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Three-dimensional (3D) bioprinting is an emerging technology that is widely used in regenerative medicine. 3D printing is a new technology that creates physical objects from digital files. With the incessant development of the technology, it has captivated the attention and exemplified promising prospects in ophthalmic applications.
Bioprinting is an additive bio fabrication method that prints target tissue engineering structures automatically by depositing bio inks in a layer-by-layer manner.[1] The technology attempts to produce original-tissue-like constructs through the precise combination of living cells, natural or synthesized biomaterials, crosslinkers, and/or other functional factors.[2]
In tissue engineering and regenerative medicine, the use of bioprinting in fabricating ocular tissues and preserving relevant biological functions still needs to be further studied. At the present time, the use of 3D printing in ophthalmology has not had much impact, but an understanding of this new technology will be beneficial to us.
The process of creating a 3DP medical device starts with the image acquisition of the patient's target organ via a Computerised Tomography (CT) or Magnetic Resonance Imaging (MRI) scan. These images are then processed to segment the target tissue and to generate a 3D model in computer-aided design (CAD) software. The 3D model is then optimized for the preparation of the final printing in a 3D printer. Printing parameters are especially important, including printing speed, printing nozzle size, material, and temperature that could affect the cell viability, the materials used, the active pharmaceutical ingredient (API), and the printability of the designs. The careful selection of each printing parameter that goes into the printing process can affect the quality and biocompatibility of the end products.
In a general sense, bioprinting refers to 3D printing for medical applications, which can be divided into four stages of development.[3] Stage I is to print non-biocompatible structures that can be used as models for surgery planning. Stage II is to print biocompatible but non-biodegradable products, such as implanted prosthesis. Stage III is to print biocompatible and biodegradable products, which can be used as scaffolds to improve tissue damage repair or regeneration. Stage IV is to print biomimetic 3D structures with cells. In the narrow sense, bioprinting can also be defined as cellular printing.
PRINTING TECHNIQUES
At present, Vat Polymerization (VP)-based, Material Extrusion-Based, and Material Jetting-Based printing strategies are the three principal printing techniques used in biological and medical applications. Due to the distinct working principles, each approach demonstrates different strengths and drawbacks.
BIOINKS
The success of using bioprinting depends on the printability and bioactivity of the bioinks. In ophthalmology, bio inks of either cell-free hydrogel or cell-laden biomaterials were developed for different purposes. To formulate a highly biocompatible environment for the cells, decellularized extracellular matrix (dECM), and nature-derived (Collagen, Hyaluronic acid, Gelatin) or semi-synthesized (Gelatin methacrylate (GelMA)) hydrogels are widely used in ophthalmic applications.
A single bioink cannot result in a functioning tissue-like structure. Novel multicomponent bioinks can combine the favorable characteristics of the individual biomaterials to provide a solution. Multicomponent bioinks are characterized by one or more types of biomaterials, cells, and the addition of different materials or biomolecules. The different categories of multicomponent bioinks are bioinks composed of natural materials, natural and synthetic materials, synthetic materials, and hydrogels and particles.
OPHTHALMIC APPLICATIONS
Orbital implant
3D printing is a flexible and low-cost method for designing customized complex orbital reconstruction implants. Based on the digital images from the orbital tumor resection/fracture, we can reconstruct a structural model, design the implant templates according to the orbital structure of the intact part, and print the 3D models to serve as a stencil for the actual implant material. The application of 3D printing technology reduces the need to adjust and manipulate the Medpor-titanium implant during the procedure and could improve various surgical indicators like reduced tissue damage, shortened surgical duration, improved clinical outcomes, and cost-effectiveness.[4] This technique can be used to design the exact shape of the implant and center the implants in patients with recurrent implant migration.
The traditional manufacturing process for Ocular prosthesis is time-consuming. But, 3DP allows customization of the design based on the anatomy of the patient's eyes and creates a mold of cosmetically appealing prosthetic eyes within a substantially shorter manufacturing time.
