17 research outputs found
Mechanical barriers and transforming growth factor beta inhibitor on epidural fibrosis in a rabbit laminectomy model
Background: TGF-β has been described as a mediator of fibrosis and scarring. Several studies achieved reduction
in experimental scarring through the inhibition of TGF-β. Fibroblasts have been defined as the cell population
originating fibrosis, blocking fibroblast invasion may impair epidural fibrosis appearance. For this purpose,
biocompatible materials used as mechanical barriers and a TGF-β inhibitor peptide were evaluated in the reduction
of epidural fibrosis.
Methods: A L6 laminectomy was performed in 40 New Zealand white rabbits. Divided into four groups, each
rabbit was assigned to receive either collagen sponge scaffold (CS group), gelatin-based gel (GCP group), P144®
(iTGFβ group), or left untreated (control group). Four weeks after surgery, cell density, collagen content, and new
bone formation of the scar area were determined by histomorphometry. Two experienced pathologists scored dura
mater adhesion, scar density, and inflammatory infiltrate in a blinded manner.
Results: In all groups, laminectomy site was filled with fibrous tissue and the dura mater presented adhesions. Only
GCP group presented a significant reduction in collagen content and scar density.
Conclusion: GCP treatment reduces epidural fibrosis although did not prevent dura mater adhesion completely
Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice
The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)-13, produced by hypertrophic chondrocytes, and the gelatinase MMP-9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization. MMP-10, Stromelysin 2, a matrix metalloproteinase with high homology to MMP-3 (Stromelysin 1), presents a wide range of putative substrates identified in vitro, but its targets and functions in vivo and especially during fracture healing and bone homeostasis are not well defined. Here, we investigated the role of MMP-10 through bone regeneration in C57BL/6 mice. During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and its maximum expression peak is associated with cartilage resorption at 14 days post fracture (dpf). In accordance with this expression pattern, when Mmp10 is globally silenced, we observed an impaired fracture-healing phenotype at 14 dpf, characterized by delayed cartilage resorption and TRAP-positive cell accumulation. This phenotype can be rescued by a non-competitive transplant of wild-type bone marrow, indicating that MMP-10 functions are required only in cells of hematopoietic linage. In addition, we found that this phenotype is a consequence of reduced gelatinase activity and the lack of proMMP-9 processing in macrophages. Our data provide evidence of the in vivo function of MMP-10 during endochondral ossification and defines the macrophages as the lead cell population in cartilage removal and vascular invasio
Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II)
Background: Mesenchymal stromal cells (MSCs) are a promising option to treat knee osteoarthritis (OA). Their safety
and usefulness have been reported in several short-term clinical trials but less information is available on the longterm efects of MSC in patients with osteoarthritis. We have evaluated patients included in our previous randomized
clinical trial (CMM-ART, NCT02123368) to determine their long-term clinical efect.
Materials: A phase I/II multicenter randomized clinical trial with active control was conducted between 2012 and
2014. Thirty patients diagnosed with knee OA were randomly assigned to Control group, intraarticularly administered
hyaluronic acid alone, or to two treatment groups, hyaluronic acid together with 10×106
or 100×106
cultured autol‑
ogous bone marrow-derived MSCs (BM-MSCs), and followed up for 12 months. After a follow up of 4 years adverse
efects and clinical evolution, assessed using VAS and WOMAC scorings are reported.
Results: No adverse efects were reported after BM-MSCs administration or during the follow-up. BM-MSCs-adminis‑
tered patients improved according to VAS, median value (IQR) for Control, Low-dose and High-dose groups changed
from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7), 2 (2, 5) and 3 (3, 4), respectively at the end of follow up (Low-dose vs Control
group, p=0.01; High-dose vs Control group, p=0.004). Patients receiving BM-MSCs also improved clinically accord‑
ing to WOMAC. Control group showed an increase median value of 4 points (−11;10) while Low-dose and Highdose groups exhibited values of −18 (−28;−9) and −10 (−21;−3) points, respectively (Low-dose vs Control group
p=0.043). No clinical diferences between the BM-MSCs receiving groups were found.
