USAGE OF 3D PRINTER TECHNOLOGY IN MEDICAL AND PHARMACEUTICAL FIELDS: A REVIEW

Along with the developing technology, 3D printers have found broad applications in medical and pharmaceutical fields. Precise digital control over layer by layer printing given by 3D printers allows drugs, cosmetics and medical devices like prostheses to be personalized for treatment. Additionaly, the physical structure of 3D printed products and their visualization is effective on surgical planning, educational and research applications alleviating the endeavior of surgeons,students and scientists, respectively. Since US FDA’s first 3D printed drug approval in 2015, the research for new approaches has been growing although the manufacturers need regularity certainty. However this technology exists for a long time and it is of public interest now due to the approval of 3-D printed tablet and other medical devices and also with the advent of US FDA’s guidance on technical considerations specific to devices using additive manufacturing which encompasses 3-dimensional (3D) printing has triggered many thoughts about this technology which needs to be considered for successful delivery of intended product. As for 3D organ printing, it remains the great expectation albeit some attempts. This review is aimed at giving brief explanations about 3D printing achievements and applications in medical and pharmaceutical fields.


INTRODUCTION
The development of 3D printer technology, which started in the 1980s, and the growth of the market have gained importance in recent years. Nowadays, the usage of 3D printer technology with three-dimensional (3D) printing has been started to be used in biomedical and cosmetics including pharmaceutical fields, and the first steps have been taken in the cosmetic industry 1,2,3, . The field of health is on its way to becoming one of the most important areas of use in 3D printing and printers.
Major usage examples include the production of bio models (artificial models of human body parts, such as bone, dental prosthesis, etc.). The development of artificial models for different individual anatomy of humans provides many benefits in the field of treatment enabling more accurate diagnosis, better execution of the planning and testing stages, more effective orientation during the operation that improves the quality and accuracy, testing opportunity of new medical methods and technologies and research, training and practice activities to be carried out more effectively. 3D printers play an active role in the design and manufacture of personalized implants, prostheses and artificial organs, and production of personalized medical materials such as hearing aids, scaffolding and mask. In addition, 3D printer technology enables the production of sensitive systems/ devices in the delivery of medicines. By means of 3D printers, human tissues and organs can be produced in layer by layer using artificial human tissue as bio-raw material (bio printing). These raw materials can be obtained by treating live human cells using various chemicals and methods. Bio printing has a remarkable potential for personalized drug development, treatment-related tests, medical research, wound healing, and even organ transplants 2,3,5 .The application of 3D printing in health products offers some advantages such as; customization and personalization of medical products, medicines and equipment; cost-effectiveness; increased productivity; the demonstration of design and ISSN: 2456-8058 40 CODEN (USA): UJPRA3 manufacturing; training for health education 6 . In the field of cosmetics, following the use of 3D human skin models in the efficacy and safety tests of cosmetic products, a limited number of 3D printer which is especially suitable for the production (in which cosmetics quality pigment and carrier mixture are used) of powdered cosmetics (eye shadow, blusher, face powder etc) to meet personal preferences in make-up products have been launched to markets. The first 3D printer was developed by Grace Choi in 2014 as a device to produce colored make-up products 4 . Different molecular biological characteristics and diseases of patients show the importance of personalized forms of drugs in reaching success on the treatment of various diseases especially cancer. While there are common approaches for drugs and patients at the centre of conventional clinical trials, there is a need for an approach centralizing patient and patientspecific treatment, especially in the treatment of cancer. The current point in the concept of customized medicine according to the needs of patient is the use of three-dimensional/3D printing, that is, 3D printer technology. This technology allows drugs to be prepared in safer and more effective dosage forms by designing their dose, size, appearance and release characteristics according to the individual needs. Spritam®, the epilepsy preparation containing active ingredient levetiracetam produced by 3D printer, was the first drug approved by the US Food and Drug Agency in August 2015 [16][17][18][19] . These tablets prepared with a 3D printer, are dosage forms that are more readily soluble in contact with liquid than conventional tablets, easily ingested even at high dose contents, and with high dosage accuracy. Other advantages of dosage form production with 3D printing include pyramidshaped tablets that can be used to allow the release of the active substance more rapidly than the cylindrical forms, dose adjustment to the microgram level and cost-effective production 4,7,8,9,10 . Apart from the advantages mentioned above, preparing 3D model which requires imaging and data processing has emerged as a time consuming effort rather than printing itself and the most healthcare personnel don't have this specific skill. Thus, total time necessary for 3D printing technology can do away with its advantages.

3D PRINTING METHODS AND APPLICATIONS
3D printing is a manufacturing method in which objects are made by fusing or depositing materials such as plastic, metal, ceramics, powders, liquids, or even living cells in layers to produce a 3D object. Some 3D printers are similar to traditional inkjet printers; however, the product differs in that a 3D object is produced. 3D printing methods can be divided in five techniques as the following 6 ; 1. Stereolithography (SLA): The first commercial version SLA-250. A process based on curing of photo resin (epoxy or acrylic resin) layers by UV triggering. 2. Thermal Inkjet (Inkjet Printing): A process based on powder-liquid bonding using the poly jet technology of photoresins or, more often, of plaster powder (hybrid between SLA and Inkjet).

Selective Laser Sintering (SLS): A method
based on heating powder PC, PVC, ABS, nylon, resin, polyester, metals, ceramic powder by laser triggering.

Fused Deposition Modeling (FDM):
A technique based on shaping melted thermoplastics such as wax blends, PC, PS, ABS, nylon, metals / ceramics (with binder).

