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1.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445516

RESUMO

In this study, we prepared core-sheath nanofiber membranes (CSNFMs) with silver nanoparticles (Ag NPs) embedding in the polylactic acid (PLA) nanofiber sheath and hyaluronic acid (HA) in the nanofiber core. The PLA/Ag NPs sheath provides mechanical support as well as anti-bacterial and anti-inflammatory properties. The controlled release of HA from the core could exert anti-adhesion effects to promote tendon sliding while reducing fibroblast attachment. From the microfibrous structural nature of CSNFMs, they function as barrier membranes to reduce fibroblast penetration without hampering nutrient transports to prevent post-operative peritendinous adhesion. As the anti-adhesion efficacy will depend on release rate of HA from the core as well as Ag NP from the sheath, we fabricated CSNFMs of comparable fiber diameter, but with thick (Tk) or thin (Tn) sheath. Similar CSNFMs with thick (Tk+) and thin (Tn+) sheath but with embedded Ag NPs in the sheath were also prepared. The physico-chemical properties of the barrier membranes were characterized in details, together with their biological response including cell penetration, cell attachment and proliferation, and cytotoxicity. Peritendinous anti-adhesion models in rabbits were used to test the efficacy of CSNFMs as anti-adhesion barriers, from gross observation, histology, and biomechanical tests. Overall, the CSNFM with thin-sheath and Ag NPs (Tn+) shows antibacterial activity with low cytotoxicity, prevents fibroblast penetration, and exerts the highest efficacy in reducing fibroblast attachment in vitro. From in vivo studies, the Tn+ membrane also shows significant improvement in preventing peritendinous adhesions as well as anti-inflammatory efficacy, compared with Tk and Tn CSNFMs and a commercial adhesion barrier film (SurgiWrap®) made from PLA.


Assuntos
Antibacterianos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Poliésteres/química , Prata/química , Traumatismos dos Tendões/tratamento farmacológico , Células 3T3 , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Nanopartículas Metálicas , Camundongos , Testes de Sensibilidade Microbiana , Nanofibras/química , Espectroscopia Fotoeletrônica , Coelhos , Traumatismos dos Tendões/cirurgia , Aderências Teciduais/prevenção & controle
2.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445313

RESUMO

High levels of hyaluronic acid (HA) in tumors correlate with poor outcomes with several types of cancers due to HA-driven support of adhesion, migration and proliferation of cells. In this study we explored how to enhance the degradation of HA into low-molecular fragments, which cannot prevent the immune system to fight tumor proliferation and metastases. The physiological solution of HA was exposed to oxidative degradation by ascorbate and cupric ions in the presence of either one of three ortho isomeric Mn(III) substituted N-alkyl- and alkoxyalkylpyridylporphyrins or para isomeric Mn(III) N-methylpyridyl analog, commonly known as mimics of superoxide dismutase. The changes in hyaluronan degradation kinetics by four Mn(III) porphyrins were monitored by measuring the alteration in the dynamic viscosity of the HA solution. The ortho compounds MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001) and MnTnHex-2-PyP5+ are able to redox cycle with ascorbate whereby producing H2O2 which is subsequently coupled with Cu(I) to produce the •OH radical essential for HA degradation. Conversely, with the para analog, MnTM-4-PyP5+, no catalysis of HA degradation was demonstrated, due to its inertness towards redox cycling with ascorbate. The impact of different Mn(III)-porphyrins on the HA decay was further clarified by electron paramagnetic resonance spectrometry. The ability to catalyze the degradation of HA in a biological milieu, in the presence of cupric ions and ascorbate under the conditions of high tumor oxidative stress provides further insight into the anticancer potential of redox-active ortho isomeric Mn(III) porphyrins.


Assuntos
Ácido Ascórbico/química , Ácido Hialurônico/química , Metaloporfirinas/química , Cobre/química , Magnésio/química , Oxirredução , Superóxido Dismutase/metabolismo
3.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200716

