Editors' ChoiceTissue Engineering

Paving the path to inpatient printing

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Science Translational Medicine  08 Jul 2020:
Vol. 12, Issue 551, eabd3082
DOI: 10.1126/scitranslmed.abd3082

Abstract

3D bioprinting in situ in various tissues in a live animal enables in vivo confined cell delivery.

Hydrogel injection into tissue is used routinely to deliver cells to specific anatomic locations for tissue engineering but is limited by poor engraftment and short half-life of cells due to rapid dispersion of the hydrogel. Now, Urciuolo et al. report an enabling technology to inject cell-laden photosensitive polymer hydrogel and subsequently selectively cross-link it using bio-orthogonal two-photon cycloaddition, thus fabricating three-dimensional (3D) constructs in situ and obviating aforementioned issues associated with dispersion of uncross-linked hydrogel.

In a technique they call “intravital 3D bioprinting (i3D)”, the authors demonstrate that they can engineer 3D structures in live mice inside tissues including skeletal muscle, brain, and skin. In another key experiment, they demonstrate that stem cells and fibroblasts derived from the donor can be printed in the hindlimb muscle of a mouse, leading to de novo formation of myofibers. This technology can also be used to print cell constructs in preexisting matrices in vitro, allowing reproducible, topographical control of cell structures (such as organoids) and providing a practical tool to study mechanisms dependent on cell structural organization.

Major technological hurdles that were overcome in this work include identifying 7-hydroxycoumarin-3-carboxylic acid as a compound that could be conjugated to polyethylene glycol/gelatin hydrogels and that creates a shift in the light absorbance spectra, thus enabling deeper penetration of light into tissue for cross-linking of the polymer at wavelengths greater than 805 nm. Clinically, the technology may have benefits in fabricating functional tissues and 3D structures directly in the human body for organ repair or reconstruction. However, current limitations include the size and possible location of 3D constructs. The dimensions of the 3D constructs and the depth of injection sites that can be exposed to light are both currently limited to the millimeter scale, preventing 3D fabrication in deep tissues. Advancements in multiphoton microscopy (including three-photon and multiphoton holographic technology) and development of minimally invasive methods to controllably deliver light to deeper tissue sites will likely contribute to overcoming these hurdles in the future.

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