additive Manufacturing Strategies for Personalized Drug Delivery Systems and Medical Devices: Fused Filament Fabrication and Semi Solid Extrusion

Novel additive manufacturing (AM) techniques and particularly 3D printing (3DP) have achieved a decade of success in pharmaceutical and biomedical fields. Highly innovative personalized therapeutical solutions may be designed and manufactured through a layer-by-layer approach starting from a digital model realized according to the needs of a specific patient or a patient group. The combination of patient-tailored drug dose, dosage, or diagnostic form (shape and size) and drug release adjustment has the potential to ensure the optimal patient therapy. Among the different 3D printing techniques, extrusion-based technologies, such as fused filament fabrication (FFF) and semi solid extrusion (SSE), are the most investigated for their high versatility, precision, feasibility, and cheapness. This review provides an overview on different 3DP techniques to produce personalized drug delivery systems and medical devices, highlighting, for each method, the critical printing process parameters, the main starting materials, as well as advantages and limitations. Furthermore, the recent developments of fused filament fabrication and semi solid extrusion 3DP are discussed. In this regard, the current state of the art, based on a detailed literature survey of the different 3D products printed via extrusion-based techniques, envisioning future directions in the clinical applications and diffusion of such systems, is summarized.     

Effects of Printing Parameters on Properties of FDM 3D Printed Residue of Astragalus/Polylactic Acid Biomass Composites

In order to develop a new kind of filament material for the fused deposition modeling (FDM) 3D printing, the residue of Astragalus (ROA), one of the most important Chinese herbal medicines, and polylactic acid were chosen as the raw materials to FDM 3D print biomass composite specimens, the effects of the printing parameters on the properties of the specimens were investigated. The results indicated that the mechanical properties and thermal stability of the printed specimen were affected obviously by the parameters while the melting and crystallization behavior of the specimens were little affected. For the wettability, it was also little affected by the printing parameter except for the printing speed. Increasing the printing temperature and the filling density or reducing the printing speed and the layer thickness could improve both the mechanical properties and the thermal stability of the FDM 3D printed PLA/ROA composite specimen; reducing the deposition angle could also improve the mechanical properties while having little effect on the thermal stability of the specimen.     

D-Sorbitol Physical Properties Effects on Filaments Used by 3D Printing Process for Personalized Medicine

Fused filament fabrication (FFF) is a process used to manufacture oral forms adapted to the needs of patients. Polyethylene oxide (PEO) filaments were produced by hot melt extrusion (HME) to obtain a filament suitable for the production of amiodarone hydrochloride oral forms by FFF 3D printing. In order to produce personalized oral forms adapted to the patient characteristics, filaments used by FFF must be controlled in terms of mass homogeneity along filament. This work highlights the relation between filament mass homogeneity and its diameter. This is why the impact of filler excipients physical properties was studied. It has been showed that the particle’s size distribution of the filler can modify the filament diameter variability which has had an impact on the mass of oral forms produced by FFF. Through this work it was shown that D-Sorbitol from Carlo Erba allows to obtain a diameter variability of less than 2% due to its unique particle’s size distribution. Using the filament produced by HME and an innovating calibration method based on the filament length, it has been possible to carry out three dosages of 125 mg, 750 mg and 1000 mg by 3D printing with acceptable mass uniformity.     

Limonene Derivative of Spherosilicate as a Polylactide Modifier for Applications in 3D Printing Technology

The first report of using limonene derivative of a spherosilicate as a modifier of polylactide used for 3D printing and injection moulding is presented. The paper presents the use of limonene-functionalized spherosilicate derivative as a functional additive. The study compared the material characteristics of polylactide modified with SS-Limonene (0.25–5.0% w/w) processed with traditional injection moulding and 3D printing (FFF, FDM). A significant improvement in the processing properties concerning rheology, inter-layer adhesion, and mechanical properties was achieved, which translated into the quality of the print and reduction of waste production. Moreover, the paper describes the elementary stages of thermal transformations of the obtained hybrid systems.     

