Revolution in The Making: A Survey of Emerging Applications and Technologies In 3D Printing

3D printing in pharmaceuticals has been under vigorous research and developments ever since the beginning, with the first researches traced back to 1996 (Wu et al., 1996). But then, times have changed-a lot of things have changed very recently with the advent of commercial-scale capabilities [8]. Most of these earlier studies have focused on exploring different aspects of 3D printing technology suitable for pharmaceutical applications. Spritam®, the very first representative product to have been FDA commercialized and manufactured in a scale significant, evidences the potential of 3D printing technologies appear to be instrumental in allowing the manufacturing of drugs in large scales [9]. Generally, all 3D printing methods for developing pharmaceutical dosage forms can be classified into four major categories: extrusion-based, powder-based, liquid-based, and sheet lamination-based [10].

3DP, or three-dimensional printing, is the technology whereby different geometric shapes are created into 3D issues layer by layer. Major advantages of 3DP technologies over conventional processes are the making of complex and sophisticated solid dosage forms, efficient on-demand manufacture, and the ability to actually personalize pharmaceuticals with individually adjusted doses [11]. Currently, there is a high degree of interest in 3DP application in pharmaceuticals for innovative design of drug delivery systems and drug manufacturing [12]. Yet, the full deployment of 3DP technology in pharmaceuticals may be impeded by some technological advancements and legal problems, though it is clear that it reflects several possible medical and commercial benefits [13].

3D printing in pharmaceutical product design

The medicines meant for the animals are needed for the maintenance and restoration of health in mammals [14]. This medicine is obtained by making dosage forms available in various strengths as would be needed for administration as veterinary medicine: that these differences are among the particular-most pharmacokinetic variations that affect the composition and operation of veterinary dosage forms [15]. Generally, a dosage regimen is adjusted according to animal weight; thus, it is A drug often shows up in different strengths [16]. An important example of this is fluralaner, clindamycin hydrochloride, and mavacoxib [17]. But it is also an everyday practice where veterinarians and pet owners extract the whole tablets and divide it into 2 or 4 parts according to the need of their pets [18]. Like humans, animals have their own preference in the way they take medications. Therefore, considering animal preference is an important aspect in veterinary drug design [19]. For other species, take for example; horses are very fond of fruits (like apple) while dogs love eating animal proteins (like chicken, pig, and beef). To make it fit to the taste of dogs, Simparica Trio contains hydrolyzed vegetable protein, sweeteners, gelatin, and pork liver powder. Generally, nowadays most frequent doses given to animals are orally and parenterally given formulations. Advancement in pharmaceutical production has led to the manufacturing of many palatable oral dosage forms. Chewable tablets are still widely used in veterinary for pet applications, particularly cats and dogs. As a matter of fact, chewable tablets are the most commonly utilized pharmaceutical dosage form in veterinary care -more than in human medicine [20]. This puts into perspective the situation as regards chewable formulations for animal purposes in the market [21]. In fact, compared to human formulations more chewable veterinary formulations are marketed. Probably because the animal does this without luring anything into its mouth [22].

Fig.1. Target product profile of medicinal products intended to be used by dermatological patient

Patient Centric Pharmaceutical Drug Product Design:

The Impact on Adherence to Medication.

The Impact of Focused on patients Pharmaceutical Drug Product Design on Medication Persistence The core principle of PCDPD is to include patients' needs and preferences into the design of a medicinal product [23]. Only 45 studies examining patients' preferences for medications were found in a recent literature review. Only 35 of them focused into dosage form design, and 11 of them only evaluated oral dosage forms [24]. surprisingly, almost no study has examined at patients' preferences for the size, shape, and colour of solid dosage forms, which are frequently used for The foundation of PCDPD is to incorporate patients' requirements and preferences into the design of a medication [25]. Only 45 studies examining patients' preferences for medicinal mixtures were found in a recent review of the literature. Only 35 of them focused into dosage form design, and 11 of these only examined oral dosage forms. remarkably, not much research have looked at patients' preferences for the size, shape, and color of solid dosage forms, which are frequently utilized to treat non-communicable illnesses [26]. The pharmaceutical business is capable of developing and manufacturing a wide range of dosage forms as well as to traditional solid dosage forms like tablets [27]. Certain pharmaceutical goods become more popular as better NCD remedies when a PCDP design is used. The pharmaceutical sector is capable of producing a wide range of dosage forms as well as to traditional solid dosage forms such tablets. In the context of a PCDP-based product design, some dis-opy of drug products seem to emerge more favourably than others for promoting adherence, and these will be addressed in greater detail with more focus on their impact on adherence to medication.