RESUMO

In this study, we report pH-responsive metal-based biopolymer nanoparticles (NPs) for tumor-specific chemotherapy. Here, aminated hyaluronic acid (aHA) coupled with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive moiety) (aHA-DMA) was electrostatically complexed with ferrous chloride tetrahydrate (FeCl2/4H2O, as a chelating metal) and doxorubicin (DOX, as an antitumor drug model), producing DOX-loaded Fe-based hyaluronate nanoparticles (DOX@aHA-DMA/Fe NPs). Importantly, the DOX@aHA-DMA/Fe NPs improved tumor cellular uptake due to HA-mediated endocytosis for tumor cells overexpressing CD44 receptors. As a result, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) was ~7.9 × 102 (DOX@HA/Fe NPs, without DMA), ~8.1 × 102 (DOX@aHA-DMA0.36/Fe NPs), and ~9.3 × 102 (DOX@aHA-DMA0.60/Fe NPs). Furthermore, the DOX@aHA-DMA/Fe NPs were destabilized due to ionic repulsion between Fe2+ and DMA-detached aHA (i.e., positively charged free aHA) in the acidic environment of tumor cells. This event accelerated the release of DOX from the destabilized NPs. Our results suggest that these NPs can be promising tumor-targeting drug carriers responding to acidic endosomal pH.


Assuntos
Doxorrubicina/química , Endossomos/química , Compostos Ferrosos/química , Ácido Hialurônico/química , Nanopartículas/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C
4.
Int J Biol Macromol ; 185: 604-619, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34216662

RESUMO

Hepatic cancer is one of the most widespread maladies worldwide that requires urgent therapies and thus reliable means for testing anti-cancer drugs. The switch from two-dimensional (2D) to three-dimensional (3D) cell cultures produced an improvement in the in vitro outcomes for testing anti-cancer drugs. We aimed to develop a novel hyaluronic acid (HA)-based 3D cell model of human hepatocellular carcinoma (HepG2 cells) for drug testing and to assess comparatively in 3D vs. 2D, the cytotoxicity and the apoptotic response to the anti-tumor agent, cisplatin. The 3D model was developed by seeding HepG2 cells in a HA/poly(methylvinylether-alt-maleic acid) (HA3P50)-based scaffold. Compared to 2D, the cells grown in the HA3P50 scaffold proliferate into larger-cellular aggregates that exhibit liver-like functions by controlling the release of hepatocyte-specific biomarkers (albumin, urea, bile acids, transaminases) and the synthesis of cytochrome-P450 (CYP)7A1 enzyme. Also, growing the cells in the scaffold sensitize the hepatocytes to the anti-tumor effect of cisplatin, by a mechanism involving the activation of ERK/p38α-MAPK and dysregulation of NF-kB/STAT3/Bcl-2 pathways. In conclusion, the newly developed HA-based 3D model is suitable for chemotherapeutic drug testing on hepatocellular carcinoma. Moreover, the system can be adapted and employed as experimental platform functioning as a proper tissue/tumor surrogate.


Assuntos
Materiais Biomiméticos/química , Carcinoma Hepatocelular/metabolismo , Cisplatino/farmacologia , Ácido Hialurônico/química , Neoplasias Hepáticas/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol 7-alfa-Hidroxilase/metabolismo , Cisplatino/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Tecidos Suporte
5.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34292870

RESUMO

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2), presents an urgent health crisis. More recently, an increasing number of mutated strains of SARS-CoV-2 have been identified globally. Such mutations, especially those on the spike glycoprotein to render its higher binding affinity to human angiotensin-converting enzyme II (hACE2) receptors, not only resulted in higher transmission of SARS-CoV-2 but also raised serious concerns regarding the efficacies of vaccines against mutated viruses. Since ACE2 is the virus-binding protein on human cells regardless of viral mutations, we design hACE2-containing nanocatchers (NCs) as the competitor with host cells for virus binding to protect cells from SARS-CoV-2 infection. The hACE2-containing NCs, derived from the cellular membrane of genetically engineered cells stably expressing hACE2, exhibited excellent neutralization ability against pseudoviruses of both wild-type SARS-CoV-2 and the D614G variant. To prevent SARS-CoV-2 infections in the lung, the most vulnerable organ for COVID-19, we develop an inhalable formulation by mixing hACE2-containing NCs with mucoadhesive excipient hyaluronic acid, the latter of which could significantly prolong the retention of NCs in the lung after inhalation. Excitingly, inhalation of our formulation could lead to potent pseudovirus inhibition ability in hACE2-expressing mouse model, without imposing any appreciable side effects. Importantly, our inhalable hACE2-containing NCs in the lyophilized formulation would allow long-term storage, facilitating their future clinical use. Thus, this work may provide an alternative tactic to inhibit SARS-CoV-2 infections even with different mutations, exhibiting great potential for treatment of the ongoing COVID-19 epidemic.


