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1.
Clin J Sport Med ; 30(1): 1-7, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31855906

RESUMO

OBJECTIVE: Pain and range of motion loss are the main clinical features of osteoarthritis (OA). Hyaluronic acid (HA) is one of the infiltrative therapies for OA treatment; however, its effectiveness is a matter of an ongoing debate in clinical practice. Polynucleotides (PNs), a DNA-derived macromolecule with natural origin and trophic activity, were found to favor cell growth and collagen production, in preclinical and clinical studies regarding cartilage regeneration. This study aimed at evaluating whether injection of PNs, in combination with HA [PNs associated with HA (PNHA)], can ameliorate pain and function of knees affected by OA, more than HA alone. DESIGN: A randomized, double-blind, controlled clinical trial. PATIENTS: The study enrolled 100 patients, then randomized to receive PNHA or HA alone (3 weekly knee I.A. injections). INTERVENTIONS AND MAIN OUTCOME MEASURES: Pain reduction, decrease of proinflammatory synovial fluid (SF) factors, and improvement in knee function were evaluated by Knee Society Score and WOMAC scores, after 2, 6, and 12 months and by biochemical and immunoenzymatic analyses of SF at the end of the treatment. RESULTS: Knee Society Score total score and pain item significantly ameliorated in both groups, showing better results in PNHA- than in the HA-treated group. A significant reduction in the WOMAC score was observed over time for both groups. No significant adverse events were reported in either group. CONCLUSIONS: These findings suggest that I.A. injection of PNs, in combination with HA, is more effective in improving knee function and pain, in a joint affected by OA, compared with HA alone.

2.
Int J Pharm ; 554: 245-255, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30423416

RESUMO

In this study, we loaded a biomimetic calcium phosphate bone cement (CPC) with relatively high amounts of a bisphosphonate through the use of Solid Lipid Microparticles (MPs) and investigated bone cells response to the composite cements. 10, 20 and 30% w/w of Alendronate (AL) were successfully introduced into microparticles of Cutina HR and Precirol, which were prepared by means of spray-congealing technique. Addition of AL-loaded MPs to the cement composition provoked a lengthening of the setting and of the hardening processes. However, setting times were still in a range useful for clinical applications, except for the cements at the highest Alendronate content. The composite cements displayed a sustained drug release over time. Cements with the best performances in terms of setting, hardening, mechanical properties and drug release were submitted to in vitro tests using a co-culture model of osteoblast and osteoclast. The results showed that the use of MPs to enrich the cement composition with Alendronate provides materials able to inhibit osteoclast viability and activity, while promoting osteoblast viability and earlier differentiation, indicating that the MPs-cements are good delivery systems for bisphosphonates.


Assuntos
Alendronato/administração & dosagem , Cimentos para Ossos/química , Conservadores da Densidade Óssea/administração & dosagem , Fosfatos de Cálcio/química , Alendronato/química , Alendronato/farmacologia , Materiais Biomiméticos/química , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Técnicas de Cocultura , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Humanos , Lipídeos , Microesferas , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos
3.
Mater Sci Eng C Mater Biol Appl ; 95: 355-362, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573259

RESUMO

PURPOSE: The purpose of this study was to comparatively investigate the posterolateral fusion rate in ovariectomized (OVX) rats using two new bone graft materials: strontium (Sr) substituted hydroxyapatite (HA) nanocrystals and alendronate (AL) functionalized HA nanocrystals. SrHA was synthesized in presence of different Sr concentrations (SrHA5; SrHA10) and HA-AL nanocrystals at increasing bisphosphonate (BP) content (HA-AL7; HA-AL28). METHODS: A posterolateral spinal fusion model in twenty-five Sham operated and in twenty-five OVX female rats was used and materials were bilaterally implanted between transverse processes of lumbar vertebrae. Sham and OVX animals were divided in five groups depending on the material: HA, SrHA5, SrHA10, HA-AL7 and HA-AL28. The assessment of bone fusion was carried out by µCT, histology and histomorphometry. RESULTS: Some gaps between the transverse processes were observed by µCT in OVXHA group, while they were not present in all the other groups. These results were consistent with the histomorphometrical analyses showing that in OVX animals SrHA and HA-AL materials displayed significantly higher BV/TV and Tb.Th and significantly lower Tb.N and Tb.Sp in comparison with HA alone. CONCLUSIONS: Results of this study suggest that in spinal fusion the incorporation of bioactive ions or drugs as Sr and AL improves the biological performance of HA representing a promising strategy especially in osteoporosis patients with high risks of spinal fusion failure. Results also suggest the existence of a Sr and AL dose response effect and that HA containing the highest AL dose could be the candidate biomaterial for spinal fusion in osteoporotic subjects.