Additive manufacturing of fire‐retardant ethylene‐vinyl acetate

Thermocompression (with also extrusion and injection molding) is a classical polymer shaping manufacturing, but it does not easily allow designing sophisticated shapes without using a complex mold, on the contrary to 3D printing (or polymer additive manufacturing), which is a very flexible technique. Among all 3D printing techniques, fused deposition modeling is of high potential for product manufacturing, with the capability to compete with conventional polymer processing techniques. This is a quite low cost 3D printing technique, but the range of filaments commercially available is limited. However, in some specific 3D printing processes, no filaments are necessary. Polymers pellets feed directly the printing nozzle allowing to investigate many polymeric matrices with no commercial limitation. This is of high interest for the design of flame‐retarded materials, but literature is scarce in that field. In this paper, a comparison between thermocompression and 3D printing processes was performed on both neat ethylene‐vinyl acetate (EVA) copolymer and EVA flame retarded with aluminum triHydroxyde (ATH) containing different loadings (30 or 65 wt%) and with expandable graphite (EG), ie, EVA/ATH (30 wt%), EVA/ATH (65 wt%), and EVA/EG (10 wt%), respectively. Morphological comparisons, using microscopic and electronic microprobe analyses, revealed that 3D printed plates have lower apparent density and higher porosity than thermocompressed plate. The fire‐retardant properties of thermocompressed and 3D printed plates were then evaluated using mass loss calorimeter test at 50 kW/m². Results highlight that 3D printing can be used to produce flame‐retardant systems. This work is a pioneer study exploring the feasibility of using polymer additive manufacturing technology for designing efficient flame‐retarded materials.     

光交联自支撑丝素蛋白水凝胶的三维快速成型

将丝素蛋白(SF)光诱导自交联原理与挤出式三维(3D)打印相结合, 开发了光交联自支撑SF水凝胶的原位成型加工技术. 采用旋转流变仪、 光流变测试系统和改装的挤出式3D打印设备等对SF溶液的流变性能、 光交联性能和成型加工性能等进行研究. 结果表明, SF溶液主要表现为黏性特征, 结构强度和稳定性均较差. 利用SF的光诱导自交联特性, 以三联吡啶氯化钌[Ru(Ⅱ)]和过硫酸钾(KPS)为蓝光引发体系, 可实现SF水凝胶的快速光交联成型. SF光交联行为符合指数函数增长模型, 因“滤镜效应”, 当Ru(Ⅱ)的浓度为0.05 mmol/L时, SF具有最佳的光交联性能. 通过调节气压、 针头孔径、 移动速度及固化速率等参数, 采用3D打印设备可实现从单层几何结构到多层三维网络构型SF凝胶材料的高效、 精准构建, 为SF的生物3D打印提供了新思路.     

Multifunctional properties of 3D printed poly(lactic acid)/graphene nanocomposites by fused deposition modeling

In this work, three-dimensional (3D) printing system based on fused deposition modeling (FDM) is used for the fabrication of conductive polymer nanocomposites. This technology consists in the additive multilayer deposition of polymeric nanocomposite based on poly(lactic acid) (PLA) and graphene by means of a in house made low-cost commercial bench-top 3D printer. Further, 3D printed PLA/graphene nanocomposites containing 10 wt% graphene in PLA matrix were characterized for their mechanical, electrical and electromagnetic induction shielding properties of the nanocomposite. Furthermore X-ray computed micro-tomography analyses showed that printed samples have good dimensional accuracy and are significantly closer to the predefined design and the results of scanning electron microscopy (SEM) printed samples showed a uniform dispersion of graphene in PLA matrix The proposed material has uniquely advantageous when implemented in 3D printed structures, because incorporation of multifunctional graphene has been shown to substantially improve the properties of the resulting nanocomposite.     

How to Obtain the Maximum Properties Flexibility of 3D Printed Ketoprofen Tablets Using Only One Drug-Loaded Filament?

The flexibility of dose and dosage forms makes 3D printing a very interesting tool for personalized medicine, with fused deposition modeling being the most promising and intensively developed method. In our research, we analyzed how various types of disintegrants and drug loading in poly(vinyl alcohol)-based filaments affect their mechanical properties and printability. We also assessed the effect of drug dosage and tablet spatial structure on the dissolution profiles. Given that the development of a method that allows the production of dosage forms with different properties from a single drug-loaded filament is desirable, we developed a method of printing ketoprofen tablets with different dose and dissolution profiles from a single feedstock filament. We optimized the filament preparation by hot-melt extrusion and characterized them. Then, we printed single, bi-, and tri-layer tablets varying with dose, infill density, internal structure, and composition. We analyzed the reproducibility of a spatial structure, phase, and degree of molecular order of ketoprofen in the tablets, and the dissolution profiles. We have printed tablets with immediate- and sustained-release characteristics using one drug-loaded filament, which demonstrates that a single filament can serve as a versatile source for the manufacturing of tablets exhibiting various release characteristics.     

