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1.
J Cell Mol Med ; 28(17): e70040, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39219020

RESUMEN

Bone tissue engineering addresses the limitations of autologous resources and the risk of allograft disease transmission in bone diseases. In this regard, engineered three-dimensional (3D) models emerge as biomimetic alternatives to natural tissues, replicating intracellular communication. Moreover, the unique properties of super-paramagnetic iron oxide nanoparticles (SPIONs) were shown to promote bone regeneration via enhanced osteogenesis and angiogenesis in bone models. This study aimed to investigate the effects of SPION on both osteogenesis and angiogenesis and characterized a co-culture of Human umbilical vein endothelial cells (HUVEC) and MG-63 cells as a model of bone microtissue. HUVECs: MG-63s with a ratio of 4:1 demonstrated the best results among other cell ratios, and 50 µg/mL of SPION was the optimum concentration for maximum survival, cell migration and mineralization. In addition, the data from gene expression illustrated that the expression of osteogenesis-related genes, including osteopontin, osteocalcin, alkaline phosphatase, and collagen-I, as well as the expression of the angiogenesis-related marker, CD-31, and the tube formation, is significantly elevated when the 50 µg/mL concentration of SPION is applied to the microtissue samples. SPION application in a designed 3D bone microtissue model involving a co-culture of osteoblast and endothelial cells resulted in increased expression of specific markers related to angiogenesis and osteogenesis. This includes the design of a novel biomimetic model to boost blood compatibility and biocompatibility of primary materials while promoting osteogenic activity in microtissue bone models. Moreover, this can improve interaction with surrounding tissues and broaden the knowledge to promote superior-performance implants, preventing device failure.


Asunto(s)
Regeneración Ósea , Técnicas de Cocultivo , Células Endoteliales de la Vena Umbilical Humana , Osteogénesis , Ingeniería de Tejidos , Humanos , Regeneración Ósea/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Ingeniería de Tejidos/métodos , Nanopartículas de Magnetita/química , Neovascularización Fisiológica/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Nanopartículas Magnéticas de Óxido de Hierro/química , Supervivencia Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Osteoblastos/metabolismo , Osteoblastos/efectos de los fármacos , Osteoblastos/citología
2.
J Cell Mol Med ; 28(13): e18527, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38984969

RESUMEN

Infected bone defects (IBDs) are the common condition in the clinical practice of orthopaedics. Although surgery and anti-infective medicine are the firstly chosen treatments, in many cases, patients experience a prolonged bone union process after anti-infective treatment. Epimedium-Curculigo herb pair (ECP) has been proved to be effective for bone repair. However, the mechanisms of ECP in IBDs are insufficiency. In this study, Effect of ECP in IBDs was verified by micro-CT and histological examination. Qualitative and quantitative analysis of the main components in ECP containing medicated serum (ECP-CS) were performed. The network pharmacological approaches were then applied to predict potential pathways for ECP associated with bone repair. In addition, the mechanism of ECP regulating LncRNA MALAT1/miRNA-34a-5p/SMAD2 signalling axis was evaluated by molecular biology experiments. In vivo experiments indicated that ECP could significantly promote bone repair. The results of the chemical components analysis and the pathway identification revealed that TGF-ß signalling pathway was related to ECP. The results of in vitro experiments indicated that ECP-CS could reverse the damage caused by LPS through inhibiting the expressions of LncRNA MALAT1 and SMAD2, and improving the expressions of miR-34a-5p, ALP, RUNX2 and Collagen type І in osteoblasts significantly. This research showed that ECP could regulate the TGF-ß/SMADs signalling pathway to promote bone repair. Meanwhile, ECP could alleviate LPS-induced bone loss by modulating the signalling axis of LncRNA MALAT1/miRNA-34a-5p/ SMAD2 in IBDs.


Asunto(s)
Epimedium , MicroARNs , Osteoblastos , ARN Largo no Codificante , Transducción de Señal , Proteína Smad2 , MicroARNs/genética , MicroARNs/metabolismo , Osteoblastos/metabolismo , Osteoblastos/efectos de los fármacos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Animales , Proteína Smad2/metabolismo , Proteína Smad2/genética , Ratones , Epimedium/química , Transducción de Señal/efectos de los fármacos , Masculino , Regeneración Ósea/efectos de los fármacos , Humanos , Regulación de la Expresión Génica/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteogénesis/genética
3.
Biochem Biophys Res Commun ; 733: 150714, 2024 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-39326258