Assuntos
Alendronato/química , Artrodese/métodos , Durapatita/química , Vértebras Lombares/patologia , Vértebras Lombares/cirurgia , Estrôncio/química , Animais , Materiais Biocompatíveis/química , Feminino , Ovariectomia , Ratos
4.
Acta Biomater ; 81: 293-303, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30273745

RESUMO

Infections represent one of the most frequent causes of arthroplasty revision. Thus, design of new antimicrobial scaffolds to reduce implant rejections, bone infections and associated medical costs is highly desired. In recent years, essential oil components (EOCs) have merged as compounds with significant antimicrobial activity that can be attached to specific surfaces to enhance and prolong their antimicrobial effect. Herein calcium phosphate CaP regenerative materials have been coated with a vanillin derivative to combine its original bone regeneration properties with antimicrobial action of EOCs. Materials in form of microparticles and blocks were prepared and fully characterized. Clonogenic viability tests demonstrated that low concentrations of material (10 mg·mL-1) resulted effective to kill 100% of E. coli DH5α bacteria. Additionally, vanillin containing scaffolds did not display any toxic effect over cells, yet they preserve the ability to express alkaline phosphatase (ALPL), collagen type 1, chain α1 (COL1A1) and bone gamma-carboxyglutamic acid-containing protein or osteocalcin (BGLAP), which are genes typically expressed by osteoblasts. These results demonstrate that commercially available scaffolds can be functionalized with EOCs, achieving antimicrobial activity and open up a new approach for the treatment and prevention of infection. STATEMENT OF SIGNIFICANCE: During the last years, the interest in bone regenerative materials with antibiotic properties has increased, since prosthesis infection is one of the most usual complications in implant surgery. In this work, we report a hybrid system composed by a calcium phosphate material (powders and scaffolds) functionalized with the derivative of an essential oil component (EOC). Our purpose was to provide the calcium phosphate material with antimicrobial activity without harming its bone regenerative capability. The obtained results were encouraging, which opens up the possibility of developing new modified materials for the prevention and treatment of bone infection.


Assuntos
Anti-Infecciosos , Benzaldeídos , Regeneração Óssea/efeitos dos fármacos , Fosfatos de Cálcio , Escherichia coli/crescimento & desenvolvimento , Osteogênese/efeitos dos fármacos , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/farmacologia , Antígenos de Diferenciação/biossíntese , Benzaldeídos/química , Benzaldeídos/farmacocinética , Benzaldeídos/farmacologia , Fosfatos de Cálcio/química , Fosfatos de Cálcio/farmacocinética , Fosfatos de Cálcio/farmacologia , Linhagem Celular , Camundongos
5.
Histol Histopathol ; 33(12): 1323-1334, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29968903

RESUMO

Tendon tissue has poor regenerative capacity due to its low vascularization, cell density and extracellular matrix (ECM) production. Therefore, tendon injuries are an increasing clinical problem because of the formation of scar tissue with traditional therapies. Regenerative medicine aims at triggering a healing response through the use of biological treatments such as mesenchymal stromal cells (MSCs) and growth factors (GFs). MSCs show several advantages in tendon clinical setting, while platelet rich plasma (PRP) has gained popularity because of its high GF concentration, although its applications in the tendon clinical setting are still controversial. The aim of the present study was to evaluate a combined treatment of MSCs and PRP in an in vitro microwound model of tendon injuries. In addition, fresh and frozen PRP were compared. Single human tenocytes cultures or co-cultures with bone marrow derived MSCs (BMSCs) were set up with or without human PRP, fresh or frozen. After 24 hours of culture, it was observed that MSCs alone significantly increased tenocyte migration speed, microwound healing rate, fibronectin, collagen I and aggrecan production. These effects were enhanced by the combination with PRP, fresh being more effective than frozen PRP. In addition, the number of MSCs and tenocytes inside the microwound was significantly increased, especially with fresh PRP. In conclusion, the combination of MSCs and PRP, especially the fresh one, increases tenocytes and MSC migration speed, as well as ECM protein production compared to the use of MSCs alone.