Assuntos
COVID-19/prevenção & controle , Nanoestruturas/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , Adesivos/administração & dosagem , Adesivos/química , Adesivos/farmacocinética , Administração por Inalação , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Crioprotetores/química , Armazenamento de Medicamentos , Células Epiteliais/metabolismo , Excipientes/administração & dosagem , Excipientes/química , Excipientes/farmacocinética , Células HEK293 , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Nanoestruturas/química , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Ligação Viral/efeitos dos fármacos
6.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299359

RESUMO

Chronic lung allograft dysfunction (CLAD) and interstitial lung disease associated with collagen tissue diseases (CTD-ILD) are two end-stage lung disorders in which different chronic triggers induce activation of myo-/fibroblasts (LFs). Everolimus, an mTOR inhibitor, can be adopted as a potential strategy for CLAD and CTD-ILD, however it exerts important side effects. This study aims to exploit nanomedicine to reduce everolimus side effects encapsulating it inside liposomes targeted against LFs, expressing a high rate of CD44. PEGylated liposomes were modified with high molecular weight hyaluronic acid and loaded with everolimus (PEG-LIP(ev)-HA400kDa). Liposomes were tested by in vitro experiments using LFs derived from broncholveolar lavage (BAL) of patients affected by CLAD and CTD-ILD, and on alveolar macrophages (AM) and lymphocytes isolated, respectively, from BAL and peripheral blood. PEG-LIP-HA400kDa demonstrated to be specific for LFs, but not for CD44-negative cells, and after loading everolimus, PEG-LIP(ev)-HA400kDa were able to arrest cell cycle arrest and to decrease phospho-mTOR level. PEG-LIP(ev)-HA400kDa showed anti-inflammatory effect on immune cells. This study opens the possibility to use everolimus in lung fibrotic diseases, demonstrating that our lipids-based vehicles can vehicle everolimus inside cells exerting the same drug molecular effect, not only in LFs, but also in immune cells.


Assuntos
Everolimo/farmacologia , Ácido Hialurônico/farmacologia , Lipossomos/química , Fibrose Pulmonar/tratamento farmacológico , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Lavagem Broncoalveolar/métodos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Sistemas de Liberação de Medicamentos/métodos , Everolimo/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Polietilenoglicóis/química , Fibrose Pulmonar/metabolismo
7.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198522

RESUMO

We synthesized phenylboronic acid pinacol ester (PBPE)-conjugated hyaluronic acid (HA) via thiobis(ethylamine) (TbEA) linkage (abbreviated as HAsPBPE conjugates) to fabricate the radiosensitive delivery of caffeic acid phenetyl ester (CAPE) and for application in radioprotection. PBPE was primarily conjugated with TbEA and then PBPE-TbEA conjugates were conjugated again with hyaluronic acid using carbodiimide chemistry. CAPE-incorporated nanoparticles of HAsPBPE were fabricated by the nanoprecipitation method and then the organic solvent was removed by dialysis. CAPE-incorporated HAsPBPE nanoparticles have a small particle size of about 80 or 100 nm and they have a spherical shape. When CAPE-incorporated HAsPBPE nanoparticles were irradiated, nanoparticles became swelled or disintegrated and their morphologies were changed. Furthermore, the CAPE release rate from HAsPBPE nanoparticles were increased according to the radiation dose, indicating that CAPE-incorporated HAsPBPE nanoparticles have radio-sensitivity. CAPE and CAPE-incorporated HAsPBPE nanoparticles appropriately prevented radiation-induced cell death and suppressed intracellular accumulation of reactive oxygen species (ROS). CAPE and CAPE-incorporated HAsPBPE nanoparticles efficiently improved survivability of mice from radiation-induced death and reduced apoptotic cell death. We suggest that HAsPBPE nanoparticles are promising candidates for the radio-sensitive delivery of CAPE.


