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Lung tissue engineering

Lung tissue engineering is a biologically-driven, emerging field of science, stemming from the broader field of tissue engineering, which aims to fill the need created by a shortage of lung transplant donors. This field focuses on the differentiation of stem cells into pneumocytes, utilizing the process by which cells in an initially unchanged state transform into a cell that can be used in the same way as a fully-specialized cell. Scientists must also select material, known as an extracellular matrix, in which the cells will reside, and finally pick a material that will act as a physical structure on which the tissue will regenerate, known as a scaffold.

Overview

The field of lung tissue engineering was developed in response to threats of lung cancer and severe ailments such as chronic obstructive pulmonary disease, which are responsible for over 280,000 deaths each year worldwide (3). Due to the large presence of these and other lung diseases (such as pulmonary hypoplasia and emphysema), supply levels of lung organ donors quickly began to dwindle in comparison to lung transplant demand. (1) One reason for the rate of mortality associated with these diseases is the lung tissues’ inability to heal macroscopically (3). Lung tissue engineering was thus developed as an alternative to transplantation, providing a means of synthetically replacing and regenerating the epithelial tissues of the lungs.

Choice of Cells for Differentiation

Some considerations that affect the choice of cells for lung engineering include quantity of supply, convenience, reproducibility, and ethics. With this in mind, research has shown that stem cells are very useful for such regenerative processes as lung tissue engineering, in particular for their capacity to become nearly any type of adult cell (4).

Embryonic Stem Cells

A buildup of promising research involving embryonic stem cells has shown the human embryonic stem cell has a proficiency for growth and differentiation into the pneumocyte cells. (2,4) However, concerns and debates about the definitions and boundaries of human life have been a polarizing issue in recent years. This polarity has not completely dissuaded scientists from pursuing the positive results that embryonic stem cells seem to provide.

Amniotic Stem Cells

Amniotic fluid is the essential fluid found in a mother’s uterus in which the embryo is sustained and suspended. This fluid is a rich source of multipotent and pluripotent cells of many varieties. The undifferentiated cells are important because of their ability to transform into any other type of cell. However, the multipotent cells also present a degree of promise due to the fact that these cells may already be transforming into a cell destined for one of the body’s organs. In this case, the conversion to lung cells may already be in progress. The fact that these cells are also easy and harmless to retrieve helps fulfill the high demand for lung repairing treatments, and their use avoids any potential ethical implications. (4)

Extracellular Matrices

Extracellular matrix (ECM) proteins are important to lung tissue engineering because they act as the media in which the stem cells are to grow and transform into the desired cells of the lung tissue. In choosing the appropriate ECM protein, scientists must consider how the substance will react in vivo, since it will be subjected to the same conditions as native tissue. Other considerations include water content, reactivity with bodily chemicals, and ability to physically recreate the function played by the original cells.

Hyaluronic acid

Hyaluronic acid (HA) is an ECM component that has many medical uses and applications, from joint lubrication of osteoarthritis patients to controlling drug release of bioactive molecules in the body. Because HA is so hydrophilic, it must be in some way altered in order to be included in any lung tissue engineering process.

HA binds with another polymer known as Poly(HEMA), an important biopolymer which has appropriate water content and permeability, and does not react with substances in the body to which it is exposed. The binding of HA to Poly(HEMA) occurs through a process known as copolymer grafting. The advantageous properties of both of these polymers make them a reasonable choice for a natural-synthetic polymer hybrid for lung tissue engineering. The binding of these polymers results in a compound which shows increased thermal stability and lack of toxicity to human cells, making it a viable compound for future research. (1)

Scaffolds

Scaffolds provide the physical, 3-dimensional material upon which tissue can be generated. Selecting the proper material for the biological scaffold upon which the lung cells are to be grown is crucial. Research on scaffolds ranges from natural-synthetic combinations of polymers (1) to using a common scaffolding polymer and, instead of binding it to another polymer, coating it with an ECM protein (2). The first strategy aims to change the unsuitable properties of natural materials through the use of artificial compounds, thereby producing a suitable scaffold. The second strategy hopes to transform an already useful scaffold to one suitable for the intended biological process. Regardless of the combination used, the polymer must fulfill the mechanical and physiological function of the structure it is replacing (1,2,5).

Elastin

Elastin is a protein and a cellular matrix component found in structures of the human body (including the lungs) that helps give body parts their elastic qualities, and also helps bodily structures retain their shape. (5)

Themicrofibers of a precursor of elastin, known as tropoelastin, can be linked together to form a polymer known as synthetic elastin (SE) which exhibits many properties of natural elastin. (5) These shared properties make SE a potentially useful scaffold for lung tissue engineering.

PDLLA

Poly(D,L-Lactide) (PDLLA) is a hydrophobic polymer with many well-established biological applications, and it is very commonly found in tissue engineering research. Because PDLLA is hydrophobic, it is unsuitable for the creation of tissue that requires the water content of lung epithelial tissue. (2)

PDLLA can be altered in order to make it suitable for lung tissue engineering processes by coating it with a number of different ECM proteins. It was shown that the most appropriate coating was dependent on the specific end-goal, which depends in turn on the type of disease affecting the lung tissue. (2)

References

1. C. Radhakumary, A. M. Nandkumar, P. D. Nair. Hyaluronic acid-g-poly(HEMA) copolymer with potential implications for lung tissue engineering. Carbohydrate Polymers, vol. 85, Elsevier, Mar. 2011, pp. 439-445.

2. Y. Lin, A. Zhang, H. J. Rippon, A. Bismarck, A.E. Bishop. Tissue Engineering of Lung: The Effect of Extracellular Matrix on the Differentiation of Embryonic Stem Cells to Pneumocytes. Tissue Engineering: Part A. 2010, Vol. 16 pp. 1515-1527.

3. E.A. Calle, T.H. Petersen, L.E. Niklason. Procedure for Lung Engineering. Journal of Visualized Experiments (Jove), doi:10.3791/2651. Mar. 2011, pp. 1-6.

4. S. Da Sacco, R. De Filippo, L. Perin. Amniotic fluid as a source of pluripotent and multipotent stem cells for organ regeneration. Current Opinion in Organ Transplantation. Feb. 2011, Vol. 16, pp. 101-105.

5. L. Nivison-Smith, J. Rnjak, A.S. Weiss. Synthetic human elastin microfibers: Stable cross-linked topoelastin and cell interactive constructs for tissue engineering applications. Acta Biomaterialia, Vol. 6, Feb. 2010, pp. 354-359.