Muiños-López, E. (Emma)
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- Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice(Wiley, 2021) Calvo, I.A. (Isabel A.); Granero-Moltó, F. (Froilán); Paramo, J.A. (José Antonio); Ripalda-Cemboráin, P. (Purificación); Montiel-Terrón, V. (Verónica); Aldazabal, J. (Javier); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Lopez, T. (Tania); Valdés-Fernández, J. (José); Muiños-López, E. (Emma); Romero-Torrecilla, J.A. (Juan Antonio); Prosper-Cardoso, F. (Felipe); Saez, B. (Borja)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 invasion
- Novel hybrid biocomposites for tendon grafts: the addition of silk to polydioxanone and poly(lactide-co-caprolactone) enhances material properties, in vitro and in vivo biocompatibility(2023) Doyle, B. (Barry); Granero-Moltó, F. (Froilán); Heidari, B.S. (Behzad Shiroud); Rajkhowa, R. (Rangam); Zheng, M. (Minghao); Allardyce, B. (Benjamin); Ruan, R. (Rui); De-Juan-Pardo, E.M. (Elena M.); Chen, P. (Peilin); Muiños-López, E. (Emma); Davachi, S.M. (Seyed Mohammad); Dilley, R. (Rodney); Harrington, E. (Emma)Biopolymers play a critical role as scaffolds used in tendon and ligament (TL) regeneration. Although advanced biopolymer materials have been proposed with optimised mechanical properties, biocompatibility, degradation, and processability, it is still challenging to find the right balance between these properties. Here, we aim to develop novel hybrid biocomposites based on poly(p-dioxanone) (PDO), poly(lactide-co-caprolactone) (LCL) and silk to produce high-performance grafts suitable for TL tissue repair. Biocomposites containing 1-15% of silk were studied through a range of characterisation techniques. We then explored biocompatibility through in vitro and in vivo studies using a mouse model. We found that adding up to 5% silk increases the tensile properties, degradation rate and miscibility between PDO and LCL phases without agglomeration of silk inside the com-posites. Furthermore, addition of silk increases surface roughness and hydrophilicity. In vitro experiments show that the silk improved attachment of tendon-derived stem cells and proliferation over 72 h, while in vivo studies indicate that the silk can reduce the expression of pro-inflammatory cytokines after six weeks of implantation. Finally, we selected a promising biocomposite and created a prototype TL graft based on extruded fibres. We found that the tensile properties of both individual fibres and braided grafts could be suitable for anterior cruciate ligament (ACL) repair applications.
- An engineered periosteum for efficient delivery of rhBMP-2 and mesenchymal progenitor cells during bone regeneration(2023) Granero-Moltó, F. (Froilán); López-Martínez, T. (Tania); Riera-Alvarez, L. (Luis); Rodriguez-Florez, N. (Naiara); Elizalde, R. (Reyes); Ripalda-Cemboráin, P. (Purificación); Ruiz-de-Galarreta-Moriones, S.(Sergio); Juan-Pardo, E.M. (Elena M.) de; Childs, P. (Peter); Echanove-González De Anleo, M. (Miguel); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Valdés-Fernández, J. (José); Salmeron-Sanchez, M. (Manuel); Muiños-López, E. (Emma); Romero-Torrecilla, J.A. (Juan Antonio); Prosper-Cardoso, F. (Felipe); López-Barberena, A. (Asier); Abizanda-Sarasa, G. (Gloria); Jayawarna, V. (Vineetha)During bone regeneration, the periosteum acts as a carrier for key regenerative cues, delivering osteochondroprogenitor cells and crucial growth factors to the injured bone. We developed a biocompatible, 3D polycaprolactone (PCL) melt electro-written membrane to act as a mimetic periosteum. Poly (ethyl acrylate) coating of the PCL membrane allowed functionalization, mediated by fibronectin and low dose recombinant human BMP-2 (rhBMP-2) (10-25 mu g/ml), resulting in efficient, sustained osteoinduction in vitro. In vivo, rhBMP-2 functionalized mimetic periosteum demonstrated regenerative potential in the treatment of rat critical-size femoral defects with highly efficient healing and functional recovery (80%-93%). Mimetic periosteum has also proven to be efficient for cell delivery, as observed through the migration of transplanted periosteum-derived mesenchymal cells to the bone defect and their survival. Ultimately, mimetic periosteum demonstrated its ability to deliver key stem cells and morphogens to an injured site, exposing a therapeutic and translational potential in vivo when combined with unprecedentedly low rhBMP-2 doses.
