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3-dimensional Bioprinting of Tissue and Organs From bench to bedside

Ryan Varghese, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University

Sahil Salvi, Poona College of Pharmacy,  Bharati Vidyapeeth (Deemed to be) University

Dileep Kumar, Department of Pharmaceutical Chemistry, Poona College of Pharmacy,  Bharati Vidyapeeth (Deemed to be) University

Over the past few decades, the fields of tissue engineering and regenerative medicine have made significant progress. However, despite these phenomenal milestones, the question about organ engineering and implantation remains unanswered. The traditional approaches comprising scaffolds, growth factors, and cells have been studied to come with considerable caveats and perils. Thus, novel approaches such as 3-dimensional bioprinting have been incorporated into the traditional techniques, to ensure optimal, equitable, and timely healthcare delivery to all those in need. This article will aim to explore the advantages, limitations, and prospects in the development and implementation of the same.

1. Background and Scope

Since time immemorial, wounds and tissue damage have inflicted enormous pain and cosmetic exasperation on humans. However, despite being a rather common phenomenon, the human body is limited by its regenerative capabilities (Varghese & Shinde, 2021). Additionally, the conventional methods employed for the management of these are filled with lacunae, perils, and caveats. For instance, the methods involving organ transplantation and xenografting are often dependent upon the availability of matching donors. To make matters worse, in several cases, graft rejection may be reported due to an immune response, despite finding a potentially suitable match. These impediments beg the question of conferring equitable and affordable healthcare to each and every individual. In an attempt to address these issues, and to ensure optimal healthcare delivery, the additive manufacturing and 3D printing techniques, primarily employed in material sciences, have been extrapolated into biology to fabricate tissue scaffolds, and functional organs (Agarwal et al., 2020). Let us now dive into the finer aspects of organ bioprinting and fabrication.

2. What is 3-dimensional Bioprinting technology?

Over the recent years, three-dimensional printing (3DP) technology has been generating significant advancements in various scientific fields, and the medicine and pharmaceutical sector is no exception. Based on recent studies, biocompatible materials, cell scaffolds, and supporting components can now be printed using the 3DP technology, into complex 3D functional living tissues (Varghese et al. 2021; Varghese et al. 2022). This 3D bioprinting (3DBP) technique can be employed in regenerative medicine to meet the ever-growing need for transplantable tissues and organs. However, 3DBP is more byzantine and intricate than the printing of non-biological materials. This can primarily be attributed to the complexities in material selection, types of cells, growth and differentiation factors, and technical impediments related to the sensitivities of living cells and tissue assembly. These obstacles may be addressed by the integration of technologies from a spectrum of fields ranging from engineering, biomaterials science, and physics to cell biology and medicine. When addressing these technical and scientific issues, 3DBP technology has been projected to potentially bridge the gap between artificially fabricated tissue constructs and biological tissues. Several researchers across the globe have successfully fabricated and transplanted, several 3DBP tissues and constructs, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue, and cartilaginous structures. In this way, the 3DBP technology can provide unparalleled flexibility in co-delivering cells and biomaterials, while exercising exact control over their compositions, spatial distributions, and architectural correctness. Additionally, it would also facilitate detailed or even individualised recapitulation of target tissues and organs. The projected applications of the development of high-throughput 3DBP tissue models often include research, drug development, and toxicology studies (Zhang et al., 2017).

3. What makes this technology stand out from the rest?

In the realm of biomedical engineering, 3DBP technology has emerged as the most promising solution for the fabrication of living and viable tissues. The success of this technology is primarily dictated by three fundamental elements. First, 3DBP techniques facilitate rapid prototyping as well as design customisation. Secondly, this technique allows for the precise co-deposition of cells and biomaterials, which is nearly unachievable using the previously developed approaches. Finally, the 3DBP techniques combine the principles of engineering, material sciences, and manufacturing to render highly accurate microstructures that aid in the growth of the cells. The aforementioned information about contemporary 3DBP techniques will be elucidated in the following parts.

3.1.    Rapid prototyping with custom features

The mechanical components, biological scaffolds, implants as well as other ancillary 3D objects can also be manufactured by standard methods, but usually follow a cumbersome and time-consuming process. However, these traditional procedures are not only costly but are also difficult to employ while producing complicated geometric elements, which limits their adaptability in the biomedical field. Additionally, the 3DBP technology may ease the development of complicated geometries that are challenging to handle with conventional processes like molding or milling. Furthermore, these novel 3DBP techniques can be tailored precisely and quickly to meet specific needs, allowing researchers and organisations to design and construct the required architecture in minutes. Essentially, the advent of 3DBP techniques eliminates the need for laborious modeling and casting procedures, since it aids in the instant production of byzantine structures and shapes, showing promise in both bench and bedside.

