3d-microtissues-for-injectable-regenerative-therapy-high-throughput

3D Microtissues for Injectable Regenerative Therapy and High-throughput Drug Screening

To upgrade traditional 2D cell culture to 3D cell culture, we have integrated microfabrication with cryogelation technology to produce macroporous ...

Tsinghua University

Keloids are fibroproliferative skin disorders characterised clinically by continuous horizontal progression and post-surgical recurrence and histologically by the accumulation of collagen and fibroblast ingredients. Till now, their aetiology remains clear, which may cover genetic, environmental and metabolic factors. Evidence in the involvement of local mechanics (e.g. predilection site and typical shape) and the progress in mechanobiology have incubated our stiffness gap hypotheses in illustrating the chronic but constant development in keloid. We put forward that the enlarged gap between extracellular matrix (ECM) stiffness and cellular stiffness potentiates keloid progression. Matrix stiffness itself provides organisational guidance cues to regulate the mechanosensitive resident cells (e.g. proliferation, migration and apoptosis). During this dynamic process, the ECM stiffness and cell stiffness are not well balanced, and the continuously enlarged stiffness gap between them potentiates keloid progression. The cushion factors, such as prestress for cell stiffness and topology for ECM stiffness, serve as compensations, the decompensation of which aggravates keloid development. It can well explain the typical shape of keloids, their progression in a horizontal but not vertical direction and the post-surgical recurrence, which were evidenced by our clinical cases. Such a stiffness gap hypothesis might be bridged to mechanotherapeutic approaches for keloid progression.

Keloid progression: a stiffness gap hypothesis.

Targeted cell delivery to lesion sites via minimally invasive approach remains an unmet need in regenerative medicine to endow satisfactory therapeutic efficacy and minimized side-effects. Here, we rationally designed a pathology-targeted cell delivery strategy leveraging injectable micro-scaffolds as cell-loading capsule and endogenous tissue transglutaminase (TGase) at lesion site as adhesive. Up-regulated TGase post-liver injury catalyzed chemical bonding between the glutamine and lysine residues on liver surface and micro-scaffolds both ex vivo and in vivo, facilitating sufficient adhesion on the pathological liver. Upon intraperitoneal injection, Mesenchymal Stem Cell-loaded capsules, exhibiting cell protection from shear-induced damage and post-transplantation anoikis, adhered to the CCl4-treated liver with a hundred-fold improvement in targeting efficiency (70.72%) compared to free-cell injection, which dramatically improved mice survival (33.3% vs. 0% for free-cell therapy) even with low-dosage treatment. This unique and widely-applicable cell delivery mechanism and strategy hold great promise for transforming cell therapy for refractory diseases.

Article	Year
Keloid progression: a stiffness gap hypothesis. International wound journal\| PubMed ID: 27995750	2016
Pathology-targeted cell delivery via injectable micro-scaffold capsule mediated by endogenous TGase. Biomaterials\| PubMed ID: 28237907	2017

Zhifeng You

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