Assuntos
Células-Tronco Mesenquimais , Plasma Rico em Plaquetas , Tenócitos , Cicatrização/fisiologia , Adulto , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Manejo de Espécimes/métodos , Traumatismos dos Tendões/terapia
6.
Macromol Biosci ; 18(7): e1800096, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29877029

RESUMO

Strontium has a beneficial role on bone remodeling and is proposed for the treatment of pathologies associated to excessive bone resorption, such as osteoporosis. Herein, the possibility to utilize a biomimetic scaffold as strontium delivery system is explored. Porous 3D gelatin scaffolds containing about 30% of strontium substituted hydroxyapatite (SrHA) or pure hydroxyapatite (HA) are prepared by freeze-drying. The scaffolds display a very high open porosity, with an interconnectivity of 100%. Reinforcement with further amount of gelatin provokes a modest decrease of the average pore size, without reducing interconnectivity. Moreover, reinforced scaffolds display reduced water uptake ability and increased values of mechanical parameters when compared to as-prepared scaffolds. Strontium displays a sustained release in phosphate buffered saline: the quantities released after 14 d from as-prepared and reinforced scaffolds are just 14 and 18% of the initial content, respectively. Coculture of osteoblasts and osteoclasts shows that SrHA-containing scaffolds promote osteoblast viability and activity when compared to HA-containing scaffolds. On the other hand, osteoclastogenesis and osteoclast differentiation are significantly inhibited on SrHA-containing scaffolds, suggesting that these systems could be usefully applied for local delivery of strontium in loci characterized by excessive bone resorption.


Assuntos
Materiais Biomiméticos/síntese química , Preparações de Ação Retardada/síntese química , Gelatina/química , Hidroxiapatitas/química , Osteoblastos/efeitos dos fármacos , Estrôncio/farmacologia , Reabsorção Óssea/prevenção & controle , Diferenciação Celular/efeitos dos fármacos , Técnicas de Cocultura , Liberação Controlada de Fármacos , Humanos , Cinética , Modelos Biológicos , Osteoblastos/citologia , Osteoblastos/fisiologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Porosidade , Estrôncio/química , Estrôncio/metabolismo , Engenharia Tecidual , Tecidos Suporte
7.
Clin J Sport Med ; 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29642095

RESUMO

OBJECTIVE: Pain and range of motion loss are the main clinical features of osteoarthritis (OA). Hyaluronic acid (HA) is one of the infiltrative therapies for OA treatment; however, its effectiveness is a matter of an ongoing debate in clinical practice. Polynucleotides (PNs), a DNA-derived macromolecule with natural origin and trophic activity, were found to favor cell growth and collagen production, in preclinical and clinical studies regarding cartilage regeneration. This study aimed at evaluating whether injection of PNs, in combination with HA [PNs associated with HA (PNHA)], can ameliorate pain and function of knees affected by OA, more than HA alone. DESIGN: A randomized, double-blind, controlled clinical trial. PATIENTS: The study enrolled 100 patients, then randomized to receive PNHA or HA alone (3 weekly knee I.A. injections). INTERVENTIONS AND MAIN OUTCOME MEASURES: Pain reduction, decrease of proinflammatory synovial fluid (SF) factors, and improvement in knee function were evaluated by Knee Society Score and WOMAC scores, after 2, 6, and 12 months and by biochemical and immunoenzymatic analyses of SF at the end of the treatment. RESULTS: Knee Society Score total score and pain item significantly ameliorated in both groups, showing better results in PNHA- than in the HA-treated group. A significant reduction in the WOMAC score was observed over time for both groups. No significant adverse events were reported in either group. CONCLUSIONS: These findings suggest that I.A. injection of PNs, in combination with HA, is more effective in improving knee function and pain, in a joint affected by OA, compared with HA alone.

8.
J Inorg Biochem ; 183: 1-8, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29525694

RESUMO

The chemistry, structure and morphology of the implant surface have a great influence on the integration of an implant material with bone tissue. In this work, we applied Combinatorial Matrix-Assisted Pulsed Laser Evaporation (C-MAPLE) to deposit gradient thin films with variable compositions of Sr-substituted hydroxyapatite (SrHA) and Zn-substituted ß-tricalcium phosphate (ZnTCP) on Titanium substrates. Five samples with different SrHA/ZnTCP composition ratios were fabricated by a single step laser procedure. SrHA was synthesized in aqueous medium, whereas ZnTCP was obtained by reaction at high temperature. Both powders were separately suspended in deionized water, frozen at liquid nitrogen temperature and used as targets for C-MAPLE experiments, which proceed via simultaneous laser vaporization of two distinct material targets. X-ray diffraction, scanning electron microscopy and energy dispersive X-ray spectroscopy analyses confirmed that the coatings contain the same crystalline phases as the as-prepared powder samples, with a homogeneous distribution of the two phosphates along deposited thin films. Human osteoclast precursor 2T-110 and human osteoblast-like cells MG63 were co-cultured on the coatings. The results indicate that osteoblast viability and production of osteocalcin were promoted by the presence of ZnTCP. On the other hand, SrHA inhibited osteoclastogenesis and osteoclast differentiation, as demonstrated by the observed increase of the osteoprotegerin/RANKL ratio and decrease of the number of TRAP-positive multinucleated cells when increasing SrHA amount in the coatings. The results indicate that the possibility to tailor the composition of the coatings provides materials able to modulate bone growth and bone resorption.