Emission Profiles of Volatiles during 3D Printing with ABS,ASA, Nylon,and PETG Polymer Filaments

In this short communication we characterize the emission of volatile organic compounds (VOCs) from fused filament fabrication (FFF) 3D printing using four polymer materials, namely polyethylene terephthalate glycol-modified (PETG), acrylonitrile styrene acrylate (ASA), Nylon, and acrylonitrile butadiene styrene (ABS). Detailed emission profiles are obtained during thermal degradation of the polymers as a function of temperature and also in real-time during 3D printing. Direct quantitative measurement was performed using proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS). Qualitative determination of the volatiles emitted from the printed elements at various temperatures was accomplished using gas chromatography-mass spectrometry (GC-MS). The emission rates of VOCs differ significantly between the different polymer filaments, with the emission from Nylon and PETG more than an order of magnitude lower than that of ABS.     

Micro-Scale Cell Patterning on Nonfouling Plasma Polymerized Tetraglyme Coatings by Protein Microcontact Printing

Nonfouling thin films were prepared by the plasma deposition of tetraethylene glycol dimethyl ether (pp4G) on fluorinated ethylene propylene polymer (FEP) and glass substrates. Ordered cell patterns were created on these surfaces by microcontact printing of proteins. Pp4G was found to be stable in aqueous environments and resistant to an ethanol sterilization procedure, as verified by surface analysis. Pp4G also reduced nonspecific protein adsorption by more than 65-fold before and after sterilization. Despite the low adsorption of proteins to pp4G in solution, protein microcontact printing was achieved and we were able to print laminin, an adhesive extracellular matrix protein, from an elastomeric stamp onto pp4G. The printed laminin supported the attachment and spreading of cardiomyocytes and the nonprinted pp4G regions remained cell repulsive in culture conditions. Microscale patterns of cardiomyocytes were maintained on printed pp4G for more than 7 days. This cell patterning process should be viable for other cell types. The potential applications include tissue engineering and microdevices for biosensor, diagnostic, and pharmacological applications.     

3D Printing in analytical sample preparation

In the last 5 years, additive manufacturing (three‐dimensional printing) has emerged as a highly valuable technology to advance the field of analytical sample preparation. Three‐dimensional printing enabled the cost‐effective and rapid fabrication of devices for sample preparation, especially in flow‐based mode, opening new possibilities for the development of automated analytical methods. Recent advances involve membrane‐based three‐dimensional printed separation devices fabricated by print‐pause‐print and multi‐material three‐dimensional printing, or improved three‐dimensional printed holders for solid‐phase extraction containing sorbent bead packings, extraction disks, fibers, and magnetic particles. Other recent developments rely on the direct three‐dimensional printing of extraction sorbents, the functionalization of commercial three‐dimensional printable resins, or the coating of three‐dimensional printed devices with functional micro/nanomaterials. In addition, improved devices for liquid–liquid extraction such as extraction chambers, or phase separators are opening new possibilities for analytical method development combined with high‐performance liquid chromatography. The present review outlines the current state‐of‐the‐art of three‐dimensional printing in analytical sample preparation.     

4D Printing of Shape Memory‐Based Personalized Endoluminal Medical Devices

The convergence of additive manufacturing and shape‐morphing materials is promising for the advancement of personalized medical devices. The capability to transform 3D objects from one shape to another, right off the print bed, is known as 4D printing. Shape memory thermosets can be tailored to have a range of thermomechanical properties favorable to medical devices, but processing them is a challenge because they are insoluble and do not flow at any temperature. This study presents here a strategy to capitalize on a series of medical imaging modalities to construct a printable shape memory endoluminal device, exemplified by a tracheal stent. A methacrylated polycaprolactone precursor with a molecular weight of 10 000 g mol⁻¹ is printed with a UV‐LED stereolithography printer based on anatomical data. This approach converges with the zeitgeist of personalized medicine and it is anticipated that it will broadly expand the application of shape memory‐exhibiting biomedical devices to myriad clinical indications.

