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.


Introduction
In the last few years, the interest in three-dimensional printing (3DP) in the scientific world, and particularly in pharmaceutical and medical research, has grown exponentially. In fact, the number of scientific papers recorded in the Web of Science Core Collection containing the term "3D printing" in the title increased from 57 in 2012 to 4623 in 2021. In addition, the number of citations of these papers in the same period grew from 23 to 28,438. Narrowing the searching results to the pharmacy/pharmacology category, no result was found in 2012, whereas 553 records were found up to 2021. In the light of this analysis, it is possible to say with certainty that 3DP represents today one of the fastest developing technologies in the healthcare field.
Although 3DP has been only recently explored for the manufacturing of personalized drug delivery systems (PDDS), such technology is well established in various biomedical areas for the creation, e.g., of customized prosthesis, orthopedic implants and anatomical models, surgical instrumentations, etc. Just think, for example, that, since 2001 Sonova has been able to produce hundreds of thousands of custom-made hearing aids every year [47]by 3DP technology. The Sonova model is a significant example of the customized manufacturing of a medical device and how personalization can change, or rather, has changed the hearing aid industry for better. A lot has been done in this specific field, but a lot remains to be done in other biomedical sectors as well as in the pharmaceutical one [48,49].
The aim of the present review is to provide an overview of the opportunities and challenges of 3DP technologies for pharmaceutical and biomedical applications, more specifically addressing the main driving force in the future developments of both 3DP techniques and products (a). A brief account of the basic aspects of a generic 3D printing process (b) is given to discuss their bridge with the main 3DP methods exploitable to produce complex and customizable dosage forms and/or medical devices (c), and related advantages and limitations. The most used and versatile extrusion-based 3DP techniques, FFF and SSE, and their main applications are finally discussed (d).

Driving Force in the Developing of 3DP Medicines and Medical Devices
The need for therapeutic approaches specific to the individual, the increasing demand for complex drug-eluting products, medical devices, and advanced drug-device combination products, as well as the growing request of on-demand manufacturing, are the main reasons strongly promoting the use of 3DP technology in both pharmaceutical and biomedical fields. Reprinted with permission from reference [42]; copyright (2016) Elsevier B.V. (b) Anti-biofilm hearing aids. Reprinted with permission from reference [43]; copyright (2021) Elsevier B.V. (c) Guide used during a surgery for tibial plateau fracture. Reprinted from reference [44]; copyright (2021). (d) Vaginal rings. Reprinted with permission from reference [45]; copyright (2018) Elsevier B.V. (e) 3D printed heart. Reprinted from reference [46]; copyright (2016).
Although 3DP has been only recently explored for the manufacturing of personalized drug delivery systems (PDDS), such technology is well established in various biomedical areas for the creation, e.g., of customized prosthesis, orthopedic implants and anatomical models, surgical instrumentations, etc. Just think, for example, that, since 2001 Sonova has been able to produce hundreds of thousands of custom-made hearing aids every year [47] by 3DP technology. The Sonova model is a significant example of the customized manufacturing of a medical device and how personalization can change, or rather, has changed the hearing aid industry for better. A lot has been done in this specific field, but a lot remains to be done in other biomedical sectors as well as in the pharmaceutical one [48,49].
The aim of the present review is to provide an overview of the opportunities and challenges of 3DP technologies for pharmaceutical and biomedical applications, more specifically addressing the main driving force in the future developments of both 3DP techniques and products (a). A brief account of the basic aspects of a generic 3D printing process (b) is given to discuss their bridge with the main 3DP methods exploitable to produce complex and customizable dosage forms and/or medical devices (c), and related advantages and limitations. The most used and versatile extrusion-based 3DP techniques, FFF and SSE, and their main applications are finally discussed (d).

Driving Force in the Developing of 3DP Medicines and Medical Devices
The need for therapeutic approaches specific to the individual, the increasing demand for complex drug-eluting products, medical devices, and advanced drug-device combination products, as well as the growing request of on-demand manufacturing, are the . Personalized medical approach. * Images adapted from reference [55]. ** Images adapted from reference [56].
3DP presents the possibility to easily develop patient-centered dosage forms, answering to the need to deliver "the right drug at the right dose and at the right time" [49], e.g., age-appropriate dosing for pediatrics and geriatrics sub-populations [57,58], multiple drug administration in polypharmacy practice [59], and innovative dosage forms, enhancing patient compliance and adherence to treatment with respect to conventional solid dosage forms [56]. Besides the proVazper drug dosage, with this approach, it is possible to produce controlled drug delivery systems with tailored drug release profile and even, multiple drug content. A "customized polypill" is a solid oral dosage [60] form 3D-printed in a complex construct of layers, capable of satisfying more than one therapeutic need at the same time. A "polypill" can be realized as a multi-drug pill, carrying and delivering a combination of drugs with various controlled release mechanisms to treat multiple diseases at once, or as a multi-dose pill, charged with different doses of the same drug to be delivered at different times. In addition, the possibility to guarantee a precise drug loading within the 3D printed structure increases, in general, the safety of all the selected drugs, above all of those characterized by a narrow therapeutic window requiring an exact dosing.
Another exciting opportunity to become a focus area for research and development lies in the powerful combination of drug eluting products and medical devices. Advanced drug-eluting devices providing significant and unique benefits to patients over conventional treatments have been recently developed by different 3DP technologies in the form of antibiotic and chemotherapeutic catheters [72], antimicrobial stents [73] and implants [74][75][76], and even anti-biofilm hearing aids [43] or anti-glaucoma contact lenses [77]. . Personalized medical approach. * Images adapted from reference [55]. ** Images adapted from reference [56].  3DP offers a forward-looking view for producing as well as dispensing medicines, moving the attention from traditional mass manufacturing to on demand manufacturing, and thus from centralized towards decentralized facilities ( Figure 5). Therefore, based on a patient specific prescription from their doctor, a customized medicinal product with complex geometry and architecture, charged with multiple doses of a specific drug, or even loaded with multiple drugs, can be designed via CAD and produced, when needed, by a 3D printer. Potentially, a hospital, clinic, community pharmacy, or even the patient's home, may be engaged in the pharmaceutical compounding/production [1]. Recently, Beer   3DP presents the possibility to easily develop patient-centered dosage forms, answering to the need to deliver "the right drug at the right dose and at the right time" [49], e.g., age-appropriate dosing for pediatrics and geriatrics sub-populations [57,58], multiple drug administration in polypharmacy practice [59], and innovative dosage forms, enhancing patient compliance and adherence to treatment with respect to conventional solid dosage forms [56]. Besides the proVazper drug dosage, with this approach, it is possible to produce controlled drug delivery systems with tailored drug release profile and even, multiple drug content. A "customized polypill" is a solid oral dosage [60] form 3D-printed in a complex construct of layers, capable of satisfying more than one therapeutic need at the same time. A "polypill" can be realized as a multi-drug pill, carrying and delivering a combination of drugs with various controlled release mechanisms to treat multiple diseases at once, or as a multi-dose pill, charged with different doses of the same drug to be delivered at different times. In addition, the possibility to guarantee a precise drug loading within the 3D printed structure increases, in general, the safety of all the selected drugs, above all of those characterized by a narrow therapeutic window requiring an exact dosing.
Another exciting opportunity to become a focus area for research and development lies in the powerful combination of drug eluting products and medical devices. Advanced drugeluting devices providing significant and unique benefits to patients over conventional treatments have been recently developed by different 3DP technologies in the form of antibiotic and chemotherapeutic catheters [72], antimicrobial stents [73] and implants [74][75][76], and even anti-biofilm hearing aids [43] or anti-glaucoma contact lenses [77].
3DP offers a forward-looking view for producing as well as dispensing medicines, moving the attention from traditional mass manufacturing to on demand manufacturing, and thus from centralized towards decentralized facilities ( Figure 5). Therefore, based on a patient specific prescription from their doctor, a customized medicinal product with complex geometry and architecture, charged with multiple doses of a specific drug, or even loaded with multiple drugs, can be designed via CAD and produced, when needed, by a 3D printer. Potentially, a hospital, clinic, community pharmacy, or even the patient's home, may be engaged in the pharmaceutical compounding/production [1]. Recently, Beer et al. investigated the possible implementation of 3DP technologies in the European pharmaceutical system. Among the various scenarios suggested (namely 3D printers in hospital pharmacies, community pharmacies, compounding facilities, patients' homes, and industry), those involving 3D printing in patients' homes was presented as the most futuristic, whereas printing at hospitals and pharmacies where other routine compounding is already taking place were shown as more realistic [48]. There is a fundamental difference when discussing printing in the context of smallscale compounding in the hospital and pharmacy setting or large-scale manufacturing in the industry setting. In the industrial setting, the main benefits deriving from decentralizing pharmaceutical manufacture are the following [ 3D manufacturing may be a good alternative to the compounding practice in hospital settings when a precise dosage, small batches for clinical studies, orphan drugs, and expensive oncology medical preparations are needed. In this case, 3DP appears cost-and material-saving, produces a smaller footprint, and may increase precision dosing, safety, and benefits to the patients. The overall printing process (materials' control, feedstock setting-up, printing, cleaning etc.) could be slower than the conventional compounding based on simple operations (such as weighing, grinding, mixing, diluting, cleaning), but it is still worth exploring. This great potential has allowed for the creation of point-of-care (PoC) 3D printing centers, which blur the line between the healthcare provider, medical center, and device manufacturer, creating regulatory ambiguity [78]. Currently, the FDA remains undecided about the best way to regulate PoC printing centers. However, they have recently begun working with stakeholders (including engineers, the medical device industry, various 3DP interesting workgroups, PoC manufacturing centers, physicians, and surgeons) through a webinar series hosted by the American Society of Mechanical Engineers (ASME) to develop a regulatory framework [79], following the way opened by the UK agency MHRA [80].
There is a fundamental difference when discussing printing in the context of smallscale compounding in the hospital and pharmacy setting or large-scale manufacturing in the industry setting. In the industrial setting, the main benefits deriving from decentralizing pharmaceutical manufacture are the following [1,30]:

1.
Reduced length and cost of transport and storage [81].

2.
Quick and real-time responses to patient and market needs due to the possibility to rapidly produce small batches of complex formulations with unique geometries and, furthermore, the concept of digital dispensing in hard-to-reach areas or developing countries [82].

