3D Printing Revolutionising Nanotechnology

Three-dimensional (3D) printing is a proto-typing method which works through layer-by-layer fabrication making rapid conversion of instruction from digital 3D diagrams into physical objects. It is a manufacturing method in which objects or any machinery are made by fusing or depositing any materials in layers-by-layers method to produce a 3D object. Initially the 3D diagram of the desired product is made in computer or using any 3D software and it is digitised and sliced into model layers withspecial software. The printer system connected with it makes 2D layers into a 3D build. The production goes further by adding each new layer on top of the previous layer and by addition of layers whole object is made. In 3D printing, objects can be of almost any shape or geometry, and are produced from a 3D model as defined in a Computer-Aided Design (CAD). Three-dimensional (3D) printing is also termed as additive manufacturing because the successive layers of material are laid down under computer control. The earlier conventional method is called as subtractive method in which the polymer or any desired material materials are given shape but the chances of wastage are more.The 3D printer consists of an extruder which moves horizontally back and forth in x-y plane to create the basic layer upon which further product is made. These two axes are connected at side by side of the printer. It also consists of a base which moves in a vertical position along the z-axis so that it can form different layers over the object. In pharmaceutical field, 3D printing is used for production of dosage forms which are printed on demand, to control the doses, to make the diagnostic tools and body organs with much other functionality. It also assists to achieve unparalleled flexibility, to save time, and exceptional manufacturing capability of pharmaceutical drug products so as to formulate drug materials into the desired dosage form.

Charles Hull in 1984 made history in 3D printing era by inventing stereolithography. Stereolithography lets designers create 3D models using digital data, which can then be used to create an object. It works with liquid photopolymer which on exposing with a UV laser beam gets converted in solid piece of plastic which can be molded into the shape of 3D-model design. In 1992, Bill Clinton made big breakthrough by creating the world’s first Stereolithographic Apparatus (SLA) machine, which made it possible to fabricate complex parts, layer by layer, in a fraction of the time. In mid-1992, world’s first Selective Laser Sintering (SLS) machine was produced which shoots a laser at a powder instead of a liquid. Afterwards, in 2000’s Scientists at Wake Forest Institute for Regenerative Medicine printed synthetic scaffolds of a human bladder and then coated them with the cells of human patients which then were implanted for trial purpose.In 1st decade of 21st century scientists from different institutions fabricated a functional miniature kidney, produced an prosthetic leg with complex component parts that were printed within the same structure, and they also produced bioprinted first blood vessels using only human cells.

3D Printing Nanotechnology

3D printing technology gives advantage of fabrication of complex objects with enhanced functionalities and improved material properties. 3D printer has ability to develop any structure from micrometre size up to several meters. Further, there is no need of any new software or equipment for different products which decreases the price of the product and hence improves the customer satisfaction.It is very well known that nanotechnology has the capacity to bridge the barrier of biological and physical sciences owing to their worthy mechanical, electrical and physicochemical properties. They also provide site specificity which makes them good tool for drug delivery and diagnosis. Combining this two blockbuster approaches i.e. 3D printing and nanotechnology, high significant targets can be achieved in healthcare sector.

1. Manufacturing of nano dosage form by 3D printing:

For highly potent drug, the dose of the drug may vary based on age and gender which demands for personalised medicine. Though, it requires the higher solubility of the drug else it may lead to wrong calculation of the dose due to poor solubility and distribution. Thus, to exclude this error and for appropriate dispensing of the dosage form, Jana Pardeike et. al. prepared nanosuspension of BCS Class IV substance folic acid which is practically insoluble in water and most organic solvents. As a pre-requisite for printability using micro-drop technology, the size of the particles was decreased by high pressure homogenisation below 5 μm. For printing through piezoelectric inkjet printer system, the nozzle apparatus of 100 μm was used. After preparation of folic acid nanosuspension by injek printing, it was compared with normal suspension which provided clear indication that nano-suspension increases dissolution rate and was found to be chemically and physically stable under ambient conditions.

2. Nano-composites formation by 3D printing:

Nano-composites have combination of properties from both the nanomaterials and the host materials matrix. Despite of various advantages, there are challenges for nano-composites production in several areas, including processing, cost, consistency and reliability in volume production, high lead time as well as oxidative and thermal instability of nanomaterials. The formulation of nano-composite product using 3D printing is possible. Multi-functionality through embedding of nanomaterials can further extend capabilities of nanocomposites to properties such as gradients in thermal and electrical conductivity, photonic emissions tuneable for wavelength, and increased strength and reduced weight which can be used in the production of diagnostic products.