RESUMEN

Reconstruction of bone defects has long been a major clinical challenge. Limited by the various shortcomings of conventional treatment like autologous bone grafting and inorganic substitutes, the development of novel bone repairing strategies is on top priority. Injectable biomimetic hydrogels that deliver stem cells and growth factors in a minimally invasive manner can effectively promote bone regeneration and thus represent a promising alternative. Therefore, in this study, we designed and constructed an injectable nanocomposite hydrogel co-loaded with Laponite (Lap) and vascular endothelial growth factor (VEGF) through a simplified and convenient scheme of physical co-mixing (G@Lap/VEGF). The introduced Lap not only optimized the injectability of GelMA by the electrostatic force between the nanoparticles, but also significantly delayed the release of VEGF-A. In addition, Lap promoted high expression of osteogenic biomarkers in mesenchymal stem cells (MSCs) and enhanced the matrix mineralization. Besides, VEGF-A exerted chemotactic effects recruiting endothelial progenitor cells (EPCs) and inducing neovascularization. Histological and micro-CT results demonstrated that the critical-sized calvarial bone defect lesions in the SD rats after treated with G@Lap/VEGF exhibited significant in vivo bone repairing. In conclusion, the injectable G@Lap/VEGF nanocomposite hydrogel constructed in our study is highly promising for clinical transformation and applications, providing a convenient and simplified scheme for clinical bone repairing, and contributing to the further development of the injectable biomimetic hydrogels.


Asunto(s)
Regeneración Ósea , Preparaciones de Acción Retardada , Gelatina , Hidrogeles , Células Madre Mesenquimatosas , Ratas Sprague-Dawley , Silicatos , Factor A de Crecimiento Endotelial Vascular , Animales , Regeneración Ósea/efectos de los fármacos , Hidrogeles/química , Factor A de Crecimiento Endotelial Vascular/metabolismo , Gelatina/química , Silicatos/química , Silicatos/farmacología , Preparaciones de Acción Retardada/química , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Ratas , Osteogénesis/efectos de los fármacos , Metacrilatos/química , Masculino
4.
Small ; 20(40): e2401989, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38855993

RESUMEN

The minimally invasive deployment of scaffolds is a key safety factor for the regeneration of cartilage and bone defects. Osteogenesis relies primarily on cell-matrix interactions, whereas chondrogenesis relies on cell-cell aggregation. Bone matrix expansion requires osteoconductive scaffold degradation. However, chondrogenic cell aggregation is promoted on the repellent scaffold surface, and minimal scaffold degradation supports the avascular nature of cartilage regeneration. Here, a material satisfying these requirements for osteochondral regeneration is developed by integrating osteoconductive hydroxyapatite (HAp) with a chondroconductive shape memory polymer (SMP). The shape memory function-derived fixity and recovery of the scaffold enabled minimally invasive deployment and expansion to fill irregular defects. The crystalline phases on the SMP surface inhibited cell aggregation by suppressing water penetration and subsequent protein adsorption. However, HAp conjugation SMP (H-SMP) enhanced surface roughness and consequent cell-matrix interactions by limiting cell aggregation using crystal peaks. After mouse subcutaneous implantation, hydrolytic H-SMP accelerated scaffold degradation compared to that by the minimal degradation observed for SMP alone for two months. H-SMP and SMP are found to promote osteogenesis and chondrogenesis, respectively, in vitro and in vivo, including the regeneration of rat osteochondral defects using the binary scaffold form, suggesting that this material is promising for osteochondral regeneration.


Asunto(s)
Condrogénesis , Osteogénesis , Andamios del Tejido , Andamios del Tejido/química , Animales , Osteogénesis/efectos de los fármacos , Durapatita/química , Ratones , Regeneración , Regeneración Ósea/efectos de los fármacos , Propiedades de Superficie , Polímeros/química , Cartílago/fisiología , Ingeniería de Tejidos/métodos
5.
Small ; 20(23): e2310734, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38143290

RESUMEN

Achieving satisfactory bone tissue regeneration in osteoporotic patients with ordinary biomaterials is challenging because of the decreased bone mineral density and aberrant bone microenvironment. In addressing this issue, a biomimetic scaffold (PMEH/SP), incorporating 4-hexylresorcinol (4HR), and substance P (SP) into the poly(lactic-go-glycolic acid) (PLGA) scaffold with magnesium hydroxide (M) and extracellular matrix (E) is introduced, enabling the consecutive release of bioactive agents. 4HR and SP induced the phosphorylation of p38 MAPK and ERK in human umbilical vein endothelial cells (HUVECs), thereby upregulating VEGF expression level. The migration and tube-forming ability of endothelial cells can be promoted by the scaffold, which accelerates the formation and maturation of the bone. Moreover, 4HR played a crucial role in the inhibition of osteoclastogenesis by interrupting the IκB/NF-κB signaling pathway and exhibiting SP, thereby enhancing the migration and angiogenesis of HUVECs. Based on such a synergistic effect, osteoporosis can be suppressed, and bone regeneration can be achieved by inhibiting the RANKL pathway in vitro and in vivo, which is a commonly known mechanism of bone physiology. Therefore, the study presents a promising approach for developing a multifunctional regenerative material for sophisticated osteoporotic bone regeneration.