Assuntos
Ácidos Borônicos/química , Ácidos Cafeicos/farmacologia , Glicóis/química , Ácido Hialurônico/química , Nanopartículas/química , Álcool Feniletílico/análogos & derivados , Proteção Radiológica , Animais , Ácidos Borônicos/síntese química , Ácidos Cafeicos/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Peróxido de Hidrogênio/toxicidade , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Tamanho da Partícula , Álcool Feniletílico/síntese química , Álcool Feniletílico/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
8.
Int J Nanomedicine ; 16: 4481-4494, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239300

RESUMO

Purpose: Apatinib (Apa) is a novel anti-vascular endothelial growth factor with the potential to treat diabetic retinopathy (DR); a serious condition leading to visual impairment and blindness. DR treatment relies on invasive techniques associated with various complications. Investigating topical routes for Apa delivery to the posterior eye segment is thus promising but also challenging due to ocular barriers. Hence, the study objective was to develop Apa-loaded bovine serum albumin nanoparticles (Apa-BSA-NPs) coated with hyaluronic acid (HA); a natural polymer possessing unique mucoadhesive and viscoelastic features with the capacity to actively target CD44 positive retinal cells, for topical administration in DR. Methods: Apa-BSA-NPs were prepared by desolvation using glutaraldehyde for cross-linking. HA-coated BSA-NPs were also prepared and HA: NPs ratio optimized. Nanoparticles were characterized for colloidal properties, entrapment efficiency (EE%), in vitro drug release and mucoadhesive potential. In vitro cytotoxicity on rabbit corneal epithelial cells (RCE) was assessed using MTT assay, while efficacy was evaluated in vivo in a diabetic rat model by histopathological examination of the retina by light and transmission electron microscopy. Retinal accumulation of fluorescently labeled BSA-NP and HA-BSA-NP was assessed using confocal microscope scanning. Results: Apa-HA-BSA-NPs prepared under optimal conditions showed size, PdI and zeta potential: 222.2±3.56 nm, 0.221±0.02 and -37.3±1.8 mV, respectively. High EE% (69±1%), biphasic sustained release profile with an initial burst effect and mucoadhesion was attained. No evidence of cytotoxicity was observed on RCE cells. In vivo histopathological studies on DR rat model revealed alleviated retinal micro- and ultrastructural changes in the topical HA-Apa-BSA-NP treated eyes with normal basement membrane and retinal thickness comparable to normal control and intravitreally injected nanoparticles. Improved retinal accumulation for HA-BSA-NP was also observed by confocal microscopy. Conclusion: Findings present HA-Apa-BSA-NPs as a platform for enhanced topical therapy of DR overcoming the devastating ocular complications of the intravitreal route.


Assuntos
Retinopatia Diabética/metabolismo , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Piridinas/administração & dosagem , Piridinas/química , Soroalbumina Bovina/química , Animais , Retinopatia Diabética/tratamento farmacológico , Liberação Controlada de Fármacos , Tamanho da Partícula , Piridinas/metabolismo , Piridinas/uso terapêutico , Coelhos , Ratos , Retina/metabolismo
9.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207389

RESUMO

Hollow nerve guidance conduits are approved for clinical use for defect lengths of up to 3 cm. This is because also in pre-clinical evaluation they are less effective in the support of nerve regeneration over critical defect lengths. Hydrogel luminal fillers are thought to improve the regeneration outcome by providing an optimized matrix inside bioartificial nerve grafts. We evaluated here a modified hyaluronic acid-laminin-hydrogel (M-HAL) as luminal filler for two clinically approved hollow nerve guides. Collagen-based and chitosan-based nerve guides were filled with M-HAL in two different concentrations and the regeneration outcome comprehensively studied in the acute repair rat sciatic nerve 15 mm critical defect size model. Autologous nerve graft (ANG) repair served as gold-standard control. At 120 days post-surgery, all ANG rats demonstrated electrodiagnostically detectable motor recovery. Both concentrations of the hydrogel luminal filler induced improved regeneration outcome over empty nerve guides. However, neither combination with collagen- nor chitosan-based nerve guides resulted in functional recovery comparable to the ANG repair. In contrast to our previous studies, we demonstrate here that M-HAL slightly improved the overall performance of either empty nerve guide type in the critical defect size model.