3. 3D Printing of Nano-structured Bone Scaffolds:

Currently, Bone-tissue regeneration by biomimetic bioactive materials is most widely used approach other than clinical ones used to treat bone loss caused by trauma or by pathological conditions such as osteoporosis. Giorgia Montalbano et.al. started an experiment to produce bone scaffold by nano-structured bioactive material which was able to reproduce the physiological environment. Reproducibility can be achieved by mimicking the natural features of bone tissue and the cell behavior during the regeneration process. Extrusion-based 3D-printing technologies have increased the scaffold manufacturing accuracy with great sort of repeatability which also exhibits bio-compatibility to the users. For bone scaffold development, type I collagen and nano-sized particles of strontium-containing Mesoporous Bioactive Glasses(MBG) were selected. They were processed combinely to obtain a bio-active ink. This ink works on a sol-to-gel transition upon physiological pH and temperature, with the subsequent reconstitution of a nanostructured fibrillary matrix. This reconstruction mimics the natural fibrillogenesis process which occurs in body. Mesh-like 3D constructs were manufactured with the help of commercial BIO X Bio-printer (Cellink). The ability to release osteo-inductive strontium ions was optimised according to the crosslinking method. To get sustained and continuous release of ions, the use of aqueous and ethanol-based solutions as a medium for genipin crosslinking was investigated. Through various experiments the material which was made proved its potential as bioactive material ink for the 3D printing of nanostructured bone-like scaffolds. Adequate bioactivity and the ability to release pro-osteogenic Sr2+ ions which gives strong suggestion about its use as scaffold development. Further morphological analysis was done at nano scale by mimic the bio structure having nano-sized MBG particles and collagen fibres.

3D Printed Lab-on-a-Chip for Micro-Nanoparticles Analysis: Federica Barbaresco et.al. produced a chip by 3D printing for analysis of nano and micro particles. They developed the method which can quantify exosomes; the nanosized lipid vesicles secreted naturally in the extracellular environment by any type of cell starting point. For the rapid and efficient collection and analysis of micro-particle and nano-particle, a novel microfluidic free-flow electrophoresis device was developed by 3D printing technology. The micro fluidic free flow device was structurally designed by 3D computer aided design software and the use of this device was checked by dimensions, surface charges and fluorescent dyes. This device indicated accurate idea about micro and nanoparticle deviation and their concentration in an operation so they are suitable for biomedical as well as pharmaceutical applications.In addition, the UV-Vis analysis allowed for the quantification of the nanoparticles and micro particles concentration.

3D bio-printing for neural tissue regeneration:The use of any biological material such as cells as ink for printing through 3D approach is called 3D bio-printing. Materials such as self-assembling nano biomaterials, carbon nano biomaterials and elctro spun nanofibres are termed as bio-ink for its use as ink in 3D bio-printing. In self-assembly bio-printing, a single biological components are organised into nanostructures, including nanofibers, nanotubes, vesicles, helical ribbons, and b-sheets. Self-assembling Peptide Nano Fibrous Scaffolds (SAPNS) have been investigated and used for regeneration of nerves of peripheral nervous system as well of brain. This all above listed structures are used for development of extra cellular matrices which mimic physical as well as chemical function of natural tissues by providing proper environment for adhesion, growth, repair as well as for regeneration of neurons and structures. By using biomaterials as ink in 3D bio-printing, fabrication of patient-specific complex neural grafts is possible through combination of bioactive factors and cells. Thus, 3D printing and nano biomaterials combination may open up the possibility of neural tissue regeneration as well as replacement.

Current Regulatory Regulations and Progress

In 2015, the U.S. Food and Drug Administration (FDA) approved first 3D printed prescription drug ‘Spritam (Levetiracetam)’ in July 31, 2015, under the 505b (2) pathway and is used to treat partial onset seizures, myoclonic seizures and primary generalised tonic-clonic seizures. Dozens of 3D printing medical devices have been approved via 510k pathway till now such as ear device, dental crowns, bone plates, skull plates, spinal platting system, facial implants, and surgical instruments.FDA has already created strict rules for the marketing and approval of 3D Printed products. FDA's CDER Office of Pharmaceutical Quality has established a technological program to investigate the use of modern technologies like 3D printing in production of pharmaceutical and healthcare products. US government have established EmergingTechnology Team (EET) within the FDA whichfocuses to build up more awareness in technological innovation in design and production. The main challenge in approving the 3D printer for dispensing drug formulation on-demand is lack of implementation of good manufacturing practices. Currently there is no mention for requirements in schedule M for 3D printing process. So challenges may arise at the time of manufacturing and dispensing drugs to verify its quality. Also there is lack of clarity about what and how should be the regulatory rules if 3D printing technology is used as manufacturing of on-demand personalised products. Moreover, it is also difficult to determine the site of printing like at hospitals or at pharmacy or at clinical study sites.

Thus, 3D printed pharmaceutical dosage forms specifically nano dosage form may revolutionise the treatment approach of the various diseases. Though, the detailed regulations regarding its manufacturing and dispensing are necessitated to fulfil the desired customised treatment to the patients.

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