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1.
Nanomedicine ; 12(3): 823-833, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26654993

RESUMEN

Biofunctionalized scaffold facilitates complete healing of large defects. Biological constraints are induction and ingrowth of vessels. Angiogenic growth factors such as vascular endothelial growth factor or angiopoietin-1 can be bound to nano-scaled diamond particles. Corresponding bioactivities need to be examined after biofunctionalization. We therefore determined the physisorptive capacity of distinctly manufactured, differently sized nDP and the corresponding activities of bound factors. The properties of biofunctionalized nDPs were investigated on cultivated human mesenchymal stem cells and on the developing chicken embryo chorio-allantoic membrane. Eventually porous bone substitution material was coated with nDP to generate an interface that allows biofactor physisorption. Angiopoietin-1 was applied shortly before scaffold implantation into an osseous defect in sheep calvaria. Biofunctionalized scaffolds exhibited significantly increased rates of angiogenesis already one month after implantation. Conclusively, nDP can be used to ease functionalization of synthetic biomaterials. FROM THE CLINICAL EDITOR: With the advances in nanotechnology, many nano-sized materials have been used in the biomedical field. This is also true for nano-diamond particles (nDP). In this article, the authors investigated the physical properties of functionalized nano-diamond particles in both in-vitro and in-vivo settings. The positive findings would help improve understanding of these nanomaterials in regenerative medicine.


Asunto(s)
Inductores de la Angiogénesis/farmacología , Angiopoyetina 1/farmacología , Diamante/química , Nanoestructuras/química , Neovascularización Fisiológica , Andamios del Tejido/química , Factor A de Crecimiento Endotelial Vascular/farmacología , Adsorción , Inductores de la Angiogénesis/química , Angiopoyetina 1/química , Animales , Sustitutos de Huesos/química , Sustitutos de Huesos/farmacología , Embrión de Pollo , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Nanoestructuras/ultraestructura , Neovascularización Fisiológica/efectos de los fármacos , Ovinos , Ingeniería de Tejidos , Factor A de Crecimiento Endotelial Vascular/química
2.
J Mater Chem B ; 9(45): 9395-9405, 2021 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-34734960

RESUMEN

Nanodiamonds (ND) have been suggested to have several potential uses in biomedicine, since they are seemingly biocompatible. However, data about the biological effects of ND in physiological conditions are scarce. In this study, we observed that prostate cancer cells (LNCaP) and breast cancer cells (MDA-MB-231 and MCF-7) cultured with ND show morphological changes and altered gene and protein expression. In 2D we could detect only slight effects of ND on cell growth and apoptosis induction. Therefore, we applied different functionalized ND in a novel 3D cell culture model that reflects better tissue conditions compared to conventional 2D cell cultures. In 3D proliferation was reduced by all nanoparticles and benzoquinone functionalized ND induced cell death. As the used decellularized scaffold maintains the tissue architecture, we could also functionally investigate if nanoparticles induce cell migration into deeper layers and if they display markers of Mesenchymal Epithelial Transition (MET). We detected in more mesenchymal and invasive growing MDA-MB-231 cells less vimentin and increased levels of pan-cytokeratin expression after ND treatment, which indicates a MET induction. Our observations suggest that the presence of ND stimulates MET, with varying degrees of transition. The observation that ND do not support the opposite, EMT, is beneficial, since EMT is known to play a major role in tumor metastasis. However, a special focus should be placed on the characterization of biological effects to be able to guarantee the safety of ND in clinical use.


Asunto(s)
Técnicas de Cultivo Tridimensional de Células , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal/efectos de los fármacos , Nanodiamantes , Apoptosis , Diferenciación Celular , Línea Celular Tumoral , Humanos
3.
Bioorg Med Chem Lett ; 20(18): 5541-3, 2010 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-20692829

RESUMEN

Allicin and derivatives thereof inhibit the CAC1 cysteine proteases falcipain 2, rhodesain, cathepsin B and L in the low micromolar range. The structure-activity relationship revealed that only derivatives with primary carbon atom in vicinity to the thiosulfinate sulfur atom attacked by the active-site Cys residue are active against the target enzymes. Some compounds also show potent antiparasitic activity against Plasmodium falciparum and Trypanosoma brucei brucei.


