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Silk fibroin (SF) is a promising biomaterial for tendon repair, but its relatively rigid mechanical properties and low cell affinity have limited its application in regenerative medicine. Meanwhile, gelatin-based polymers have advantages in cell attachment and tissue remodeling but have insufficient mechanical strength to regenerate tough tissue such as tendons. Taking these aspects into account, in this study, gelatin methacryloyl (GelMA) is combined with SF to create a mechanically strong and bioactive nanofibrous scaffold (SG). The mechanical properties of SG nanofibers can be flexibly modulated by varying the ratio of SF and GelMA. Compared to SF nanofibers, mesenchymal stem cells (MSCs) seeded on SG fibers with optimal composition (SG7) exhibit enhanced growth, proliferation, vascular endothelial growth factor production, and tenogenic gene expression behavior. Conditioned media from MSCs cultured on SG7 scaffolds can greatly promote the migration and proliferation of tenocytes. Histological analysis and tenogenesis-related immunofluorescence staining indicate SG7 scaffolds demonstrate enhanced in vivo tendon tissue regeneration compared to other groups. Therefore, rational combinations of SF and GelMA hybrid nanofibers may help to improve therapeutic outcomes and address the challenges of tissue-engineered scaffolds for tendon regeneration.
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Fibroínas , Células-Tronco Mesenquimais , Nanofibras , Proliferação de Células , Gelatina , Células-Tronco Mesenquimais/metabolismo , Metacrilatos , Seda , Tendões , Engenharia Tecidual , Alicerces Teciduais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Despite considerable efforts in modeling liver disease in vitro, it remains difficult to recapitulate the pathogenesis of the advanced phases of non-alcoholic fatty liver disease (NAFLD) with inflammation and fibrosis. Here, a liver-on-a-chip platform with bioengineered multicellular liver microtissues is developed, composed of four major types of liver cells (hepatocytes, endothelial cells, Kupffer cells, and stellate cells) to implement a human hepatic fibrosis model driven by NAFLD: i) lipid accumulation in hepatocytes (steatosis), ii) neovascularization by endothelial cells, iii) inflammation by activated Kupffer cells (steatohepatitis), and iv) extracellular matrix deposition by activated stellate cells (fibrosis). In this model, the presence of stellate cells in the liver-on-a-chip model with fat supplementation showed elevated inflammatory responses and fibrosis marker up-regulation. Compared to transforming growth factor-beta-induced hepatic fibrosis models, this model includes the native pathological and chronological steps of NAFLD which shows i) higher fibrotic phenotypes, ii) increased expression of fibrosis markers, and iii) efficient drug transport and metabolism. Taken together, the proposed platform will enable a better understanding of the mechanisms underlying fibrosis progression in NAFLD as well as the identification of new drugs for the different stages of NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Células Endoteliais , Hepatócitos , Humanos , Fígado/patologia , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
The physiological and toxicological evaluation of nano-silicon dioxide (nano-SiO2) particles in food is important for ensuring food safety. In this study, nano-SiO2 particles isolated from five brands of instant coffee, were structurally characterized using transmission electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, dynamic light scattering, and zeta potential analyses. Their toxicity was assessed by measuring cell viability, membrane integrity, and reactive oxygen species (ROS) levels in model gastrointestinal cells (GES-1 and Caco-2). Additionally, mortality, deformity rate, heart rate and death of whole zebra fish embryos were measured. The five types of nano-SiO2 samples comprised amorphous particles with a purity of approximately 99%, which met the food additive standard. Considering that the original particle size ranged from 10 to 50 nm, the samples were classified as nano-SiO2 food additives. Nano-SiO2 did not significantly impact the activity of GES-1 or Caco-2 cells, and no significant cell membrane damage was observed (Caco-2 cells exhibited mild micro damage); however, a slight increase in intracellular RPS levels was detected. Moreover, nano-SiO2 was found to cause head deformity, pericardial edema, yolk sac edema and tail bending. Collectively, the results show that nano-SiO2 time- and dose-dependently affects GES-1 and Caco-2 cell viability, as well as the mortality, heart rate, and abnormality rate of zebra fish embryos. Specifically, a high concentration (≥ 200 µg/mL) and long exposure time (≥ 48 h) of food additive nano-SiO2 affected GES-1, Caco-2 cells, and the gastrointestinal tract in zebra fish embryos.
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Mesenchymal stem cells (MSCs) have been widely used for regenerative therapy. In most current clinical applications, MSCs are delivered by injection but face significant issues with cell viability and penetration into the target tissue due to a limited migration capacity. Some therapies have attempted to improve MSC stability by their encapsulation within biomaterials; however, these treatments still require an enormous number of cells to achieve therapeutic efficacy due to low efficiency. Additionally, while local injection allows for targeted delivery, injections with conventional syringes are highly invasive. Due to the challenges associated with stem cell delivery, a local and minimally invasive approach with high efficiency and improved cell viability is highly desired. In this study, we present a detachable hybrid microneedle depot (d-HMND) for cell delivery. Our system consists of an array of microneedles with an outer poly(lactic-co-glycolic) acid (PLGA) shell and an internal gelatin methacryloyl (GelMA)-MSC mixture (GMM). The GMM was characterized and optimized for cell viability and mechanical strength of the d-HMND required to penetrate mouse skin tissue was also determined. MSC viability and function within the d-HMND was characterized in vitro and the regenerative efficacy of the d-HMND was demonstrated in vivo using a mouse skin wound model.