Faster formulation development by formulation design.

The selection of excipients and the design of the tablet are complex and should be made with a proper understanding of the formulation. The excipients must exhibit performance characteristics expected, such as stability with the active pharmaceutical ingredient (API), ease of tableting, and the required disintegration rate [28]. The tablet structure may influence delivery of the desired pharmacokinetic profile. This phenomenon occurs in conventional as well as 3D printed tablets. Thus, in light of these factors, the newly devised 3D Printing Formulation by Design (3DFbD) came into being [29]. The best formulation among others can thus be achieved by considering tablet structure information in conjunction with the physicochemical and biopharma-ceutical characteristics of the API and excipients [30]. The formulation would thus be controlled based on physicochemical data that would decrease the uncertainty in the traditional formulation approaches. 3D printings work such that they can produce structures controlling the rate, duration, and mode of release. Therefore, the traditional empirical method gives way to a rational design based on the Formulation-by-Design process. This decides the necessary release mode, the start, and the rate of release through physiological parameters like GI transit time and site of absorption to assure knowledge of the amount of drug delivered at different times during absorption. The tablet design is to be selected from a comprehensive list of previously known tablet designs that provide the desired mode, rate, and time of onset of release [31]. In such a "stackable approach", tablet components are added toward tablet formation, just like Legos stack to create a structure. This allows for rather easy construction of tablet structures yielding complex release profiles. after the formation of the tablet structure, excipients with the necessary physicochemical properties to enable formulation and performance upon construction compatibility with API form pharmacological excipients and Generally Recognized as Safe (GRAS) substances. Once the structures and excipients have been determined, the computer codes will be drawn upon to print prototypes for rapid performance assessment both in vivo and in vitro. The designs can be modified within hours instead of days or weeks as required, owing to the dSemonstrated application in the in vitro release profile and the specific in vivo PKs using the 3DFbD® and 3D printing. Zheng et al. showed this potential realization of the target value in the in vitro release profile and PK results in vivo through application of 3DFbD and 3D printing to the molecule. Its overall tendency is oriented more favorably towards 3D printing technologies, as the release profile can be altered in a much accurate and precise way [32].

Fig 2. 3D Printing Formulation by Design (3DPFbD@) Schematics.

Patient preferences

Several surveys have been done regarding the adoption and preference of patients for 3D printed tablets. One of the surveys reported was conducted by Goyanes et al., wherein patient preference was elicited on 10 different types of 3D printed tablets (PrintletsTM), available in four different sizes and nine different colors. (Goyanes et al., 2017) [33]. It is common for people to find smaller-sized drugs more amiable-the reason is that most patients generally associate extremely bright colors to under-rating; yet, variance in responses regarding the range of colors available was evident. Pre- and post- swallowing ratings were all higher for tablet forms easily identified, i.e. Caplet or withmore rounded areas compared with sharper-edged or cube tablet forms, both of which received lower ratings. Such results were also seen in findings from other studies (Fastø et al., 2019), which indicated that "indications of preference for traditional shapes were recorded from the patients, probably due to the factor of being quite familiar, but wanted clashing colors." Some research studies were also done with the subjects being in the pediatric population but targetted this particular research towards only one subject - single-shaped Print lets™. produced using one or other of the four different printing technologies: digital light processing (DLP), selective laser sintering (SLS), semi-solid extrusion (SSE), and fused deposition modeling (FDM) (Januskaite et al., 2020). Table DLP-processed tablets were most preferred by most pediatric volunteers because they are bright-colored, clean-cut tablets. Most significantly, SSE tablets were least preferred at first sight but children's marked preference changed after learning that SSE technology has the capacity to produce swallowing-friendly tablets [34]. Following up on their and other researchers work interested in exploring the preference given to the various shapes of the resulting tablets, the research has been conducted on how the patients defined and rated their swallowing reactions before and after consuming them. This was done through observational methods around comparison of patients to the tablets where some were viewed as similar to or lower rated than others in respect to desirability, while others have forms that could be more artificial, thus higher accepted, which included sharper-edged or cube shapes. Similar observation was made in another study where the preference of the patients coincided with the use of unfamiliar colors contrary to reported preference for conventional shapes (Fastø et al., 2019). Other studies have also been done in the context of the pediatric population, but specifically, they have looked into only one shape of the tablet, which in this case is Print lets™, created by any of the Digital light processing (DLP), selective laser sintering (SLS), semi-solid extrusion (SSE), and fused deposition modeling (FDM) are the four categories of printing technologies (Januskaite et al., 2020) [35].

