2024-03-29T06:57:21Zhttps://www.tdx.cat/oai/requestoai:www.tdx.cat:10803/6718672021-06-15T18:11:43Zcom_10803_369col_10803_83927
nam a 5i 4500
Macrophage
Inflammation
Guided Bone Regeneration
Ion
Drug Release
Modulation of the inflammatory response using a guided bone regeneration membrane with dual drug delivery capacity
[Barcelona] :
Universitat Internacional de Catalunya,
2021
Accés lliure
http://hdl.handle.net/10803/671867
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Díez Tercero, Leire,
autor
1 recurs en línia (255 pàgines)
Tesi
Doctorat
Universitat Internacional de Catalunya. Departament de Ciències Bàsiques
2021
Universitat Internacional de Catalunya. Departament de Ciències Bàsiques
Tesis i dissertacions electròniques
Pérez Antoñanzas, Román,
supervisor acadèmic
Delgado Garoña, Luis María,
supervisor acadèmic
TDX
Bone is a complex and dynamic tissue that fulfills several critical functions such as
protecting vital organs including the brain, heart and lungs; providing sites of attachment
for muscles to allow movement and maintaining ion homeostasis. Moreover, bone has a
remarkable regenerative capacity which allows the complete healing of the tissue upon
damage. However, this capacity can be exceeded when the size of the defect is too large
due to clinical procedures such as tumor resection or the presence of traumatic fracture
or osteolysis, which constitute a significant clinical challenge nowadays. Autologous grafts,
as well as allografts and xenografts present several limitations to their clinical application
such as limited bone supply, disease transmission and ethical issues. Therefore, tissue
engineering combining biomaterials and stimulatory molecules to guide bone
regeneration presents as an alternative to these methods.
Recent advances in bone biology have shown that osteogenesis occurs due to the
interaction of multiple systems and not only by the actions of the bone tissue. In this
sense, the immune system has gained great importance since the inflammatory response
promoted by either tissue damage or the immune recognition of the implanted
biomaterial can direct the outcome of the bone healing response. More precisely,
macrophages have been described to have a central role in bone regeneration. Their
differentiation to a pro-inflammatory phenotype (M1) phenotype can lead to the
development of chronic inflammation, which impairs bone healing, whereas their
differentiation to an anti-inflammatory phenotype (M2) can lead to enhanced biomaterial
integration and improved bone regeneration. Therefore, the design of biomaterials has
focused on modulating macrophage differentiation to M2 phenotype to improve bone
regeneration.
One of the approaches to modulate macrophage response has been the release of antiinflammatory
modulators such as cytokines, viral vectors or siRNAs. However, their short
half-life and concerns in their efficiency in cellular uptake, as well as long term safety limit
VI
their clinical application. Ions have risen as a promising alternative since they are stable
cues which are present at low concentrations in the body and have already shown
benefits on angiogenesis and bone regeneration when delivered from scaffolds. However,
there are limited evidences showing their immunomodulatory potential.
This thesis is focused on modulating macrophage response by developing a dual drug
delivery system with the ability to release ions, as well as small drugs, to promote the M2
macrophage phenotype. First, an initial screening of three bioactive ions was performed
to determine the cytotoxic and therapeutic concentrations in macrophages. Those
concentrations that induced macrophage differentiation towards the M2 phenotype were
tested in presence of different concentrations of a pro-inflammatory stimulus, which
allowed to determine the anti-inflammatory potential of these ions. Then, the effect of
the ions combined with an anti-inflammatory drug was tested in macrophages to observe
a possible synergistic effect between both molecules, although no major differences were
observed compared to the effect of the drug alone.
Following these assays, the dual drug delivery system was developed, which consisted of a
collagen film with ion loaded microparticles and drug loaded microspheres. The results
showed that these films not only were able to release controlled concentrations of the
ion, but they were also able to perform a sustained release of the drug. Finally,
macrophages and mesenchymal stem cells (MSCs) were exposed to the films, showing
that they were able to induce M2 macrophage differentiation and osteogenesis.
Moreover, treating MSCs with conditioned media from film-induced M2 macrophages
further improved the osteogenic differentiation.
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