Bone tissue scaffolds made from either natural or synthetic polymers are employed to promote bone healing. However, lack of sufficient or poor mechanical properties such as low integrity and ...stability reduces their medical applications. Crosslinking, defined as induction of chemical or physical links among polymer chains, is a simple method generally used to modify mechanical, biological and degradation properties of hydrogels. Although crosslinking through chemical reactions improves the mechanical properties of bone substitutes, most of the reagents used for this aim demonstrate undesirable effects and may exert toxic reactions. Glutaraldehyde is a widely-used chemical crosslinker with unique ability to crosslink a wide variety of biomaterials; however, many contradictory views have been recently raised on its cytotoxic effects. By keeping this limit in mind, green chemicals or natural crosslinking agents have been shown to provide desired improvements in mechanical properties of bone scaffolds. Therefore, developing more efficient crosslinking materials and methods are desirable to obtain crosslinked scaffolds with perfect properties in bone tissue engineering from different biopolymers such as collagen, gelatin, cellulose, chitosan, alginate, etc. In this review, we focused on developed or developing modalities used to improve mechanical properties of various bone scaffolds and matrices based on common crosslinking reagents.
Statins are known for their beneficial effects on cardiovascular diseases. Besides the lipid-lowering properties, statins exert their anabolic effects on the bone by differentiating mesenchymal cells ...to osteoblasts via upregulating BMP-2 and protecting osteoblasts from apoptosis. In addition, statins have been suggested to be anti-osteoclastic by reducing the osteoclast differentiation and activity. Several in vivo and clinical studies have confirmed the beneficial effects of statins in the treatment of osteoporosis and fracture injuries. However, controversial results exist showing statins may have no benefit and in some instances, they may retard bone repair. Different factors such as type, route of administration, dose and dosage of statins, and the injury model seem to be involved for such controversies. In the present study, the most important issues regarding statins have been reviewed to find out how statins may be beneficial and statin therapy can be improved for treating osteoporosis and fracture injuries. The lipophilic statins particularly simvastatin and atorvastatin are the most investigated statins with beneficial results on bone healing and turnover. Most of the in vivo and clinical studies performed systemic route of administration for treating osteoporosis, with much higher clinical doses than the lipid lowering therapy, which increases the statin related side and out of target effects. In contrast, most of the in vivo studies that used statins for fracture repair have applied local delivery methods with much lower doses via tissue engineering approaches. However, local delivery of statins and statin therapy for fracture repair both have low application in the clinical setting and such methods are still under in vivo investigation. Future clinical trials are needed to elucidate how delivery systems and tissue engineering technologies are able to improve the outcome of statin therapy.
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Healing and regeneration of bone injuries, particularly those that are associated with large bone defects, are a complicated process. There is growing interest in the application of osteoinductive ...and osteogenic growth factors and mesenchymal stem cells (MSCs) in order to significantly improve bone repair and regeneration. MSCs are multipotent stromal stem cells that can be harvested from many different sources and differentiated into a variety of cell types, such as preosteogenic chondroblasts and osteoblasts. The effectiveness of MSC therapy is dependent on several factors, including the differentiating state of the MSCs at the time of application, the method of their delivery, the concentration of MSCs per injection, the vehicle used, and the nature and extent of injury, for example. Tissue engineering and regenerative medicine, together with genetic engineering and gene therapy, are advanced options that may have the potential to improve the outcome of cell therapy. Although several in vitro and in vivo investigations have suggested the potential roles of MSCs in bone repair and regeneration, the mechanism of MSC therapy in bone repair has not been fully elucidated, the efficacy of MSC therapy has not been strongly proven in clinical trials, and several controversies exist, making it difficult to draw conclusions from the results. In this review, we update the recent advances in the mechanisms of MSC action and the delivery approaches in bone regenerative medicine. We will also review the most recent clinical trials to find out how MSCs may be beneficial for treating bone defects.