Assuntos
Regeneração Tecidual Guiada/métodos , Ácido Hialurônico/química , Hidrogéis/química , Laminina/química , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/cirurgia , Animais , Células Cultivadas , Feminino , Ratos , Ratos Endogâmicos Lew
10.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199374

RESUMO

BACKGROUND: Skinboosters represent the latest category of hyaluronan (HA) hydrogels released for aesthetic purposes. Different from originally developed gels, they are intended for more superficial injections, claiming a skin rejuvenation effect through hydration and possibly prompting biochemical effects in place of the conventional volumetric action. Here, three commercial skinboosters were characterized to unravel the scientific basis for such indication and to compare their performances. METHODS: Gels were evaluated for water-soluble/insoluble-HA composition, rheology, hydration, cohesivity, stability and effect, in vitro, on human dermal fibroblasts towards the production of extracellular matrix components. RESULTS: Marked differences in the insoluble-hydrogel amount and in the hydrodynamic parameters for water-soluble-HA chains were evidenced among the gels. Hydration, rigidity and cohesivity also varied over a wide range. Sensitivity to hyaluronidases and Reactive Oxygen Species was demonstrated allowing a stability ranking. Slight differences were found in gels' ability to prompt elastin expression and in ColIV/ColI ratio. CONCLUSIONS: A wide panel of biophysical and biochemical parameters for skinboosters was provided, supporting clinicians in the conscious tuning of their use. Data revealed great variability in gels' behavior notwithstanding the same clinical indication and unexpected similarities to the volumetric formulations. Data may be useful to improve customization of gel design toward specific uses.


Assuntos
Ácido Hialurônico/química , Hialuronoglucosaminidase/genética , Hidrogéis/química , Pele/efeitos dos fármacos , Elastina/química , Fibroblastos/efeitos dos fármacos , Humanos , Hialuronoglucosaminidase/química , Injeções , Espécies Reativas de Oxigênio/química , Rejuvenescimento/fisiologia , Reologia , Pele/crescimento & desenvolvimento , Pele/patologia , Envelhecimento da Pele/genética , Viscosidade
11.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201769

RESUMO

Hyaluronic acid (HA) and gelatin (Gel) are major components of the extracellular matrix of different tissues, and thus are largely appealing for the construction of hybrid hydrogels to combine the favorable characteristics of each biopolymer, such as the gel adhesiveness of Gel and the better mechanical strength of HA, respectively. However, despite previous studies conducted so far, the relationship between composition and scaffold structure and physico-chemical properties has not been completely and systematically established. In this work, pure and hybrid hydrogels of methacroyl-modified HA (HAMA) and Gel (GelMA) were prepared by UV photopolymerization and an extensive characterization was done to elucidate such correlations. Methacrylation degrees of ca. 40% and 11% for GelMA and HAMA, respectively, were obtained, which allows to improve the hydrogels' mechanical properties. Hybrid GelMA/HAMA hydrogels were stiffer, with elastic modulus up to ca. 30 kPa, and porous (up to 91%) compared with pure GelMA ones at similar GelMA concentrations thanks to the interaction between HAMA and GelMA chains in the polymeric matrix. The progressive presence of HAMA gave rise to scaffolds with more disorganized, stiffer, and less porous structures owing to the net increase of mass in the hydrogel compositions. HAMA also made hybrid hydrogels more swellable and resistant to collagenase biodegradation. Hence, the suitable choice of polymeric composition allows to regulate the hydrogels´ physical properties to look for the most optimal characteristics required for the intended tissue engineering application.


Assuntos
Materiais Biocompatíveis/química , Gelatina/química , Ácido Hialurônico/química , Hidrogéis/química , Metacrilatos/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Humanos , Polímeros/química
12.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202183

RESUMO

The buzz about hyaluronan (HA) is real. Whether found in face cream to increase water volume loss and viscoelasticity or injected into the knee to restore the properties of synovial fluid, the impact of HA can be recognized in many disciplines from dermatology to orthopedics. HA is the most abundant polysaccharide of the extracellular matrix of connective tissues. HA can impact cell behavior in specific ways by binding cellular HA receptors, which can influence signals that facilitate cell survival, proliferation, adhesion, as well as migration. Characteristics of HA, such as its abundance in a variety of tissues and its responsiveness to chemical, mechanical and hormonal modifications, has made HA an attractive molecule for a wide range of applications. Despite being discovered over 80 years ago, its properties within the world of fascia have only recently received attention. Our fascial system penetrates and envelopes all organs, muscles, bones and nerve fibers, providing the body with a functional structure and an environment that enables all bodily systems to operate in an integrated manner. Recognized interactions between cells and their HA-rich extracellular microenvironment support the importance of studying the relationship between HA and the body's fascial system. From fasciacytes to chronic pain, this review aims to highlight the connections between HA and fascial health.


