The Retina Blueprint
Taking retinal tissue research from the bench to the bedside with decellularized extracellular matrix bioinks and 3D cell printing
Why is AMD – the most common cause of blindness – still without any effective treatment? There are various reasons, but a significant issue is the lack of an effective research platform in drug development that drives translation from bench to bedside.
Boot camp blues
Before entering the clinical stages of research, drug candidates (recruits) must pass boot camp – more formally known as in vitro and animal testing. Unfortunately, traditional cell culture and animal experiments do not reflect the exact condition of human organs, which causes many recruits to drop out of the pipeline.
Our aim is to improve the process by making a human tissue testing platform. By being able to more accurately mimic function in a living and breathing human, several serious problems could be resolved.
Our approach is to use a combination of decellularized extracellular matrix (dECM) and 3D cell printing technology to better create a working human model in the lab (1). The dECM – a hydrogel rich in extracellular matrix components from the actual tissue – acts as a “bioink” when mixed with the cells – enabling superior cell maturation compared with conventional bioink. Furthermore, the latest 3D cell printing technology facilitates the fabrication of complex and functional multicellular tissue structures.
We have expertise in both of these technologies. Recently, we developed the retina dECM (RdECM) bioink, and printed a retina using 3D cell printing technology. In cultured retinas, cells not only proliferate well, but also express retinal-related markers that were not shown in previous in vitro studies. Our aim is to use the platform for drug development to treat AMD (and eventually other diseases), ultimately helping blind patients around the world.
Our key concept is “the right thing in the right place.” The more natural functions that can be obtained result in tissue that is more similar to the real tissue environment. The eye in general – and the retina in particular – have complex structures made up of different cells and ECM materials. However, traditional technologies cannot reproduce the 3D structure and ECM environment of the organ. dECM bioinks and 3D cell printing technology help overcome these limitations. And as 3D printing technology constantly advances, so too does 3D cell printing, enabling us to recreate the complex structure of human organs in an increasingly accurate way.
Our work with dECM has led us to develop various types of tissue alternatives and in vitro models using 3D cell printing and dECM bioinks – finding the advantages and disadvantages to each. The dECM bioinks are rich in ECM materials related to tissue-specific microenvironments and help cells mature with their natural functions. By using more advanced bioinks, 3D cell printing technology is able to create models that better replicate the real tissue; for example, by facilitating proper intercommunication between each cell type and between the cells and the ECM – both of which are crucial to effective and realistic tissue functions.
One element that we add to the bioink is collagen. This is crucial to enable the crosslinking and solidification of dECM based bioinks, and without collagen the RdECM, in particular, will not form a suitable 3D structure. We actually chose collagen because it is widely used for 3D tissue engineering and very conventional. Collagen is well known to be biocompatible with cells and the crosslinking capabilities make it a good companion for our dECM bioinks – enabling the formation of a 3D structure whilst also reinforcing the physical properties that are necessary for 3D printing.
Although our major focus has been the development of retinal tissue, we have developed or are currently developing other alternative tissues using our dECM and 3D cell printing processes – including brain, heart, liver, skin, and even the cornea and Bruch’s membrane of the eye.
Impact on the visual field
So where does our developed retina lead us? Functional retinas are in demand not only for development and testing of new drugs but also for transplantation – and our 3D printed retina could be used in both cases.
But we don’t want to stop developing the model. We have plans to improve upon our retina tissue model by introducing other components of the eye, including the retinal pigment epithelium (RPE) and choroid. The integration of more components makes the tissue more complex, bringing it yet another step closer to the healthy functioning retinas that most of us are lucky to have – and thus producing even better tissue for transplantation and drug testing.
- J Kim et al., “Maturation and Protection Effect of Retinal Tissue-Derived Bioink for 3D Cell Printing Technology,” Pharmaceutics, 13, 934 (2021). PMID: 34201702.
