Macromolecular crowding meets tissue engineering by self-ssembly: A paradigm shift in regenerative medicine

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2014-02-06Author
Satyam, Abhigyan
Kumar, Pramod
Fan, Xingliang
Gorelov, Alexander
Rochev, Yury
Joshi, Lokesh
Peinado, Héctor
Lyden, David
Thomas, Benjamin
Rodriguez, Brian
Raghunath, Michael
Pandit, Abhay
Zeugolis, Dimitrios I.
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Satyam, Abhigyan, Kumar, Pramod, Fan, Xingliang, Gorelov, Alexander, Rochev, Yury, Joshi, Lokesh, Héctor Peinado , David Lyden,Benjamin Thomas, Brian Rodriguez, Michael Raghunath, Abhay Pandit, Zeugolis, Dimitrios. (2014). Macromolecular Crowding Meets Tissue Engineering by Self-Assembly: A Paradigm Shift in Regenerative Medicine. Advanced Materials, 26(19), 3024-3034. doi: 10.1002/adma.201304428
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Abstract
Advancements in molecular and cell biology have led to the development of cell-based
therapies to treat injured or degenerated tissues.
[1] The rationale of this concept is that
functional regeneration can be achieved best by using the innate capacity of cells to create
their own tissue-specific extracellular matrix (ECM) avoiding the shortfalls of man-made
devices. Although direct cell injections have demonstrated very promising preclinical and
clinical outcomes,
[2] the mode of administration offers little control over local retention and
distribution of the injected cell suspensions[3] leading to scattered therapeutic efficiency. This
deficiency has led to the development of living substitutes for skin[4] and blood vessel[5]
composed of cells seeded on a collagen scaffold. Notwithstanding the efficacious results in
preclinical models and clinical trials, it soon became apparent that the presence of the scaffold
hinders tissue remodelling and function.
[6] These drawbacks led to the development of the
scaffold-free cell-sheet tissue engineering (CSTE)[7] or tissue engineering by self-assembly
(TESA),
[8] a therapy that offers the fabrication of a contiguous cell sheet that is stabilised by
cell-cell contacts and endogenously produced ECM. Despite the documented, in preclinical
and clinical setting, positive outcomes for skin,
[9] blood vessel,
[10, 11] cornea,
[12, 13] heart,
[14]
lung,
[15] liver[16] and bone[17] replacement, only Epicel® (Genzyme, USA) for skin and
LifeLine™ for blood vessel (Cytograft, USA) have been commercialised so far. This limited
technology transfer from bench-top to clinic has been attributed to the substantial long period
of time required for ex vivo culture (e.g. 14-35 days for corneal epithelium;
[13] 84 days for
corneal stromal;
[18] 28 days for corneal endothelium;[19] 70 days for lung cell-sheet;
[15] and
196 days for blood vessel[11]
) that often leads to loss of native phenotype and cell
senescence.[20]
Here, we propose a biophysical approach, termed macromolecular crowding (MMC), that
increases thermodynamic activities and biological processes by several orders of
magnitude,[21] as means to create ECM-rich tissue equivalents. The principle of MMC is
derived from the notion that in vivo cells reside in a highly crowded/dense extracellular space
and therefore the conversion of the de novo synthesised procollagen to collagen I is rapid.
[22]
However, in the even substantially more dilute than body fluids (e.g. urine: 36-50g/l; blood:
80g/l) culture conditions (e.g. HAM F10 nutrient medium: 16.55g/l; DMEM/F12 medium:
16.78g/l; DMEM high glucose and L-glutamine medium: 17.22g/l), the rate limiting
conversion of procollagen to collagen I is very slow (Figure 1a). We propose that the
addition of inert polydispersed macromolecules (presented as spherical objects of variable
diameter in Figure 1b) in the culture media will facilitate amplified production of ECM-rich
living substitutes.
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