3.
Reduced waste and hence reduced costs of developing and dosing due to a precise spatial control over the deposition of materials, limiting the amounts of API (active pharmaceutical ingredient) and excipients in comparison to conventional technologies [83].
Despite these benefits, there are several technical and regulatory challenges that need to be overcome before 3D printing may be widely used for pharmaceutical applications in clinical practice, as shown by only one FDA approval of a 3D printed drug on the market [3], and one on its way [33]. In the industrial setting, a 3D printed product must comply with the current manufacturing and control standards for medical products and devices, specifically the well-stablished Good Manufacturing Practices (GMP). However, 3DP manufacturing has many more issues involving design and production, raw material storage and transport, quality control, risk of counterfeit production, etc. In this regard, significant progress has been made for medical devices, ranging from surgical planning tool to custom surgical devices [84]. In the last few years, various papers have focused on the analysis of critical process parameters as well as product quality attributes and performance criteria, which must be addressed considering the industrial system of quality assurance to guarantee the fulfilment of regulatory standards [84,85]. Implantable medical devices require, for example, along with the careful characterization of starting materials as well as the optimization of 3D printing parameters, additional considerations about cleaning, finishing, and sterilization procedures [86]. In the attempt to allow the overcoming of such hurdles, the FDA released in December 2017 guidance detailing the technical considerations for additive manufactured medical devices, from software and hardware requirements, quality control, up to process validation procedures [87]. As the FDA document highlighted, due to the variability of additive manufacturing methods, there is no possibility to give one universal set of 3DP guidelines. It seems that every single printing method needs different equipment, starting materials, post-processing treatments, laboratories, and hence separate regulatory requirements [84]. The situation is complicated even more with the inclusion of one or more APIs, as it happens for multi-drug medicinal products which must considered possible incompatibilities and APIs' stability problems. Generally, requirements for drug-eluting products are more demanding than those for medical devices and this is the key reason why there are still no regulations. However, to fully understand the real motivation causing the actual regulatory difficulties, it is essential to analyze this new production approach from a strictly technical point of view.
3. 3D Printing: Technical Aspects 3.1. What Is 3D-Printing from a Technical Point of View?
Technically, 3DP can be defined as a layer-by-layer production of 3D objects from digital designs. This technology belongs to the so-called additive manufacturing (AM) processes because the object is produced through the layer-by-layer deposition of starting materials using a print head, nozzle, or another printer technology. Even the term rapid prototyping (RP) is often used to define 3DP since it generally refers to all techniques able to construct objects from digital models created with CAD software. Therefore, additive manufacturing is mainly referred to as the productive step, involving rapid prototyping through the whole procedure [88]. Despite of the diversity of 3DP methods, all exploit a CAD-CAM system. The process starts from the design of a digital model using CAD software; the latter is converted in a STL. file, a machine-readable format which describes the external surface of a 3D model. After this step, the STL. file is imported to the printer software (CAM software) that, through a slicing process, generates the layers which will be printed in an additive way by the printer. The height of the printed layer essentially influences the quality of the printed object as well as printing time. In addition, a specific post-processing step could be required to get the final product, based on the specific 3DP method selected. Figure 6 shows in a detailed way the main steps involved during the 3DP of a printlet (3D printed tablet) using fused deposition modeling as the productive technology. products which must considered possible incompatibilities and APIs' stability problems. Generally, requirements for drug-eluting products are more demanding than those for medical devices and this is the key reason why there are still no regulations. However, to fully understand the real motivation causing the actual regulatory difficulties, it is essential to analyze this new production approach from a strictly technical point of view.

What Is 3D-Printing from a Technical Point of View?
Technically, 3DP can be defined as a layer-by-layer production of 3D objects from digital designs. This technology belongs to the so-called additive manufacturing (AM) processes because the object is produced through the layer-by-layer deposition of starting materials using a print head, nozzle, or another printer technology. Even the term rapid prototyping (RP) is often used to define 3DP since it generally refers to all techniques able to construct objects from digital models created with CAD software. Therefore, additive manufacturing is mainly referred to as the productive step, involving rapid prototyping through the whole procedure [88]. Despite of the diversity of 3DP methods, all exploit a CAD-CAM system. The process starts from the design of a digital model using CAD software; the latter is converted in a STL. file, a machine-readable format which describes the external surface of a 3D model. After this step, the STL. file is imported to the printer software (CAM software) that, through a slicing process, generates the layers which will be printed in an additive way by the printer. The height of the printed layer essentially influences the quality of the printed object as well as printing time. In addition, a specific post-processing step could be required to get the final product, based on the specific 3DP method selected. Figure 6 shows in a detailed way the main steps involved during the 3DP of a printlet (3D printed tablet) using fused deposition modeling as the productive technology.

3D Printing Methods
Various and very different 3D printing techniques exist, depending on the specific technology used. All of them fall within the common definition of solid freeform fabrication (SFF) aiming to focus on the possibility to produce solid free forms with a complex

3D Printing Methods
Various and very different 3D printing techniques exist, depending on the specific technology used. All of them fall within the common definition of solid freeform fabrication (SFF) aiming to focus on the possibility to produce solid free forms with a complex and well-defined architecture. According to the American Society for Testing and Materials (ASTM F2792-12a), AM processes can be classified in seven categories, namely: (1) material jetting, (2) binder jetting, (3) vat photopolymerization, (4) powder bed fusion, (5) material extrusion, (6) energy deposition, and (7) sheet lamination [89] (Figure 7). Further AM classifications may be done based on the physical state of the starting material used to form the product (solid, liquid, and powder-based processes), or even the medium used for its processing (laser beam, ultraviolet rays, thermal means, etc.) [90]. A commonly accepted classification of the different 3DP systems used for pharmaceutical and medical applications is based on three main groups, namely: 1.
Printing based ink-jet systems 2.
Molecules 2022, 27, x FOR PEER REVIEW 9 of 54 and well-defined architecture. According to the American Society for Testing and Materials (ASTM F2792-12a), AM processes can be classified in seven categories, namely: (1) material jetting, (2) binder jetting, (3) vat photopolymerization, (4) powder bed fusion, (5) material extrusion, (6) energy deposition, and (7) sheet lamination [89] (Figure 7). Further AM classifications may be done based on the physical state of the starting material used to form the product (solid, liquid, and powder-based processes), or even the medium used for its processing (laser beam, ultraviolet rays, thermal means, etc.) [90]. A commonly accepted classification of the different 3DP systems used for pharmaceutical and medical applications is based on three main groups, namely: 1. Printing based ink-jet systems 2. Laser-based writing systems, 3. Nozzle-based deposition systems [54,91].  [89,90], with in evidence the main AM methods applied in pharmaceutical and biomedical field [54,91].

Ink-Jet Based 3D-Printing Technologies
The idea of "ink-jet" systems originated from computer-operated ink-jet printing, which recreates digital images by propelling ink droplets onto paper. This was adapted for pharmaceutical application by the replacement of the ink with liquid solutions containing APIs and excipients, and normal paper with edible sheets known as substrates. In this case, the major challenge, often underestimated, is the formulation of an API-containing ink with appropriate properties. Specifically, during a generic inkjet-based 3DP process, the ink must be sprayed at a set speed, and through specific motions, into droplets with precise sizes. Operative conditions must be well established to facilitate reliable jetting and homogeneous droplet formation with minimal satellites [88,92]. In addition, the choice of the solvent for the ink formulation, as well as the ink drying rate, could influence the solid state of the loaded API after deposition, and hence its bioavailability [93].
As illustrated in Figure 7, the ink-jet based 3DP technologies can be divided into two types: continuous (CIJ) and drop-on-demand (DoD) inkjet printing [56]. In the first case, the ink is sprayed, mainly through piezoelectric crystals, in a continuous flow. On the contrary, during a DoD process, the ink flow, either provided by a thermal or a piezoelectric device, is provided only as needed. This latter process can be also defined as drop-ondrop deposition (DOD) if the drops are allowed to deposit on each other to form a bed,   [89,90], with in evidence the main AM methods applied in pharmaceutical and biomedical field [54,91].

Ink-Jet Based 3D-Printing Technologies
The idea of "ink-jet" systems originated from computer-operated ink-jet printing, which recreates digital images by propelling ink droplets onto paper. This was adapted for pharmaceutical application by the replacement of the ink with liquid solutions containing APIs and excipients, and normal paper with edible sheets known as substrates. In this case, the major challenge, often underestimated, is the formulation of an API-containing ink with appropriate properties. Specifically, during a generic inkjet-based 3DP process, the ink must be sprayed at a set speed, and through specific motions, into droplets with precise sizes. Operative conditions must be well established to facilitate reliable jetting and homogeneous droplet formation with minimal satellites [88,92]. In addition, the choice of the solvent for the ink formulation, as well as the ink drying rate, could influence the solid state of the loaded API after deposition, and hence its bioavailability [93].
As illustrated in Figure 7, the ink-jet based 3DP technologies can be divided into two types: continuous (CIJ) and drop-on-demand (DoD) inkjet printing [56]. In the first case, the ink is sprayed, mainly through piezoelectric crystals, in a continuous flow. On the contrary, during a DoD process, the ink flow, either provided by a thermal or a piezoelectric device, is provided only as needed. This latter process can be also defined as drop-on-drop deposition (DOD) if the drops are allowed to deposit on each other to form a bed, and drop-on-powder deposition (drop-on-solid, DOS) if the droplets are allowed to deposit on the powder bed; this approach is also known as the TERIFORM ® process.