Drug delivery systems
Chitosan is one of the hemi-synthetic, highly biocompatible, and biodegradable hydrogels considered suitable for ocular drug delivery. Chitosan nanoparticles could prolong drug delivery, facilitate penetration through physiological barriers, and enhance mucoadhesive properties.[5] Meanwhile, the preparation of nano gels of personalized medication using 3D printing technology has begun to gain attraction. The drug-release implants are used for glaucoma and cataract patients and can be customized using 3DP technology depending on individual preferences. Hydrogel-based lyophilized eye patches equipped with the antibiotic drug were flexible in terms of releasing different dosages by adjusting the bio ink compositions. The customizable 3DP is also beneficial for designing drug-eluting systems to treat glaucoma.
TISSUES AND ORGANS
Cornea
It is feasible to use biomaterials combined with human proteins to create 3D bio prints for corneal tissues. Bioprinting offers the possibility of producing artificial cornea. The human corneal scanning model is used to print artificial cornea with complex structures through bioprinting, but the tissue function of artificial cornea still needs to be further validated in clinical trials. The challenge in bioprinting the cornea lies in the transparency, microporosity, and specific shape properties of the structure. 3D bioprinting technologies embody great potential and show promising prospects in the fabrication of artificial cornea. The invention of the 3DP cornea can help solve the severe shortage of donor corneas.
Retina
The challenges in creating a functional retina through printing include achieving a sufficient number of cells and maintaining the cell phenotype and viability post-printing. Validation of the functionalities of the printed retina is also very important to create transplantable tissues, while the construction of blood vessels is critical to ensure the supply of nutrients and oxygen to the tissues.
Surgical training
3D models are currently being used in medical schools to introduce surgical techniques to trainees prior to their exposure to patients. Theoretically, this shortens the learning curve while standardizing the teaching and assessment of these trainees. The customized 3DP instruments can be produced according to the specific needs of the surgeon. Their production time has been greatly reduced compared to conventional manufacturing methods.
Of late, four-dimensional printing (4DP) incorporating the 4th dimension (time) is slowly emerging as a newly unconventional printing technique for medical applications. The 4DP technology allows biomaterials to change over time physically and functionally. It helps to construct realistic tissue organizations with added flexibility. The biomaterials used for 4DP can change their physical appearances by responding to changes in temperature, pH, ion concentrations, etc.
There are still many challenges ahead before 3DP ophthalmic products can be proved in clinical trials and eventually reach the stage of commercialisation. A current concern is the sterility of the materials and biocompatibility in patients. Also, despite the favorable aspects of 3D Printing applications in the medical field, the legal regulations of 3D Printing technology are not complete. 3DP in the ophthalmic field is still not fully understood and developed, but its potential to provide revolutionary solutions for various eye diseases is irrefutable.
REFERENCES
1. Di Marzio N, Eglin D, Serra T, Moroni L. Bio-fabrication: Convergence of 3D bioprinting and nano-biomaterials in tissue engineering and regenerative medicine Front Bioeng Biotechnol. 2020;8:326
2. Moroni L, Burdick JA, Highley C, Lee SJ, Morimoto Y, Takeuchi S, et al Biofabrication strategies for 3D
in vitro models and regenerative medicine Nat Rev Mater. 2018;3:21–37
3. Yong HE, Qing GA, Liu A, Sun M, Fu J-Z. 3D bioprinting: From structure to function J Zhejiang Univ. 2019;53:407–19
4. Callahan AB, Campbell AA, Petris C, Kazim M. Low-cost 3D printing orbital implant templates in secondary orbital reconstructions Ophthalmic Plast Reconstr Surg. 2017;33:376–80
5. Lynch C, Kondiah PP, Choonara YE, du Toit LC, Ally N, Pillay V. Advances in biodegradable nano-sized polymer-based ocular drug delivery Polymers. 2019;11:1371