Assuntos
Fosfatos de Cálcio/química , Hidroxiapatitas/química , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Estrôncio/química , Fosfatos de Cálcio/farmacologia , Linhagem Celular , Técnicas de Cocultura , Humanos , Hidroxiapatitas/farmacologia , Microscopia Eletrônica de Varredura , Osteoblastos/ultraestrutura , Osteoclastos/ultraestrutura , Espectrometria por Raios X , Estrôncio/farmacologia , Difração de Raios X , Zinco/química
9.
Eur J Pharm Biopharm ; 127: 120-129, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29454808

RESUMO

The development of new biomaterials able to favor bone formation and to inhibit bone abnormal resorption is mandatory to face the increasing number of age-related musculo-skeletal disorders. Moreover, the increasing antibiotic resistance of clinically important bacteria, which is among the main causes of implant failure, requires new antimicrobial systems. In this study, we prepared multifunctional materials consisting of hydroxyapatite-zoledronate composite crystals decorated with Ag Nanoparticles (AgNPs). Zoledronate, a potent bisphosphonate widely applied for the treatment of pathologies associated to abnormal bone loss, was incorporated into hydroxyapatite up to about 8 wt%. Loading of poly(ethylenimine) - stabilized AgNPs onto the crystals was promoted by zoledronate functionalization and provoked a significant variation of the values of zeta potential. The results of in vitro tests demonstrate that the multifunctional materials combine the beneficial actions of zoledronate and AgNPs. In fact, they improve osteoblast differentiation and activity, whereas they inhibit osteoclastogenesis and osteoclast differentiation, and significantly hinder the growth of multi-drug resistant Gram positive and Gram negative bacteria. As a consequence, they can be exploited both as antiresorptive agents and as antimicrobial materials able to prevent the development of bone-associated infections.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Nanopartículas Metálicas/química , Osteoclastos/efeitos dos fármacos , Prata/química , Materiais Biocompatíveis/química , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Difosfonatos/química , Difosfonatos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Testes de Sensibilidade Microbiana/métodos , Osteoblastos/efeitos dos fármacos , Ácido Zoledrônico
10.
J Cell Physiol ; 233(1): 291-301, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28240358

RESUMO

The dynamic metabolism and the numerous roles of bone tissue necessitate a suitable in vitro model to represent them. In order to investigate the interaction among the several cell types composing bone microenvironment, we studied a tri-culture model including human osteoblasts (OBs), osteoclasts (OCs), and endothelial cells (HUVEC). While OBs are essential for bone deposition and OCs for bone resorption, the vasculature is necessary to provide growth factors, nutrients, and oxygen in the mature tissue. The results of this study showed a strong mutual influence between OBs, OCs, and HUVEC in term of proliferation, viability, and activity (release of ALP, Coll I, OPG, RANKL, VEGF, CTSK, TGFß, and IL-6). The behavior of the single cultures demonstrated to be different compared to the bi- or tri-cultures and depending on the cell types involved: the coexistence of OBs and OCs stimulated the synthetic activity of both cell types, while the presence of HUVEC induced a stimulating role for OBs but mainly an inhibitory effect for OC. In addition, evidence of the effects of OBs and OCs on HUVEC is highlighted by their morphology: regular and able to "sketch" little vessels in presence of OBs, more disorganized and heterogeneous in presence of OCs. Taken together, these observations well characterize an advanced cellular model to be used as starting point for mimicking bone microenvironment in vivo, thus reducing the use of animals in the preclinical phase and offering a more reliable tool to test new and innovative biomaterials.


Assuntos
Remodelação Óssea , Comunicação Celular , Técnicas de Cultura de Células , Microambiente Celular , Células Endoteliais da Veia Umbilical Humana/fisiologia , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Osteogênese , Biomarcadores/metabolismo , Linhagem Celular , Forma Celular , Sobrevivência Celular , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neovascularização Fisiológica , Fenótipo , Fatores de Tempo
11.
J Inorg Biochem ; 178: 43-53, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29049953