Conclusions: Single intraarticular injection of in vitro expanded autologous BM-MSCs is a safe and feasible proce‑
dure that results in long-term clinical and functional improvement of knee OA
Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II)
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 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
Inyección intraarticular de células madre mesenquimales autólogas derivadas de médula ósea en el tratamiento de la artrosis de rodilla: Ensayo clÃnico multicéntrico aleatorizado (Fase I/II)
El objetivo principal de este ensayo clÃnico es determinar la seguridad y viabilidad del tratamiento de la artrosis de rodilla mediante la administración intraarticular de BM-MSCs autólogas junto con ácido hialurónico (AH). Como objetivo secundario queremos determinar la eficacia terapéutica del tratamiento intraarticular con BM-MSCs autólogas en combinación con AH en
pacientes con artrosis de rodilla, mediante la utilización de dos dosis celulares diferentes y comparándolo con el tratamiento aislado de AH. La determinación de la eficacia se realizará utilizando como variables principales del estudio: 1) Escalas clÃnicas de dolor y funcionalidad. 2) Valoración radiológica utilizando radiologÃa simple y resonancia magnética. Las técnicas y escalas se detallan en la metodologÃa del ensayo
Efecto de barreras mecánicas y péptido inhibidor del factor de crecimiento transformante beta sobre la fibrosis epidural de conejo
Con el objetivo de valorar el efecto y seguridad de diferentes métodos para reducir la fibrosis epidural se evaluaron materiales biocompatibles, usados a modo de barrera mecánica, y el péptido inhibidor del TGF-β (P144®) en un modelo de laminectomÃa L6 en conejo. Se realizó una laminectomÃa completa de L6 a conejos de la estirpe New Zealand White y se crearon 4 grupos experimentales según el tratamiento administrado. Los animales recibieron una lámina de esponja de colágeno (Grupo CS), un gel de gelatina porcina (Grupo GCP), P144® (Grupo iTGFβ) o sin tratamiento (Grupo Control). Cuatro semanas tras la cirugÃa se sacrificó al animal y se determinó la densidad celular, el contenido de colágeno y el hueso neoformado de la zona cicatricial mediante histomorfometrÃa. Dos anatomopatólogos cuantificaron la adherencia de la duramadre, la densidad de la cicatriz y el infiltrado inflamatorio de manera ciega. Todos los grupos, presentaron formación de fibrosis y adherencias a la
duramadre tras la laminectomÃa. Solo el grupo GCP presentó una disminución significativa del contenido de colágeno y densidad de la cicatriz. En conclusión, solo el tratamiento con GCP reduce la fibrosis epidural, aunque no evitó completamente las adherencias a la duramadre
Mechanical barriers and transforming growth factor beta inhibitor on epidural fibrosis in a rabbit laminectomy model
Background: TGF-β has been described as a mediator of fibrosis and scarring. Several studies achieved reduction
in experimental scarring through the inhibition of TGF-β. Fibroblasts have been defined as the cell population
originating fibrosis, blocking fibroblast invasion may impair epidural fibrosis appearance. For this purpose,
biocompatible materials used as mechanical barriers and a TGF-β inhibitor peptide were evaluated in the reduction
of epidural fibrosis.
Methods: A L6 laminectomy was performed in 40 New Zealand white rabbits. Divided into four groups, each
rabbit was assigned to receive either collagen sponge scaffold (CS group), gelatin-based gel (GCP group), P144®
(iTGFβ group), or left untreated (control group). Four weeks after surgery, cell density, collagen content, and new
bone formation of the scar area were determined by histomorphometry. Two experienced pathologists scored dura
mater adhesion, scar density, and inflammatory infiltrate in a blinded manner.
Results: In all groups, laminectomy site was filled with fibrous tissue and the dura mater presented adhesions. Only
GCP group presented a significant reduction in collagen content and scar density.
Conclusion: GCP treatment reduces epidural fibrosis although did not prevent dura mater adhesion completely
Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II)
Abstract Background Mesenchymal stromal cells (MSCs) are a promising option to treat knee osteoarthritis (OA). Their safety and usefulness have been reported in several short-term clinical trials but less information is available on the long-term effects of MSC in patients with osteoarthritis. We have evaluated patients included in our previous randomized clinical trial (CMM-ART, NCT02123368) to determine their long-term clinical effect. Materials A phase I/II multicenter randomized clinical trial with active control was conducted between 2012 and 2014. Thirty patients diagnosed with knee OA were randomly assigned to Control group, intraarticularly administered hyaluronic acid alone, or to two treatment groups, hyaluronic acid together with 10 × 106 or 100 × 106 cultured autologous bone marrow-derived MSCs (BM-MSCs), and followed up for 12 months. After a follow up of 4 years adverse effects and clinical evolution, assessed using VAS and WOMAC scorings are reported. Results No adverse effects were reported after BM-MSCs administration or during the follow-up. BM-MSCs-administered patients improved according to VAS, median value (IQR) for Control, Low-dose and High-dose groups changed from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7), 2 (2, 5) and 3 (3, 4), respectively at the end of follow up (Low-dose vs Control group, p = 0.01; High-dose vs Control group, p = 0.004). Patients receiving BM-MSCs also improved clinically according to WOMAC. Control group showed an increase median value of 4 points (− 11;10) while Low-dose and High-dose groups exhibited values of − 18 (− 28;− 9) and − 10 (− 21;− 3) points, respectively (Low-dose vs Control group p = 0.043). No clinical differences between the BM-MSCs receiving groups were found. Conclusions Single intraarticular injection of in vitro expanded autologous BM-MSCs is a safe and feasible procedure that results in long-term clinical and functional improvement of knee OA