Publicação
Innovative approaches to the use of nanotools for creating tendon tissue-mimetic constructs and disease models
| Resumo: | The intricate composition and architecture of living tissues determine their functionality, resulting from the complex interplay between cells and the extracellular matrix (ECM). Properly addressing these characteristics is crucial for the development of 3D in vitro advanced platforms that have the potential to enhance the efficacy of knowledge-based therapy development, while significantly reducing the need for animal experimentation. This Thesis aimed at addressing specific research challenges for the development of effective tendon-mimetic constructs for tissue regeneration and disease modeling. These challenges include i) recreating the complex hierarchical and fibrillar architecture of tendon extracellular matrix; ii) the ability to remotely actuate mechanotransduction mechanisms in tissue engineered construct; iii) delivering biochemical cues involved in tendon tissue development and healing and iv) incorporating multiple cell types to replicate the complex biological processes that occur in native tissue. To address these challenges, we used state-of-the-art technologies such as 3D bioprinting and organ-on-chip technology and biomaterials, in particular nanoparticles, with unique (bio) functional properties. Building on these concepts, In the first experimental chapter (Chapter 3), cellulose nanocrystals (CNCs) surface charge chemistry was exploited to induce their ion-mediated self-assembly to recreate the unique biophysical cues provided by native tissue fibrillar Extracellular Matrix (ECMs) while allowing the design of embedded bioengineered constructs with arbitrary geometries. This system was further explored in Chapter 4, by combining magnetically- and matrix assisted 3D bioprinting for creating anisotropic microstructures. The topographical and biochemical cues of this biomimetic microstructure were combined with its magneto-mechanical stimulation during in vitro maturation, to boost stem cells mechanosignaling and to promote their commitment toward tenogenic lineage. Resourcing zinc-doped iron oxide magnetic nanoparticles incorporated into electrospun fibers (sMRF) specifically designed for this purpose. In Chapter 5 sMRF served as inspiration for developing a compartmentalized tendon-on-chip (3D-TenoC) model to study crosstalk and biochemical signaling in tendon physiology and pathophysiology. This 3D-TenoC model faithfully recreated essential characteristics of human tendons, including anisotropy and spatiotemporal distribution of cells. Overall, this thesis showcases that by combining specific bionanomaterials and advanced 3D bioprinting technologies for the construction of 3D models with an unprecedented ability to mimic native tendon tissue ECM anisotropy, physical stimulus, and customizable biochemical cues, while accommodating multiple cell types. These strategies have the potential to play a significant role in generating valuable biological data and integrating ongoing advancements in tendon tissue engineering. |
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| Autores principais: | Bakht, Syeda Mahwish |
| Assunto: | Nanoparticles Tissue mimetics 3D Bioprinting 3D tissue models Nanopartículas Miméticos de tecido Bioimpressão 3D Modelos de tecido 3D |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | The intricate composition and architecture of living tissues determine their functionality, resulting from the complex interplay between cells and the extracellular matrix (ECM). Properly addressing these characteristics is crucial for the development of 3D in vitro advanced platforms that have the potential to enhance the efficacy of knowledge-based therapy development, while significantly reducing the need for animal experimentation. This Thesis aimed at addressing specific research challenges for the development of effective tendon-mimetic constructs for tissue regeneration and disease modeling. These challenges include i) recreating the complex hierarchical and fibrillar architecture of tendon extracellular matrix; ii) the ability to remotely actuate mechanotransduction mechanisms in tissue engineered construct; iii) delivering biochemical cues involved in tendon tissue development and healing and iv) incorporating multiple cell types to replicate the complex biological processes that occur in native tissue. To address these challenges, we used state-of-the-art technologies such as 3D bioprinting and organ-on-chip technology and biomaterials, in particular nanoparticles, with unique (bio) functional properties. Building on these concepts, In the first experimental chapter (Chapter 3), cellulose nanocrystals (CNCs) surface charge chemistry was exploited to induce their ion-mediated self-assembly to recreate the unique biophysical cues provided by native tissue fibrillar Extracellular Matrix (ECMs) while allowing the design of embedded bioengineered constructs with arbitrary geometries. This system was further explored in Chapter 4, by combining magnetically- and matrix assisted 3D bioprinting for creating anisotropic microstructures. The topographical and biochemical cues of this biomimetic microstructure were combined with its magneto-mechanical stimulation during in vitro maturation, to boost stem cells mechanosignaling and to promote their commitment toward tenogenic lineage. Resourcing zinc-doped iron oxide magnetic nanoparticles incorporated into electrospun fibers (sMRF) specifically designed for this purpose. In Chapter 5 sMRF served as inspiration for developing a compartmentalized tendon-on-chip (3D-TenoC) model to study crosstalk and biochemical signaling in tendon physiology and pathophysiology. This 3D-TenoC model faithfully recreated essential characteristics of human tendons, including anisotropy and spatiotemporal distribution of cells. Overall, this thesis showcases that by combining specific bionanomaterials and advanced 3D bioprinting technologies for the construction of 3D models with an unprecedented ability to mimic native tendon tissue ECM anisotropy, physical stimulus, and customizable biochemical cues, while accommodating multiple cell types. These strategies have the potential to play a significant role in generating valuable biological data and integrating ongoing advancements in tendon tissue engineering. |
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