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Gelatin methacryloyl (GelMA) is a widely used hydrogel with skin-derived gelatin acting as the main constituent. However, GelMA has not been used in the development of wearable biosensors, which are emerging devices that enable personalized healthcare monitoring. This work highlights the potential of GelMA for wearable biosensing applications by demonstrating a fully solution-processable and transparent capacitive tactile sensor with microstructured GelMA as the core dielectric layer. A robust chemical bonding and a reliable encapsulation approach are introduced to overcome detachment and water-evaporation issues in hydrogel biosensors. The resultant GelMA tactile sensor shows a high-pressure sensitivity of 0.19 kPa-1 and one order of magnitude lower limit of detection (0.1 Pa) compared to previous hydrogel pressure sensors owing to its excellent mechanical and electrical properties (dielectric constant). Furthermore, it shows durability up to 3000 test cycles because of tough chemical bonding, and long-term stability of 3 days due to the inclusion of an encapsulation layer, which prevents water evaporation (80% water content). Successful monitoring of various human physiological and motion signals demonstrates the potential of these GelMA tactile sensors for wearable biosensing applications.
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Cell separation is a key step in many biomedical research areas including biotechnology, cancer research, regenerative medicine, and drug discovery. While conventional cell sorting approaches have led to high-efficiency sorting by exploiting the cell's specific properties, microfluidics has shown great promise in cell separation by exploiting different physical principles and using different properties of the cells. In particular, label-free cell separation techniques are highly recommended to minimize cell damage and avoid costly and labor-intensive steps of labeling molecular signatures of cells. In general, microfluidic-based cell sorting approaches can separate cells using "intrinsic" (e.g., fluid dynamic forces) versus "extrinsic" external forces (e.g., magnetic, electric field, etc.) and by using different properties of cells including size, density, deformability, shape, as well as electrical, magnetic, and compressibility/acoustic properties to select target cells from a heterogeneous cell population. In this work, principles and applications of the most commonly used label-free microfluidic-based cell separation methods are described. In particular, applications of microfluidic methods for the separation of circulating tumor cells, blood cells, immune cells, stem cells, and other biological cells are summarized. Computational approaches complementing such microfluidic methods are also explained. Finally, challenges and perspectives to further develop microfluidic-based cell separation methods are discussed.
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Técnicas Analíticas Microfluídicas , Células Neoplásicas Circulantes , Contagem de Células , Separação Celular , Humanos , MicrofluídicaRESUMO
Stem cells secrete trophic factors that induce angiogenesis. These soluble factors are promising candidates for stem cell-based therapies, especially for cardiovascular diseases. Mechanical stimuli and biophysical factors presented in the stem cell microenvironment play important roles in guiding their behaviors. However, the complex interplay and precise role of these cues in directing pro-angiogenic signaling remain unclear. Here, a platform is designed using gelatin methacryloyl hydrogels with tunable rigidity and a dynamic mechanical compression bioreactor to evaluate the influence of matrix rigidity and mechanical stimuli on the secretion of pro-angiogenic factors from human mesenchymal stem cells (hMSCs). Cells cultured in matrices mimicking mechanical elasticity of bone tissues in vivo show elevated secretion of vascular endothelial growth factor (VEGF), one of representative signaling proteins promoting angiogenesis, as well as increased vascularization of human umbilical vein endothelial cells (HUVECs) with a supplement of conditioned media from hMSCs cultured across different conditions. When hMSCs are cultured in matrices stimulated with a range of cyclic compressions, increased VEGF secretion is observed with increasing mechanical strains, which is also in line with the enhanced tubulogenesis of HUVECs. Moreover, it is demonstrated that matrix stiffness and cyclic compression modulate secretion of pro-angiogenic molecules from hMSCs through yes-associated protein activity.
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Células-Tronco Mesenquimais , Células Cultivadas , Sinais (Psicologia) , Meios de Cultivo Condicionados , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Fisiológica , Fator A de Crescimento do Endotélio VascularRESUMO
The extraction of interstitial fluid (ISF) from skin using microneedles (MNs) has attracted growing interest in recent years due to its potential for minimally invasive diagnostics and biosensors. ISF collection by absorption into a hydrogel MN patch is a promising way that requires the materials to have outstanding swelling ability. Here, a gelatin methacryloyl (GelMA) patch is developed with an 11 × 11 array of MNs for minimally invasive sampling of ISF. The properties of the patch can be tuned by altering the concentration of the GelMA prepolymer and the crosslinking time; patches are created with swelling ratios between 293% and 423% and compressive moduli between 3.34 MPa and 7.23 MPa. The optimized GelMA MN patch demonstrates efficient extraction of ISF. Furthermore, it efficiently and quantitatively detects glucose and vancomycin in ISF in an in vivo study. This minimally invasive approach of extracting ISF with a GelMA MN patch has the potential to complement blood sampling for the monitoring of target molecules from patients.