Asunto(s)
Antiparasitarios/química , Antiparasitarios/farmacología , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Plasmodium falciparum/enzimología , Ácidos Sulfínicos/química , Ácidos Sulfínicos/farmacología , Trypanosoma brucei brucei/enzimología , Animales , Cisteína Endopeptidasas/metabolismo , Disulfuros , Ajo/química , Humanos , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Trypanosoma brucei brucei/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológico
4.
J Mater Chem B ; 5(32): 6629-6636, 2017 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-32264425

RESUMEN

One of the major challenges in bone tissue engineering is adequate vascularization within bone substituents for nutrients and oxygen supply. In this study, the production and results of a new, highly functional bone construct consisting of a commercial three-dimensional ß-tricalcium phosphate scaffold (ß-TCP, ChronOS®) and hydrophilic, functionalized nanodiamond (ND) particles are reported. A 30-fold increase in the active surface area of the ChronOS + ND scaffold was achieved after modification with ND. In addition, immobilization of angiopoietin-1 (Ang-1) via physisorption within the ß-TCP + ND scaffold retained the bioactivity of the growth factor. Homogeneous distribution of the ND and Ang-1 within the core of the three-dimensional scaffold was confirmed using ND covalently labelled with Oregon Green. The biological responses of the ß-TCP + ND scaffold with and without Ang-1 were studied in a sheep calvaria critical size defect model showing that the ß-TCP + ND scaffold improved the blood vessel ingrowth and the ß-TCP + ND + ND + Ang-1 scaffold further promoted vascularization and new bone formation. The results demonstrate that the modification of scaffolds with tailored diamond nanoparticles is a valuable method for improving the characteristics of bone implants and enables new approaches in bone tissue engineering.

5.
Macromol Biosci ; 17(6)2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28116858

RESUMEN

Functionalizing polymer scaffolds with nanodiamond particles (nDPs) has pronounced effect on the surface properties, such as improved wettability, an increased active area and binding sites for cellular attachment and adhesion, and increased ability to immobilize biomolecules by physical adsorption. This study aims to evaluate the effect of poly(l-lactide-co-ε-caprolactone) (poly(LLA-co-CL)) scaffolds, functionalized with nDPs, on bone regeneration in a rat calvarial critical size defect. Poly(LLA-co-CL) scaffolds functionalized with nDPs are also compared with pristine scaffolds with reference to albumin adsorption and seeding efficiency of bone marrow stromal cells (BMSCs). Compared with pristine scaffolds, the experimental scaffolds exhibit a reduction in albumin adsorption and a significant increase in the seeding efficiency of BMSCs (p = 0.027). In the calvarial defects implanted with BMSC-seeded poly(LLA-co-CL)/nDPs scaffolds, live imaging at 12 weeks discloses a significant increase in osteogenic metabolic activity (p = 0.016). Microcomputed tomography, confirmed by histological data, reveals a substantial increase in bone volume (p = 0.021). The results show that compared with conventional poly(LLA-co-CL) scaffolds those functionalized with nDPs promote osteogenic metabolic activity and mineralization capacity. It is concluded that poly(LLA-co-CL) composite matrices functionalized with nDPs enhance osteoconductivity and therefore warrant further study as potential scaffolding material for bone tissue engineering.


Asunto(s)
Regeneración Ósea/efectos de los fármacos , Nanodiamantes/química , Osteogénesis/efectos de los fármacos , Andamios del Tejido/química , Animales , Caproatos/química , Caproatos/uso terapéutico , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Lactonas/química , Lactonas/uso terapéutico , Nanodiamantes/uso terapéutico , Ratas , Propiedades de Superficie/efectos de los fármacos
6.
Adv Healthc Mater ; 5(6): 730-42, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26853449