3D Printing Types Several 3D printing

While the various technologies try to do different things, ASTM considers 3D printing technologies to fall within seven classifications-binding jetting, directed energy deposition, material extrusion, material jetting, powder bed fusion, sheet lamination, and vat photopolymerization, as per ASTM Standard F2792. Since each piece of machinery or technology does a different job, comparing which is better really does not hold any merit. The way ASTM defines 3D printing technology overweighted, it falls in different categories-under its there are seven forms of binding techniques namely jetting, directed energy deposition, material extrusion, material jetting, powder bed fusion, sheet lamination, and vat photopolymerization. All this machinery or technology does a different work; therefore, it does not matter comparing which one is better.

Binder jetting

Binder jetting is the rapid and additive manufacturing process in which selective application of a liquid binder gives enough adhesion to powder particles. Here, the liquid chemical binder might be "jetted" onto the spread powder to form a layer. This material ranges from casting patterns to semi-finished parts, raw sintered products, or very high-volume products manufactured via sand. Binder jetting can therefore cover numerous applications. It is a method found in metals, sand and polymers, hybrids, and ceramics. In making products from this technique, for example, you need not treat sand. Also, it is quick, easy, and cheap because the particles are simply bonded together; the biggest thing: binder jetting can print really huge items [36].

Directed energy deposition

Directed energy deposition (DED) is an advanced technology generally used for the amelioration or repair of already existing components. In turn, the monetary system of controlled grain structure and product quality could thus be produced by controlled parameters in directed energy deposition. Unlike some deposition types, where the nozzle is oriented strictly in one direction and can only move in different orientations, directed energy deposition more truly adopts the principle of material extrusion. Mostly regarded now for metals and metal hybrid materials in the forms of wire or powder, it can also be applied with polymers and ceramics. Some of the techniques included in this category are Laser cladding and laser-added net shaping (LAENS) are processes of metal material forming where a layer-by-layer powder deposition is used. The new process, termed laser deposition technology, can be applied to building objects.

Material extrusion

While plastics, food, and living cell structures, to mention just a few, can be 3D printed from a pool of colors and materials with material extrusion-based 3D printing technology, this cheap technique has its widespread use. It also offers a pathway to the build-up of fully functional parts of products. An example of such a class of material extrusions is fused deposition modeling (FDM). Other uses of FDM, invented in the early 1990s, included the melting and extruding from the bottom upward, layer by layer, thermoplastic filaments: this was the primary polymer used. Below are ways in which an FDM operates: I. After the thermoplastic is heated to a semi-liquid state, ultra-fine beads of it are deposited along the path of extrusion [37].

Material jetting

Material Jetting is defined by the ASTM standards as a 3D printing procedure characterized by the selected layer-by-layer deposition of a build material drop by drop. That is, jets deposit droplets of ultraviolet radiation curable material from a printhead for layered solidification into a part. Having very good surface finish and dimensional precision, parts manufactured using material jetting are also capable of multiple-material printing and offer an extensive range of materials from polymers, ceramics, and composites to biologicals and hybrids.