Drop-on-Drop (DOD)
During a drop-on-drop deposition process, droplets of ink are sprayed from the thermal or piezoelectric print head, deposited on the thin layers, and then cured by cooling air or in the presence of high energy light (Figure 8b). In this case, to create support for overhang geometries, it is necessary to use additional material acting as support. The most common materials used for DOD are waxes and ceramics, and this low selection of materials certainly represents a disadvantage. By contrast, the main advantages of DOD are the instantaneous solidification, the efficacy, and the cost-effectiveness. and drop-on-powder deposition (drop-on-solid, DOS) if the droplets are allowed to deposit on the powder bed; this approach is also known as the TERIFORM ® process.

Drop-on-Drop (DOD)
During a drop-on-drop deposition process, droplets of ink are sprayed from the thermal or piezoelectric print head, deposited on the thin layers, and then cured by cooling air or in the presence of high energy light (Figure 8b). In this case, to create support for overhang geometries, it is necessary to use additional material acting as support. The most common materials used for DOD are waxes and ceramics, and this low selection of materials certainly represents a disadvantage. By contrast, the main advantages of DOD are the instantaneous solidification, the efficacy, and the cost-effectiveness.

Drop-on-Solid (DOS)
In a drop-on-solid process, droplets of ink sprayed from the print head bind the layer of the free excipient powder bed, while unbound powder particles act as a support material preventing the collapse of overhanging or porous structures. After each step, the formed object is lowered, and a layer of free powder is applied by a roller or powder jetting system and the process proceeds ( Figure 9). The product quality attributes are strictly dependent on both ink and powder properties. The ink constituents, such as APIs, solvents, or excipients, can influence viscosity and droplet size, and thus the efficiency of powder binding. Instead, the particle size, flowability, and wettability of the powder bed, as well as the cohesion force between particles and printer components, mainly influence the layer height and, consequently, the final resolution of the printed object [56,94]. Moreover, printing speed, droplet volume, and distance from powder bed may play an important role, particularly in affecting the powder bonding between layers along the Z-axis, where they could negatively influence its mechanical strength [1].

Drop-on-Solid (DOS)
In a drop-on-solid process, droplets of ink sprayed from the print head bind the layer of the free excipient powder bed, while unbound powder particles act as a support material preventing the collapse of overhanging or porous structures. After each step, the formed object is lowered, and a layer of free powder is applied by a roller or powder jetting system and the process proceeds ( Figure 9). The product quality attributes are strictly dependent on both ink and powder properties. The ink constituents, such as APIs, solvents, or excipients, can influence viscosity and droplet size, and thus the efficiency of powder binding. Instead, the particle size, flowability, and wettability of the powder bed, as well as the cohesion force between particles and printer components, mainly influence the layer height and, consequently, the final resolution of the printed object [56,94]. Moreover, printing speed, droplet volume, and distance from powder bed may play an important role, particularly in affecting the powder bonding between layers along the Z-axis, where they could negatively influence its mechanical strength [1].
The main advantage of such technique relies in the high similarity with wet granulation, presenting the possibility to use as starting materials various common excipients of solid dosage forms [95][96][97]. Similar binders work with a wide range of API powders allowing to greatly reduce the complexity of ink formulation. Besides the possibility of a precise location of an exact drug dose, this approach also allows an easy modification of the excipients within the powdered bed to obtain, in the same product, several compartments with different composition or mode of action. The main disadvantage of the DOS approach is represented by the need to perform different post-printing steps, such as drying to eliminate residual solvents and improve the physical resistance or unbound powder removal, and this latter step requires a specialized powder facility [1].
In the literature, there are a lot of examples concerning the application of the DOS method for the fabrication of tablets [97][98][99][100][101], and the greatest success of this technology was achieved in 2015 with just a tablet, namely Spritam ® , based on ZipDose ® technol-ogy [4,5]. In contrast with conventional compression, the technology yields a product layer-by-layer without using compression forces, punches, or dies. During the process, a powder blend is first deposited as a single layer. Then, an aqueous binding fluid is applied, and interactions between the powder and liquid bind the materials together. The process is repeated several times to produce solid, yet highly porous, friable formulations, even at high dose loading (up to 1000 mg). The main advantage of such technique relies in the high similarity with wet granulation, presenting the possibility to use as starting materials various common excipients of solid dosage forms [95][96][97]. Similar binders work with a wide range of API powders allowing to greatly reduce the complexity of ink formulation. Besides the possibility of a precise location of an exact drug dose, this approach also allows an easy modification of the excipients within the powdered bed to obtain, in the same product, several compartments with different composition or mode of action. The main disadvantage of the DOS approach is represented by the need to perform different post-printing steps, such as drying to eliminate residual solvents and improve the physical resistance or unbound powder removal, and this latter step requires a specialized powder facility [1].
In the literature, there are a lot of examples concerning the application of the DOS method for the fabrication of tablets [97][98][99][100][101], and the greatest success of this technology was achieved in 2015 with just a tablet, namely Spritam ® , based on ZipDose ® technology [4,5]. In contrast with conventional compression, the technology yields a product layerby-layer without using compression forces, punches, or dies. During the process, a powder blend is first deposited as a single layer. Then, an aqueous binding fluid is applied, and interactions between the powder and liquid bind the materials together. The process is repeated several times to produce solid, yet highly porous, friable formulations, even at high dose loading (up to 1000 mg).
The DOS method could also be exploited in the large-scale production of modified release multicomponent tablets. In this case, small variations in porosity resulting from the different adhesion between the layers could alter the structural density of the produced tablets and, consequently, the drug dissolution profile and bioavailability. The technical solution could be the application of a greater amount of binder, which, however, causes an increase of drying time as well as the risk of limited removal of residual solvent [1]. This aspect strongly limits the application of DOS for the production of multicomponent modified release tablets with high quality. The DOS method could also be exploited in the large-scale production of modified release multicomponent tablets. In this case, small variations in porosity resulting from the different adhesion between the layers could alter the structural density of the produced tablets and, consequently, the drug dissolution profile and bioavailability. The technical solution could be the application of a greater amount of binder, which, however, causes an increase of drying time as well as the risk of limited removal of residual solvent [1]. This aspect strongly limits the application of DOS for the production of multicomponent modified release tablets with high quality.

Laser Based 3D-Printing Technologies
The second set of 3DP technologies is that laser-based 3DP technologies. This group includes selective laser sintering (SLS), or selective laser melting (SLM), whose constructive assumptions are similar to the DOS method, and stereolithography (SLA), for which the object is built by the solidification of photosensitive liquids.

Selective Laser Sintering (SLS)
SLS is a laser based 3DP technique based on powder solidification by applying a highenergy beam [94,102,103]. As illustrated in Figure 10a, a layer of free powder is applied by roller and each layer is formed by sintering via laser beam that is able to heat just below melting temperature [1]. This technique can be applied to ceramic powders as well as to thermoplastic or metal powders. In this latter case, laser beam must melt the powdered bed and the specific technique is referred to as selective laser melting (SLM) [103].
facilities. Other disadvantages are due to the risk of API decomposition after exposure to laser beam, the high variability of mechanical properties, and the limited speed for sintering [1]. The drug degradation in particular has severely limited the use of SLS in the production drug-loaded devices, and a few examples are available [105][106][107][108][109][110][111]. Nevertheless, SLS has been used to process soft materials both in the bioprinting for tissue engineering and in the food industry [112].

Stereolithography (SLA)
The production of a 3D object by SLA is based on the controlled solidification of subsequent layers of resin by photo-polymerization via ultraviolet laser beam or light from a projector (digital light projector, DLP) [113]. During the SLA process, the printed object is bound to the built platform that is immersed in the photopolymer solution ( Figure 10b). A digital mirroring device starts a chemical reaction in the photopolymer, which causes the cross-linking of the exposed area. The layer is traced on the surface of the resin. Many are the advantages and the disadvantages of such a technique. Ideally, almost any dosage form can be fabricated by SLS with a high level of precision, accuracy, and resolution. In fact, even objects of several cubic centimeters (and hence rather large) can be built with a resolution down to 0.2 micron [104]. SLS can be successfully applied to produce porous, rapidly disintegrating, as well as modified release dosage forms without binding agent, with high drug loading efficiency and good mechanical properties. The latter aspect is very important, because it cannot be reached with other powder solidification methods such as DOS [1]. However post-printing processing is required as the object is built into a powder, and such a step requires specific powder removal procedures and facilities. Other disadvantages are due to the risk of API decomposition after exposure to laser beam, the high variability of mechanical properties, and the limited speed for sintering [1]. The drug degradation in particular has severely limited the use of SLS in the production drug-loaded devices, and a few examples are available [105][106][107][108][109][110][111]. Nevertheless, SLS has been used to process soft materials both in the bioprinting for tissue engineering and in the food industry [112].

Stereolithography (SLA)
The production of a 3D object by SLA is based on the controlled solidification of subsequent layers of resin by photo-polymerization via ultraviolet laser beam or light from a projector (digital light projector, DLP) [113]. During the SLA process, the printed object is bound to the built platform that is immersed in the photopolymer solution ( Figure 10b). A digital mirroring device starts a chemical reaction in the photopolymer, which causes the cross-linking of the exposed area. The layer is traced on the surface of the resin.
As with SLS, SLA also is a highly versatile technique allowing to produce objects with high level of precision, accuracy, and resolution. The major disadvantage is represented by the need for post printing treatments to remove residual solvents, eventual supports, and in general, to improve final product properties, e.g., mechanical integrity. Another disadvantage is the potential health hazard due to the use of photo-sensible resins usually considered as carcinogens as well as responsible for a decrease of final product stability and its mechanical properties over time [56]. In addition, the systems exploiting this 3DP method require costly equipment and a long printing time. All these aspects have limited the application of SLA in the pharmaceutical and biomedical fields [114]. However, some applicative examples of SLA are described in the scientific literature [40,59,115,116], also in combination with other 3DP techniques [41,95,117,118].