RESUMEN

The aim is to evaluate the effect of modifying poly[(l-lactide)-co-(ε-caprolactone)] scaffolds (PLCL) with nanodiamonds (nDP) or with nDP+physisorbed BMP-2 (nDP+BMP-2) on in vivo host tissue response and degradation. The scaffolds are implanted subcutaneously in Balb/c mice and retrieved after 1, 8, and 27 weeks. Molecular weight analysis shows that modified scaffolds degrade faster than the unmodified. Gene analysis at week 1 shows highest expression of proinflammatory markers around nDP scaffolds; although the presence of inflammatory cells and foreign body giant cells is more prominent around the PLCL. Tissue regeneration markers are highly expressed in the nDP+BMP-2 scaffolds at week 8. A fibrous capsule is detectable by week 8, thinnest around nDP scaffolds and at week 27 thickest around PLCL scaffolds. mRNA levels of ALP, COL1α2, and ANGPT1 are significantly upregulating in the nDP+BMP-2 scaffolds at week 1 with ectopic bone seen at week 8. Even when almost 90% of the scaffold is degraded at week 27, nDP are observable at implantation areas without adverse effects. In conclusion, modifying PLCL scaffolds with nDP does not aggravate the host response and physisorbed BMP-2 delivery attenuates inflammation while lowering the dose of BMP-2 to a relatively safe and economical level.


Asunto(s)
Proteína Morfogenética Ósea 2/química , Nanodiamantes/química , Poliésteres/química , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Angiopoyetina 1/genética , Angiopoyetina 1/metabolismo , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/metabolismo , Materiales Biocompatibles/farmacología , Proteína Morfogenética Ósea 2/metabolismo , Regeneración Ósea/fisiología , Huesos/diagnóstico por imagen , Huesos/fisiología , Quimiocinas/deficiencia , Quimiocinas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Femenino , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos BALB C , Neovascularización Fisiológica , Prótesis e Implantes , Piel/metabolismo , Piel/patología , Regulación hacia Arriba/efectos de los fármacos , Microtomografía por Rayos X
7.
Biomaterials ; 95: 11-21, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27108402

RESUMEN

This study aimed to evaluate the tumorigenic potential of functionalising poly(LLA-co-CL) scaffolds. The copolymer scaffolds were functionalised with nanodiamonds (nDP) or with nDP and physisorbed BMP-2 (nDP-PHY) to enhance osteoinductivity. Culturing early neoplastic dysplastic keratinocytes (DOK(Luc)) on nDP modified scaffolds reduced significantly their subsequent sphere formation ability and decreased significantly the cells' proliferation in the supra-basal layers of in vitro 3D oral neoplastic mucosa (3D-OT) when compared to DOK(Luc) previously cultured on nDP-PHY scaffolds. Using an in vivo non-invasive environmentally-induced oral carcinogenesis model, nDP scaffolds were observed to reduce bioluminescence intensity of tumours formed by DOK(Luc) + carcinoma associated fibroblasts (CAF). nDP modification was also found to promote differentiation of DOK(Luc) both in vitro in 3D-OT and in vivo in xenografts formed by DOK(Luc) alone. The nDP-PHY scaffold had the highest number of invasive tumours formed by DOK(Luc) + CAF outside the scaffold area compared to the nDP and control scaffolds. In conclusion, in vitro and in vivo results presented here demonstrate that nDP modified copolymer scaffolds are able to decrease the tumorigenic potential of DOK(Luc), while confirming concerns for the therapeutic use of BMP-2 for reconstruction of bone defects in oral cancer patients due to its tumour promoting capabilities.


Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Queratinocitos/patología , Neoplasias de la Boca/terapia , Nanodiamantes/química , Nanodiamantes/uso terapéutico , Poliésteres/química , Animales , Proteína Morfogenética Ósea 2/metabolismo , Huesos/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Queratinocitos/metabolismo , Ratones , Mucosa Bucal/patología , Imagen Óptica , Andamios del Tejido
8.
J Control Release ; 197: 148-57, 2015 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-25445698