RESUMO

In this work we developed new antibacterial composite materials using polydopamine (PDA) to trigger the deposition of silver nanoparticles (AgNPs) onto calcium phosphates, namely octacalcium phosphate (OCP) and α-tricalcium phosphate (αTCP). Functionalization of OCP and αTCP with a self-polymerized polydopamine layer was obtained by soaking the calcium phosphates in dopamine solution. The PDA surface of functionalized calcium phosphates (OCPd and αTCPd) promoted the deposition of AgNPs by reducing silver ions when soaked in a silver nitrate solution. The amount of deposited AgNPs can be modulated by varying the concentration of silver nitrate solution and the type of substrate. The results of in vitro tests carried out with osteoblast-like MG63 cells indicate that the combination of AgNPs with OCP provides more biocompatible materials than those obtained using αTCP as substrate. In particular, the study of osteoblast activity and differentiation was focused on the samples OCPdAg5 (silver content=8.2wt%) and αTCPdAg5 (silver content=4.7wt%), which did not show any cytotoxicity, and compared with those obtained on pure OCP and αTCP. The results demonstrate that the AgNPs loaded materials support osteoblast viability and differentiation, whereas they significantly inhibit the growth of relevant antibiotic-resistant pathogenic bacteria.


Assuntos
Antibacterianos/síntese química , Biomimética , Fosfatos de Cálcio/química , Indóis/química , Polímeros/química , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular , Materiais Revestidos Biocompatíveis/química , Humanos , Nanopartículas/química , Osteoblastos/química , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Reação em Cadeia da Polimerase , Prata/química , Propriedades de Superfície
12.
J Biomed Mater Res A ; 105(12): 3293-3303, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28865182

RESUMO

In spite of its remarkable anti-oxidant, anti-inflammatory, anti-cancer properties and its possible inhibition activity towards bone resorption, quercetin therapeutic use is limited by its poor bioavailability. Herein we developed a new multifunctionalized system for the local administration of quercetin and alendronate, one of the most potent anti-osteoporotic drugs, with the aim to get a material with enhanced properties. To this purpose we loaded quercetin on hydroxyapatite functionalized with alendronate, as well as on hydroxyapatite. Characterization was performed by means of X-ray diffraction, FT-IR and Raman spectroscopies, thermogravimetric and spectrophotometric analyses. Loading of quercetin from hydro-alcoholic solution increased with time and reached a constant value of about 5 weight% on both substrates, without causing significant structural and morphological modifications. Quercetin functionalized materials exhibit relevant anti-oxidant properties, in agreement with their high radical scavenging activity, and a quercetin sustained release in phosphate buffer. In vitro osteoblast and osteoclast co-culture in a microenvironment altered by oxidative stress shows that both alendronate and quercetin significantly reduce osteoclast viability, whereas they are able to counteract the negative effect of oxidative stress on osteoblast viability and differentiation, suggesting that their relative amount in the functionalized materials can be utilized to tailor bone cells response. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3293-3303, 2017.


Assuntos
Alendronato/farmacologia , Antioxidantes/farmacologia , Conservadores da Densidade Óssea/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Alendronato/administração & dosagem , Antioxidantes/administração & dosagem , Materiais Biocompatíveis/química , Conservadores da Densidade Óssea/administração & dosagem , Linhagem Celular , Técnicas de Cocultura , Sistemas de Liberação de Medicamentos/métodos , Durapatita/química , Humanos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Quercetina/administração & dosagem , Difração de Raios X
13.
Sci Rep ; 7(1): 2712, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28578416

RESUMO

The development of biomaterials able to act against a wide range of bacteria, including antibiotic resistant bacteria, is of great importance since bacterial colonization is one of the main causes of implant failure. In this work, we explored the possibility to functionalize hydroxyapatite (HA) nanocrystals with some monocyclic N-thio-substituted ß-lactams. To this aim, a series of non-polar azetidinones have been synthesized and characterized. The amount of azetidinones loaded on HA could be properly controlled on changing the polarity of the loading solution and it can reach values up to 17 wt%. Data on cumulative release in aqueous solution show different trends which can be related to the lipophilicity of the molecules and can be modulated by suitable groups on the azetidinone. The examined ß-lactams-HA composites display good antibacterial activity against reference Gram-positive and Gram-negative bacteria. However, the results of citotoxicity and antibacterial tests indicate that HA loaded with 4-acetoxy-1-(methylthio)-azetidin-2-one displays the best performance. In fact, this material strongly inhibited the bacterial growth of both methicillin resistant and methicillin susceptible clinical isolates of S. aureus from surgical bone biopsies, showing to be a very good candidate as a new functional biomaterial with enhanced antibacterial activity.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Materiais Biocompatíveis/química , Durapatita/química , Monobactamas/química , Monobactamas/farmacologia , Antibacterianos/síntese química , Azetidinas/química , Azetidinas/farmacologia , Bactérias/efeitos dos fármacos , Portadores de Fármacos , Liberação Controlada de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier
14.
Photodermatol Photoimmunol Photomed ; 33(3): 156-163, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28140474