Asunto(s)
Regeneración Ósea , Células Endoteliales de la Vena Umbilical Humana , Osteoporosis , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Andamios del Tejido , Regeneración Ósea/efectos de los fármacos , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Andamios del Tejido/química , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Animales , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Osteogénesis/efectos de los fármacos
6.
Small ; 20(40): e2403681, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38804867

RESUMEN

Infected bone defects are one of the most challenging problems in the treatment of bone defects due to the high antibiotic failure rate and the lack of ideal bone grafts. In this paper, inspired by clinical bone cement filling treatment, α-c phosphate (α-TCP) with self-curing properties is composited with ß-tricalcium phosphate (ß-TCP) and constructed a bionic cancellous bone scaffolding system α/ß-tricalcium phosphate (α/ß-TCP) by low-temperature 3D printing, and gelatin is preserved inside the scaffolds as an organic phase, and later loaded with a metal-polyphenol network structure of tea polyphenol-magnesium (TP-Mg) nanoparticles. The scaffolds mimic the structure and components of cancellous bone with high mechanical strength (>100 MPa) based on α-TCP self-curing properties through low-temperature 3D printing. Meanwhile, the scaffolds loaded with TP-Mg exhibit significant inhibition of Staphylococcus aureus (S.aureus) and promote the transition of macrophages from M1 pro-inflammatory to M2 anti-inflammatory phenotype. In addition, the composite scaffold also exhibits excellent bone-enhancing effects based on the synergistic effect of Mg2+ and Ca2+. In this study, a multifunctional ceramic scaffold (α/ß-TCP@TP-Mg) that integrates anti-inflammatory, antibacterial, and osteoinduction is constructed, which promotes late bone regenerative healing while modulating the early microenvironment of infected bone defects, has a promising application in the treatment of infected bone defects.


Asunto(s)
Magnesio , Nanopartículas , Impresión Tridimensional , Staphylococcus aureus , Andamios del Tejido , Andamios del Tejido/química , Staphylococcus aureus/efectos de los fármacos , Magnesio/química , Magnesio/farmacología , Animales , Nanopartículas/química , Huesos/efectos de los fármacos , Polifenoles/química , Polifenoles/farmacología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacología , Ratones , Biomimética/métodos , Regeneración Ósea/efectos de los fármacos
7.
Small ; 20(19): e2309230, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38112271

RESUMEN

Bone infection poses a major clinical challenge that can hinder patient recovery and exacerbate postoperative complications. This study has developed a bioactive composite scaffold through the co-assembly and intrafibrillar mineralization of collagen fibrils and zinc oxide (ZnO) nanowires (IMC/ZnO). The IMC/ZnO exhibits bone-like hierarchical structures and enhances capabilities for osteogenesis, antibacterial activity, and bacteria-infected bone healing. During co-cultivation with human bone marrow mesenchymal stem cells (BMMSCs), the IMC/ZnO improves BMMSC adhesion, proliferation, and osteogenic differentiation even under inflammatory conditions. Moreover, it suppresses the activity of Gram-negative Porphyromonas gingivalis and Gram-positive Streptococcus mutans by releasing zinc ions within the acidic infectious microenvironment. In vivo, the IMC/ZnO enables near-complete healing of infected bone defects within the intricate oral bacterial milieu, which is attributed to IMC/ZnO orchestrating M2 macrophage polarization, and fostering an osteogenic and anti-inflammatory microenvironment. Overall, these findings demonstrate the promise of the bioactive scaffold IMC/ZnO for treating bacteria-infected bone defects.


Asunto(s)
Regeneración Ósea , Colágeno , Células Madre Mesenquimatosas , Nanocables , Osteogénesis , Andamios del Tejido , Óxido de Zinc , Óxido de Zinc/química , Óxido de Zinc/farmacología , Nanocables/química , Regeneración Ósea/efectos de los fármacos , Andamios del Tejido/química , Humanos , Colágeno/química , Células Madre Mesenquimatosas/citología , Osteogénesis/efectos de los fármacos , Animales , Porphyromonas gingivalis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Streptococcus mutans/fisiología , Streptococcus mutans/efectos de los fármacos , Proliferación Celular/efectos de los fármacos
8.
Small ; 20(33): e2311344, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38661278

RESUMEN

The effect of immunoinflammation on bone repair during the recovery process of bone defects needs to be further explored. It is reported that Mg2+ can promote bone repair with immunoregulatory effect, but the underlying mechanism on adaptive immunity is still unclear. Here, by using chitosan and hyaluronic acid-coated Mg2+ (CSHA-Mg) in bone-deficient mice, it is shown that Mg2+ can inhibit the activation of CD4+ T cells and increase regulatory T cell formation by inducing immunosuppressive dendritic cells (imDCs). Mechanistically, Mg2+ initiates the activation of the MAPK signaling pathway through TRPM7 channels on DCs. This process subsequently induces the downstream HIF-1α expression, a transcription factor that amplifies TGF-ß production and inhibits the effective T cell function. In vivo, knock-out of HIF-1α in DCs or using a HIF-1α inhibitor PX-478 reverses inhibition of bone inflammation and repair promotion upon Mg2+-treatment. Moreover, roxadustat, which stabilizes HIF-1α protein expression, can significantly promote immunosuppression and bone repair in synergism with CSHA-Mg. Thus, the findings identify a key mechanism for DCs and its HIF-1α-TGF-ß axis in the induction of immunosuppressive bone microenvironment, providing potential targets for bone regeneration.