Powder bed fusion

The processes of powder bed fusion include electron beam melting (EBM), selective laser sintering (SLS), and selective heat sintering (SHS). The joining of material powder is melted or glued together by a laser or an electron beam. The so-called powder bed fusion covers quite a wide area: metals, ceramics, polymers, composite materials, and also hybrids. SLS is an outstanding example of powder-based technology in 3D printing. SLS technology was conceived by Carl Deckard back in 1987. SLS 3D printing technology has advantages such as excellent accuracy, rapid speed, and surface polish variability. Selective laser sintering can produce ceramic products as well as plastic and metal products, each with different power levels. SLS used a laser source capable of sintering polymer powders to produce 3D products. In parallel, SHS technologies denote a second form of those thermal printing-heads technology in 3D printing applied to melt thermoplastic powder into the fabrication of 3D printed objects. Finally, electron-beam melting raises the energy deposition to start the heating of the material [38].

Sheet lamination

Sheet lamination, as defined by ASTM, is a 3D printing process characterized by the bonding of sheets together so as to make a part of an article. Some of the 3D technologies that perform this process are laminated object manufacturing and ultrasound additive manufacture. Some advantages of this technology include a full spectrum of colors for printing, low cost applications, relatively easy material handling, and recycling of excess materials.

Vat photopolymerization.

Generally, photopolymerization is described as the curing of photo-reactive polymers by laser-visible light-UV radiation. The photopolymerization 3D printing technologies include SLA and DLP. For SLA, besides photo-initiators and specific irradiate exposure conditions, any dye, pigment, or other added UV-absorbers would also affect it. DLP is similar to stereolithography and uses photopolymers but so far as the illumination source is concerned they are different. With DLP being an older type of illumination, some have used an arc lamp in conjunction with a liquid crystal display panel. DLP has the capability of imaging the whole bonding area that the vat of photopolymer resin provides had been traversed at one go and therefore tends to print faster than Stereolithography. The parameters of Vat Photo polymerization generally refer to its time of exposure, wavelength, and time under the power supply. The markings in this stage would usually be obtained using materials that are liquid but that harden when ultra-violent light is supplied. Thus, these photopolymers give the best result with high detail in making expensive consumer goods [39].

3D Printing Classification

Fig 3: Classification of 3D Printing

3D printing materials and technology

These new 3D printing methods entirely rely on gallery deposition of materials in three dimensions to form a machine product. Recently launched materials and newer printing technologies have made rapid printing and multi-material printing one of the most important avenues for opening new applications from an added utilization perspective [40]. The different classes of 3D printers make use of an enormous range of materials, ranging from polymers, metal alloys, and ceramics to silicates and composites. Therefore, polymers are almost exclusively the raw material for all forms of 3D printing method (with the exception of directed energy deposition-priority), given the multi-faceted applications these have potential. Materials are expected to come in various forms; having examples including forms of chemicals, such as photosensitive polymer resins, thermosetting powders, and thermoplastic polymers, as modes of printing and interest differ. Although most studies and intense research work focus on 3D printing as the magic key to customized production and complex structures, various technical challenges such as defects in printing, lack of uniformity in mechanical properties, high manufacturing costs, limitations in manufactured quantity, and so forth still exist. However, with the advent of advanced materials and technology and backing from scientific research improvement, these issues are progressively being addressed, thus laying a robust foundation for transformational future development in the novel application field of 3D printing method.

Challenges in 3 D Printing

Material-related problems, printer setups, and administration are the principal challenges for 3D printing in the manufacture of biomedical products:

1. Materials: An appropriate binder should be selected because not all binders are appropriate for sintering and organic binders in some cases affect the printing equipment. For a long time, mechanical optimization of scaffolds especially those meant for bone tissue found it as an uphill task. Limited biocompatible and biodegradable materials exist; other factors compromising the quality of scaffolds would include powder size, interconnectivity and porosity.