RESUMO

BACKGROUND: Polypodium leucotomos (PL) exerts potent antioxidant, photo-protective, and immune-modulatory activities. A reconstructed human epidermis (RHE) (Episkin) is a suitable model for the evaluation of acute UV-induced cell damage. No data regarding the photo-protective action of PL in this model are available. PURPOSE: We evaluated the effects of PL on the prevention of UVB-induced cell damage assessing sunburn cells, CPD formation, p53, Ki-67, p21 expression, and epidermal growth factor (EGF) production. MATERIALS & METHODS: RHE was incubated in standard conditions. PL was topically applied at the concentration of 2 mg/cm2 , immediately before UVB exposition. UVB exposition (300 mJ/cm2 ) was performed using a dedicated UVB lamp. Irradiated samples without PL and non-irradiated samples were used as positive and negative controls. Expression of p53, p21, and Ki-67 was evaluated with immune-histochemical methods. CPD were measured using a monoclonal antibody. RESULTS: PL significantly reduced sunburned cells (-80%) in comparison with positive control. PL significantly prevented the increase in EGF production at tested times. PL significantly reduced the p53 (-80%), p21 (-84%), and Ki-67 (-48%) positive cells. Finally, PL prevented the formation of CPD (0% vs. 20% positive cells). CONCLUSION: In this model, PL has shown to prevent UVB cell damage, the upregulation of proliferating proteins, and fully blocking the formation of CPD.


Assuntos
Epiderme/efeitos dos fármacos , Epiderme/efeitos da radiação , Extratos Vegetais/farmacologia , Polypodium , Queimadura Solar/prevenção & controle , Raios Ultravioleta/efeitos adversos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fator de Crescimento Epidérmico/biossíntese , Epiderme/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Modelos Biológicos , Dímeros de Pirimidina/metabolismo , Queimadura Solar/etiologia , Queimadura Solar/patologia , Proteína Supressora de Tumor p53/metabolismo
15.
Acta Biomater ; 54: 419-428, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28238916

RESUMO

Development of new materials for the local administration of bisphosphonates (BPs) is aimed to avoid the negative side effects of prolonged systemic use of these potent drugs. In this work, we synthesized octacalcium phosphate (OCP) in the presence of two potent BPs and obtained a single crystalline phase up to a zoledronate and alendronate content of 3.5wt% and 5.2wt%, respectively. Both BPs provoke minor structural modifications and a reduction of the crystal dimensions of OCP, which suggests a preferential interaction of the BPs with the structure of the calcium phosphate. Alendronate containing samples display increased values of zeta potential with respect to that of OCP, and an initial burst release of the BP in solution. At variance, the zeta potential of zoledronate functionalized samples decreases on increasing the content of zoledronate, which is not appreciably released in solution. Bone microenvironment response to the composite materials was investigated in vitro using a triculture model. BP functionalized samples downregulate the viability of the cells, sustain osteoblast differentiation and accelerate the production of collagen type I and osteocalcin. At variance, they inhibit monocyte differentiation into osteoclast and provoke a dose dependent reduction of VEGF production, exhibiting antiresorptive and anti-angiogenetic properties that can be usefully exploited for the local treatment of abnormal bone losses. STATEMENT OF SIGNIFICANCE: Bisphosphonates (BPs) are powerful drugs for the treatment of bone diseases. However, BPs systemic administration suffers several undesirable side effects, which stimulate the development of suitable systems for their local administration. In this study we functionalized octacalcium phosphate (OCP) with alendronate and zoledronate in order to get biomaterials able to couple the good biological performance of OCP with the therapeutic properties of the BPs. The results provide novel information on the interaction between these two potent BPs and octacalcium phosphate. Moreover, the triculture in vitro study indicates that the synthesized composite materials stimulate the production of bone extracellular matrix, inhibit monocytes differentiation into osteoclasts and downregulate the release of Vascular Endothelial Growth Factor (VEGF) in a dose dependent way. The data allow to state that the new composite materials can be usefully employed for the local treatment of diseases involving abnormally high bone resorption.


Assuntos
Fosfatos de Cálcio , Difosfonatos , Imidazóis , Fosfatos de Cálcio/química , Fosfatos de Cálcio/farmacocinética , Fosfatos de Cálcio/farmacologia , Linhagem Celular , Técnicas de Cocultura , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Difosfonatos/química , Difosfonatos/farmacocinética , Difosfonatos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Ácido Zoledrônico
16.
J Cell Physiol ; 232(7): 1826-1834, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27925188