Osteoconductive biomaterials were used to find the most reliable materials in bone healing. Our focus was on the bone healing capacity of the stem cell–loaded and unloaded PLA/PCL/HA scaffolds. The ...3D scaffold of PLA/PCL/HA was characterized by scanning electron microscopy (SEM), rheology, X-ray diffraction (XRD), and Fourier transform-infrared (FT-IR) spectroscopy. Bone marrow stem cells (BMSCs) have multipotential differentiation into osteoblasts. Forty Wistar male rats were used to organize four experimental groups: control, autograft, scaffold, and BMSCs-loaded scaffold groups. qRT-PCR showed that the BMSCs-loaded scaffold had a higher expression level of CD31 and osteogenic markers compared with the control group (
P
< 0.05). Radiology and computed tomography (CT) scan evaluations showed significant improvement in the BMSCs-loaded scaffold compared with the control group (
P
< 0.001). Biomechanical estimation demonstrated significantly higher stress (
P
< 0.01), stiffness (
P
< 0.001), and ultimate load (
P
< 0.01) in the autograft and BMSCs-loaded scaffold groups compared with the untreated group and higher strain was seen in the control group than the other groups (
P
< 0.01). Histomorphometric and immunohistochemical (IHC) investigations showed significantly improved regeneration scores in the autograft and BMSCs-loaded scaffold groups compared with the control group (
P
< 0.05). Also, there was a significant difference between the scaffold and control groups in all tests (
P
< 0.05). The results depicted that our novel approach will allow to develop PLA/PCL/HA 3D scaffold in bone healing via BMSC loading.
Extracellular vesicles (EVs) have therapeutic effects on osteoarthritis (OA). Some recent strategies could elevate EV's therapeutic properties including cell aggregation, co-culture, and 3D culture. ...It seems that a combination of these strategies could augment EV production and therapeutic potential. The current study aims to evaluate the quantity of EV yield and the therapeutic effect of EVs harvested from rabbit mesenchymal stem cells (MSCs) aggregates, chondrocyte aggregates, and their co-aggregates in a dynamic 3D culture in a rat osteoarthritis model. MSC and chondrocytes were aggregated and co-aggregated by spinner flasks, and their conditioned medium was collected. EVs were isolated by size exclusion chromatography and characterized in terms of size, morphology and surface markers. The chondrogenic potential of the MSC-ag, Cho-ag and Co-ag EVs on MSC micromass differentiation in chondrogenic media were assessed by qRT-PCR, histological and immunohistochemical analysis. 50 μg of MSC-ag-EVs, Cho-ag-EVs and Co-ag-EVs was injected intra-articularly per knee of OA models established by monoiodoacetate in rats. After 8 weeks follow up, the knee joints were harvested and analyzed by radiographic, histological and immunohistochemical features. MSC/chondrocyte co-aggregation in comparison to MSC or chondrocyte aggregation could increase EV yield during dynamic 3D culture by spinner flasks. Although MSC-ag-, Cho-ag- and Co-ag-derived EVs could induce chondrogenesis similar to transforming growth factor-beta during in vitro study, Co-ag-EV could more effectively prevent OA progression than MSC-ag- and Cho-ag-EVs. Our study demonstrated that EVs harvested from the co-aggregation of MSCs and chondrocytes could be considered as a new therapeutic potential for OA treatment.
Aim
In order to obtain a 3‐dimentional scaffold with predictable clinical results for pulp regeneration, this study aims to fabricate and characterize a porous decellularized human amniotic membrane ...(HAM) extracellular matrix (ECM) scaffold, and evaluate its potential to promote pulp regeneration in vitro and in vivo.
Methodology
The HAM was decellularized, and its histology and DNA content were analysed to confirm decellularization. The scaffolds were synthesized with 15, 22.5 and 30 mg/ml concentrations. The porosity, pore size, phosphate‐buffered saline (PBS) absorption and degradation rate of the scaffolds were assessed. In vitro experiments were performed on human dental pulp stem cells (hDPSCs) to assess their viability, proliferation, adhesion and migration on the scaffolds. The optimal group was selected for in vivo immunogenicity assessment and was also used as the cell‐free or cell‐loaded scaffold in root segment models to evaluate pulp regeneration. All nonparametric data were analysed with the Kruskal–Wallis test followed by Dunn's post hoc test, whilst quantitative data were analysed with one‐way anova.