Laminated Object Manufacturing (LOM):
A method based on cutting the sheets of adhesive coated polymers, papers, cellulose, metals with laser or razor. The 3D printing methods are having importance in the field of pharmaceutical and medical applications due to the possibility of rapid preparation of tailor-made objects that can be applied in personalized therapy or medicine. The introduction of 3D printing into the pharmaceutical technology particularly aims at the development of patient-cantered dosage forms based on structure design. It is still a new research direction with potential to create the targeted release drug delivery systems in freeform geometries.

Application in biomedical field Surgical Planning
Surgeons can perform operations with better outcomes by planning via 3D printed models of human specimens such as brain and heart. Although the complexity of the nature of these organs, prototyping technology with 3D printing improves the understanding and conceptualization of the anatomy before operation compared to 3D simulated models on screen. The study with 3D printed models being done for defects is also more efficient enabling various approaches and hands-on experience. Due to the possible contributions to shorter and successful operations, 3D printing technology has been widely used in this application. Prostheses Patient-specific prostheses of hands, arms, feet and legs can be cost efficiently printed by anyone at anywhere. This high accessibility and affordability makes 3D printed prostheses essential for people especially children with missing or damaged limbs so as to keep on their normal life 21-23 . In proper model and dimensions, both functional and aesthetically pleasing 3D printed prostheses are fully customizable with high precision to the wearer. However, as metal usage in 3D printing is not so common, they are generally lack of long term durability.

Medical Education and Training
Realistic 3D printed anatomical models which can be customized for any clinical scenario reduce many apprenticeship observations of medical students and help gaining required memorable skills in shorter time.
In addition to their ability to be copied many times with different sizes, damage-free transportation and handling during procedures is also possible and they can be thought as an alternate for high cost cadaver. 3D printed tissue mimicking materials are durable to withstand punctures facilitating medical practice. Thus, they have promising utility in the assessment of interventional radiology 24 .

Medical research
The drug response depending on in vitro or in vivo animal platforms varies and is different than that in human body. As one of the solutions to this problem, the usage of biomaterials or cells in 3D printing is possible and has allowed tissues to be reproducibly made. These tissues containing multiple types of cells represent the microenvironment needed to get a suitable response for a drug. Therefore, 3D printing technology for testing purposes to understand drug metabolism and toxicity is so attractive. Because of importance on toxicity, vasularized liver tissues have been commonly created which may open the doors of individual drug screening. Furthermore, researchers exploit 3D printed synthetic tumours to investigate disease profile.

Organ Printing
One of the main causes of the deaths in many countries is the lacking of transplant tissues. Organs which can be 3D printed and function have potential to be used as replacement. With lower biochemical reactions happening compared to liver and kidneys, fully functional 3D printed heart is the most possible. In this way, the first 3D printed heart with necessary blood cells, ventricles and chambers has been managed to produce by using cells and biological materials from a patient in Tel Aviv University 11 . Although vascularisation problems, that is, difficulty for forming the smallest vessels, that they can be implantable in human is not far away with developing research technology.

Application in pharmaceutical field Drug Dosage and Delivery
3D printing method presents the opportunity for fabrication of tablets with different microstructures in which more than one active ingredient exist. Unlike conventional tablets which break unequally and lose its mass after splitting, the precise control over the geometry and amount of these ingredients can lead to the tablets with intended dissolution profiles based on the patient. Focusing on the patient-centric drug product development, the release profiles of chlorpheniramine and acetaminophen tablets were modified 12,13 . By means of 3D printing technology, dosage form adjustment according to the patient's body weight and lifestyle has been also applied to multifunctional drug delivery systems. 3D printing is promising for individually developed dosage forms and drug delivery systems but operable dosage form formulation on the industry needs to be investigated with further research.

Application in cosmetics field
Due to the application of cosmetics to the human body, the use of 3D printer technology in the cosmetic field which health authorities play active role is quite new. The use of 3D printing technology in the cosmetic field has begun with the use of three-dimensional human skin models in effectiveness studies. It is known that 100,000 tissue samples of 0.5 cm 2 size are produced from skin samples donated by plastic surgery patients.
Home-type first 3D printer in the market by which especially colourful make-up products (eye shadow, eyebrows, blush, powder, etc.) can be produced according to personal preferences in the cosmetic field is seen as the most important development. In May 2014, Grace Choi presented his invention called "Mink" in the US for the first time for the home-type production of colored make-up products with 3D printer and designed it as a practical production method which can be performed at home according to especially the personal color preferences. Mink is a desktop printer that prints makeup by mixing of pigment and carrier material. Choi's motto for 3D production of cosmetics was "DIY Cosmetics". 3D printing is created with Mink by processing FDAapproved ink (cosmetic quality pigment and carrier mixture) on the printer for a color that can be selected from the internet 14 .
The use of 3D Printer Technology, which is also used in the field of packaging, in the production of Cosmetic Packaging is an important development for the cosmetics industry. Packaging design and visuality in cosmetics industry is an important parameter in terms of creating a demand 25 . In 2013, Collcap Packing in the UK began to produce perfumes and other cosmetic packaging with Stratasys Objet 30 Pro 3D printer. With seven different material options, they started to produce high-temperature packaging with transparentto-mat, in colours ranging from blue, gray, white and black. While transparent material is an alternative to glass and PMMA, the cosmetic manufacturers are allowed to produce the packaging samples which can be designed and presented in a short time with the 3D Printer and there exists multiple alternatives in the selection and easy production of them 15 .

CONCLUSION
As a result, it is expected that 3D printer technology, which is one of the current applications of technological developments and inventions that bring design and manufacture together, will progress rapidly, diversify and grow and that these will have critical reflections on the pharmaceutical industry. However some extensive research is needed for topical, oral and other dosage forms by the means of this technology to gain the maximum benefits.

AUTHOR'S CONTRIBUTION
All authors have worked equally for this work.