Asunto(s)
Células Dendríticas , Subunidad alfa del Factor 1 Inducible por Hipoxia , Magnesio , Factor de Crecimiento Transformador beta , Animales , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Magnesio/farmacología , Ratones , Ratones Endogámicos C57BL , Microambiente Celular/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/metabolismo , Regeneración Ósea/efectos de los fármacos , Isoquinolinas/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Canales Catiónicos TRPM/metabolismo , Transducción de Señal/efectos de los fármacos , Quitosano/farmacología , Quitosano/química , Compuestos de Mostaza , Fenilpropionatos
9.
Biotechnol Bioeng ; 121(9): 2767-2779, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38837342

RESUMEN

Injectable, tissue mimetic, bioactive, and biodegradable hydrogels offer less invasive regeneration and repair of tissues. The monitoring swelling and in vitro degradation capacities of hydrogels are highly important for drug delivery and tissue regeneration processes. Bioactivity of bone tissue engineered constructs in terms of mineralized apatite formation capacity is also pivotal. We have previously reported in situ forming chitosan-based injectable hydrogels integrated with hydroxyapatite and heparin for bone regeneration, promoting angiogenesis. These hydrogels were functionalized by glycerol and pH to improve their mechano-structural properties. In the present study, functionalized hybrid hydrogels were investigated for their swelling, in vitro degradation, and bioactivity performances. Hydrogels have degraded gradually in phosphate-buffered saline (PBS) with and without lysozyme enzyme. The percentage weight loss of hydrogels and their morphological and chemical properties, and pH of media were analyzed. The swelling ratio of hydrogels (55%-68%(wt), 6 h of equilibrium) indicated a high degree of cross-linking, can be suitable for controlled drug release. Hydrogels have gradually degraded reaching to 60%-70% (wt%) in 42 days in the presence and absence of lysozyme, respectively. Simulated body fluid (SBF)-treated hydrogels containing hydroxyapatite-induced needle-like carbonated-apatite mineralization was further enhanced by heparin content significantly.


Asunto(s)
Regeneración Ósea , Quitosano , Hidrogeles , Quitosano/química , Hidrogeles/química , Hidrogeles/farmacología , Regeneración Ósea/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Durapatita/química , Durapatita/farmacología , Muramidasa/química , Muramidasa/farmacología , Concentración de Iones de Hidrógeno , Materiales Biocompatibles/química , Heparina/química , Heparina/farmacología
10.
Mol Pharm ; 21(10): 4827-4848, 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39290162

RESUMEN

Hydrogels, composed of hydrophilic polymer networks, have emerged as versatile materials in biomedical applications due to their high water content, biocompatibility, and tunable properties. They mimic natural tissue environments, enhancing cell viability and function. Hydrogels' tunable physical properties allow for tailored antibacterial biomaterial, wound dressings, cancer treatment, and tissue engineering scaffolds. Their ability to respond to physiological stimuli enables the controlled release of therapeutics, while their porous structure supports nutrient diffusion and waste removal, fostering tissue regeneration and repair. In wound healing, hydrogels provide a moist environment, promote cell migration, and deliver bioactive agents and antibiotics, enhancing the healing process. For cancer therapy, they offer localized drug delivery systems that target tumors, minimizing systemic toxicity and improving therapeutic efficacy. Ocular therapy benefits from hydrogels' capacity to form contact lenses and drug delivery systems that maintain prolonged contact with the eye surface, improving treatment outcomes for various eye diseases. In mucosal delivery, hydrogels facilitate the administration of therapeutics across mucosal barriers, ensuring sustained release and the improved bioavailability of drugs. Tissue regeneration sees hydrogels as scaffolds that mimic the extracellular matrix, supporting cell growth and differentiation for repairing damaged tissues. Similarly, in bone regeneration, hydrogels loaded with growth factors and stem cells promote osteogenesis and accelerate bone healing. This article highlights some of the recent advances in the use of hydrogels for various biomedical applications, driven by their ability to be engineered for specific therapeutic needs and their interactive properties with biological tissues.


