Recent Advances in Tissue Engineering and Regenerative Medicine

Organ transplantation has been the only feasible option for millions of people around the world with organ failure, and this problem is further challenged with increasing wait list for the organ transplantation and increase in mortality rate due to organ failure. The issues associated with organ transplantation are complicated by finding a suitable donor for organ transplantation and storing it for a longer period of time. According to the U.S government on organ donation and transplantation report, more than 100,000 patients are in the 2019 waiting list for organ transplantation and the organ donor shortage is at its peak than ever.

Tissue engineering is considered as the “holy grail” in the medical field and is growing at the fast pace allowing the tailormade organs to be an alternative and a viable solution to replace failed organs. Tissue engineering has made the dream come to reality of having a fully functional artificially produced organ. Every year, there is exponential increase in the number of publications in the field of tissue engineering and regenerative medicines. Although the non-vascularized organs such as skin, urinary bladder, urinary tract, bone and blood vessels are commercially available, thick vascularized organs such as liver, kidney and heart are still far from reality. Commercial applications of tissue engineering are high and versatile.

Traditional Tissue Engineering

The idea of grafting or organ transplantation is not new. First skin grafting can be traced back to 3000 BC in India. Although, the foundation of tissue engineering was laid by Dr. Ross in 1907. Dr. Ross studied nerve fiber development from embryonic tissue. After four decades, in the year 1948, the first artificial kidney was made. Although it was a failure but conceived the idea of tissue engineering to produce artificial organs. From early 1950s to 1960s, numerous articles were published on tissue assembly on which the present regenerative medicine and tissue engineering is established. The tissue engineering can be defined as the methodology to replace the damaged tissues or organs with new tissues or working organ. There are three ways by which it can be achieved:

a. Damaged cells can be replaced with new cells,b. Injecting specific growth factors such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neutrophin-3 (NT-3) and recombinanthuman bone morphogenetic protein 2 (rhBMP-2) as the differentiation marker; andc. Growing entire organ artificially in vitro.

The first two methods are useful when damage is minimum, but to third method can be employed when there is need to replace larger part of organ or whole organ. The organ can be grown either as tissue scaffolds using 3D bioprinter or recolonization of decolorized organ. The major challenge in tissue engineering is to mimic the microenvironment of extracellular matrix and to arrange different cell types correctly when multiple cell types are present.

Advances in Tissue Engineering

In 1985, 3D printing technology was patented. Three years later, Kelbe et al (1988) published a paper on 3D positioning of the cells, or “Conscribing”. Initially, 3D printing was used for printing of the scaffold and cells were seeded in it. Shortcomings of the scaffold-based technology have motivated researchers to find other strategies. The need of organs for transplant has not been fulfilled by organ donations and therefore need to regenerate organs through tissue engineering is gaining popularity. Tissue engineering has the ability to revolutionize the medical field with the bio fabricated organs and tissues. In 1995, 3D printing technology and regenerative medicine converged together and gave rise to new era of 3D organ printing. Bio fabrication is defined as the process of using living cells, biomaterials, extracellular matrices and molecules to generate complex living as well as non-living biological products. 3D printing provides more mechanical stability and nutrition diffusion than that of scaffold and applying 3D printing technology, tissues of different shapes and sizes can be fabricated.

In 2003, Inkjet bioprinter was introduced. Bio-inkjet printer is similar to that of the desktop printer but in the cartridge, it consists of bioink . Bioinks are the ECM materials such as fibrin, hormones and growth factors that are printed as layers and cells are deposited in it. It also requires a computer-aided software for deposition of the cells. Bioprinting technology involves three processes: Preprocess, process and post process. In the preprocessing step, blueprint of the organ and tissue is designed with the help of computer. After designing, processing takes place. Bioprinter prints layers of cells over ECM. In the last step, bioreactor is used for tissue maturation and differentiation. The main challenges in 3D bioprinting are lack of growth factors needed for the cell differentiation , production of the branched vascular network where new blood vessels are grown with having same structure and biological function , and scarcity of the technical aspect of bioprinting process such as material and resolution of bioprinting. 3D printing technology provides more cell to cell interactions and it closely mimic the indigenous microenvironment for tissue growth. After two-decades, Organovo launched the first commercial bioprinter in the market. Due to its expectation of usefulness in the field of organ transplantation and drug studies, many companies have launched commercial bioprinters, and Stryker had invested around 400 million US dollars in 2016.

DECM Bio ink

In order to overcome the shortcomings of the decellularized organs and bio inkjet printing organ new technology is emerged by merging both. In this method, organs are decellularized first and then ECM from decellularized organs is used as the bioink for the bioprinter. Decellularized matrix is considered as next generation bioink. Pati et al (2014) developed this technology and year later in 2015 they developed soft tissue using decellularized adipose tissue. By this method, a layer of 400- 300μm thickness is made and stacked up to 10 layers which is twice the size of the traditional printing method. This technology is so far found to be useful in producing the whole organ and the mechanical property of decolorized organs was improved by hybrid technology, which uses re-absorbable polymer scaffold.

Future Aspect

Advances in tissue engineering research and its methodology lead to the formation of scaffold to bioprinter and then to the decellularized organs. More research in methodologies are overcoming the shortcomings of previous ones. Improving knowledge in the biology of regeneration, development in microelectronics and 3D printing technology is helping in further overcoming the hurdles. Production of commercially available organs is not the distant future anymore. FDA regulations, associated cost and ethical issues may delay the technology, however research trend suggests deeath due to organ scarcity will be reduced in foreseeable future.

Author:Pardeep Sidhu

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