Smurf1 Knocked-Down, Mesenchymal Stem Cells and BMP-2 in an Electrospun System for Bone Regeneration

Rodríguez-Évora, María; García-Pizarro, Emiliano; Rosario, Carlos del; Pérez-López, Javier; Reyes, Ricardo; Delgado, Araceli; Rodríguez‐Rey, José C.; Évora, Carmen

doi:10.1021/bm401854d

Cited by 19 publications

(27 citation statements)

References 43 publications

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“…The thickness of the newly formed bone-like tissue with the highest repair rate (around 85%) was observed after 12 weeks of post-transplantation when rMSCs73 interacted with BMP-2, which is independent of cell density. [29] The BMP-2 of 0.625 μg showed significantly higher bone growth when PLGA combined with cyanoacrylate. Addition of acrylate showed elongated time of GF release.…”

Section: Growth-factor-encapsulated Microspherementioning

confidence: 93%

“…This sandwich system in presence of rMSCS73 (knock down of Smurf1 expression) showed better bone regeneration due to the suppression of the Smurf1, which is negative regulatory of bone formation compared with rat bone marrow mesenchymal stem cells (rMSCs). The thickness of the newly formed bone‐like tissue with the highest repair rate (around 85%) was observed after 12 weeks of post‐transplantation when rMSCs73 interacted with BMP‐2, which is independent of cell density . The BMP‐2 of 0.625 μg showed significantly higher bone growth when PLGA combined with cyanoacrylate.…”

Section: Growth‐factor‐encapsulated Microspherementioning

confidence: 99%

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Polymeric microspheres: a delivery system for osteogenic differentiation

Patel

Kwak

et al. 2017

Polymers for Advanced Techs

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Advanced drug delivery systems employing controlled release technology are being developed to address many of the difficulties associated with traditional methods of drug administration. Controlled release technology involves the use of devices such as polymer‐based disks, rods, pellets, or microspheres (MSs) that encapsulate drugs, genes, cytokines, and growth factors and release them in specific location within the body in a controlled fashion, for relatively long periods of time. Among these, microencapsulation is one of the core technologies used in polymer‐based drug delivery systems. In this regard, MS serves as microcarriers for sustain drug release facilitating their use for invasive or minimally invasive treatment. MS has significant potential for the application in bone repair, intra‐articular treatment of osteoarthritis, and biological bone growth. The present review compiles the recent advances in polymeric MS for application in bone and cartilage regeneration. Copyright © 2017 John Wiley & Sons, Ltd.

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Section: Growth-factor-encapsulated Microspherementioning

confidence: 93%

Section: Growth‐factor‐encapsulated Microspherementioning

confidence: 99%

Polymeric microspheres: a delivery system for osteogenic differentiation

Patel

Kwak

et al. 2017

Polymers for Advanced Techs

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“…Sandwich‐like scaffolds (membrane‐microspheres‐membrane), denoted S(50:50) and S(75:25), were assembled in situ and consisted of two PLGA electrospun sheets of 1 cm 2 with 25 mg of microspheres (prepared with the same PLGA) in between them. Electrospun membranes of PLGA 50:50 and PLGA 75:25 were prepared as previously described . Briefly, 700 µL of a 16% (w/v) hexafluoroisopropanol (HFIP, Fluka, Switzerland) polymer solution was loaded into a syringe and pumped at 1 mL/h.…”

Section: Methodsmentioning

confidence: 99%

“…Membranes were characterized in terms of membrane quality and fiber diameter by SEM. Membrane thickness were measured by stereo microscopy (Leica M205 C, Leica LAS, v3 software) and porosity was calculated by gravimetric method as described previously …”

Section: Methodsmentioning

confidence: 99%

“…In the first group the samples were wrapped in gauze previously soaked in PBS and frozen at −20 °C until testing, as described by . At each time point, the three samples in the second group were fixed in 10% formalin solution (pH 7.4) and decalcified in Histofix® Decalcifier 3D (Panreac, Spain) for histological analysis as previously described . In addition, the in vivo BMP‐2 release assays were carried out in 5 rats per scaffold type.…”

