“4D tissue” building technique creates self curving synthetic cornea

Newcastle team develops biological system that creates cell structures of "4D tissues" which can change shape over time into a desired form

An acute shortage of donated corneas – the clear bowl -shaped layer at the front of the eyeball – has inspired tissue engineers at Newcastle University to develop the new technique.  "Currently there is a shortage of donated corneas which has worsened in recent years, as they cannot be used from anyone who has had laser eye surgery so we need to explore alternatives such as these self-curving corneas,” said Prof Che Connon, a professor of tissue engineering at Newcastle University. "The cells are triggered into forming a complex 3D structure, but as this requires time to occur, the fourth dimension in this equation, we have labelled them 4D structures."

Lead author Martrina Miotto in the lab (Newcastle University)

The synthetic cornea was formed from corneal stem cells encapsulated into a collagen gel. This gel was cast into two concentric flat circles. These circles were then treated with serum containing peptide amphiphile molecules. The serum turned the cells into biological actuators, which over time pulled the flat structure into the desired three-dimensional shape.

In a paper in Advanced Functional Materials, Connon and his team explain how in one ring the activated cells were pulling on the internal structure of the gel. In the other, pulling the peptide amphiphile molecules. The cells preferred to bind to the peptide molecules rather than the internal structure of the gel, leading to a difference in contraction between the two concentric rings. Connon added: "Because all the process was orchestrated by the cells themselves, we can envision them as bio-machines remodelling these structures from the inside.”

The lead author on the paper, Martina Miotto, went into more detail.  "This is a cutting-edge example of the strict relationship between form and function,” she said. “The research also showed that the biomechanical and bio-functional properties of these 4D structures reproduced those of the native tissue, with undifferentiated corneal limbal epithelial stem cells located in the softer limbus and the differentiated epithelium spanning the stiffer centre of the anterior cornea.”

Connon explained that the technique could have implications beyond corneas. "The technology and understanding we have developed holds enormous potential as these corneas show that engineered tissue shape can be controlled by cell actuators. This may lead us to imagine a future where such an approach can be combined with key-hole surgery enabling a surgeon to implant tissue in one shape which then develops into a more complex, functional shape within the body, driven by the behaviour of the cells themselves."

In the next stage of their research, Connon, Miotto and their colleagues are planning to refine the technique as a potential method to make corneas suitable for human transplant.