RESUMEN

A low dose of 1µg rhBMP-2 was immobilised by four different functionalising techniques on recently developed poly(l-lactide)-co-(ε-caprolactone) [(poly(LLA-co-CL)] scaffolds. It was either (i) physisorbed on unmodified scaffolds [PHY], (ii) physisorbed onto scaffolds modified with nanodiamond particles [nDP-PHY], (iii) covalently linked onto nDPs that were used to modify the scaffolds [nDP-COV] or (iv) encapsulated in microspheres distributed on the scaffolds [MICS]. Release kinetics of BMP-2 from the different scaffolds was quantified using targeted mass spectrometry for up to 70days. PHY scaffolds had an initial burst of release while MICS showed a gradual and sustained increase in release. In contrast, NDP-PHY and nDP-COV scaffolds showed no significant release, although nDP-PHY scaffolds maintained bioactivity of BMP-2. Human mesenchymal stem cells cultured in vitro showed upregulated BMP-2 and osteocalcin gene expression at both week 1 and week 3 in the MICS and nDP-PHY scaffold groups. These groups also demonstrated the highest BMP-2 extracellular protein levels as assessed by ELISA, and mineralization confirmed by Alizarin red. Cells grown on the PHY scaffolds in vitro expressed collagen type 1 alpha 2 early but the scaffold could not sustain rhBMP-2 release to express mineralization. After 4weeks post-implantation using a rat mandible critical-sized defect model, micro-CT and Masson trichrome results showed accelerated bone regeneration in the PHY, nDP-PHY and MICS groups. The results demonstrate that PHY scaffolds may not be desirable for clinical use, since similar osteogenic potential was not seen under both in vitro and in vivo conditions, in contrast to nDP-PHY and MICS groups, where continuous low doses of BMP-2 induced satisfactory bone regeneration in both conditions. The nDP-PHY scaffolds used here in critical-sized bone defects for the first time appear to have promise compared to growth factors adsorbed onto a polymer alone and the short distance effect prevents adverse systemic side effects.


Asunto(s)
Proteína Morfogenética Ósea 2 , Andamios del Tejido , Animales , Proteína Morfogenética Ósea 2/administración & dosificación , Proteína Morfogenética Ósea 2/química , Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 2/metabolismo , Regeneración Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Microesferas , Poliésteres/química , Ratas Sprague-Dawley , Transducción de Señal
9.
Tissue Eng Part A ; 19(15-16): 1783-91, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23574424

RESUMEN

Significant evidence has indicated that poly(L-lactide)-co-(ɛ-caprolactone) [(poly(LLA-co-CL)] scaffolds could be one of the suitable candidates for bone tissue engineering. Oxygen-terminated nanodiamond particles (n-DP) were combined with poly(LLA-co-CL) and revealed to be positive for cell growth. In this study, we evaluated the influence of poly(LLA-co-CL) scaffolds modified by n-DP on attachment, proliferation, differentiation of bone marrow stromal cells (BMSCs) in vitro, and on bone formation using a sheep calvarial defect model. BMSCs were seeded on either poly(LLA-co-CL)- or n-DP-coated scaffolds and incubated for 1 h. Scanning electron microscopy (SEM) and fluorescence microscopy were used in addition to protein and DNA measurements to evaluate cellular attachment on the scaffolds. To determine the effect of n-DP on proliferation of BMSCs, cell/scaffold constructs were harvested after 3 days and evaluated by Bicinchoninic Acid (BCA) protein assay and SEM. In addition, the osteogenic differentiation of cells grown for 2 weeks on the various scaffolds and in a dynamic culture condition was evaluated by real-time RT-PCR. Unmodified and modified scaffolds were implanted into the calvaria of six-year-old sheep. The expression of collagen type I (COL I) and bone morphogenetic protein-2 (BMP-2) after 4 weeks as well as the formation of new bone after 12 and 24 weeks were analyzed by immunohistochemistry and histology. Scaffolds modified with n-DP supported increased cell attachment and the mRNA expression of osteopontin (OPN), bone sialoprotein (BSP), and BMP-2 were significantly increased after 2 weeks of culture. The BMSCs had spread well on the various scaffolds investigated after 3 days in the study with no significant difference in cell proliferation. Furthermore, the in vivo data revealed more positive staining of COL I and BMP-2 in relation to the n-DP-coated scaffolds after 4 weeks and presented more bone formation after 12 and 24 weeks. n-DP modification significantly increased cell attachment and differentiation of BMSCs on poly(LLA-co-CL) scaffolds in vitro and enhanced bone formation in vivo.


Asunto(s)
Nanodiamantes/química , Polímeros/química , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Animales , Proliferación Celular , Células Cultivadas , Colágeno Tipo I/química , Femenino , Humanos , Sialoproteína de Unión a Integrina/química , Microscopía de Fuerza Atómica , Microscopía Electrónica de Rastreo , Microscopía Fluorescente , Osteogénesis/fisiología , Osteopontina/química , Ovinos
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