Assuntos
Fáscia/metabolismo , Ácido Hialurônico/metabolismo , Animais , Colágeno , Gerenciamento Clínico , Suscetibilidade a Doenças , Matriz Extracelular/metabolismo , Fáscia/patologia , Fibroblastos/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209222

RESUMO

Hyaluronan (HA) is a natural glycosaminoglycan present in many tissues of all vertebrates. HA has various biological functions, which are dependent on its molar mass. High-molar-mass HA has anti-angiogenic, immunosuppressive and anti-inflammatory properties, while low-molar-mass HA has opposite effects. HA has also antioxidative properties, however on the other hand it can be readily degraded by reactive oxygen species. For many years it has been used in treatment of osteoarthritis, cosmetics and in ophthalmology. In the last years there has been a growing interest of HA to also be applied in other fields of medicine such as skin wound healing, tissue engineering, dentistry and gene delivery. In this review we summarize information on modes of HA administration, properties and effects of HA in various fields of medicine including recent progress in the investigation of HA.


Assuntos
Cosméticos , Técnicas de Transferência de Genes , Ácido Hialurônico , Osteoartrite/tratamento farmacológico , Engenharia Tecidual , Cicatrização/efeitos dos fármacos , Cosméticos/química , Cosméticos/uso terapêutico , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/uso terapêutico
14.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198955

RESUMO

Hyaluronic acid (HA) is one of the most used biopolymers in the development of drug delivery systems, due to its biocompatibility, biodegradability, non-immunogenicity and intrinsic-targeting properties. HA specifically binds to CD44; this property combined to the EPR effect could provide an option for reinforced active tumor targeting by nanocarriers, improving drug uptake by the cancer cells via the HA-CD44 receptor-mediated endocytosis pathway. Moreover, HA can be easily chemically modified to tailor its physico-chemical properties in view of specific applications. The derivatization with cholesterol confers to HA an amphiphilic character, and then the ability of anchoring to niosomes. HA-Chol was then used to coat Span® or Tween® niosomes providing them with an intrinsic targeting shell. The nanocarrier physico-chemical properties were analyzed in terms of hydrodynamic diameter, ζ-potential, and bilayer structural features to evaluate the difference between naked and HA-coated niosomes. Niosomes stability was evaluated over time and in bovine serum. Moreover, interaction properties of HA-coated nanovesicles with model membranes, namely liposomes, were studied, to obtain insights on their interaction behavior with biological membranes in future experiments. The obtained coated systems showed good chemical physical features and represent a good opportunity to carry out active targeting strategies.


Assuntos
Materiais Biomiméticos/química , Colesterol/química , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/farmacologia , Animais , Bovinos , Membrana Celular , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Ácido Hialurônico/síntese química , Ácido Hialurônico/química , Lipossomos , Nanoestruturas , Tamanho da Partícula , Soro/química
15.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298939

RESUMO

The present study deals with the mathematical modeling of crosslinking kinetics of polymer-phenol conjugates mediated by the Horseradish Peroxidase (HRP)-hydrogen peroxide (H2O2) initiation system. More specifically, a dynamic Monte Carlo (MC) kinetic model is developed to quantify the effects of crosslinking conditions (i.e., polymer concentration, degree of phenol substitution and HRP and H2O2 concentrations) on the gelation onset time; evolution of molecular weight distribution and number and weight average molecular weights of the crosslinkable polymer chains and gel fraction. It is shown that the MC kinetic model can faithfully describe the crosslinking kinetics of a finite sample of crosslinkable polymer chains with time, providing detailed molecular information for the crosslinkable system before and after the gelation point. The MC model is validated using experimental measurements on the crosslinking of a tyramine modified Hyaluronic Acid (HA-Tyr) polymer solution reported in the literature. Based on the rubber elasticity theory and the MC results, the dynamic evolution of hydrogel viscoelastic and molecular properties (i.e., number average molecular weight between crosslinks, Mc, and hydrogel mesh size, ξ) are calculated.