2. Printers: Technologically, it is difficult to meet the desired dimensional tolerances and resolutions, especially for complex structures or nanoscale ones. Powder agglomeration and sintering problems influence the quality of printed goods. Scan speed and nozzle size used for printing also determine the quality of end products.

3. Management: In implementing 3D printing in the company, a reeducation process about its basics would be required. An operator must possess unique skills at each stage of processing. Cost elements of materials, utilities, and maintenance make this more complex. Moreover, small enterprises may find it difficult to implement the technology due to poor organizational structure. Lack of standardized procedures and regulatory structures for biomedical devices is only adding to the challenge. And, with connectivity comes a whole new set of cybersecurity risks [41].

Fig 4: Challenges of 3D Printing

APPLICATION

Healthcare and medical sector

The term 3-D printing refers to a variety of three-dimensional printing technologies which have been designed to make or manufacture skin, drugs, pharmaceuticals; tissues; organs; replacements; bones; and cancer research visualization modelsapplications in education and communication. The benefits of 3D printing are numerous. Technologies that can be applied to biomedicine:

• 3D technology simulates life-like skins with lower-cost values. 3D skin provides an acceptable way to test the pharmaceutical, cosmetic, and chemical products without having to test using animal skins, thus giving the researcher a much bigger chance of getting reliable results by mimicking the skin.

• 3D-printed drugs will also increase efficiency, accurate control over fallen size and dose, great reproducibility, and yield dosage forms with complex profiles of drug release.

• In 3D printing replacing bony deficiencies in bone or cartilage with bone tissue and cartilage after an incurring accident or a diseased injury; the therapy strays from auto-grafts and allografts as this therapy was aimed towards the formation of bone in vivo, sustaining or enhancing its function.

• Someday, with the 3D printing technology might be used in replacing or restoring tissues or boosting their function. These replacement tissues fabricated by 3D printing technology comprise interconnected pore architecture, biocompatibility, suitable surface chemistry, and relevant mechanical properties.

• 3D printing technology can also be employed to recreate organs with failed function due to disease, trauma, or congenital defects.

• 3D printing is capable of creating highly individualized models of cancer matrices, and this holds great promise for fast-tracking investigations into cancer. By utilizing this 3D printing technology, patients will be able to extract much more exact and dependable information.

• 3D print models can assist neurosurgeons in practicing surgical maneuvers. With the help of a 3D model, it can provide more accuracy; may shorten the learning curve for the actual clinical procedure; and will provide hands-on training to the surgeons, as the 3D model represents the actual pathological condition of the patient [42].

Veterinary Applications

Veterinary drugs are recognized as an ancient facility for the treatment of animals' diseases and the restoration of animal health. Forms of drugs that are especially suitable for administration in varying amounts to animals form an equally important domain of animal pharmacy, because they not only cater to the needs of the animals. Some rare species-related parameters that affect the build and function of a veterinary dosage form include feeding habits, environmental conditions, age, variations in pharmacokinetics, and handling practices. The drug is normally measured based on the weight of the animal, hence it is likely that the same drug may have different strengths. Animals' taste preferences thus come to be one of the parameters worthy of consideration during the development of veterinary drugs. For instance, dogs prefer protein flavors like beef, pork, and chicken, while horses favor fruity flavors like apple. Furthermore, the Simparica Trio chewables for dogs are flavored with pork liver powder, hydrolyzed vegetable protein, sugar, and gelatin to create a sensory profile that appeals to dogs. In traditional veterinary medicine, only two forms were by and large considered: oral and parenteral. Nowadays, however, with advanced pharmaceutical development, oral formulations that offer much promise (e.g., palatable tablets) for animal use have been introduced. The administration of chewable tablets into pets that are dogs and cats fits in the practice of veterinary medicine. Within veterinary medicine, chewable tablets are somewhat considered second-rate in comparison with human medicine; however, concerning their application for animal health, they become paramount. They include materials that can be and are presently manufactured as chewable preparations for animals to ingest. There are actually more chewable products commercially available owing to their use in veterinary care than there are for human medicines, probably because they are easy to give to the animals since the animals accept them as edible [43].

Fig 5: Applications of 3D Printing Technology