     

Three‐dimensional printing of poly(lactic acid) bio‐based composites with sugarcane bagasse fiber: Effect of printing orientation on tensile performance

The cellulose fiber was extracted from the abandoned crop sugarcane bagasse (SCB) by means of chemical treatment methods. Poly(lactic acid) (PLA) bio‐based composites with SCB were prepared through fused deposition modeling (FDM) 3D‐printing technology, and the morphologies, mechanical properties, crystallization properties, and thermal stability of 3D‐printed composites were investigated. Compared with the neat PLA, the incorporation of SCB into PLA reduces the tensile strength and flexural strength of 3D‐printed samples but increases the flexural modulus. The difference in tensile performance and bending performance is that the tensile strength of 3D‐printed samples is best when the SCB content is 6 wt%, while the flexural modulus continuously decreases as the SCB content increases. Furthermore, the effects of various printing methods on the tensile performance of 3D‐printed samples were explored via modifying G‐code of 3D models. The results indicate that the optimum SCB fiber content is identical for all printing methods except method “vertical.” Due to the fibers and molecular chains are oriented to varying degrees with altering raster angle in 3D‐printed samples, the fully oriented sample printed by method “parallel” has a better tensile strength. Besides, SCB exhibits enough high thermal decomposition temperature to meet requirements for melt extrusion processing of PLA composites, and SCB fiber is capable of promoting the crystallization of PLA.     

Rapid Formation of a Supramolecular Polypeptide–DNA Hydrogel for In Situ Three‐Dimensional Multilayer Bioprinting

A rapidly formed supramolecular polypeptide–DNA hydrogel was prepared and used for in situ multilayer three‐dimensional bioprinting for the first time. By alternative deposition of two complementary bio‐inks, designed structures can be printed. Based on their healing properties and high mechanical strengths, the printed structures are geometrically uniform without boundaries and can keep their shapes up to the millimeter scale without collapse. 3D cell printing was demonstrated to fabricate live‐cell‐containing structures with normal cellular functions. Together with the unique properties of biocompatibility, permeability, and biodegradability, the hydrogel becomes an ideal biomaterial for 3D bioprinting to produce designable 3D constructs for applications in tissue engineering.     

3D‐Printing inside the Glovebox: A Versatile Tool for Inert‐Gas Chemistry Combined with Spectroscopy

3D‐Printing with the well‐established ‘Fused Deposition Modeling’ technology was used to print totally gas‐tight reaction vessels, combined with printed cuvettes, inside the inert‐gas atmosphere of a glovebox. During pauses of the print, the reaction flasks out of acrylonitrile butadiene styrene were filled with various reactants. After the basic test reactions to proof the oxygen tightness and investigations of the influence of printing within an inert‐gas atmosphere, scope and limitations of the method are presented by syntheses of new compounds with highly reactive reagents, such as trimethylaluminium, and reaction monitoring via UV/VIS, IR, and NMR spectroscopy. The applicable temperature range, the choice of solvents, the reaction times, and the analytical methods have been investigated in detail. A set of reaction flasks is presented, which allow routine inert‐gas syntheses and combined spectroscopy without modifications of the glovebox, the 3D‐printer, or the spectrometers. Overall, this demonstrates the potential of 3D‐printed reaction cuvettes to become a complementary standard method in inert‐gas chemistry.     

Comparative Study of Silk Fibroin-Based Hydrogels and Their Potential as Material for 3-Dimensional (3D) Printing

Three-dimensional (3D) printing is regarded as a critical technology in material engineering for biomedical applications. From a previous report, silk fibroin (SF) has been used as a biomaterial for tissue engineering due to its biocompatibility, biodegradability, non-toxicity and robust mechanical properties which provide a potential as material for 3D-printing. In this study, SF-based hydrogels with different formulations and SF concentrations (1–3%wt) were prepared by natural gelation (SF/self-gelled), sodium tetradecyl sulfate-induced (SF/STS) and dimyristoyl glycerophosphorylglycerol-induced (SF/DMPG). From the results, 2%wt SF-based (2SF) hydrogels showed suitable properties for extrusion, such as storage modulus, shear-thinning behavior and degree of structure recovery. The 4-layer box structure of all 2SF-based hydrogel formulations could be printed without structural collapse. In addition, the mechanical stability of printed structures after three-step post-treatment was investigated. The printed structure of 2SF/STS and 2SF/DMPG hydrogels exhibited high stability with high degree of structure recovery as 70.4% and 53.7%, respectively, compared to 2SF/self-gelled construct as 38.9%. The 2SF/STS and 2SF/DMPG hydrogels showed a great potential to use as material for 3D-printing due to its rheological properties, printability and structure stability.     

