Abstract
In regenerative medicine and tissue engineering, many materials are developed to mimic the extracellular matrix (ECM). However, these ECM-mimicking materials do not yet completely recapitulate the diversity and complexity of biological tissue-specific ECM. In this review, an alternative strategy is proposed to generate ECM, namely synthesizing a material that functions as a drug delivery system, releasing molecules that target cellular metabolic pathways and thereby stimulate the local cells to create their own ECM. This is based on the fact that ECM synthesis, modification, composition, signaling, stiffness, and degradation are modulated by cellular metabolism. Metabolism can be targeted at different levels, ranging from modulating the availability of substrates or co-factors to regulating the activity of essential transcription factors. Depending on the drug of interest, its characteristics, mechanism of action, cellular target, and application, a different drug delivery system should be designed. Metabolic drugs modulating the ECM require cellular uptake for their function, therefore reversible linkers are recommended. Preferably the metabolic modulators are only released when needed, which will be upon a specific metabolic state, a change in ECM stiffness, or ECM remodeling. Therefore, reversible linkers that respond to an environmental stimulus could be incorporated. All in all, a novel strategy is suggested to develop a tissue-specific ECM by generating a synthetic material that releases metabolic molecules modulating the ECM. Various ways to modulate the ECM properties via the metabolism are reviewed and guidelines for the development of these materials are provided.
Highlights
In regenerative medicine and tissue engineering, a variety of approaches have been taken to engineer the extracellular matrix (ECM) using synthetic or natural building blocks
The best known example of this approach is the addition of an RGD peptide to a scaffold, which cells can use for integrin-mediated adhesion and subsequent signaling (Ingavle et al, 2014; Xing et al, 2020)
Methods to modulation the ECM by influencing cellular metabolism can be incorporated in the design of materials or scaffolds for tissue engineering
Summary
In regenerative medicine and tissue engineering, a variety of approaches have been taken to engineer the extracellular matrix (ECM) using synthetic or natural building blocks. The best known example of this approach is the addition of an RGD peptide to a scaffold, which cells can use for integrin-mediated adhesion and subsequent signaling (Ingavle et al, 2014; Xing et al, 2020). While these approaches may capture some of the important features of the ECM, it remains challenging to produce tissue-specific ECM with the correct biological (e.g., expression of specific ECM proteins and post-translational modifications) and physical (e.g., stiffness, viscoelasticity) properties. Many approaches are hindered by additional disadvantages such as the lack of reproducibility and tunability
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