Nozzle Based 3D-Printing Technologies
The third group of 3D-printing technologies is represented by nozzle-based deposition systems allowing direct writing through extrusion. Such systems deposit ink direct through a nozzle to create a 3D pattern layer-by-layer with controlled composition and architecture [119]. They can be basically divided into processes based on material melting, such as fused filament fabrication (FFF), also referred to as fused deposition modelling (FDM), and processes without material melting, such as semi solid extrusion (SSE), also known as pressure-assisted microsyringe (PAM). Nozzle based 3DP technologies have been highly investigated due to their great versatility, reproducibility, and high scalability potential. A lot of papers in the literature have focused on the application of such techniques to develop pharmaceutical as well as biomedical products.

Fused Filament Fabrication (FFF)
FFF is a really very investigated 3DP technique because it is cheap, easy to use, and readily available [119][120][121]. Its increasing popularity is mainly due to the progressive availability of compact sized and relatively inexpensive equipment [1,56]. During a FFF process, a thermoplastic polymeric material (mainly in form of filament) is extruded through a warmed-up nozzle and printed layer-by-layer (Figure 11a). Nozzle diameter varies from 0.2 to 0.4 mm, and it has an impact on the final resolution of 3D printed product. Generally, the width of the printed path corresponds to the nozzle diameter, while its height is equal to the half of the width. However, properties of the selected starting material as well as printer settings may induce modifications. During the process, the paths are arranged in layers until the formation of the final object, the resolution of which depends on layer height. Differently, the mechanical characteristics of the printed product are related to a number of outlines that build the external wall of the object and infill pattern (e.g., linear, or hexagonal).
The development of dosage forms and medical devices by the FFF approach requires a deep understanding of the printing process parameters as well as a thorough formulation study to properly select raw materials. Several critical material requirements need to be considered for their influence on FFF processability as well as 3D printed product quality. In more detail, filament mechanical properties (e.g., elastic modulus and strain at yield) and viscosity at the melted state mainly influence the extrusion step. Rheological properties, and particularly viscosity, surface tension, and relaxation dynamics, have impact above all on layer and intralayer adhesion, and thus on object precision and resolution. Finally, thermal properties (e.g., conductivity, heat capacity, coefficient of thermal expansion, and crystallinity), besides specifically driving process parameter set-up, are often responsible for fiber shrinkage and warpage [122]. Therefore, the careful evaluation of such aspects may avoid processing issues [1]. In general, the main disadvantages of FFF rely in the poor choice of starting materials which, as introduced, is limited to thermoplastic polymers, and the need of preparing filaments in advance, eventually loaded with the drug. Moreover, due to the elevated temperatures associated with this process, the potential risk of drug degradation is a significant issue hindering its use in pharmaceutical field.
Molecules 2022, 27, x FOR PEER REVIEW 14 of 54 potential risk of drug degradation is a significant issue hindering its use in pharmaceutical field.

Semi Solid Extrusion (SSE)
Differently from FFF, the SSE process involves a semisolid starting material (in the form of gel or paste) that is extruded through an orifice by compressed air pressure, a syringe plunger, or screw, depending on the specific equipment used, and deposited layer by layer (Figure 11b). Semisolid materials can be easily obtained by excipients commonly employed in the pharmaceutical industry by mixing them in optimal ratios with appropriate solvent(s) to obtain a viscosity suitable for printing. SSE does not require high temperatures but, using materials in form of pastes or gels, a further drying process is needed, implying shrinking or deformation of the printed product. The fabricated object may also collapse during 3D printing if a constructed layer did not harden sufficiently to withstand confinement of the successive layer. The technique is usually confined to a low resolution since an orifice with a size of 0.4-0.8 mm is typically employed. However, an accurate parameterization of the dispensing of the semisolid mass, as well as the use of nozzles smaller in diameter, allows to obtain dosage forms with a good resolution and mass uniformity [123,124]. The main advantage of SSE resides in the possibility to fabricate dosage forms with high drug loading. By using multi-syringe printing, "polypills" may also be obtained containing 3-5 APIs released with different kinetics [125,126].
The data shown earlier indicate that each 3DP approach presents specific advantages and disadvantages, and suggest the choice that must be made based on the properties of the starting materials as well as the drug to load and the desired performances for the final 3DP products, without forgetting system cost-effectiveness and realizable scale-up.
To give the reader a rapid comparison and insight into the different available techniques, the above discussed topics are summarized in Table 1.

Semi Solid Extrusion (SSE)
Differently from FFF, the SSE process involves a semisolid starting material (in the form of gel or paste) that is extruded through an orifice by compressed air pressure, a syringe plunger, or screw, depending on the specific equipment used, and deposited layer by layer (Figure 11b). Semisolid materials can be easily obtained by excipients commonly employed in the pharmaceutical industry by mixing them in optimal ratios with appropriate solvent(s) to obtain a viscosity suitable for printing. SSE does not require high temperatures but, using materials in form of pastes or gels, a further drying process is needed, implying shrinking or deformation of the printed product. The fabricated object may also collapse during 3D printing if a constructed layer did not harden sufficiently to withstand confinement of the successive layer. The technique is usually confined to a low resolution since an orifice with a size of 0.4-0.8 mm is typically employed. However, an accurate parameterization of the dispensing of the semisolid mass, as well as the use of nozzles smaller in diameter, allows to obtain dosage forms with a good resolution and mass uniformity [123,124]. The main advantage of SSE resides in the possibility to fabricate dosage forms with high drug loading. By using multi-syringe printing, "polypills" may also be obtained containing 3-5 APIs released with different kinetics [125,126].
The data shown earlier indicate that each 3DP approach presents specific advantages and disadvantages, and suggest the choice that must be made based on the properties of the starting materials as well as the drug to load and the desired performances for the final 3DP products, without forgetting system cost-effectiveness and realizable scale-up.
To give the reader a rapid comparison and insight into the different available techniques, the above discussed topics are summarized in Table 1.

