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Design of injectable physical meta-materials for cell transplantation and tissue regeneration

Number of pages105
Imprimatur date2024-02-25
Defense date2024-02-02
Abstract

Biomaterials are increasingly used to address tissue loss arising through disease, trauma, or ageing. Beyond mere mechanical replacement, the induction of new tissue and cell-based therapy are emerging. Minimally invasive delivery of biomaterials avoids further tissue damage and thereby limits the inflammatory reaction, but injection of large, sophisticated structures and sensible cells remains a formidable challenge. Here, we present a compilation of 5 studies describing the development of a novel shape-stable biomaterial for tissue induction and cell therapy. The first two studies describe material design and in-vivo testing to overcome the tradeoff between injectability and mechanical stability in porous injectable materials. To achieve this, we implement a novel reversible strain softening transition in an injectable biomaterial. Reversible strain softening is found in selected biological materials but was not replicated rationally in a man-made biomaterial. Reversible strain softening facilitates injectability: as the material gets increasingly deformed when approaching needle or cannula entry in the syringe, it simultaneously becomes softer and thus easier to inject. Once implanted, the biomaterial recovers its original stiffness thanks to the reversibility of the transition. The reversible softening transition permits us for the first time to match the dynamic shear response not only statically, but over the entire range of physiological deformation in the target tissues. This is a meta-material strategy: the novel properties arise through geometry rather than explicit material chemistry.

In-vivo, the material avoids growing encapsulation, and instead becomes colonized with a vascularized loose connective tissue: an induced stroma. This favorable evolution is related to a mild inflammatory response, and the unique mechanical design. Novel physical tissue integration mechanisms could be at play, as suggested by the third study of this compilation.

In the final two studies presented, the application of the biomaterial is extended to minimally invasive cell delivery. In the context of cell therapy for Parkinson’s disease, we exploit the cell-protective capacity of porous injectable threads by transplanting dopaminergic neurons at mature stages of differentiation, where neurites and neural networks have already formed. At this stage, detachment from the culture substrate would cause extensive cell death. Transplantation of more mature cells adds to the set of emerging strategies aiming at avoiding tumorigenicity due to insufficiently differentiated stem-cells.

We finally use our injectable material to enable the direct transfer of co-cultures of hematopoietic and stromal cells from the dish into mice. We demonstrate seamless transition from in-vitro culture to a tissue-like structure with integration between host and implanted stroma and protracted hematopoietic survival. Our biomaterial provides an avenue to an injectable, porous niche with exquisitely matched mechanical properties for new tissue induction and regenerative cell therapy, with applications only starting to be explored.

eng
Keywords
  • Biomaterial
  • Meta-material
  • Cell transplantation
  • Regeneration
Citation (ISO format)
BRASCHLER, Thomas Michaël. Design of injectable physical meta-materials for cell transplantation and tissue regeneration. 2024. doi: 10.13097/archive-ouverte/unige:175121
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Creation02/25/2024 7:51:16 AM
First validation02/26/2024 5:03:14 PM
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