Assuntos
Ácido Hialurônico/química , Tiramina/química , Elasticidade , Peroxidase do Rábano Silvestre/química , Hidrogéis/química , Peróxido de Hidrogênio/química , Cinética , Modelos Teóricos , Método de Monte Carlo , Polímeros/química , Reologia
16.
J Ayub Med Coll Abbottabad ; 33(2): 315-321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34137552

RESUMO

BACKGROUND: Osteoarthritis is the most common degenerative disease of the synovial joints in the elderly population with hip osteoarthritis as the second most commonly affected joint. A multitude of conservative treatments is used for pain relief and functional improvement including acetaminophen, NSAID, intra-articular corticosteroid, and viscosupplementation (VS). Different preparations of VS based on different molecular weights are commercially available. No systematic review or meta-analysis regarding the use of intra-articular high molecular weight hyaluronic acid (HMWHA) injection for the hip joint was published before. This review analyzes the efficacy of intra-articular HMWHA for hip osteoarthritis. METHODS: PubMed, Google Scholar, Cochrane Library for randomized trials describing the efficacy of HMWHA for hip osteoarthritis was searched. The search terms were osteoarthritis, hip joint, outcomes, viscosupplementation, and high molecular weight hyaluronic acid in different combinations. Standardized mean difference (SMD) in VAS for pain relief and Lequesne index for functional outcomes while risk ratio (RR) for complications was used for data pooling. RESULTS: Four studies comprising 185 and 189 patients in HMWHA and control groups were included, respectively. SMD for VAS and Lequesne index was -0.056 and -0.114, respectively while RR for complication was 0.879. CONCLUSIONS: Intra-articular HMWHA injection provided pain relief, functional improvement, and no severe complications on immediate short term basis. However, the results do not favor treatment with HMWHA over other treatment methods. Randomized trials are further necessary to provide data regarding comparisons between HMWHA for hip osteoarthritis concerning clinicians' convenience, compliance, duration of relief, and cost-effectiveness.


Assuntos
Ácido Hialurônico/administração & dosagem , Osteoartrite do Quadril/tratamento farmacológico , Viscossuplementos/administração & dosagem , Idoso , Humanos , Ácido Hialurônico/química , Injeções Intra-Articulares , Peso Molecular , Osteoartrite do Quadril/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Escala Visual Analógica
17.
Int J Biol Macromol ; 185: 350-368, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34171251

RESUMO

Injectable hydrogel with multifunctional tunable properties comprising biocompatibility, anti-oxidative, anti-bacterial, and/or anti-infection are highly preferred to efficiently promote diabetic wound repair and its development remains a challenge. In this study, we report hyaluronic acid and Pullulan-based injectable hydrogel loaded with curcumin that could potentiate reepithelization, increase angiogenesis, and collagen deposition at wound microenvironment to endorse healing cascade compared to other treatment groups. The physical interaction and self-assembly of hyaluronic acid-Pullulan-grafted-pluronic F127 injectable hydrogel were confirmed using nuclear magnetic resonance (1H NMR) and Fourier transformed infrared spectroscopy (FT-IR), and cytocompatibility was confirmed by fibroblast viability assay. The CUR-laden hyaluronic acid-Pullulan-g-F127 injectable hydrogel promptly undergoes a sol-gel transition and has proved to potentiate wound healing in a streptozotocin-induced diabetic rat model by promoting 93% of wound closure compared to other groups having 35%, 38%, and 62%. The comparative in vivo study and histological examination was conducted which demonstrated an expeditious recovery rate by significantly reducing the wound healing days i.e. 35 days in a control group, 33 days in the CUR suspension group, 21 days in unloaded injectable, and 13 days was observed in CUR loaded hydrogel group. Furthermore, we suggest that the injectable hydrogel laden with CUR showed a prompt wound healing potential by increasing the cell proliferation and serves as a drug delivery platform for sustained and targeted delivery of hydrophobic moieties.


Assuntos
Curcumina/administração & dosagem , Complicações do Diabetes/tratamento farmacológico , Glucanos/química , Ácido Hialurônico/administração & dosagem , Cicatrização/efeitos dos fármacos , Células 3T3-L1 , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Hidrogéis , Injeções , Masculino , Camundongos , Tamanho da Partícula , Coelhos , Ratos , Reologia , Estreptozocina/efeitos adversos
18.
Int J Biol Macromol ; 185: 98-110, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34119550