FFF: Applications, Challenges and Perspectives
An overview of the main applications, common issues, challenges, progresses, and perspectives in FFF is presented in this section. In the last years, the application of FFF in manufacturing personalized drug dosage forms and medical devices has grown notably, and the number of analyzable research exploiting FFF is unbelievably high in the current scientific literature. A picture of the overall theme and a guideline for scientists working in this specific field is presented in Table 2, summarizing an accurate selection of both biomedical and pharmaceutical products realized via FFF-3DP technology. For each analyzed product, the main personalization possibilities (e.g., in terms of drug combination, dose, and release) as well as the encountered drawbacks (mainly related to the intrinsic limits of the FFF approach, such as high process temperatures) are highlighted.
Some case-studios reported in Table 2 (as considered more relevant) are examples of a successful response to different pharmaceutical needs and are deeply discussed below.
Generally, FFF printing requires a thermoplastic polymeric filament, the production of which is without doubt one of the most critical steps of the whole process, and responsible for a generally high production cost [127]. The filament for the 3D printing process must have key quality attributes, such as constant dimension, elasticity, and mechanical resistance [128]. During printing, filaments are bent and compressed between feeding and driving equipment. Therefore, filaments too brittle can be broken by the gears, whereas those too soft can be squeezed aside by the feeding gear [1]. There are a lot of ready-to-use filaments commercially available for FFF-3D printers. Their dimensions usually range between 1.75 mm and 2.85-3 mm and the most employed materials for standard filament production are thermoplastic polymers, such as acrylonitrile butadiene styrene (ABS), poly (lactic acid) (PLA), poly (vinyl alcohol) (PVA), polycaprolactone (PCL), high impact polystyrene (HIPS), polyethylene terephthalate glycol-modified (PET-G), polyurethanes (PU), and nylon (N). However, high quality filaments, produced from medical grade polymers as raw materials for research or industry are still scarce on the market, and those containing APIs are not available. This issue has led to the practice of offering consulting and/or manufacturing services for the development of drug loaded polymeric filaments from companies as well as academic research groups. Technically, various drug loading strategies are useful. However, each method may present limitations and should be chosen based on drug physico-chemical properties, printing material, and final desired performances of the printed product [75]. Drugs can be loaded into the preformed filament by soaking/swelling in a volatile solvent solution containing API, and subsequent drying [1,13,[129][130][131][132]. The critical point of this method is to properly select the solvent or the solvent mixture that must be able to swell the polymeric material and at once solubilize the drug, allowing its loading within filament by diffusion [133]. At the same time, this approach is simple and easy to realize, but generally limited to the preparation of filaments with low drug content [1].
A challenge of regenerative medicine is to realize controlled drug-releasing tissue engineered platforms able to exert both an initial burst release as well as a sustained or long-term release of the loaded drug/s. In this case, a sequential or multiphasic release patterns is required, which may aid to enhance the speed, quantity, and quality of tissue regeneration. With this in mind, recently, Farto-Vaamonde et al. explored the soaking/swelling of PLA to personalize the steroidal anti-inflammatory drugs (SAIDs) release profile from scaffolds intended for regenerative purposes [134]. Two different drug loading strategies were exploited (see Figure 12). In the first case, to obtain feedstock for 3D FDM printer, the soaking of PLA filaments into a volatile solvent mixture containing the drug followed by drying was applied. The second strategy consisted in first printing the 3D PLA scaffolds followed by soaking in a suitable SAID solution. Results showed that during 3DP of drug loaded PLA filament, the melting of PLA contributes to the efficient encapsulation of the SAID inside the printed strand, leading to a sustained drug release profile from the scaffold for several months. Differently, 3D PLA scaffolds, loaded after printing with either prednisolone or dexamethasone, show that the coating of the scaffold strands with a layer of crystalline drug nanoparticles, consequently leading to a burst rapid release. This evidence led us to design a dually loaded scaffold exhibiting distinct drug release patterns. Dexamethasone loaded within the strand core showed a sustained release, whereas prednisolone loaded on the strand surface gave an immediate release thanks to the combination of two loading methods.
As reported in Table 2, many other examples of thermoplastic polymeric filaments loaded with drug/s via soaking/swelling and involved in the manufacturing of different dosage forms, as well as medical devices, can be found in the literature.
To produce filaments with higher drug content and mechanical properties suitable for 3DP, commercially available filaments can be shredded or milled with APIs by hot melt extrusion (HME). In this case, different additives, such as plasticizers, fillers, and lubricants can also be added to API-polymer blend to improve both the processability and the final printability of the extruded filaments [135]. Clearly, drug loading within the extruded filaments depends on physicochemical properties of drugs and excipients as well as the extruder construction (i.e., single-screw or twin-screw extruder, screw segment arrangement and size, types of barrel surfaces, types of thermocouple junctions). Moreover, process parameters (i.e., extrusion temperature, screw speed, torque, feed rate) [1,136] may affect drug charging. Table 2 summarizes various materials exploited by HME technology to produce drug loaded filaments. Good performances have been shown by PCL [137], PLA [138], thermoplastic polyurethane (TPU) [139], poly (ethylene vinyl acetate) (EVA) [140], polyethylene oxide (PEO) [141], Eudragit ® L100, Eudragit ® RL, Eudragit ® PO [142], Soluplus ® [143,144], HPC [145], hydroxypropyl methylcellulose (HPMC) [146], ethyl cellulose (EC) [143], used alone or in combination [121,147]. However, Poly (vinyl alcohol) (PVA) remains the most investigated. PVA is a water-soluble semi-crystalline polymer prepared by the partial or complete hydrolysis of the acetate group from polyvinyl acetate. PVA is a safe excipient highly employed in pharmaceutical technology to develop drug delivery systems, particularly tablets [148][149][150]. PVA is largely used as solubilizer, base, binder, coating agent, sugar coating, adhesive, thickener, etc. Various biomedical applications are known, e.g., to realize contact lenses, synthetic tear eye-drops, or surgical sponges [151][152][153]. Recently, Wei et al. [133] proposed PVA to produce tablets with a rapid release profile of carvedilol and haloperidol (both weakly basic and poorly water-soluble) via hot melt-extruded filaments and FFF printing. This study discusses in depth the main development issues of using PVA, namely the high processing temperature and limited drug-polymer miscibility. The interest of this research resides in the testing of the miscibility of selected drugs with PVA, with and without added sorbitol as plasticizer. The aim was to verify whether any amorphous solid dispersion (ASD) was formed able to promote a rapid and pH-independent dissolution. Results showed a miscibility of carvedilol and haloperidol with PVA of, respectively,~20% and <10%. Specifically, PVA provided complete drug release from 3D printed tablets with 10% and 20% carvedilol and 60% infill in~45 min at both pH 2 and 6.8. patterns is required, which may aid to enhance the speed, quantity, and quality of tissue regeneration. With this in mind, recently, Farto-Vaamonde et al. explored the soaking/swelling of PLA to personalize the steroidal anti-inflammatory drugs (SAIDs) release profile from scaffolds intended for regenerative purposes [134]. Two different drug loading strategies were exploited (see Figure 12). In the first case, to obtain feedstock for 3D FDM printer, the soaking of PLA filaments into a volatile solvent mixture containing the drug followed by drying was applied. The second strategy consisted in first printing the 3D PLA scaffolds followed by soaking in a suitable SAID solution. Results showed that during 3DP of drug loaded PLA filament, the melting of PLA contributes to the efficient encapsulation of the SAID inside the printed strand, leading to a sustained drug release profile from the scaffold for several months. Differently, 3D PLA scaffolds, loaded after printing with either prednisolone or dexamethasone, show that the coating of the scaffold strands with a layer of crystalline drug nanoparticles, consequently leading to a burst rapid release. This evidence led us to design a dually loaded scaffold exhibiting distinct drug release patterns. Dexamethasone loaded within the strand core showed a sustained release, whereas prednisolone loaded on the strand surface gave an immediate release thanks to the combination of two loading methods. As reported in Table 2, many other examples of thermoplastic polymeric filaments loaded with drug/s via soaking/swelling and involved in the manufacturing of different dosage forms, as well as medical devices, can be found in the literature.
To produce filaments with higher drug content and mechanical properties suitable for 3DP, commercially available filaments can be shredded or milled with APIs by hot melt extrusion (HME). In this case, different additives, such as plasticizers, fillers, and lubricants can also be added to API-polymer blend to improve both the processability and the final printability of the extruded filaments [135]. Clearly, drug loading within the extruded filaments depends on physicochemical properties of drugs and excipients as well as the extruder construction (i.e., single-screw or twin-screw extruder, screw segment arrangement and size, types of barrel surfaces, types of thermocouple junctions). Moreover, process parameters (i.e., extrusion temperature, screw speed, torque, feed rate) [1,136] may affect drug charging. Another interesting example of systematic testing of PVA by HME technology was the development of PVA filaments loaded with ciprofloxacin hydrochloride in different concentrations to use as feedstock for a 3D FDM printer and to produce a printlet (3Dprinted-tablet) [154]. With this aim, several solid mixtures were prepared, using five PVA batches (4000-5000 µm, 1000-2000 µm, 600-1000 µm, 250-600 µm, <250 µm) and ciprofloxacin hydrochloride in different ratios. This study on the influence of polymer size distribution on drug loading capability showed that the best results in terms of HME processability are obtained for the finest PVA batches. Particularly, moderately fine particles (250-600 µm) showed a positive impact on mixing-extrusion-printing steps, allowing a complete adhesion of the drug on the polymer surface and a greater drug homogeneity of both filaments and printlets.
In addition Goyanes et al. explored such an approach in different researches. For example, this research group successfully obtained through HME paracetamol (4.3 and 8.2%) or caffeine (4.7 and 9.5%) loaded filaments of PVA with characteristics suitable for FFF. The produced drug loaded filaments were used as feed for a multi-nozzle FFF 3D printer to produce oral drug delivery devices with different inner structures (multilayer device and DuoCaplet, see Figure 13a). The obtained devices exhibited unique drug release profiles, which would be challenging to obtain by a conventional manufacturing method [155]. In another work, Goyanes et al. employed this strategy to produce a system intended for the treatment of inflammatory bowel disease. 3D-printable PVA filaments loaded with budesonide were engineered into caplets (capsule-shaped tablets) containing 9 mg budesonide using a FDM 3D printer. The caplets were subsequently overcoated with a layer of enteric polymer (Eudragit L100) [156]. Moreover, Goyanes et al. [157] prepared filaments based on hypromellose acetate succinate (HPMCAS) incorporating up to 50% of paracetamol, thanks to the addition to the polymeric matrix of methylparaben as plasticizer and magnesium stearate as lubricant. The filaments were obtained using a single-screw extruder and were subsequently processed by FDM in enteric printlets, exhibiting delayed drug release profiles in biorelevant bicarbonate dissolution media. Interestingly, the specific drug release performance from each group of 3D printed tablets was dependent on the polymer composition (HPMCAS grade, that is LG, MG or HG), drug loading (5% or 50%), and the internal structure of the formulations (infill percentage of 20% or 100%).
Zang et al. [147] successfully developed cellulose-based solid-dispersion filaments with the API (Acetaminophen) dissolved or dispersed in the polymer matrix by a twinscrew extruder. Filaments were obtained starting from binary polymer blends of HPMC E5 and EC N14 with either HPC EF and LF, Soluplus ® , or Eudragit ® L100. All the extruded filaments showed good mechanical properties and they were printed well via FFF to produce controlled-release tablets.
Further, thermoplastic polyurethanes (TPU) [158] have potential good performance in HME. Melt-extruded filaments based on different grades of hydrophilic and hydrophobic TPU may load a high quantity of the crystalline drugs, such as theophylline and metformin (up to 60%). The high content of the crystalline drug resulted in a very rough surface of the produced filaments. However, after API milling, filaments showed a smoother surface as well as consistent diameter, good mechanical properties, and were therefore successfully converted via FFF into tablets whose drug release performances proved to be mainly influenced by matrix composition and infill degree. (5% or 50%), and the internal structure of the formulations (infill percentage of 20% or 100%). Zang et al. [147] successfully developed cellulose-based solid-dispersion filaments with the API (Acetaminophen) dissolved or dispersed in the polymer matrix by a twinscrew extruder. Filaments were obtained starting from binary polymer blends of HPMC E5 and EC N14 with either HPC EF and LF, Soluplus ® , or Eudragit ® L100. All the extruded filaments showed good mechanical properties and they were printed well via FFF to produce controlled-release tablets.
Further, thermoplastic polyurethanes (TPU) [158] have potential good performance in HME. Melt-extruded filaments based on different grades of hydrophilic and hydrophobic TPU may load a high quantity of the crystalline drugs, such as theophylline and metformin (up to 60%). The high content of the crystalline drug resulted in a very rough surface of the produced filaments. However, after API milling, filaments showed a smoother surface as well as consistent diameter, good mechanical properties, and were therefore successfully converted via FFF into tablets whose drug release performances proved to be mainly influenced by matrix composition and infill degree. In the literature, there are also many reports on the use of PCL for the development of HME filaments intended for a pharmaceutical FFF-3D printing. PCL is a biodegradable, water-insoluble, FDA-approved polymer with a low melting point (Tmp 50-60 °C ) [160] and highly employed as a carrier to produce patient-specific, 3D-printed, drug-eluting implants (e.g., scaffolds [161,162], gynecological devices [163,164], antimicrobial wound dressings [165], and biodegradable/bioabsorbable stents [166]. More recently some re- In the literature, there are also many reports on the use of PCL for the development of HME filaments intended for a pharmaceutical FFF-3D printing. PCL is a biodegradable, water-insoluble, FDA-approved polymer with a low melting point (T mp 50-60 • C) [160] and highly employed as a carrier to produce patient-specific, 3D-printed, drug-eluting implants (e.g., scaffolds [161,162], gynecological devices [163,164], antimicrobial wound dressings [165], and biodegradable/bioabsorbable stents [166]. More recently some researchers have investigated the potential use of such polymer in combination with natural gums (e.g., arabic gum, ARA) to prepare hot-melt extruded polycaprolactone-based filaments intended for 3D-printing of tablets. Particularly, Viidik et al. [136] used a single-screw hot-melt extruder to produce drug loaded filaments of PCL and ARA, and, in particular, with 20%, 30%, and 40% (w/w) of indomethacin (IDM) and theophylline (THEO). These HME filaments exhibited properties suitable for FFF, such as smooth surface and sufficient mechanical properties. Special attention was paid to the uniform distribution of the drug and the overall homogeneity of the HME filaments as well as to their physical stability. Results showed that, if properly stored, the extruded filaments can be successfully 3D-printed into tablets. Furthermore, by modifying the size, shape, and texture of the cylinder-shape 3D-printed tablet (i.e., a lattice "honeycomb" tablet form, see Figure 13b), an aspect easily approachable by means of 3D printing, the release of the loaded drug can be significantly improved.
The factors affecting the uniform drug distribution within PCL after HME and FFF 3D-printing processes was deeply investigated by Holländer et al. [164]. In this study, indomethacin-loaded, PCL-based filaments with three different drug contents, namely 5%, 15%, and 30%, were produced by hot-melt extrusion. The extruded filaments were further used to 3D print long-lasting implantable drug loaded IUS (intrauterine system, see Figure 14c). Results showed that the amount of the loaded drug affected the filament roughness, solid state, printability, and drug release performances of the 3D printed devices. The higher the drug content, the higher the crystallinity degree, and the lower the percentage of drug dissolved in the polymer, and hence released.
To ensure a greater uniformity of drug loading within the extruded filament, an alternative way to the direct extrusion of the physical mixture API/polymers (and additives) could be the loading of the drug in solution. In this case, one of the most challenging process steps is the selection of a solvent or a solvent mixture able to dissolve both the API and polymer/s. An interesting application is the possibility to produce antimicrobic dressing. For example, Muwaffak et al. [165] explored such a strategy to load antimicrobial metals, such as zinc, copper, and silver, inside PCL, and produce polymeric filaments for 3DP. In this work, HME technology using a Filabot filament hot-melt extruder with a single screw and a 1.75 mm nozzle head was used to extrude pellets obtained by vacuum-drying solutions containing PCL and Silver (10% loading w/w), Copper (10% and 25% loading w/w), or Zinc (10% and 25% loading w/w). Tetrahydrofuran (THF) and dichloromethane (DCM) were selected as solvents to dissolve the PCL pellets, which were added to the metal solutions (aqueous, methanolic, and ethanolic for silver, copper, and zinc, respectively) and obtain homogeneous mixtures. The extruded filaments were then processed by an FDM-3D printer to manufacture wound dressings with different shapes, whose digital models were obtained by 3D scanning. Release data determined by inductively coupled plasma atomic emission spectroscopy showed for all the different metal dressings a fast release (up to 24 h) followed by slow release (up to 72 h), while the best bactericidal properties were found for the dressings based on silver and copper. HME-FFF have great potential. However, the filament production step plays a critical role in consuming time and materials. So, in the last years, the possibility to print in 3D by FFF, avoiding the intermediate HME process necessary for the development of filaments, has been investigated. Recent advances in this field have made available equipment able to directly 3D print by FFF technology starting materials in the form of powders or pellets [56,168,169]. Goyanes et al. reported for the first time in 2019 a novel single-step printing process to produce 3D printed tablets directly from powdered materials, and specifically hydroxypropylcellulose and itraconazole. All the obtained printlets showed good mechanical and physical characteristics and no drug degradation. This possibility may represent a notable advantage from a productive point of view. Indeed, it could revolutionize the preparation of amorphous solid dispersions (ASD) as final formulations and it may be especially suited for preclinical studies, where the amount of drug is often limited [170]. Some machines based on this single step approach are already on the market. CellInk ® , for example, has developed a thermoplastic printhead for its BIO X TM 3D-printer for whose use the cartridge must be loaded directly with a powder. To guarantee a uniform product printing when starting from thermoplastic materials in mixture among them or with APIs, many additional aspects must be considered, but all the profuse efforts being made may help in the near future to maximize the already high versatility of the FFF 3DP technique. (c) Long-lasting implantable drug loaded intrauterine system. Reprinted with permission from reference [164]; copyright (2016) Elsevier B.V. HME-FFF have great potential. However, the filament production step plays a critical role in consuming time and materials. So, in the last years, the possibility to print in 3D by FFF, avoiding the intermediate HME process necessary for the development of filaments, has been investigated. Recent advances in this field have made available equipment able to directly 3D print by FFF technology starting materials in the form of powders or pellets [56,168,169]. Goyanes et al. reported for the first time in 2019 a novel single-step printing process to produce 3D printed tablets directly from powdered materials, and specifically hydroxypropylcellulose and itraconazole. All the obtained printlets showed good mechanical and physical characteristics and no drug degradation. This possibility may represent a notable advantage from a productive point of view. Indeed, it could revolutionize the preparation of amorphous solid dispersions (ASD) as final formulations and it may be especially suited for preclinical studies, where the amount of drug is often limited [170]. Some machines based on this single step approach are already on the market. CellInk ® , for example, has developed a thermoplastic printhead for its BIO X TM 3D-printer for whose use the cartridge must be loaded directly with a powder. To guarantee a uniform product printing when starting from thermoplastic materials in mixture among them or with APIs, many additional aspects must be considered, but all the profuse efforts being made may help in the near future to maximize the already high versatility of the FFF 3DP technique. To avoid drug degradation The use of a higher processing temperature had a negative effect on the integrity of the model drugs particularly for lisinopril To find the optimal plasticizer The authors explored an evaporable plasticizer, that can initially facilitate polymer extrusion, and then followed by its partial or complete removal (in a secondary step) is able to restore filament mechanical rigidity towards printer ready robustness.
Triethyl citrate (TEC), Kolliphor ® TPGS (vitamin E polyethylene glycol succinate, d-alpha tocopherol) were used as plasticizers in some formulations HME (twin-screw extruder) Filament hygroscopicity and fragility, which negatively affect printing process [171]  The adhesion of fine drug powder to the equipment It's important to have comparable particle size [155] Tablets Acetaminophen (A) and Caffeine (CAFF) PVA HME (single-screw filament extruder) The adhesion of fine drug powder to the equipment [172] Tablets with controlled release profiles 4-Aminosalicylic acid (4-ASA) and 5-Aminosalicylic acid (5-ASA) PVA API loading in pre-formed filaments by soaking.
Very low API loading in the strands [13]  Nozzle Clogging To control T during HME process for avoiding clogging, initial T is higher than the extruding T [174]  Partial PVP degradation at the recommended 3D printing temperatures; Difficulties to obtain by HME stable structure due to poor flow of the polymer from the hot nozzle of the printer and the formation of collapsed structure To obtain by HME stable structure and allow rapid solidification of the filament from the hot nozzle, talc was added a thermostable filler to the composition of the filament.
[176]   The realization of a unidirectional drug release profile EC was added as hydrophobic printed layer and a backing layer (commercial wafer sheets) was also selected as efficient barrier to drug release from the corresponding surface [181]