Asunto(s)
Materiales Biocompatibles , Sistemas de Liberación de Medicamentos , Hidrogeles , Ingeniería de Tejidos , Cicatrización de Heridas , Hidrogeles/química , Humanos , Materiales Biocompatibles/química , Sistemas de Liberación de Medicamentos/métodos , Animales , Ingeniería de Tejidos/métodos , Cicatrización de Heridas/efectos de los fármacos , Andamios del Tejido/química , Regeneración Ósea/efectos de los fármacos , Neoplasias/terapia , Neoplasias/tratamiento farmacológico
11.
Biomacromolecules ; 25(6): 3475-3485, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38741285

RESUMEN

Material reinforcement commonly exists in a contradiction between strength and toughness enhancement. Herein, a reinforced strategy through self-assembly is proposed for alginate fibers. Sodium alginate (SA) microstructures with regulated secondary structures are assembled in acidic and ethanol as reinforcing units for alginate fibers. Acidity increases the flexibility of the helix and contributes to enhanced extendibility. Ethanol is responsible for formation of a stiff ß-sheet, which enhances the modulus and strength. The structurally engineered SA assembly exhibits robust mechanical compatibility, and thus reinforced alginate fibers possess an improved tensile strength of 2.1 times, a prolonged elongation of 1.5 times, and an enhanced toughness of 3.0 times compared with SA fibers without reinforcement. The reinforcement through self-assembly provides an understanding of strengthening and toughening mechanism based on secondary structures. Due to a similar modulus with bones, reinforced alginate fibers exhibit good efficacy in accelerating bone regeneration in vivo.


Asunto(s)
Alginatos , Regeneración Ósea , Resistencia a la Tracción , Alginatos/química , Regeneración Ósea/efectos de los fármacos , Animales , Materiales Biocompatibles/química , Ácido Glucurónico/química , Ensayo de Materiales , Ácidos Hexurónicos/química , Andamios del Tejido/química
12.
Biomacromolecules ; 25(9): 5512-5540, 2024 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-39133748

RESUMEN

Current bone repair methods have limitations, prompting the exploration of innovative approaches. Tissue engineering emerges as a promising solution, leveraging biomaterials to craft scaffolds replicating the natural bone environment, facilitating cell growth and differentiation. Among fabrication techniques, three-dimensional (3D) printing stands out for its ability to tailor intricate scaffolds. Silk proteins (SPs), known for their mechanical strength and biocompatibility, are an excellent choice for engineering 3D-printed bone tissue engineering (BTE) scaffolds. This article comprehensively reviews bone biology, 3D printing, and the unique attributes of SPs, specifically detailing criteria for scaffold fabrication such as composition, structure, mechanics, and cellular responses. It examines the structural, mechanical, and biological attributes of SPs, emphasizing their suitability for BTE. Recent studies on diverse 3D printing approaches using SPs-based for BTE are highlighted, alongside advancements in their 3D and four-dimensional (4D) printing and their role in osteo-immunomodulation. Future directions in the use of SPs for 3D printing in BTE are outlined.


Asunto(s)
Regeneración Ósea , Inmunomodulación , Impresión Tridimensional , Seda , Ingeniería de Tejidos , Andamios del Tejido , Regeneración Ósea/efectos de los fármacos , Humanos , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Seda/química , Animales , Inmunomodulación/efectos de los fármacos , Materiales Biocompatibles/química , Huesos/metabolismo
13.
Biomacromolecules ; 25(7): 4139-4155, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38924768

RESUMEN

Extracellular vesicles (EVs) derived from bone progenitor cells are advantageous as cell-free and non-immunogenic cargo delivery vehicles. In this study, EVs are isolated from MC3T3-E1 cells before (GM-EVs) and after mineralization for 7 and 14 days (DM-EVs). It was observed that DM-EVs accelerate the process of differentiation in recipient cells more prominently. The small RNA sequencing of EVs revealed that miR-204-5p, miR-221-3p, and miR-148a-3p are among the highly upregulated miRNAs that have an inhibitory effect on the function of mRNAs, Sox11, Timp3, and Ccna2 in host cells, which is probably responsible for enhancing the activity of osteoblastic genes. To enhance the bioavailability of EVs, they are encapsulated in a chitosan-collagen composite hydrogel that serves as a bioresorbable extracellular matrix (ECM). The EVs-integrated scaffold (DM-EVs + Scaffold) enhances bone regeneration in critical-sized calvarial bone defects in rats within 8 weeks of implantation by providing the ECM cues. The shelf life of DM-EVs + Scaffold indicates that the bioactivity of EVs and their cargo in the polymer matrix remains intact for up to 30 days. Integrating mineralized cell-derived EVs into an ECM represents a bioresorbable matrix with a cell-free method for promoting new bone formation through the miRNA-mRNA regulatory axis.


