Cell engineering is the future

The projected median age in Europe for 2050 is 47.4 years, with one in three people expected to be over the age of 60. A drastic increase in those requiring treatment to amend age-related disorders and degenerative disease is putting further strain on the healthcare sector. In 1995, there were just over 40 000 people on the US organ transplant waiting list, and by 2006 this number had risen to 100 000, with only around 17 000 donors. A lack of organ donors has encouraged a shift from traditional patient treatment to new alternative treatments.

A colony of embryonic stem cells. Cells like these can be used to treat degenerative conditions Image: Ryddragyn

The fields of cell and tissue engineering have been developed massively over the past few decades, and increasing bodies of evidence suggest artificial organ substitutes are a potential solution to the donor problem.

Tissue engineering is an incredibly exciting combination of the life sciences and engineering, which aims to create biological substitutes to help restore, maintain or improve the function of a tissue or whole organ. This can be done in many ways, in vivo or vitro. Cell engineering is similar; it is the application of cell modification techniques for therapeutic purposes which can involve genetic, mechanical or chemical adjustments. The most obvious cellular modification may be that of a genetic nature;CRISPR/Cas9 is a relatively new, and still very much developing, revolutionary method of altering genetic information. Based on natural systems observed in bacteria when infected with double stranded viral RNA, a simpler modification has been developed to edit genomes. CRISPR technology holds the potential to fix ‘faulty’ genes and even replace mutations with a correct, functional copy, which holds potential for alleviating the effects of genetic disease or disorders. Some genes can also be regulatedby RNA interference (RNAi) which involves small sequences of nucleotides that can bind an mRNA sequence ready to be translated into a protein. Binding to the mRNA sequence, in a RISC complex involving an endonuclease, the mRNA is cut, preventing the translation of the transcript. Experimental evidence suggests that this can reduce or eradicate the negative impacts of faulty genes through interruption of protein synthesis. This has proven successful in treating Pachyonychia Congenita, a rare genetic disorder caused by a single mutant in one of the four keratin genes. Viral and non-viral vectors, DNA injection and gene-activated matrices using a collagen sponge are further examples of methods used to deliver required genes to a particular area of the body.

From the field of biomaterials, tissue engineering has evolved to allow organ replacements formed in vitro from scaffolds, cells and bioactive agents. Stem cells hold great potential for these methods, as their ability to be manipulated into various cell types (depending on where they are extracted) is key for culturing cells that are required for the production of a graft or tis sue. Various methods of extracting embryonic and ‘embryonic-like’ stem cells are used, such as somatic cell nuclear transfer (SCNT). SCNT was first successful in the cloning of Dolly the sheep in 1996. This method involves the removal of the nucleus from an egg cell and then the addition of a nucleus from a cell of the patient, which can then be fertilised in vitro.

Embryonic stem cells can be extracted from the inner cell mass. This isn’t as common now due to the movement toward induced pluripotent stem (iPS) cells. A pluripotent stem cell refers to a cell that has the potential to differentiate into any of the three germ layers – in other words, they are very useful for tissue engineering. First pioneered in 2006 from mice fibroblasts, iPS cells are artificially derived from a non-pluripotent adult cell. They can be reprogrammed to ‘embryonic-like stem cells’ through manipulation of certain genes and transcription factors. These can then be dedifferentiated and used in culture for many different cell types. This technique earned Shinya Yamanaka and John Gurdon the Nobel Prize in Physiology or Medicine in 2012.

In the rare case that a donor is available, it is possible to remove the organ or tissue required, decellularise it, and then add the patient’s own cells to avoid immuno-rejection. Through the application of specific bioreactors and other techniques, this method can be very effective and a natural, extracellular matrix scaffold can be available after multiple rounds of the decellularisation protocol . However, donors are scarce, and other methods have had to develop as a result. It is possible to use synthetic or natural polymers, such as polylactic acid or alginate to form structures that can then be developed to become biocompatible elements ready for insertion to help aid tissue repair or replacement. Synthetic and natural polymers can be used in additive manufacturing techniques such as selective laser sintering (SLS), 3D printing, nozzle-based systems and stereolithography. SLS is very effective for creating bone grafts. Following a CT or MRI scan, the data is processed by computer-aided design manufacturing (CAD/ CAM systems) into a series of thin cross-sectional layers, which are bound together using these various technologies.

Based on a CAD system, the synthetic polymer, such as polycaprolactone, can be used to engineer a bone graft scaffold. Bone growth can be promoted onto the polymer scaffold in order to leave a custom-made graft ready for the patient. Cell and tissue engineering is incredible but has shortcomings within the field, which is why these techniques are constantly being developed.

Increasing research in cellular manipulation, bioreactor technology and scaffold-forming techniques will be imperative in order to help alleviate health disorders and disease-related conditions. This is especially relevant with our increasing global population and consequentially, increasing demand for such treatments. The day when tissues and organs can be synthesised in vitro and tailored to the genetic make up of an individual is close. It is only a matter of time before such methods become common medical practices.

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