In IPF, remodelling of the lung tissue structure is an important contributor to the pathology [101–106]. These changes include increased deposits of fibrotic ECM proteins in the interstitium and air spaces, thickening of the airway walls and the collapse of air spaces. These tissues have increased staining for hyaluronic acid [11], the foetal form of cellular fibronectin (containing the EIIIA domain) [107] and collagen I and III [80, 108, 109], which are usually located in or around the fibrotic foci of fibroblasts that are characteristic in IPF lung tissues [106, 110, 111].

The highly complex structure of the ECM and its importance in the regulation of cellular behaviours in vivo have made it a challenging structure to study [112–114]. Early studies using light and electron microscopy showed that the matrices were widespread with distinct structural arrangements that underlay many cells. Exploration of the biology of the development and functionality of the ECM has been, and continues to be, challenging due to the fact that the ECM is, by nature, crosslinked and highly insoluble [1]. The traditional two-dimensional (2D) in vitro cell culture model that is often employed in pursuit of these answers does not sufficiently reflect native biology for cost-effective and efficient translational medical research. Owing to the many limitations of in vitro studies, translating the findings from in vitro studies to in vivo and eventually human studies is an ongoing challenge (Fig. 11.2).

Among the many limitations of the in vitro 2D culture systems is the fact that they do not accurately represent the in vivo 3D structures. Furthermore, most in vitro culture systems utilise a plastic/glass surface—which are both non-biological, in terms of the surface composition presented to the cells, and the mechanical properties are at odds with those in the in vivo system [115]. Whilst advancements have been made in the in vitro systems utilising surfaces coated with ECM-derived materials such as collagen and fibronectin [115] or mixtures of homogenised and dissolved decellularised tissues [116], this is merely a small step towards replicating the true ECM environment in vivo.

Three-dimensional cell culture is a further advancement for the field, bringing the experimental outcome closer to biological significance. However, in vitro 3D cell culture techniques such as spheroid suspensions [117] and 3D gel cultures [115, 118–120] retain some of the limitations described for 2D systems, primarily the question of: “What are the appropriate components and structure of the ECM?” Whilst there are many studies investigating the precise combination of ECM components in various tissues using techniques such as mass spectrometry [121, 122], current in vitro 3D model systems utilise single ECM components such as collagen, fibronectin or fibrin gels [115] or combinations of a few ECM components [123]; which pale in comparison to in vivo ECM that is composed of hundreds of different components [1]. Further complications are added by the interactions between ECM components which ultimately dictate the “net biological properties” of the scaffold . As such, the construction of a biologically accurate artificial/synthetic ECM scaffold remains a major hurdle in translational research.

To counter this highly complex problem, the technique of tissue decellularisation has been developed. Decellularisation is a novel technique that produces scaffolds through the removal of cells from viable tissue (utilising a combination of chemical and mechanical treatments), thus preserving much of the original ECM content and architecture (Fig. 11.3). Scaffolds created using this technique maintain most (but not all) of their ECM components and mechanical properties, making them a suitable platform for translational studies. As with any technique, there are also limitations, the first of which is that the decellularisation process can remove some of the less adhesive components of the ECM and introduce some small structural changes. There are many different decellularisation techniques emerging, each with its own advantages and disadvantages (Table 11.1) [172] but the field is yet to agree on a standardised approach. The ideal approach would be for the protocol used for the production of the decellularised tissue to be tailored towards the type of tissue used and the study in question to ensure preservation of as many of the ECM properties as possible.

One of the major issues for organ transplantation programmes is the shortage of viable donor organs, followed by the immunological rejection of the implanted organ by the recipient [173–175]. The ultimate goal of tissue decellularisation is to eventually enable the re-cellularisation and repopulation of generated ECM scaffolds with recipient autologous cells to regenerate a viable tissue/organ for implantation.

The ECM scaffold has limited immunogenicity [167, 176] and through re-cellularisation of the scaffold with the recipient’s cells it should be possible to create graft tissue material for treatment purposes [141, 151, 157, 176, 177]. Whilst this process has had success in simple organ systems such as skin [172], to date it is yet to be successful in the long term for complex organs such as the lungs [153]. Current research has successfully re-cellularised the lungs from various different species with a variety of cell types (Table 11.2). Whilst re-cellularised organs can perform organ-specific functions for short periods of time [140], further research is necessary to progress and exploit this new emerging treatment possibility.

Stem cells have been highlighted as ideal cells for re-cellularisation of the ECM scaffold as not only does the ECM scaffold possess the required structure and mechanical properties, but ECM components can also assist in guiding the cell differentiation and migration processes for optimal regeneration of the tissue/organ for implantation [5, 157]. Whether the defined populations of progenitor cells within the lung can be re-established in healthy lung niches is an exciting prospect that needs extensive investigation.

The ECM provides structural support and environmental cues for cells within its microenvirons. This local regulatory system enacts dedicated stem cell niches within the lung which allow for the maintenance of specialised progenitor cell populations. Greater understanding of cell signalling, preferential attachment, migration and differentiation by cells as directed by the ECM microenvironment will provide valuable insights to cell/matrix dynamics. This will lead to advances in knowledge about the roles of various ECM components and their structural interactions with cells. The field is moving towards the ultimate goal of the development of a synthetic matrix scaffold suitable for re-cellularisation [185] and eventual re-construction of a viable lung for transplant purposes.