Asunto(s)
Regeneración Ósea , Matriz Extracelular , Vesículas Extracelulares , MicroARNs , Osteoblastos , ARN Mensajero , Regeneración Ósea/efectos de los fármacos , Animales , MicroARNs/genética , Osteoblastos/metabolismo , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Ratas , Ratones , Matriz Extracelular/metabolismo , ARN Mensajero/genética , Diferenciación Celular , Andamios del Tejido/química , Osteogénesis/efectos de los fármacos , Polisacáridos/química , Ratas Sprague-Dawley , Masculino
14.
Biomacromolecules ; 25(6): 3784-3794, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38743836

RESUMEN

The effective regeneration of large bone defects via bone tissue engineering is challenging due to the difficulty in creating an osteogenic microenvironment. Inspired by the fibrillar architecture of the natural extracellular matrix, we developed a nanoscale bioengineering strategy to produce bone fibril-like composite scaffolds with enhanced osteogenic capability. To activate the surface for biofunctionalization, self-adaptive ridge-like nanolamellae were constructed on poly(ε-caprolactone) (PCL) electrospinning scaffolds via surface-directed epitaxial crystallization. This unique nanotopography with a markedly increased specific surface area offered abundant nucleation sites for Ca2+ recruitment, leading to a 5-fold greater deposition weight of hydroxyapatite than that of the pristine PCL scaffold under stimulated physiological conditions. Bone marrow mesenchymal stem cells (BMSCs) cultured on bone fibril-like scaffolds exhibited enhanced adhesion, proliferation, and osteogenic differentiation in vitro. In a rat calvarial defect model, the bone fibril-like scaffold significantly accelerated bone regeneration, as evidenced by micro-CT, histological histological and immunofluorescence staining. This work provides the way for recapitulating the osteogenic microenvironment in tissue-engineered scaffolds for bone repair.


Asunto(s)
Regeneración Ósea , Células Madre Mesenquimatosas , Osteogénesis , Poliésteres , Ingeniería de Tejidos , Andamios del Tejido , Animales , Andamios del Tejido/química , Ratas , Regeneración Ósea/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Osteogénesis/efectos de los fármacos , Osteogénesis/fisiología , Ingeniería de Tejidos/métodos , Poliésteres/química , Diferenciación Celular , Ratas Sprague-Dawley , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Células Cultivadas , Proliferación Celular , Cráneo/lesiones , Cráneo/patología , Durapatita/química , Durapatita/farmacología
15.
Biomacromolecules ; 25(7): 4074-4086, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38838242

RESUMEN

The presence of oxidative stress in bone defects leads to delayed regeneration, especially in the aged population and patients receiving cancer treatment. This delay is attributed to the increased levels of reactive oxygen species (ROS) in these populations due to the accumulation of senescent cells. Tissue-engineered scaffolds are emerging as an alternative method to treat bone defects. In this study, we engineered tissue scaffolds tailored to modulate the adverse effects of oxidative stress and promote bone regeneration. We used polycaprolactone to fabricate nanofibrous mats by using electrospinning. We exploited the ROS-scavenging properties of cerium oxide nanoparticles to alleviate the high oxidative stress microenvironment caused by the presence of senescent cells. We characterized the nanofibers for their physical and mechanical properties and utilized an ionization-radiation-based model to induce senescence in bone cells. We demonstrate that the presence of ceria can modulate ROS levels, thereby reducing the level of senescence and promoting osteogenesis. Overall, this study demonstrates that ceria-infused nanofibrous scaffolds can be used for augmenting the osteogenic activity of senescent progenitor cells, which has important implications for engineering bone tissue scaffolds for patients with low regeneration capabilities.


Asunto(s)
Regeneración Ósea , Senescencia Celular , Cerio , Nanofibras , Osteogénesis , Especies Reactivas de Oxígeno , Ingeniería de Tejidos , Andamios del Tejido , Cerio/química , Cerio/farmacología , Regeneración Ósea/efectos de los fármacos , Andamios del Tejido/química , Senescencia Celular/efectos de los fármacos , Nanofibras/química , Osteogénesis/efectos de los fármacos , Humanos , Ingeniería de Tejidos/métodos , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Poliésteres/química , Animales , Huesos/efectos de los fármacos
16.
Soft Matter ; 20(33): 6655-6667, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39109674

RESUMEN

In this study, porous networks were efficiently prepared by crosslinking hydrophilic poly(2-isopropenyl-2-oxazoline) (PiPOx) with dicarboxylic polyesters (HOOC-PLA-COOH or HOOC-PCL-COOH) in the presence of sodium chloride as a water-soluble porogen. Importantly, by using a relatively simple synthetic protocol, the resulting spongy materials were freely formed to the desired size and shape while maintaining stable dimensions. According to the SEM data, the porous 3D structure can be altered by the pore dimensions, which are dependent on the porogen crystal size. After porosity characterization, the mechanical properties were also evaluated via uniaxial compression and tensile tests. The porous networks formed hydrogels with a high water absorption capacity. Finally, after showing cytocompatibility by the MTT assay, we also demonstrated the applicability of the porous hydrogels as scaffolds for cell cultivation. The presented results suggest that this type of hydrogels is a promising material for tissue engineering.