Using atmospheric pressure plasma for enhancing the deposition of printing paste on cotton fabric for digital ink-jet printing

Atmospheric pressure plasma (APP) treatment was applied as a pretreatment process to enhance the deposition of printing paste in order to improve the final colour properties of digital ink-jet printed cotton fabrics. Three printing pastes containing natural polymers, i.e. (1) sodium alginate, (2) chitosan and (3) sodium alginate-chitosan mixture, were prepared separately. After APP treatment, cotton fabric was padded with different printing pastes prior to digital ink-jet printing. Experimental results showed that APP pretreatment could increase the colour yield of the digital ink-jet printed cotton fabric significantly even after washing. In addition, other properties such as colour fastness to crocking, colour fastness to laundering, outline sharpness and anti-bacterial properties were also improved when compared with those of the control cotton fabric printed without APP pretreatment. However, the influence of printing paste on the colour properties of the digital ink-jet printed cotton fabrics depended very much on the composition of the printing paste. The scanning electron microscope images evidenced that the APP treatment could enhance the deposition of printing paste on the cotton fabric surface as proved qualitatively by both the contact angle and wetting time measurement as well as quantitatively by both the X-ray photoelectron spectroscopy and carboxyl group/nitrogen content analysis.     

The effect of nucleating agent on radiation stability of polypropylene

The radiation stability of polypropylene (PP) with and without nucleating agent (NA) is compared in relation to radiation sterilization of medical devices. In both cases high-and-low-molecular weight PP, the addition of NA increased the transparency and peak crystallization temperature of the PP. On the other hand, in poly(propylene-co-6%ethylene) copolymer, the addition of NA did not improve the transparency but crystallization occurred at higher temperature. Thus, adding NA to PP and copolymer give the advantage of shorter moulding time in the production of medical devices. It is found that both PP and copolymer with NA are less stable during irradiation and during storage after irradiation than without NA, this being the case especially for the lower molecular weight PP. The higher transparency and peak crystallization temperature in the PP and CP with NA were found to be due to smaller spherulites. As the effect of irradiation on polymer, addition of NA induce reduction of radiation stability of polymer owing to the change in morphology.     

3D Printing of Silk Protein Structures by Aqueous Solvent‐Directed Molecular Assembly

Hierarchical molecular assembly is a fundamental strategy for manufacturing protein structures in nature. However, to translate this natural strategy into advanced digital manufacturing like three‐dimensional (3D) printing remains a technical challenge. This work presents a 3D printing technique with silk fibroin to address this challenge, by rationally designing an aqueous salt bath capable of directing the hierarchical assembly of the protein molecules. This technique, conducted under aqueous and ambient conditions, results in 3D proteinaceous architectures characterized by intrinsic biocompatibility/biodegradability and robust mechanical features. The versatility of this method is shown in a diversity of 3D shapes and a range of functional components integrated into the 3D prints. The manufacturing capability is exemplified by the single‐step construction of perfusable microfluidic chips which eliminates the use of supporting or sacrificial materials. The 3D shaping capability of the protein material can benefit a multitude of biomedical devices, from drug delivery to surgical implants to tissue scaffolds. This work also provides insights into the recapitulation of solvent‐directed hierarchical molecular assembly for artificial manufacturing.     

In Vitro Tests of FDM 3D-Printed Diclofenac Sodium-Containing Implants

One of the most promising emerging innovations in personalized medication is based on 3D printing technology. For use as authorized medications, 3D-printed products require different in vitro tests, including dissolution and biocompatibility investigations. Our objective was to manufacture implantable drug delivery systems using fused deposition modeling, and in vitro tests were performed for the assessment of these products. Polylactic acid, antibacterial polylactic acid, polyethylene terephthalate glycol, and poly(methyl methacrylate) filaments were selected, and samples with 16, 19, or 22 mm diameters and 0%, 5%, 10%, or 15% infill percentages were produced. The dissolution test was performed by a USP dissolution apparatus 1. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide dye (MTT)-based prolonged cytotoxicity test was performed on Caco-2 cells to certify the cytocompatibility properties. The implantable drug delivery systems were characterized by thermogravimetric and heatflow assay, contact angle measurement, scanning electron microscopy, microcomputed tomography, and Raman spectroscopy. Based on our results, it can be stated that the samples are considered nontoxic. The dissolution profiles are influenced by the material properties of the polymers, the diameter, and the infill percentage. Our results confirm the potential of fused deposition modeling (FDM) 3D printing for the manufacturing of different implantable drug delivery systems in personalized medicine and may be applied during surgical interventions.