- Anisotropic cryostructured collagen scaffolds for efficient delivery of RhBMP–2 and enhanced bone regeneration(MDPI AG, 2019) Ewald, A. (Andrea); Andreu-Arzuaga, I. (Ion); Granero-Moltó, F. (Froilán); Groll, J. (Jürgen); Flandes-Iparraguirre, M. (María); Elizalde, R. (Reyes); Ripalda-Cemboráin, P. (Purificación); Stuckensen, K. (Kai); Lopez, T. (Tania); Pons-de-Villanueva, J. (Juan); Muiños-López, E. (Emma); Nickel, J. (Joachim); Iglesias, E. (Elena); Prosper-Cardoso, F. (Felipe); Lamo-Espinosa, J.M. (J. M.); Abizanda-Sarasa, G. (Gloria); Gbureck, U. (Uwe)In the treatment of bone non-unions, an alternative to bone autografts is the use of bone morphogenetic proteins (BMPs), e.g., BMP–2, BMP–7, with powerful osteoinductive and osteogenic properties. In clinical settings, these osteogenic factors are applied using absorbable collagen sponges for local controlled delivery. Major side effects of this strategy are derived from the supraphysiological doses of BMPs needed, which may induce ectopic bone formation, chronic inflammation, and excessive bone resorption. In order to increase the efficiency of the delivered BMPs, we designed cryostructured collagen scaffolds functionalized with hydroxyapatite, mimicking the structure of cortical bone (aligned porosity, anisotropic) or trabecular bone (random distributed porosity, isotropic). We hypothesize that an anisotropic structure would enhance the osteoconductive properties of the scaffolds by increasing the regenerative performance of the provided rhBMP–2. In vitro, both scaffolds presented similar mechanical properties, rhBMP–2 retention and delivery capacity, as well as scaffold degradation time. In vivo, anisotropic scaffolds demonstrated better bone regeneration capabilities in a rat femoral critical-size defect model by increasing the defect bridging. In conclusion, anisotropic cryostructured collagen scaffolds improve bone regeneration by increasing the efficiency of rhBMP–2 mediated bone healing.
- Silane-modified hydroxyapatite nanoparticles incorporated into polydioxanone/poly(lactide-co-caprolactone) creates a novel toughened nanocomposite with improved material properties and in vivo inflammatory responses(2023) Doyle, B. (Barry); Granero-Moltó, F. (Froilán); Heidari, B.S. (Behzad Shiroud); Zheng, M. (Minghao); Juan-Pardo, E.M. (Elena M.) de; Ruan, R. (Rui); Chen, P. (Peilin); Muiños-López, E. (Emma); Vahabli, E. (Ebrahim); Davachi, S.M. (Seyed Mohammad)The interface tissue between bone and soft tissues, such as tendon and ligament (TL), is highly prone to injury. Although different biomaterials have been developed for TL regeneration, few address the challenges of the TL bone interface. Here, we aim to develop novel hybrid nanocomposites based on poly(p-dioxanone) (PDO), poly (lactide-co-caprolactone) (LCL), and hydroxyapatite (HA) nanoparticles suitable for TL-bone interface repair. Nanocomposites, containing 3-10% of both unmodified and chemically modified hydroxyapatite (mHA) with a silane coupling agent. We then explored biocompatibility through in vitro and in vivo studies using a subcutaneous mouse model. Through different characterisation tests, we found that mHA increases tensile properties, creates rougher surfaces, and reduces crystallinity and hydrophilicity. Morphological observations indicate that mHA nanoparticles are attracted by PDO rather than LCL phase, resulting in a higher degradation rate for mHA group. We found that adding the 5% of nanoparticles gives a balance between the properties. In vitro experiments show that osteoblasts' activities are more affected by increasing the nanoparticle content compared with fibroblasts. Animal studies indicate that both HA and mHA nanoparticles (10%) can reduce the expression of pro inflammatory cytokines after six weeks of implantation. In summary, this work highlights the potential of PDO/ LCL/HA nanocomposites as an excellent biomaterial for TL-bone interface tissue engineering applications.