Asunto(s)
Materiales Biocompatibles , Hidrogeles , Poliésteres , Andamios del Tejido , Hidrogeles/química , Hidrogeles/farmacología , Porosidad , Andamios del Tejido/química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Poliésteres/química , Regeneración Ósea/efectos de los fármacos , Ingeniería de Tejidos , Oxazoles/química , Oxazoles/farmacología , Humanos , Ensayo de Materiales , Animales
17.
Cell Biol Int ; 48(6): 808-820, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38433534

RESUMEN

Bone defects are characterized by a hypoxic environment, which affects bone tissue repair. However, the role of hypoxia in the repair of alveolar bone defects remains unclear. Human periodontal ligament stem cells (hPDLSCs) are high-quality seed cells for repairing alveolar bone defects, whose behavior changes under hypoxia. However, their mechanism of action is not known and needs to be elucidated. We hypothesized that hypoxia might be beneficial to alveolar bone defect repair and the osteogenic differentiation of hPDLSCs. To test this hypothesis, cobalt chloride (CoCl2) was used to create a hypoxic environment, both in vitro and in vivo. In vitro study, the best osteogenic effect was observed after 48 h of hypoxia in hPDLSCs, and the AKT/mammalian target of rapamycin/eukaryotic translation initiation factor 4e-binding protein 1 (AKT/mTOR/4EBP-1) signaling pathway was significantly upregulated. Inhibition of the AKT/mTOR/4EBP-1 signaling pathway decreased the osteogenic ability of hPDLSCs under hypoxia and hypoxia-inducible factor 1 alpha (HIF-1α) expression. The inhibition of HIF-1α also decreased the osteogenic capacity of hPDLSCs under hypoxia without significantly affecting the level of phosphorylation of AKT/mTOR/4EBP-1. In vitro study, Micro-CT and tissue staining results show better bone regeneration in hypoxic group than control group. These results suggested that hypoxia promoted alveolar bone defect repair and osteogenic differentiation of hPDLSCs, probably through AKT/mTOR/4EBP-1/HIF-1α signaling. These findings provided important insights into the regulatory mechanism of hypoxia in hPDLSCs and elucidated the effect of hypoxia on the healing of alveolar bone defects. This study highlighted the importance of physiological oxygen conditions for tissue engineering.


Asunto(s)
Pérdida de Hueso Alveolar , Diferenciación Celular , Hipoxia de la Célula , Cobalto , Subunidad alfa del Factor 1 Inducible por Hipoxia , Osteogénesis , Ligamento Periodontal , Humanos , Proteínas Adaptadoras Transductoras de Señales/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Pérdida de Hueso Alveolar/metabolismo , Regeneración Ósea/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Cobalto/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Osteogénesis/efectos de los fármacos , Ligamento Periodontal/metabolismo , Ligamento Periodontal/citología , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/metabolismo , Serina-Treonina Quinasas TOR/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
18.
Nanotechnology ; 35(32)2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38688249

RESUMEN

Dealing with bone defects is a significant challenge to global health. Electrospinning in bone tissue engineering has emerged as a solution to this problem. In this study, we designed a PVDF-b-PTFE block copolymer by incorporating TFE, which induced a phase shift in PVDF fromαtoß, thereby enhancing the piezoelectric effect. Utilizing the electrospinning process, we not only converted the material into a film with a significant surface area and high porosity but also intensified the piezoelectric effect. Then we used polydopamine to immobilize BMP-2 onto PVDF-b-PTFE electrospun nanofibrous membranes, achieving a controlled release of BMP-2. The scaffold's characters were examined using SEM and XRD. To assess its osteogenic effectsin vitro, we monitored the proliferation of MC3T3-E1 cells on the fibers, conducted ARS staining, and measured the expression of osteogenic genes.In vivo, bone regeneration effects were analyzed through micro-CT scanning and HE staining. ELISA assays confirmed that the sustained release of BMP-2 can be maintained for at least 28 d. SEM images and CCK-8 results demonstrated enhanced cell viability and improved adhesion in the experimental group. Furthermore, the experimental group exhibited more calcium nodules and higher expression levels of osteogenic genes, including COL-I, OCN, and RUNX2. HE staining and micro-CT scans revealed enhanced bone tissue regeneration in the defective area of the PDB group. Through extensive experimentation, we evaluated the scaffold's effectiveness in augmenting osteoblast proliferation and differentiation. This study emphasized the potential of piezoelectric PVDF-b-PTFE nanofibrous membranes with controlled BMP-2 release as a promising approach for bone tissue engineering, providing a viable solution for addressing bone defects.