SSE: Applications, Challenges and Perspectives
Apart from FFF, EBP (extrusion-based 3D printing) comprises semisolid-extrusion technology (SSE). This section provides an overview of advanced design solutions, strengths and weaknesses, opportunities, and challenges in SSE printing.
The current state of art based on a detailed literature analysis regarding SSE capability to develop pharmaceutical and medical products is summarized in Table 3. Generally, SSE is based on the pressure-assisted extrusion of a paste or gel through a syringe-based printing head followed by deposition of the material on the printing platform. As it clearly emerges from Table 3, such a technique has been highly explored in the production of various pharmaceutical dosage forms, different types of tablets, and polypills (e.g., loaded with single API or multiple APIs, floating, orodispersible or chewable), many of which for pediatric requirements. Moreover, an interesting application is the manufacturing of orodispersible films [183].
A remarkable example of a five-in-one polypill with strictly controlled drug release has been designed by Khaled et al. [126], who developed a novel tablet with a complex geometry able to deliver five APIs with two independently well-defined release profiles. The first three compartments were designed to release in a sustained manner pravastatin, atenolol, and ramipril. These sections were covered with an immediate release compartment of aspirin and hydrochlorothiazide (see Figure 15a). The combination of such drugs in a single polypill for the prevention and treatment of cardiovascular diseases allows to optimize therapy as well as patient compliance while avoiding incompatibility issues thanks to the physical separation of each drug within the compartments. The three drugs, atenolol, pravastatin, and ramipril, mixed with a hydrophilic matrix (HPMC) were extruded into the segmented compartments, whose barrier for the APIs sustained release was obtained by the extrusion of a hydrophobic cellulose acetate membrane. Aspirin and hydrochlorothiazide, mixed with a disintegrant and other excipients, were extruded directly on the top of the cellulose acetate compartments to realize the immediate release compartment. In another work, Khaled et al. used SSE to design a polypill with compartments exhibiting release mechanisms of a different type, namely osmotic release through a controlled porosity shell and diffusion through gel layers [125]. As reported in Figure 15c, the captopril-loaded core of the polypill obtained using hypromellose hydro-alcoholic gel as binder and sodium chloride as osmogen acts as an osmotic pump, whereas the other two compartments realized with a HPMC hydrophilic matrix act as sustained release platforms of nifedipine and glipizide. SSE has also been exploited for the fabrication of gastro-floating tablets to improve the bioavailability, and thus therapeutic efficacy of some drugs. Li et al. [184] successfully developed gastro-floating tablets with a fine lattice internal structure (see Figure 15b) loaded with dipyridamole, a poorly water-soluble drug with a short biological half-life. Tablets were prepared starting from pastes of hydroxypropyl methylcellulose (HPMC K4M) and hydroxypropyl methylcellulose (HPMC E15), two traditional pharmaceutical excipients, and applying three different infill percentages (30%, 50%, and 70%).
In the last few years, 3D printing via SSE has become consistently popular to produce oro dispersible tablets (ODT) [185]. Recently, some researchers explored this technique to produce carbamazepine (CBZ) loaded ODTs using cyclodextrins to increase the solubility and bioavailability of the drug [186]. Hydroalcoholic wet masses containing mixtures of CBZ, hydroxypropyl-β-cyclodextrin (HPβCD), and various cellulose ethers enabled in situ drug-HPβCD complex formation with suitable rheological properties for SSE-3DP. In more detail, the authors focused their attention on: (i) the choice of the best binder agent among HPMC E4M, HPMC F4M, sodium carboxymethylcellulose, and PVP K25; (ii) the optimal amount of wetting liquid; (iii) the influence of the croscarmellose sodium on both tablet disintegration time and mechanical resistance; and (iv) the printing operative parameters (e.g., tablet size, pore size, perimeters, total number of layers, infill pattern, flow speed, infill speed, and travel speed). The most homogeneous printable pastes were obtained using HPMC F4M as binder, water: ethanol 90:10 v/v as moistening liquid, and croscarmellose sodium 2.5% w/w as disintegrant. The porosity of the extruded tablets was properly regulated through slicing and printing parameter set-up, allowing to obtain porous tablets with fast release characteristics as well as physical properties appropriate for handling. This research highlights the close relationship between the paste rheology properties and its performance as 3D ink for SSE, in terms of consistency and homogeneity of the strand and printing resolution, and how much rheological analysis of the wet masses is a pre-condition to identify the best printable compositions. SSE has also been exploited for the fabrication of gastro-floating tablets to improve the bioavailability, and thus therapeutic efficacy of some drugs. Li et al. [184] successfully developed gastro-floating tablets with a fine lattice internal structure (see Figure 15b) loaded with dipyridamole, a poorly water-soluble drug with a short biological half-life. Tablets were prepared starting from pastes of hydroxypropyl methylcellulose (HPMC K4M) and hydroxypropyl methylcellulose (HPMC E15), two traditional pharmaceutical excipients, and applying three different infill percentages (30%, 50%, and 70%).
In the last few years, 3D printing via SSE has become consistently popular to produce oro dispersible tablets (ODT) [185]. Recently, some researchers explored this technique to produce carbamazepine (CBZ) loaded ODTs using cyclodextrins to increase the solubility and bioavailability of the drug [186]. Hydroalcoholic wet masses containing mixtures of CBZ, hydroxypropyl-β-cyclodextrin (HPβCD), and various cellulose ethers enabled in situ drug-HPβCD complex formation with suitable rheological properties for SSE-3DP. In more detail, the authors focused their attention on: (i) the choice of the best binder agent among HPMC E4M, HPMC F4M, sodium carboxymethylcellulose, and PVP K25; (ii) the optimal amount of wetting liquid; (iii) the influence of the croscarmellose sodium on both tablet disintegration time and mechanical resistance; and (iv) the printing operative parameters (e.g., tablet size, pore size, perimeters, total number of layers, infill pattern, flow speed, infill speed, and travel speed). The most homogeneous printable pastes were obtained using HPMC F4M as binder, water: ethanol 90:10 v/v as moistening liquid, and croscarmellose sodium 2.5% w/w as disintegrant. The porosity of the extruded tablets was properly regulated through slicing and printing parameter set-up, allowing to obtain porous tablets with fast release characteristics as well as physical properties appropriate for handling. This research highlights the close relationship between the paste rheology properties and its performance as 3D ink for SSE, in terms of consistency and homogeneity of SSE is an important tool in personalizing pediatric formulations. Indeed, the number of papers reporting the use of SSE 3DP in the manufacturing of pediatric-friendly chewable printlets for the oral administration of both hydrophilic and lipophilic drugs is growing. Goyanes et al., for example, evaluated for the first time the use of SSE 3D printing in a hospital setting for the administration of isoleucine in the form of personalized chewable printlets to treat a rare metabolic disorder, maple syrup urine disease (MSUD), in pediatric patients [187]. Isoleucine blood levels after six months of treatment with personalized chewable formulations prepared at the hospital by automated 3D printing were comparable to those obtained with conventional capsules prepared by manual compounding. However, the 3D printlet therapy caused mean levels closer to the target value and less variability. As regards acceptability, 3DP formulations prepared with different flavours and colors were well accepted by the children, although each patient had different preferences.
Personalized chewable medicines for children were produced via semisolid extrusion in the form of gummies with different shapes too, e.g., heart, bear, or disc, loaded with pediatric doses of ranitidine hydrochloride [188]. In this case, a syringe-based extrusion mechanism used mixtures of gelatin, carrageenan, xanthan gum, and sweeteners [189]. Mass as well as dose uniformity were guaranteed, fitting standards that only well-established tableting technologies can reproduce. The added value of the personalized pediatric formulations resides in the easy handling and intake, high dosage flexibility, and personalization of the final products by simple changing the size, infill density, or design of the digital model. Moreover, the attractive, funny, and appetizing appearance of the gummies could enhance treatment adherence and help to decrease the emotional impact of the disease in children.
Recently, Lego™-like chewable bricks made of edible soft material (gelatin-based matrix) were also proposed by a variant of SSE, namely embedded three-dimensional printing (e-3DP). E-3DP implies the extrusion of semisolids within a solidifying liquid matrix [190]. Such chewable dosage forms with dual drug loading (paracetamol and ibuprofen) were produced by directly extruding novel printing patterns of model drug ink (embedded phase) into a liquid gelatin-based matrix (embedding phase) at an elevated temperature (70 • C), followed by solidification at room temperature. The main advantage of this technology is the possibility to encapsulate the drug paste within a matrix that masks its flavor, as in the case of bitter-tasting drugs.
One more application of SSE is in printing lipid-based formulations (LBFs) loaded with poorly water-soluble APIs into solid oral dosage forms for the delivery of poorly water-soluble APIs. Johannesson et al., for example, used SSE to produce solid lipid tablets based on printable emulsion gels with appropriate rheological properties by the addition of methyl cellulose as viscosity enhancer [191]. Tablets loaded with fenofibrate were successfully 3D-printed, showing good mechanical and dimensional properties as well as high mass uniformity and dose accuracy. Moreover, as expected for immediate release formulations, the produced tablets were able to disintegrate in less than 15 min. The combination of the advantages of an established formulation strategy for poorly watersoluble drugs as LBFs with such a novel and flexible production technique as 3DP via SSE opens new horizons to delivery highly potent, poorly water-soluble APIs for which dose adjustments may be required in some patient categories.
ODFs (orodispersible films) may be manufactured by SSE [22][23][24]. ODFs are polymeric thin film strips loaded with drugs that rapidly dissolve upon contact with saliva [192,193]. SSE 3D printing in the production of such systems provides a very increased flexibility in terms of drug dosage as the drug dose can be established based on the dimensions of the ODF itself, representing a great advantage to realize a personalized pharmacotherapy. Yan et al. printed individualized ODFs in doses of 1.25 mg, 2.5 mg, and 5 mg of levocetirizine hydrochloride [19]. HPMC was used as water-soluble and film-forming polymer, pregelatinized starch as filling agent, and maltitol and sucralose as flavoring agents. For this kind of application, the critical point is the careful selection of the relative ratios among such components to obtain a printable ink, that is a gel with consistency and viscosity suitable for 3D printing process. Whilst the main advantage resides in the drug content uniformity and dose accuracy, high flexibility, and rapid drug release performances (complete drug dissolution within 2 min).
As FFF potential is limited by the possible thermal degradation of the APIs during the heating step, there are noteworthy examples of how the FFF-printer can be adapted for the SSE process to produce formulations while avoiding the use of high temperatures. Falcone et al. reports an example of a technological advancement fixing to the printhead of the Ultimaker3 printer a customized coaxial extruder for SSE 3D printing. The coaxial extruder was connected through tubes to the syringe pump system, allowing the simultaneous dispensing of ink gel (sodium alginate 6% w/v) and crosslinking gel (hydroxyethyl cellulose 3% w/v, calcium chloride 0.1 M and Tween 85 0.1% v/v). The innovation of this single-step approach made possible the manufacturing of innovative floating delivery systems loaded with propranolol hydrochloride and designed for personalized therapy [194].
SSE is a relevant tool in the manufacturing of medical devices (MD) as an alternative to FFF. Some interesting examples of devices produced by SSE can be found in the literature. Holländer et al., for example, applied SSE in combination with the UV-assisted crosslinking technology to produce polydimethylsiloxane (PDMS) devices for the delivery of prednisolone [26]. In this case, critical variables are the set-up of printing as well as of curing conditions, allowing the manufacture of 3D printed structures with good morphology, adequate mechanical strength, and controlled drug release.
The great potential of SEE 3DP for biomedical applications, and specifically for the manufacture of polymeric scaffolds incorporating thermolabile drugs, and hence requiring low process temperatures, has been recently evidenced. Naseri et al. reported a novel low-temperature (20 • C) 3D printing technique based on SSE poly-lactic-co-glycolic acid scaffolds using methyl ethyl ketone (MEK) as a mild organic solvent [195]. In this paper, the printability study of PLGA scaffolds was performed on different starting bio-inks obtained by varying the PLGA concentration in MEK solvent, lactic to glycolic ratio, and molecular weight of PLGA. For 3DP via SSE of PLGA scaffolds with high shape fidelity, good flexibility, and elasticity, the authors recommend PLGA concentrations higher than 80% w/v, lactic to glycolic ratio greater than 75%, molecular weight more than 100-200 kDa, and printing through nozzles smaller than 0.96 mm in internal diameter.
The same research group, starting from the above interesting results, explored semisolid extrusion 3DP in combination with the proposed and well-characterized bio-ink of PLGA to produce bioabsorbable scaffolds and, specifically, 'biopierces' loaded with the antibiotic mupirocin [27]. The main goal was to realize novel, bio-absorbable, drug eluting scaffolds able to cover piercing studs and prevent possible infections during the healing process. Antimicrobial sensitivity testing showed an effective release of the drug against S. aureus with an inhibition zone constant for 14 days.
More recently, drug-eluting polycaprolactone/nano-hydroxylapatite (PCL/nHA) nanocomposites loaded with vancomycin and ceftazidime and with extended drug release was fabricated using a lab-made SSE-based printer [196]. During this study, the influence of distinct printing parameters on the printed part quality was examined. The obtained results show that the tensile strength of post-printed PCL/nHA specimens increases with the fill density yet reduces with a decrease in the ratio of PCL/nHA to dichloromethane (DCM) and print speed. Dually drug loaded PCL/nHA screws were also prepared and characterized with different analytical techniques. Specifically, drug release results show for 3D printed screws an extended elution of high levels of vancomycin/ceftazidime over a 14-day period. Need for proper selection of 3D printing speed to regulate mass transfer processes during both processing and post processing intervals, guaranteeing good quality standards [197]  Need to enhance of HA-PQ10 sludge printability as well as its gastro-resistance. CAP was added as binder and modified-release excipient [198] Four-in-one oral polypill with multiple release profiles caffeine (CAFF) and vitamin B analogues      To determine the optimal amount of APIs to load within feed solutions to obtain printable inks (formulations containing more than 40% of PCM and 28% of IBU were too viscous for efficient printing) [190]      To properly set post printing processing (e.g., UV exposure time) to control shape as well as DOX release [208] Hydrogel wound dressing Lidocaine hydrochloride (LDC HCl) Chitosan (C) and pectin (P) To prepare a hydrogel-based ink viscous enough to maintain a proper extrusion speed during 3D printing without over-liquefying or blocking in the nozzle and to conserve the geometries after printing. Being the selected material a thermoreversible hydrogel, its viscosity was adjusted by modulating the process temperature. The optimized operative conditions led to 3D printed systems with good printability, dimensional integrity, and adhesive properties.
[209] To opportunely select bioink composition to have the rheological properties adequate for printing and guarantee shape fidelity of the 3D printed structure SAlg and HA were selected for ink preparation at 15 wt% and 8 wt%, respectively.
[212] To load an optimal amount of API, ensure its integrity after processing (being sensitive to hydrolysis), and guarantee its slow release from 3D printed scaffold. [27] Devices cured with UV light Prednisolone (PRED) polydimethylsiloxane (Silopren UV LSR 2030) To properly select printing speed and pressure as well as post printing conditions of curing (e.g., time, intensity of the UV lamp) for hardening 3D printed structure and avoiding its collapsing Need for loading an optimal amount of API to guarantee ink printability. Ink containing more than 1.5% PRED are too viscous for efficient printing [26]   To properly select gelatin concentration and 3D printing parameters (T, pressure, and speed) for avoiding nozzle tip clogging as well as the spreading of the 3D printed structure on the print bed and the alteration of its shape after drying