RESUMO

Despite consistent improvements in diagnostic and therapeutic strategies for breast cancer, up to 40% of patients will develop bone metastases. To reduce the morbidity and complications related with bone metastases, it is imperative to reduce their etiological factors. Osteoporosis, being characterized by a sudden estrogen deficiency, may provide a favorable condition for bone metastasis. This work, using a humanized 3D in vitro model, aims at evaluating the relationship between osteoporosis and breast cancer-derived bone metastases. Bone tissue discarded from total hip replacement surgery of healthy and osteoporotic patients was cultured in a rolling apparatus system in hypoxic environment. Protein levels (i.e., vascular endothelial growth factor (VEGF), VEGF receptor 1, VEGF receptor 2, interleukin (IL)-6, IL-1ß, IL-8 IL-10, tumor necrosis factor α (TNF-α), osteoprotegerin (OPG), receptor activator for nuclear factor KB ligand (RANKL)) and histological and immunohistochemical (i.e., cytokeratin 8 and 18) analyses showed a noticeable specificity of breast cancer cells for the colonization of osteoporotic bone. These data are the first to demonstrate that using humanized 3D in vitro systems, which individually model the pre- and postmenopausal bone microenvironment, it is possible to recognize major differences in tumor growth and colonization between healthy and osteoporotic status. Thus, this system might help to develop a shared system between basic and clinical sciences where a personalized diagnosis is associated to a therapeutic strategy designed for a single patient: a model able to achieve a translational research approach in the clinical setting, which may lead to the application and dissemination of personalized medicine. J. Cell. Physiol. 232: 1826-1834, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Osso e Ossos/patologia , Neoplasias da Mama/patologia , Modelos Biológicos , Osteoporose/patologia , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Cabeça do Fêmur/patologia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
J Cell Physiol ; 232(6): 1478-1488, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27739057

RESUMO

Primarily, to compare the behavior of human mesenchymal stem cells (MSCs) derived from bone marrow (hBMSCs) and adipose tissue (hADSCs) in an osteoarthritic (OA) microenvironment; secondly, to investigate the reaction of these cell types in two alternative in vitro culture systems, obtained by using TNFα and/or IL1ß as inflammation mediators, or by using synovial fluid harvested by OA patients (OSF) to simulate the complex inflamed knee microenvironment. 3D micromass cultures of hBMSCs or hADSCs were grown in chondrogenic medium (CTR), in the presence of TNFα and/or IL1ß, or synovial fluid from OA patients. After 1 month of culture, the chondrogenic differentiation of micromasses was evaluated by gene expression, matrix composition, and organization. Both hMSCs types formed mature micromasses in CTR, but a better response of hADSCs to the inflammatory environment was documented by micromass area and Bern score evaluations. The addition of OSF elicited a milder reaction than with TNFα and/or IL1ß by both cell types, probably due to the presence of both catabolic and protective factors. In particular, SOX9 and ACAN gene expression and GAG synthesis were more abundant in hADSCs than hBMSCs when cultured in OSF. The expression of MMP1 was increased for both hMSCs in inflammatory conditions, but in particular by hBMSCs. hADSCs showed an increased chondrogenic potential in inflammatory culture systems, suggesting a better response of hADSCs in the OA environment, thus underlining the importance of appropriate in vitro models to study MSCs and potential advantages of using these cells for future clinical applications. J. Cell. Physiol. 232: 1478-1488, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Tecido Adiposo/citologia , Células da Medula Óssea/citologia , Condrogênese , Células-Tronco Mesenquimais/citologia , Modelos Biológicos , Osteoartrite/patologia , Agregação Celular , Microambiente Celular , Colágeno Tipo II/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/patologia , Interleucina-1beta/metabolismo , Líquido Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Macromol Biosci ; 17(3)2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27748576

RESUMO

The systemic administration of bisphosphonates (BPs) for the treatment of metabolic diseases characterized by abnormal bone loss suffers from several adverse side effects, which can be reduced by implementation of alternative modes of administration. In this work, glutaraldehyde cross-linked gelatin scaffolds are proposed as delivery systems of calcium alendronate monohydrate (CaAL•H2 O). The 3D highly porous scaffolds display a relevant interconnected porosity (>94%), independently from CaAL•H2 O content (0, 3, and 6 wt%). At variance, pore size varies with composition. The relative increase of the number of smaller pores on increasing BP content is in agreement with the parallel significant increase of the compressive modulus and collapse strength. The scaffolds exhibit a sustained CaAL•H2 O release profile, and a significant amount of the drug is retained in the scaffolds even after 14 d. In vitro tests are carried out using cocultures of osteoblast (OB) and osteoclast (OC). The evaluation of differentiation markers is performed both on the supernatants of cell culture and by means of quantitative polymerase chain reaction. The results indicate that BP containing scaffolds support osteoblast proliferation and differentiation, whereas they inhibit osteoclast viability and activity, displaying a promising beneficial role on bone repair processes.


