Optimization of mimetic periosteum autografts for the treatment of nonunions
Bone presents truly regenerative capacity being able to regenerate into a native state in response to injuries. Despite this self-renewal potential, bone healing is not absent of complications and different conditions can interfere with the regenerative process, leading to delayed fracture and in...
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| Format: | info:eu-repo/semantics/doctoralThesis |
| Language: | eng |
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Universidad de Navarra
2024
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10171/68418 |
| _version_ | 1793400516043079680 |
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| author | Romero-Torrecilla, J.A. (Juan Antonio) Granero-Moltó, F. (Froilán) |
| author_facet | Romero-Torrecilla, J.A. (Juan Antonio) Granero-Moltó, F. (Froilán) |
| author_sort | Romero-Torrecilla, J.A. (Juan Antonio) |
| collection | DSpace |
| description | Bone presents truly regenerative capacity being able to regenerate into a native state in
response to injuries. Despite this self-renewal potential, bone healing is not absent of
complications and different conditions can interfere with the regenerative process,
leading to delayed fracture and in some cases fracture nonunion. Fracture nonunion is
a major cause of chronic pain and disability and, despite the low incidence of nonunion
and delayed union fractures (5-10%), the numerous fractures that take place globally
(~180 million every year) emphasizes the huge economic burden that fracture nonunion
represents.
Once detected, fracture nonunion requires a surgical approach, and the use of bone
autografts that provide and osteoinductive, osteogenic and osteoconductive environment
for a successful repair. However, the availability of bone grafts is limited. The scarcity of
bone tissue that can be used for autografts have consolidated the need for novel tissue
engineering approaches as potential candidates for the treatment of nonunion and for
long bone defects, prone to evolve to nonunions. Tissue engineering strategies allow for
the combination of novel tunable materials along with different biological adjuvants,
including growth factors and cells. During the bone regenerative response, the
periosteum, a fibrous layer surrounding the bone, plays a key role delivering
osteochondroprogenitor cells and crucial growth factors into the injured tissue. Thus, we
developed a tissue engineering strategy where biocompatible, 3D melt-electro-written
polycaprolactone membrane would act as a mimetic periosteum.
The engineered mimetic periosteum allows vascularization of the construct either when
implanted ectopically or orthotopically. Additionally, we demonstrated its capacity to be
functionalized with rhBMP-2, the most important morphogen for bone regeneration, both
exposed on the membrane surface attached through PEA-hFN or encapsulated in
microparticles covalently bound to the PCL membrane.
When functionalized with low doses of rhBMP-2 the mimetic periosteum demonstrated
great osteogenic potential in vitro, inducing human MSCs differentiation into osteoblasts.
More importantly, in vivo results indicate that the functionalization of the mimetic
periosteum with rhBMP-2 allows regenerative properties able to heal critical size femoral
defects in SD rats with high efficiency and reproducibility using unpreceded low doses of
rhBMP-2. Ultimately, the mimetic periosteum demonstrated its ability to deliver key
mesenchymal progenitor cells into the injured site.
All these results indicate that our engineered mimetic periosteum represents an efficient
system for rhBMP-2 and progenitor cells delivery with important translational potential. |
| format | info:eu-repo/semantics/doctoralThesis |
| id | oai:dadun.unav.edu:10171-68418 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2024 |
| publisher | Universidad de Navarra |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-684182024-01-22T06:06:13Z Optimization of mimetic periosteum autografts for the treatment of nonunions Romero-Torrecilla, J.A. (Juan Antonio) Granero-Moltó, F. (Froilán) Materias Investigacion::Ciencias de la Salud::Reumatología Nonunions Mimetic periosteum autografts Pseudoarthrosis Bone presents truly regenerative capacity being able to regenerate into a native state in response to injuries. Despite this self-renewal potential, bone healing is not absent of complications and different conditions can interfere with the regenerative process, leading to delayed fracture and in some cases fracture nonunion. Fracture nonunion is a major cause of chronic pain and disability and, despite the low incidence of nonunion and delayed union fractures (5-10%), the numerous fractures that take place globally (~180 million every year) emphasizes the huge economic burden that fracture nonunion represents. Once detected, fracture nonunion requires a surgical approach, and the use of bone autografts that provide and osteoinductive, osteogenic and osteoconductive environment for a successful repair. However, the availability of bone grafts is limited. The scarcity of bone tissue that can be used for autografts have consolidated the need for novel tissue engineering approaches as potential candidates for the treatment of nonunion and for long bone defects, prone to evolve to nonunions. Tissue engineering strategies allow for the combination of novel tunable materials along with different biological adjuvants, including growth factors and cells. During the bone regenerative response, the periosteum, a fibrous layer surrounding the bone, plays a key role delivering osteochondroprogenitor cells and crucial growth factors into the injured tissue. Thus, we developed a tissue engineering strategy where biocompatible, 3D melt-electro-written polycaprolactone membrane would act as a mimetic periosteum. The engineered mimetic periosteum allows vascularization of the construct either when implanted ectopically or orthotopically. Additionally, we demonstrated its capacity to be functionalized with rhBMP-2, the most important morphogen for bone regeneration, both exposed on the membrane surface attached through PEA-hFN or encapsulated in microparticles covalently bound to the PCL membrane. When functionalized with low doses of rhBMP-2 the mimetic periosteum demonstrated great osteogenic potential in vitro, inducing human MSCs differentiation into osteoblasts. More importantly, in vivo results indicate that the functionalization of the mimetic periosteum with rhBMP-2 allows regenerative properties able to heal critical size femoral defects in SD rats with high efficiency and reproducibility using unpreceded low doses of rhBMP-2. Ultimately, the mimetic periosteum demonstrated its ability to deliver key mesenchymal progenitor cells into the injured site. All these results indicate that our engineered mimetic periosteum represents an efficient system for rhBMP-2 and progenitor cells delivery with important translational potential. 2024-01-18T12:36:55Z 2024-01-18T12:36:55Z 2024-01-18 2023-12-14 info:eu-repo/semantics/doctoralThesis https://hdl.handle.net/10171/68418 eng info:eu-repo/semantics/openAccess application/pdf Universidad de Navarra |
| spellingShingle | Materias Investigacion::Ciencias de la Salud::Reumatología Nonunions Mimetic periosteum autografts Pseudoarthrosis Romero-Torrecilla, J.A. (Juan Antonio) Granero-Moltó, F. (Froilán) Optimization of mimetic periosteum autografts for the treatment of nonunions |
| title | Optimization of mimetic periosteum autografts for the treatment of nonunions |
| title_full | Optimization of mimetic periosteum autografts for the treatment of nonunions |
| title_fullStr | Optimization of mimetic periosteum autografts for the treatment of nonunions |
| title_full_unstemmed | Optimization of mimetic periosteum autografts for the treatment of nonunions |
| title_short | Optimization of mimetic periosteum autografts for the treatment of nonunions |
| title_sort | optimization of mimetic periosteum autografts for the treatment of nonunions |
| topic | Materias Investigacion::Ciencias de la Salud::Reumatología Nonunions Mimetic periosteum autografts Pseudoarthrosis |
| url | https://hdl.handle.net/10171/68418 |
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