FFF and SSE: Comparative Analysis
The product review provided in Sections 4.1 and 4.2 confirms the high potential of extrusion-based 3DP technologies in the manufacturing of personalized drug delivery systems and medical devices, highlighting for both FFF and SSE the general advantages and disadvantages discussed early (Table 1).
Regarding FFF, filament production, as well as drug loading method, along with other formulative (e.g., starting material composition and presence of specific additives) and printing parameters (e.g., size and shape, layer height, number of overlapped layers, infill density, infill pattern, pore size, porosity, temperature of the nozzle and build platform, etc.) have a significant impact on the final performances of the 3D printed product, e.g., in terms of drug dose, release mechanism, and kinetic or mechanical strength. In more detail, physical and chemical properties of both the drug and the polymer matrix, as well as the drug loading strategy within the polymer, specifically influence the drug release mechanism (i.e., diffusion, erosion, swelling, and osmosis) [164,[217][218][219][220]. For example, erosion can be predominant when the drug is loaded by impregnation within polymeric filament, while it stops to be dominant, and swelling occurs first, when the drug is loaded via HME [220]. The 3D geometric design also plays an important role in predefining and programming drug release at a defined rate, over a specified timeframe. A lot of researchers exploited FFF flexibility to vary the infill degree, and obtain an increasing or decreasing drug release rate, or a pulsatile pattern [155,156,173,181,[221][222][223][224][225][226]. Another key parameter to modulate drug release kinetic is the surface area to volume ratio. Goyanes et al. [37], for example, discussed such an aspect when investigating drug release performances from different 3D printed structures (cube, pyramid, cylinder, sphere, and torus) based on eroding matrices. The geometry freedom of FFF also presents the possibility to compartmentalize the printed product without particular difficulties, obtaining, e.g., capsular devices with tailored drug combinations, doses, and release profiles [223,224,227]. Such systems can either be realized as empty compartments to be loaded with the drug later, or as outer shell and inner core in a single process [224] and allow for combinations of drugs, doses, and release kinetics [225]. The FFF critical process parameters also impact the stiffness, hardness, and mechanical strength of the final 3D printed product, aspects important for drug delivery systems (e.g., handling) [189,191,205], but even more for medical devices [85].
Differently from FFF, SSE printing uses pastes or gels. Due to the semisolid consistence of the starting materials, the main issues encountered by researchers were the nozzle clogging (due to critical rheological parameters, e.g., viscosity, yield stress under shear and compression, and viscoelastic properties) and the need for post-printing treatments (e.g., drying, cross-linking), with the following reduction of 3D printed object resolution. Material rheological properties play a crucial role in determining optimal processing conditions during SSE printing. Their careful analysis and optimization promote the homogeneous gel/paste extrusion through the nozzle, guaranteeing (1) the high reproducibility of 3D printed object; (2) the possibility to improve its mechanical properties, and (3) to control the release performances of the loaded drug [22]. As with FFF, also SSE gives high flexibility in geometry design (e.g., compartmentalization, infill degree, etc.), offering the great possibility to control drug release mechanism and kinetic. A great variety of SSE drug delivery systems, e.g., polypill [125,126,199] or floating systems [184,194,204] with unique drug release profiles, were produced by simply varying the design and printing parameters. In addition, the possibility to work with a wide range of excipients of well-established use in the pharmaceutical field, and at room temperature (suitable for thermolabile APIs and excipients), highly increases the application domain of such a 3DP approach in this sector. In fact, SSE has been highly investigated to produce immediate release tablets [12,16,203] or orodispersible films [19,22,186], using traditional super disintegrants and other excipients as ink components.
In general, both extrusion-based 3DP techniques FFF and SSE allow the preparation of complex structures with high control over the pore size, pore architecture and wall thickness, exposed surface area, and pore interconnectivity, key factors to control drug release profiles, mechanical strength, and other critical products, guaranteeing the successful production of personalized drug delivery systems as well as medical devices. However, their pertinency is not overlapping due to the respective disadvantages that limit some specific applications. Using one technique or the other depends on the starting materials used as well as on the final performances of the 3D printed products.