3.2.    Precise co-deposition of cells and biomaterials

Another added benefit of the 3DBP technology is that it can precisely co-deposit all the components and excipients of the live tissues, such as cells, matrix materials, and growth factors, to fabricate tissue-like constructions. The traditional methods of cell delivery are extremely chaotic, because of the continuously shifting external environment, such as freeze-drying, or the use of organic solvents that inflict damage to living cells, throughout the manufacturing process. However, by employing laser-assisted bioprinting, the overall survival rate of cells is much higher, and with subtle modifications in current technologies, it is projected to attain a hundred percent cell viability. Furthermore, when compared to the limitations of biomaterials available in conventional techniques, 3DBP technology offers a much wider spectrum to choose from, which aids in modulating the nature of the material and the viscosity range.

3.3. Engineering with highly regulable microenvironments:

To accomplish the function of the fabricated tissue, it is imperative to construct appropriate microstructures. With the advancement of relevant disciplines, 3DBP technologies can produce scaffolds with controlled microstructures that allow cells to survive and grow for a simple and quick in-vivo transplantation in the future. The scaffolds are porous and are primarily employed in the delivery of medicines, materials research, and cell behavior research. The pore sizes and networks of these scaffolds are vital for the diffusion of nutrients and oxygen, as well as for the elimination of waste. This porous surface also promotes mechanical interaction between the scaffold and the surrounding tissue, thereby improving the mechanical stability of the implant. The structure of the pores also facilitates and stimulates the creation of new structural organisations. Although traditional procedures such as salt leaching, gas formation, phase separation, freeze-drying, fiber bonding, and solvent casting can render scaffolds with pores inside, several problems, including size control, microstructures, and interconnectivity of the pores, remain unanswered. Thus, these lacunas presented by conventional techniques have been properly addressed by employing the rapid prototyping method assisted by computer-aided design. Thus, with the help of these methods, it is possible to precisely control the internal intricacies and architectures of tissue and organ scaffolds, validating their potential to revolutionise tissue and organ grafting processes.

4. What are some hurdles in its way to revolutionising the healthcare system?

One of the main yet prototype limitations of the 3DBP technique is a lack of consensus that stems from a broad spectrum of parameters. There is a multitude of variants available in bioink composition (cell type and biomaterial employed), printing parameters (type of printer, oxygen flow rate, nozzle speed, deposition speed, and operating temperature), and maturation procedure (signals and bioreactors), for which developing a standard method and optimal ratio becomes a very daunting task, especially when repeatability and reproducibility of results are expected. Another mammoth task would be the vascularisation of printed tissues, especially when grafting with the vasculature of host tissue. Additionally, the success rate of the engineered tissue implants is solely dependent on the success of microvessel formation, maturation, patterning, and immune compatibility. Furthermore, living pieces of tissue larger than 1 mm thick cannot be printed as a cell must be close to the source of nutrition through the blood vasculature by a distance of less than 400 mm. Recent studies have also reported that the integration of a complete vascular network, from capillaries to larger vessels, into bioprinted tissues cannot be achieved using current state-of-the-art technologies, which is a major setback to complete organ development (Sigaux et al., 2019). Furthermore, there are also ethical, regulatory, and compliance issues that exacerbate these issues, thereby impeding its overall utility and potential alike.