Asunto(s)
Proteína Morfogenética Ósea 2 , Regeneración Ósea , Indoles , Nanofibras , Osteogénesis , Polímeros , Ingeniería de Tejidos , Andamios del Tejido , Proteína Morfogenética Ósea 2/farmacología , Proteína Morfogenética Ósea 2/metabolismo , Nanofibras/química , Regeneración Ósea/efectos de los fármacos , Animales , Ratones , Indoles/química , Indoles/farmacología , Polímeros/química , Polímeros/farmacología , Ingeniería de Tejidos/métodos , Osteogénesis/efectos de los fármacos , Andamios del Tejido/química , Proliferación Celular/efectos de los fármacos , Línea Celular , Proteínas Inmovilizadas/farmacología , Proteínas Inmovilizadas/química , Supervivencia Celular/efectos de los fármacos
19.
J Periodontal Res ; 59(3): 521-529, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38356157

RESUMEN

OBJECTIVE: This study aimed to evaluate the regenerative capacities of octacalcium phosphate collagen composite (OCP/Col) in one-wall intrabony defects in dogs. The background data discuss the present state of the field: No study has assessed the efficacy of OCP/Col for periodontal regeneration therapy despite the fact that OCP/Col has proved to be efficient for bone regeneration. METHODS: In six beagle dogs, the mandibular left third premolars were extracted 12 weeks before the experimental surgery. Standardized bone defects (5 mm in height and 4 mm in width) were simulated on the distal surface of the second premolars and mesially on the fourth premolars. The defect was filled with either OCP/Col (experimental group) or left empty (control group). Histological and histomorphometric characteristics were compared 8 weeks after surgery. RESULTS: No infectious or ankylotic complications were detected at any of the tested sites. The experimental group exhibited a significantly greater volume, height, and area of newly formed bone than the control group. The former also showed a greater height of the newly formed cementum than the latter, although the results were not statistically significant. The newly formed periodontal ligaments were inserted into newly formed bone and cementum in the experimental group. CONCLUSION: OCP/Col demonstrated high efficacy for bone and periodontal tissue regeneration that can be successfully applied for one-wall intrabony defects.


Asunto(s)
Regeneración Ósea , Fosfatos de Calcio , Colágeno , Animales , Perros , Fosfatos de Calcio/uso terapéutico , Regeneración Ósea/efectos de los fármacos , Colágeno/uso terapéutico , Pérdida de Hueso Alveolar/cirugía , Ligamento Periodontal/patología , Sustitutos de Huesos/uso terapéutico , Regeneración Tisular Guiada Periodontal/métodos , Masculino , Mandíbula/cirugía , Cemento Dental/patología
20.
J Periodontal Res ; 59(4): 679-688, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38527968

RESUMEN

OBJECTIVE: This study aimed to investigate the factors influencing the clinical outcomes of regenerative therapy using recombinant human fibroblast growth factor-2 (rhFGF-2). BACKGROUND: rhFGF-2 promotes periodontal regeneration, and identifying the factors influencing this regeneration is important for optimizing the effectiveness of rhFGF-2. METHODS AND MATERIALS: This study used a hospital information-integrated database to identify patients who underwent periodontal regenerative therapy with rhFGF-2. Factors included age, smoking status, diabetes mellitus (DM), periodontal inflamed surface area (PISA) at the initial visit, whether the most posterior tooth was involved or not, and preoperative radiological bone defect angle. Periodontal regenerative therapy outcomes were defined as good if radiographic bone fill ≥35% or periodontal pocket closure at 9-15 months after surgery. Bone fill rate (%) and periodontal pocket depth (mm) were also used as outcome measures. Factors were evaluated by simple regression analysis, and then the association between factors and the outcomes was determined by multivariate analysis. RESULTS: PISA and age at the first visit did not significantly influence the success or failure of bone fill rate byrhFGF-2. However, DM, radiographic bone defect angle, and the most posterior tooth significantly influenced the regenerative effect (success/failure in bone fill) of rhFGF-2. The most posterior tooth was significantly associated with bone fill rate by rhFGF-2. Examination of the association between pocket closure and factors shows that the most posterior tooth significantly influenced. The most posterior tooth and preoperative PPD were significantly associated with pocket reduction depth. For the most posterior tooth, a significantly higher bone regeneration rate (p < .05) was observed with a combination of autologous bone graft and rhFGF-2 than with rhFGF-2 alone, and the effect was significant in multivariate analysis. CONCLUSIONS: The radiographic bone defect angle, the involvement of most posterior teeth, and the presence of DM influenced the effectiveness of rhFGF-2 in periodontal regeneration. However, PISA values and age at the initial visit had no significant effect.


Asunto(s)
Factor 2 de Crecimiento de Fibroblastos , Regeneración Tisular Guiada Periodontal , Proteínas Recombinantes , Humanos , Masculino , Factor 2 de Crecimiento de Fibroblastos/uso terapéutico , Factor 2 de Crecimiento de Fibroblastos/farmacología , Persona de Mediana Edad , Femenino , Estudios de Casos y Controles , Regeneración Tisular Guiada Periodontal/métodos , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/farmacología , Resultado del Tratamiento , Adulto , Anciano , Regeneración Ósea/efectos de los fármacos , Pérdida de Hueso Alveolar/diagnóstico por imagen
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