Conclusions
The technology evolution pathway of 3DP from 2012 to date is very notable. It is a fact that at present there is a contribution of 3D-printing to many aspects of healthcare. However, the full range of application remains to be explored in depth.
In the last few years, the healthcare needs of the population have changed, also thanks to the adoption and enhancement of omics technologies in healthcare. There is an increasing demand of patient-tailored treatments to improve efficacy, safety, patient compliance, therapeutic adherence, as well as cost-efficiency. This has strongly moved the attention towards 3D printing technology, which offers innovative, digitally designed solutions able to overcome the issues of the currently marketed traditional products.
Problems impacting 3DP application are mainly four-fold: the strict requirements for excipients, the development of printing software and equipment, the optimization of mechanical properties of products, and the regulatory framework. As regards excipients for pharmaceutical 3D printing, they are relatively restricted, compared to conventional manufacturing processes, mainly for technologies using heat. Much research has updated this field. However, further studies concerning biocompatible, biodegradable, and stable excipients peculiar for 3DP are required. As the complexity of product structure increases, the modeling and slicing software used to design and drive its manufacture as well as equipment, operative procedures, and control system must be constantly refreshed.
From a regulatory point of view, there are still several open questions surrounding how 3D-printed healthcare products can be monitored and evaluated for quality. Although the FDA authorized in 2015 the first 3D-printed tablets, no regulations or guidelines regarding 3D-printed medicines are currently available. Progress has been made for 3D printed medical devices, for which the FDA released in 2017 guidance detailing some technical considerations. However, there is no possibility to give universal guidelines for all 3D-printed technologies and medical devices. A separate assessment of safety and effectiveness may be required for each technology and product, especially for those personalized. Furthermore, when products are customized to the patient, the question of whether 3D printing is classed as a manufacturing or compounding process also has a great impact on regulatory requirements.
The present review was addressed to show how 3D printing (3DP) can develop in the next years focusing on the identification of areas where current research is more proactive and tentatively providing directions for future research. Particularly, given the implementation of existing technologies, the investigation of new or re-designed materials and apparatus appears necessary for arriving at decentralized and customized digital manufacturing perfectly integrated into manufacturing systems for medicines and medical devices.
Overall, 3D printing has the potential to revolutionize the existing healthcare scenario, allowing not only the development of new materials and drug delivery systems, but also the choice between centralized/decentralized manufacturing, customized/personalized medicines and medical devices, and on demand/by market order request production. However, we will have to wait and see whether the technical and regulatory challenges facing the market can be overcome, enabling the technology to reach its full therapeutic potential.
Author Contributions: G.A. and R.P.A. conceptualized and wrote the initial draft of the manuscript; C.T., G.F., T.E. and C.S. participated in data curation and literature search; the review and final editing of the manuscript was carried out by G.A and C.T.; the supervision of the manuscript writing was performed by G.A. and R.P.A.; R.P.A. obtained funding. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest.