3D Printing in Biomedical Applications
Ridhish Kumar
Undergraduate Student, Department of
Chemical Engineering
BITS Pilani Goa
Arijit Chakraborty
Undergraduate Student, Department of
Chemical Engineering
BITS Pilani Goa

Anupam Mukherjee
PhD Candidate, Department of
Chemical Engineering
BITS Pilani Goa

Prabhash Dadhich
Research Fellow
Wake Forest Institute of Regenerative
Medicine, USA

Anirban Roy
Assistant Professor, Department of
Chemical Engineering
BITS Pilani Goa


Three-dimensional (3D) printing is an additive manufacturing process . This technology provides us with the opportunity to create 3D structures by adding material on a layer-by-layer basis, using different kinds of materials such as ceramics, metals, plastics, and polymers. Nowadays, tissue engineering investigations are taking place on a widespread basis in the fields of regeneration, restoration, or replacement of defective or injured functional living organs and tissues. For this reason, it is important to understand the basic concept of 3D bioprinting as a tool for producing a 3D structure combining living cells and biomaterials and controlling cell proliferation, attachment, and migration within 3D structures.

3D printing technology has garnered huge attention of medical researchers because of its ability to build human tissues. With the help of advanced biomaterials and proper polymerization technique a lots of unique features of human tissues can be recapitulated. Microfluidic approach in 3D cell printing has led to a significant leap in the vascularization of engineering .

Recent advancement in the field of genetic engineering and stem cell development can be adapted to the 3D tissue fabrication technique. It also has huge potential of disease modelling and carrying out study of unknown disease mechanisms required for precise medication.

The primary aim of Tissue engineering is to develop functional tissues /organs for transplantation purpose. Not only this. It also helps in studying disease mechanisms and discover drugs. There is requirement of mimicry of the cellular components and extracellular matrix of the human body for the reproduction of functional tissues/organs. The in-depth understanding of human disease is crucial to determine appropriate therapeutic approaches.

A lots of new drugs and therapeutic targets are being developed and they are mostly examined by 2D or 3D cell cultures or genetically modified transgenic animals. But these technologies have limitations because they are unable to mimic human physiological conditions because of their insufficient complexity. In such scenario 3D tissue model is an outstanding alternative because it represents the spatial and chemical complexity of living tissue in more detailed way than their 2D counterpart. Thus, engineered tissues apart from being used as testing device outside human body , It can also be used in implantation of regenerative medicine.

Recently, 3D cell printing technique is proved to be the one of the most emerging technology for precise cell-positioning fabrication method. The best advantage of this technique is that it enables in recapitulation of unique features of human tissue. It also has the ability to deliver multiple types of cells in controlled distribution.

Printing Technology
For the fabrication of tissues, cellular components are surrounded by flowable and biologically compatible hydrogels to prevent damage of components from shear stress.There is great advantage of using bioinks as it can mimic the tissu-specific microenvironments under the provision of a natural ECM-like nanofibrous structure. 3D cell printing techniques for biomedical application has been categorized into four major types: 1) Laser assisted, 2)Stereolithography (SLA)-based, 3) Jettingbased, 4)Micro extrusion printingsystem .

Types of Biomaterial Inks Used in 3D Printing
For a material to be used in biomedical applications materials used must: (1 )be bio-compatible, (2) not form toxic substances, and (3) have appropriate structural properties, among other characteristics. There are various inks that have resulted either from a need for better biomaterials or those, which are application specific. Some of them are:

Hydrogels: These are hydrated networks of crosslinked or synthetic polymers. They are hydrophilic and have the ability to swell. The extent of swelling can be controlled using factors such as the polymer material, viscosity, shear stress among others. Higher swelling capacity hydrogels are used in hygiene fields where retention of water is expected. For drug delivery applications, hydrogels with lower swelling capacity is used.

Ceramic-Based Inks: Ceramic based materials have high stiffness, and provide a surface naturally needed in bone tissue development . Current technology is limited to provide direct printing of such materials . Some commonly used ceramic-based inks are Hydroxyapatite (HA) and Tricalcium Phosphates. These materials enhance mechanical strength in scaffolds.

Polymer-Based Inks: These inks come in the forms of powder, gels and solutions. Some of the commonly used polymers are Polylactic acid (PLA), Polycaprolactone(PCL) and Acrylonitrile Butadiene Styrene (ABS). Their usage ranges from craniofacial implants and bone scaffolds which assist bone formation and regeneration, to musculoskeletal tissue engineering applications. The advantage of polymeric biomaterial inks is that their properties can be altered by choosing suitable monomers and processing techniques.

Composite Inks: These are primarily used in tissue engineering applications. With additives such as carbon nanotubes and biomolecules, their usability expands across multiple fields. The main reason these inks are used is to enhance mechanical properties and bioactivity. There are two major types of composite based inks-hydrogel -based and polymer-based. There has been evidence that particular composite inks enhance ability to accelerate healing.


Figure 1: Representation of 3D printer used in biomedical application

The current spectrum of biomaterial inks has limited scope of alteration in properties to enhance their use. Therefore, this is a challenge to overcome in 3D printing and there is tremendous potential to develop such biocompatible inks which offer application-specific characteristics.

3D Printing in Bio-Medical Application

Dental Implants: For more than 20 years, researchers have been trying to automate conventional manual processes in dental technology with the hope of producing more uniform-quality materials, standardizing manufacturing processes and reducing production costs. Existing dental CAD /CAM systems cannot yet acquire data directly in the mouth and produce the full spectrum of restoration types (with the breadth of material choices) that can be created by traditional techniques. Emerging technologies may expand dramatically the capabilities of future systems, but they also may require a different type of training to use them effectively.


Figure 2: 3D cell printing techniques for biomedical applications

Bio-printing: 3D bio-printing is a versatile emerging technology that is finding its way through all aspects of human life. The potential of 3D printers can be exploited in areas of biomedical engineering such as fundamental research, drug delivery, testing, as well as in clinical practice. Nearly all current medical non-biological implants, such as ear prostheses, are manufactured in predetermined sizes and configurations that are widely used for patients. This technique allows more accurate personalized manufacturing of devices created to the patient’s own specifications. Bio-printing is being used to create more accurate non -biologic and biologic research models for research purposes in a wide variety of applications like cancer research.

Drug Delivery: The drug development process is extremely costly and it takes around ten years before a new drug gets regulatory approval. Currently, drugs are tested in 2D cell culture formats, followed by animal testing and clinical trials. 2D cell cultures fail to represent the complex 3D nature of human tissues, making them non-predictive and unreliable. 3D cell culture platforms together with perfusion culture technologies are creating more representative and predictive models of the behaviour of cells in vivo. 3D bioprinting is able to generate 3D models containing human cells to create a microenvironment that most closely resembles the native environment, and facilitates cell-cell and cell-matrix interactions. These allow high -throughput screening of compounds to accelerate the drug discovery process.

Tissue Engineering:Tissue engineering technology has the potential to resolve the organ transplantation crisis. However, assembly of vascularized 3D soft organs remains an enormous challenge. Organ printing, which we define as computeraided, jet-based 3D tissue-engineering of living human organs, offers a possible solution. A cell printer that can print gels , single cells and cell aggregates have been developed. Computer-aided layer -bylayer assembly of biological tissues and organs, is presently possible, fast evolving and predicted to be a major technology in tissue engineering. It is safe to predict that within the 21st century, cell and organ printers are going to be as broadly used as medical analysis tools as was the electron microscope within the twentieth century.


Figure 3: Chronological order of 3D Printing tecnology in various applications

Conclusion
It is evident that 3D printing technology has truly revolutionized the biomedical engineering sector offering flexibilities both in terms of functionality and design. However, there are challenges to beaddressed for not only furthering the technology but also pose 3D printing as one-stop solution for biomedical engineering solutions. Presently a universal bioink able to print variety of organs can be a real breakthrough technology lending more versatility to the technology. Shifting from simple crisscross patterned scaffold structure and mimicking true structure of the transplant can also be researched into. Importantly there is lot of scope of improvement in design of 3D printer themselves in order to lend versatility to its applications. From a holistic perspective, 3D printing technology can be developed to cover the entire range of medical application beginning from diagnosis ending with prognosis.

References:
(1) Guvendiren, M., Molde, J., Soares, R.M. D., & Kohn, J. (2016). Designing Biomaterials for 3D Printing. ACS Biomaterials Science and Engineering. https://doi.org/10.1021/acsbiomaterials.6b00121
(2) Donderwinkel, I., van Hest, J. C. M., & Cameron, N. R. (2017). Bio-inks for 3D bioprinting: recent advances and future prospects. Polym. Chem., 8(31 ), 4451–4471. https://doi.org/10.1039/C7PY00826K
(3) Bose, S., Vahabzadeh, S., & Bandyopadhyay, A. (2013). Bone tissue engineering using 3D printing. Materials Today. https://doi.org/10.1016/j.mattod.2013.11.017