Section: Methodsmentioning

confidence: 99%

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Evaluation of nanostructure and microstructure of bone regenerated by BMP‐2‐porous scaffolds

Rosario

Rodríguez-Évora

Reyes

et al. 2015

J Biomedical Materials Res

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In this study, three systems containing BMP-2 were fabricated, including two electrospun sandwich-like-systems of PLGA 75:25 and PLGA 50:50 and a microsphere system of PLGA 50:50 to be implanted in a critical size defect in rat calvaria. The in vivo BMP-2 release profiles of the three systems were similar. The total dose was released during the first two weeks. To evaluate the nano and microstructure of the regenerated bone a multi-technique analysis was used, including stereo microscope, X-Ray; AFM, micro-CT, and histological analyses. The progression of bone regeneration was followed at 4, 8, and 12 weeks after the microsphere system implantation whereas the two electrospun systems were evaluated at fixed 12 weeks. All the techniques applied showed high bone regeneration. The average values of bone volume density, bone mineral density, Young's modulus, and the percent of bone repair were ∼70% of the values of the native bone. Besides, SEM-EDX analysis indicated that the main chemical elements in the new bone were oxygen, calcium, and phosphorus in a ratio similar to that of native bone. In comparison, the micro-CT may provide an alternative to histology for the evaluation of bone formation at the defect size.

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Smurf1 Silencing Using a LNA-ASOs/Lipid Nanoparticle System to Promote Bone Regeneration

García-García

Ruiz

Reyes

et al. 2019

Stem Cells Translational Medicine

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Despite the great advance of bone tissue engineering in the last few years, repair of bone defects remains a major problem. Low cell engraftment and dose-dependent side effects linked to the concomitant administration of bone morphogenetic proteins (BMPs) are the main problems currently hindering the clinical use of mesenchymal stem cell (MSC)-based therapies in this field. We have managed to bypass these drawbacks by combining the silencing the Smurf1 ubiquitin ligase in MSCs with the use of a scaffold that sustainably releases low doses of BMP-2. In this system, Smurf1 silencing is achieved by using GapmeRs, a clinically safe method that avoids the use of viral vectors, facilitating its translation to the clinic. Here, we show that a single transient transfection with a small quantity of a Smurf1-specific GapmeR is able to induce a significant level of silencing of the target gene, enough to prime MSCs for osteogenic differentiation. Smurf1 silencing highly increases MSCs responsiveness to BMP-2, allowing a dramatic reduction of the dose needed to achieve the desired therapeutic effect. The combination of these primed cells with alginate scaffolds designed to sustainably and locally release low doses of BMP-2 to the defect microenvironment is able to induce the formation of a mature bone matrix both in an osteoporotic rat calvaria system and in a mouse ectopic model. Importantly, this approach also enhances osteogenic differentiation in MSCs from osteoporotic patients, characterized by a reduced bone-forming potential, even at low BMP doses, underscoring the regenerative potential of this system. STEM CELLS The need to administrate high doses of bone morphogenetic proteins (BMPs) to promote osteogenesis in certain orthopedic applications, along with their associated detrimental effects, is hindering the clinical use of tissue engineering techniques in this particular field. Silencing of the Smurf1 gene in mesenchymal stem cells (MSCs) by in situ transfecting these cells with an antisense oligonucleotide, a clinically safe approach, significantly increases the susceptibility of MSCs to BMP-2. The use of MSCs expressing low levels of Smurf1, together with biocompatible scaffolds that sustainably release low doses of BMP in a controlled manner, might be able to promote bone formation, avoiding the harmful effects linked to the presence of high concentration of BMPs in circulating blood.

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Smurf1 Knocked-Down, Mesenchymal Stem Cells and BMP-2 in an Electrospun System for Bone Regeneration

Cited by 19 publications

References 43 publications

Polymeric microspheres: a delivery system for osteogenic differentiation

Polymeric microspheres: a delivery system for osteogenic differentiation

Evaluation of nanostructure and microstructure of bone regenerated by BMP‐2‐porous scaffolds

Smurf1 Silencing Using a LNA-ASOs/Lipid Nanoparticle System to Promote Bone Regeneration

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