Results
Decellularization of HAM was confirmed (p < .05). The porosity of all scaffolds was more than 95%, and the pore size decreased with an increase in ECM concentration (p < .01). PBS absorption was not significantly different amongst the groups, whilst 30 mg/ml ECM scaffold had the highest degradation rate (p < .01). The hDPSCs adhered to the scaffold, whilst their proliferation rate increased over time in all groups (p < .001). Cell migration was higher in 30 mg/ml ECM scaffold (p < .05). In vivo investigation with 30 mg/ml ECM scaffold revealed mild to moderate inflammatory response. In root segments, both cell‐free and cell‐loaded 30 mg/ml scaffolds were replaced with newly formed, pulp‐like tissue with no significant difference between groups. Immunohistochemical assessments revealed high revascularization and collagen content with no significant difference amongst the groups.
Conclusion
The 30 mg/ml HAM ECM scaffold had optimal physical properties and better supported hDPSC migration. The HAM ECM scaffold did not interfere with formation of pulp‐like tissue and revascularization within the root canal when employed as both cell‐free and cell‐loaded scaffold. These results highlight the potential of HAM ECM membrane for further investigations in regenerative endodontics.
Purpose
In addition to lipid-lowering properties, statins have been suggested to affect bone turnover by increasing the osteoblastic bone formation and blocking the osteoclastogenesis. However, there ...are many controversial reports regarding the beneficial effect of statins on osteoporosis. In this study, we investigated the therapeutic effects of the most important lipophilic statins administered orally for 60 days to the ovariectomized (OVX) female Sprague–Dawley rats and compared the effects on different harvested trabecular and compact bones.
Methods
Thirty female rats were divided into five equal groups including the normal rats, untreated OVX rats (negative control), and the OVX rats treated with atorvastatin (20 mg/kg/day), simvastatin (25 mg/kg/day), and lovastatin (20 mg/kg/day). The osteoporotic animals were treated daily for 60 days and euthanized at the end of experiments. The effectiveness of these treatments was evaluated by biomechanical testing, histopathologic, histomorphometric, micro-CT scan, real-time PCR, and serum biochemical analysis. Moreover, the hepatotoxicity and rhabdomyolysis related with these treatments were assessed by biochemistry analysis and histopathological evaluation.
Results
The results and statistical analysis showed that systemic delivery of simvastatin and lovastatin significantly increased serum calcium level, expression of osteogenic genes, bone mineral density (BMD), and biomechanical properties in comparison to the untreated OVX rats, especially in trabecular bones (
P
< 0.05). The results of different analysis also indicated that there was no statistical difference between the atorvastatin-treated animals and the negative control. Among all treatments, only atorvastatin showed an evident hepatotoxicity and myopathy.
Conclusions
It was concluded that the lovastatin and simvastatin efficiently ameliorated the OVX-induced osteoporosis. Moreover, the simvastatin-treated animals showed more resemblance to the normal group in terms of BMD, expression of osteogenic genes, serum biochemical parameters, histomorphometric findings, and biomechanical performance with no significant side-effects.
Osteoarthritis (OA) is one of the most common musculoskeletal degenerative diseases and contributes to heavy socioeconomic burden. Current pharmacological and conventional non-pharmacological ...therapies aim at relieving the symptoms like pain and disability rather than modifying the underlying disease. Surgical treatment and ultimately joint replacement arthroplasty are indicated in advanced stages of OA. Since the underlying mechanisms of OA onset and progression have not been fully elucidated yet, the development of novel therapeutics to prevent, halt, or reverse the disease is laborious. Recently, small molecules of herbal origin have been reported to show potent anti-inflammatory, anti-catabolic, and anabolic effects, implying their potential for treatment of OA. Herein, the molecular mechanisms of these small molecules, their effect on physiological or pathological signaling pathways, the advancement of the extraction methods, and their potential clinical translation based on in vitro and in vivo evidence are comprehensively reviewed.
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