5. What is the projected future of this technology?

Similar to the 3DP technology, the 3DBP facilitates the fabrication of solid 3D structures by mounting the biological substances and living cells, one layer at a time, with utmost caution. Later, this technique was utilised to manufacture disposable resin molds for the creation of 3D scaffolds using biological substances. These advancements have paved the way for the direct printing of 3D scaffolds for transplantations, with or without the seeded cells (Nakamura et al., 2010). Due to recent developments and advances in materials sciences, these 3DBP techniques could be leveraged to fabricate tissues and organ grafts. Furthermore, these techniques could also be modified to extrapolate their utility in the production of personalised stents, splints, and medical devices (Murphy et al. 2014). With the scientific fraternity working relentlessly to develop new printing modalities and improve the existing ones, the 3DBP technology is progressing at a respectable rate. However, transitioning from the laboratory scale into real-world clinical practice raises a slew of hurdles. For instance, only a few of the currently available bioinks are both printable and adequately reflect the tissue architecture required to restore organ functioning post-printing. While the bioinks manufactured from organically sourced hydrogels promote cell growth, synthetic hydrogels have been reported to be more mechanically durable. Therefore, to optimally incorporate all of these features, hybrid bioinks should be developed. Additionally, the 3DBP technique must be modified to make the overall process more cell-friendly. The shear stress which is imparted to the cells during the printing process is often harmful to cell growth and may potentially damage the gene expression profiles. Extrapolating such physical stresses to stem cells, such as induced pluripotent stem cells (iPSCs), may harm them and may not even survive the printing process. Furthermore, since most stem cell research has been conducted in 2-dimensional (2D) environments, there are many uncharted territories when it comes to 3-dimensional (3D) stem cell culture. Additionally, effective approaches must be devised for the high-throughput production and bioprinting of organoids, to efficiently develop and validate individual drug testing and predictive disease models. Moreover, the vascularisation of the bioprinted constructs for optimal exchange of nutrients and gases and the integration of the printed vasculature with the host vasculature after organ implantation is another herculean challenge. In conclusion, the 3DBP technique is an interesting and fast-expanding field of science, with enormous potential to alter the current face of organ grafting and revolutionise the global healthcare system. However, it comes with its own set of perils and caveats that must be diligently addressed before segueing into a clinical and bedside setting (Dey et al. 2020).

References

Agarwal S, Saha S, Balla VK, Pal A, Barui A, Bodhak S. Current developments in 3D bioprinting for tissue and organ regeneration–a review. Frontiers in Mechanical Engineering. 2020:90.
Dey M, Ozbolat IT. 3D bioprinting of cells, tissues and organs. Scientific reports. 2020 Aug 18;10(1):1-3.
Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nature biotechnology. 2014 Aug;32(8):773-85.
Nakamura M, Iwanaga S, Henmi C, Arai K, Nishiyama Y. Biomatrices and biomaterials for future developments of bioprinting and biofabrication. Biofabrication. 2010 Mar 10;2(1):014110.
Sigaux N, Pourchet L, Breton P, Brosset S, Louvrier A, Marquette CA. 3D Bioprinting: principles, fantasies and prospects. Journal of stomatology, oral and maxillofacial surgery. 2019 Apr 1;120(2):128-32.
Varghese R, Salvi S, Sood P, Karsiya J, Kumar D. 3D printed medicine for the management of Chronic Diseases: The road less travelled. Annals of 3D Printed Medicine. 2021 Dec 28:100043.
Varghese R, Shinde V (2021). Novel therapeutics and treatment regimen in wound healing. International Journal of Herbal Medicine, 9(1):12-18.
Varghese R, Sood P, Salvi S, Karsiya J, Kumar D. 3D printing in the pharmaceutical sector: Advances and evidences. Sensors International. 2022 Apr 25:100177.
Zhang YS, Yue K, Aleman J, Mollazadeh-Moghaddam K, Bakht SM, Yang J, Jia W, Dell’Erba V, Assawes P, Shin SR, Dokmeci MR. 3D bioprinting for tissue and organ fabrication. Annals of biomedical engineering. 2017 Jan;45(1):148-63.

Ryan Varghese

Ryan Varghese is a student and researcher affiliated with the Department of Pharmaceutical Chemistry, Poona College of Pharmacy, India. His work spans a spectrum of topics from artificial intelligence to cancer theranostics and drug delivery in Alzheimer's disease.His specialisation lies in the drug delivery modalities in chronic diseases. He has curated several articles on the lacunae in the Government public policies while providing solutions for the same. His recent works include the proposal of drug repurposing and affordable hospitalisation to mitigate the risk stemming from COVID-19 in India.

Sahil Salvi

Sahil Salvi is a student and researcher associated with the Department of Pharmaceutical Chemistry, Poona College of Pharmacy, India. His works spans across a broad variety of topics, with specialisations in drug delivery and pharmaceutics, especially in chronic diseases. His keen interest in the latter has driven him to curate scientific articles in pharmaceutics and pharmacology.

Dileep Kumar

Dileep Kumar is an associate professor in the Department of Pharmaceutical Chemistry at Poona College of Pharmacy. He is a pioneer in his field with his forte in the treatment and novel drug delivery in Cancer and Alzheimer’s disease, especially adamantyl analogs as GluN2B selective NMDA receptor agonists. He is also an awardee of the Junior Research Fellowship from the National Medicinal Plant Board (NMPB) New Delhi, Senior Research Fellowship from the University Grants Commission (UGC), Teaching Assistantship, and Institute Post-Doctoral Fellowship from IIT (BHU) Varanasi. He is the Guest editor of Prestigious journals like Current Topics in Medicinal Chemistry, CTMC, Current drug target, combinatorial chemistry, and molecules.

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