RESUMO

With increasing interest in aging and skin care, the use of fillers to increase the volume of soft tissue volume is increasing globally. However, the side effects caused by the residual chemical crosslinking agents present in these fillers limit the effective application of commercialized filler products. Therefore, the development of a novel crosslinking system with a non-toxic chemical crosslinking agent is required to overcome the limitations of commercial hyaluronate (HA)-based fillers. In this paper, a new injectable hydrogel with enhanced mechanical properties, tissue adhesion, injectability, and biocompatibility is reported. The HA derivatives modified with catechol groups (HA-DA) were crosslinked by self-oxidation under in vivo physiological conditions (pH 7.4) without chemical crosslinkers to form hydrogels, which can be further accelerated by the dissolved oxygen in the body. The fabricated HA-DA filler showed excellent mechanical properties and could be easily injected with a low injection force. Further, the HA-DA filler stably attached to the injection site due to the tissue adhesion properties of the catechol groups, thus leading to an improved displacement stability. In addition, the HA-DA filler showed excellent cell viability, cell proliferation, and biocompatibility. Therefore, the HA-DA hydrogel is a novel soft tissue filler with great potential to overcome the limitations of commercial soft tissue fillers.


Assuntos
Preenchedores Dérmicos/síntese química , Ácido Hialurônico/administração & dosagem , Hidrogéis/síntese química , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Preenchedores Dérmicos/química , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Hidrogéis/química , Concentração de Íons de Hidrogênio , Injeções , Masculino , Camundongos , Células NIH 3T3
19.
ACS Appl Mater Interfaces ; 13(24): 28774-28781, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34114469

RESUMO

Three-dimensional (3D) scaffolds with chemical diversity are significant to direct cell adhesion onto targeted surfaces, which provides solutions to further control over cell fates and even tissue formation. However, the site-specific modification of specific biomolecules to realize selective cell adhesion has been a challenge with the current methods when building 3D scaffolds. Conventional methods of immersing as-prepared structures in solutions of biomolecules lead to nonselective adsorption; recent printing methods have to address the problem of switching multiple nozzles containing different biomolecules. The recently developed concept of macroscopic supramolecular assembly (MSA) based on the idea of "modular assembly" is promising to fabricate such 3D scaffolds with advantages of flexible design and combination of diverse modules with different surface chemistry. Herein we report an MSA method to fabricate 3D ordered structures with internal chemical diversity for site-selective cell adhesion. The 3D structure is prepared via 3D alignment of polydimethylsiloxane (PDMS) building blocks with magnetic pick-and-place operation and subsequent interfacial bindings between PDMS based on host/guest molecular recognition. The site-specific cell affinity is realized by distributing targeted building blocks that are modified with polylysine molecules of opposite chiralities: PDMS modified with films containing poly-l-lysine (PLL) show higher cell density than those with poly-d-lysine (PDL). This principle of selective cell adhesion directed simply by spatial distribution of chiral molecules has been proven effective for five different cell lines. This facile MSA strategy holds promise to build complex 3D microenvironment with on-demand chemical/biological diversities, which is meaningful to study cell/material interactions and even tissue formation.


Assuntos
Adesão Celular/efeitos dos fármacos , Dimetilpolisiloxanos/química , Polilisina/química , Animais , Linhagem Celular , Humanos , Ácido Hialurônico/química , Fenômenos Magnéticos , Camundongos , Polieletrólitos/química , Coelhos , Ratos , Estereoisomerismo , beta-Ciclodextrinas/química
20.
Int J Biol Macromol ; 184: 768-775, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34174305

RESUMO

Polysaccharide hydrogels are promising candidate matrices for recapitulating the characteristics of extracellular matrix (ECM) in breast tumors in terms of their structure and composition. Herein, to obtain an ECM-mimetic matrix, hydroxyethyl chitosan (HECS) hydrogels were prepared through Schiff-base crosslinking reaction using dialdehyde hyaluronic acid as crosslinker. The obtained HECS hydrogels displayed a highly porous structure, a stiffness comparable to that of breast tissue, and a fast water-absorption speed. The amount of crosslinker had great effects on the swelling and rheological behaviors of the HECS hydrogels. Preliminary results from in vitro biological assessments confirmed that MCF-7 cells incubated within HECS hydrogels preferred to grow into three-dimensional spheroids. Importantly, the cells displayed enhanced migrative capability and upregulated expression levels of MMP-2, TGF-ß and VEGF in comparison to two-dimension cultured cells. Hence, the HECS hydrogels show great promise as a biomimetic ECM in constructing breast tumor models.


Assuntos
Neoplasias da Mama/metabolismo , Quitosana/química , Matriz Extracelular/metabolismo , Ácido Hialurônico/química , Hidrogéis/síntese química , Esferoides Celulares/citologia , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Células MCF-7 , Metaloproteinase 2 da Matriz/metabolismo , Porosidade , Bases de Schiff , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo
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