Assuntos
Alginatos/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Alginatos/química , Gelatina/administração & dosagem , Gelatina/química , Ácido Glucurônico/administração & dosagem , Ácido Glucurônico/química , Glutaral/administração & dosagem , Glutaral/química , Ácidos Hexurônicos/administração & dosagem , Ácidos Hexurônicos/química , Humanos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Porosidade , Tecidos Suporte/química
19.
Biomed Mater ; 11(2): 025007, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26987305

RESUMO

Crosslinking of gelatin nanofibers maintaining a fibrous morphology after exposure to an aqueous solution is still a challenge. In this work, we developed an innovative method based on the use of an ad hoc designed co-axial needle to fabricate gelatin mats crosslinked with a very small amount of genipin and still able to retain their morphology when immersed in aqueous solution. Genipin-containing gelatin nanofibers are obtained by allowing mixing of the two solutions just within the needle. Genipin content of the electrospun mats can be modulated by varying feeding rates of the inner and outer solutions and their relative concentration. A subsequent thermal treatment of the mats, performed at 55 °C or 37 °C for 1 or 3 days and followed by rapid rinsing in ethanol and then in PB, allows one to obtain highly crosslinked gelatin nanofibers that perfectly maintain their morphology after immersion in an aqueous solution, display improved mechanical properties and enhanced stability. This new approach allows us to achieve gelatin mat stabilization using a very small amount of genipin with respect to other methods and to avoid post-treatment of the mats with the crosslinking agent, with a consequent significant reduction of the final cost of the materials. Moreover, in vitro tests demonstrate that the crosslinked mats support normal human primary chondrocyte culture, promoting their differentiation.


Assuntos
Gelatina/química , Nanofibras/química , Tecidos Suporte/química , Materiais Biocompatíveis/química , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Condrócitos/citologia , Condrócitos/enzimologia , Reagentes para Ligações Cruzadas , Humanos , Iridoides , L-Lactato Desidrogenase/metabolismo , Teste de Materiais , Microscopia Eletrônica de Varredura , Nanofibras/ultraestrutura , Nanotecnologia , Engenharia Tecidual/métodos
20.
Am J Sports Med ; 44(3): 664-71, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26797697

RESUMO

BACKGROUND: The effectiveness of intra-articular platelet-rich plasma (PRP) injections has been evaluated in knee chondroplasty and osteoarthritis (OA); however, little evidence of its efficacy in hip OA exists. PURPOSE: To compare the therapeutic efficacy of autologous PRP, hyaluronic acid (HA), or a combination of both (PRP+HA) in hip OA. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients aged between 18 and 65 years who were treated with outpatient surgery and who had hip OA and pain intensity at baseline of >20 on a 100-mm visual analog scale (VAS) were recruited for this study. Exclusion criteria were extensive surgery; presence of excessive deformities; or rheumatic, infective, cardiovascular, or immune system disorders. The primary outcome measure was a change in pain intensity as assessed by the VAS at 2, 6, and 12 months after treatment. Secondary outcome measures were the Harris Hip Score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and concentration of growth factors in PRP and their correlation with clinical outcomes. Clinical outcomes were evaluated by assessors and collectors blinded to the type of treatment administered. RESULTS: A total of 111 patients were randomly assigned to 3 groups and received 3 weekly injections of either PRP (44 patients), PRP+HA (31 patients), or HA (36 patients). At all follow-ups, the PRP group had the lowest VAS scores. In particular, at 6-month follow-up, the mean VAS score was 21 (95% CI, 15-28) in the PRP group, 35 (95% CI, 26-45) in the PRP+HA group, and 44 (95% CI, 36-52) in the HA group (P < .0005 [PRP vs HA] and P = .007 [PRP vs PRP+HA]; F = 0.663). The WOMAC score of the PRP group was significantly better at 2-month follow-up (mean, 73; 95% CI, 68-78) and 6-month follow-up (mean, 72; 95% CI, 67-76) but not at 12-month follow-up. A significant, "moderate" correlation was found between interleukin-10 and variations of the VAS score (r = 0.392; P = .040). Significant improvements were achieved in reducing pain and ameliorating quality of life and functional recovery. CONCLUSION: Results indicated that intra-articular PRP injections offer a significant clinical improvement in patients with hip OA without relevant side effects. The benefit was significantly more stable up to 12 months as compared with the other tested treatments. The addition of PRP+HA did not lead to a significant improvement in pain symptoms.


Assuntos
Ácido Hialurônico/administração & dosagem , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/terapia , Plasma Rico em Plaquetas , Viscossuplementos/administração & dosagem , Adulto , Terapia Combinada , Feminino , Humanos , Injeções Intra-Articulares/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Resultado do Tratamento , Ultrassonografia de Intervenção/estatística & dados numéricos
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