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Líquido Extracelular , Gelatina , Hidrogéis , Agulhas/classificação , Pele , HumanosRESUMO
In this study, a hydrophobic and antibacterial pad was prepared to preserve Channel Catfish (Ictalurus punctatus). The pad composite the microfibrillated cellulose and ß-cyclodextrin/nisin microcapsules. The hydrophobic pad ensures a dry surface in contact with the fish, reducing microbial contamination. The pad has a low density and high porosity, making it lightweight and suitable for packaging applications, while also providing a large surface area for antibacterial activity. Results demonstrated that this antibacterial pad exhibits an ultralow density of 9.0 mg/cm3 and an ultrahigh porosity of 99.10%. It can extend the shelf life of Channel Catfish fillets to 9 days at 4 °C, with a total volatile base nitrogen below 20 mg/100 g. The study proposes a novel solution for preserving aquatic products by combining antibacterial substances with the natural base material aerogel. This approach also extends the utilization of aerogel and nisin in food packaging.
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Antibacterianos , Celulose , Embalagem de Alimentos , Conservação de Alimentos , Géis , Ictaluridae , Nisina , beta-Ciclodextrinas , Animais , Celulose/química , Antibacterianos/farmacologia , Antibacterianos/química , beta-Ciclodextrinas/química , Nisina/química , Nisina/farmacologia , Conservação de Alimentos/métodos , Conservação de Alimentos/instrumentação , Embalagem de Alimentos/instrumentação , Ictaluridae/microbiologia , Géis/química , Cápsulas/químicaRESUMO
Responsive heat resistance (by heat shock protein upregulation) and spontaneous reactive oxygen species (ROS) detoxification have been regarded as the major obstacles for photothermal/photodynamic therapy of cancer. To overcome the thermal resistance and improve ROS susceptibility in breast cancer therapy, Au ion-crosslinked hydrogels including indocyanine green (ICG) and polyphenol are devised. Au ion has been introduced for gel crosslinking (by catechol-Au3+ coordination), cellular glutathione depletion, and O2 production from cellular H2O2. ICG can generate singlet oxygen from O2 (for photodynamic therapy) and induce hyperthermia (for photothermal therapy) under the near-infrared laser exposure. (-)-Epigallocatechin gallate downregulates heat shock protein to overcome heat resistance during hyperthermia and exerts multiple anticancer functions in spite of its ironical antioxidant features. Those molecules are concinnously engaged in the hydrogel structure to offer fast gel transformation, syringe injection, self-restoration, and rheological tuning for augmented photo/chemotherapy of cancer. Intratumoral injection of multifunctional hydrogel efficiently suppressed the growth of primary breast cancer and completely eliminated the residual tumor mass. Proposed hydrogel system can be applied to tumor size reduction prior to surgery of breast cancer and the complete remission after its surgery.
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Neoplasias da Mama , Hipertermia Induzida , Fotoquimioterapia , Humanos , Feminino , Espécies Reativas de Oxigênio/metabolismo , Hidrogéis/uso terapêutico , Peróxido de Hidrogênio , Verde de Indocianina/uso terapêutico , Verde de Indocianina/química , Neoplasias da Mama/tratamento farmacológico , Proteínas de Choque TérmicoRESUMO
Indocyanine green (ICG), glucose oxidase (GOx), and copper(II) sulfate (Cu)-installed hybrid gel based on organic nanorod (cellulose nanocrystal [CNC]) and inorganic nanodisk (Laponite [LAP]) was developed to perform a combination of starvation therapy (ST), chemodynamic therapy (CDT), and photothermal therapy (PTT) for localized cancers. A hybrid CNC/LAP network with a nematic phase was designed to enable instant gelation, controlled viscoelasticity, syringe injectability, and longer in vivo retention. Moreover, ICG was introduced into the CNC/LAP gel system to induce hyperthermia of tumor tissue, amplifying the CDT effect; GOx was used for glucose deprivation (related to the Warburg effect); and Cu was introduced for hydroxyl radical generation (based on Fenton-like chemistry) and cellular glutathione (GSH) degradation in cancer cells. The ICG/GOx/Cu-installed CNC/LAP gel in combination with near-infrared (NIR) laser realized improved antiproliferation, cellular reactive oxygen species (ROS) generation, cellular GSH degradation, and apoptosis induction in colorectal cancer (CT-26) cells. In addition, local injection of the CNC/ICG/GOx/Cu/LAP gel into the implanted CT-26 tumor while irradiating it with NIR laser provided strong tumor growth suppression effects. In conclusion, the designed hybrid nanorod/nanodisk gel network can be efficiently applied to the local PTT/ST/CDT of cancer cells.
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INTRODUCTION: Microneedles (MNs) have undergone great advances in transdermal drug delivery, and commercialized MN applications are currently available in vaccination and cosmetic products. Despite the development of MN technologies, common limitations of MN products still exist. Typical MN patches are applied to target tissues, where the substrate of an MN patch must remain until the drug is delivered, which reduces patients' compliance and hinders the applicability of the MN technique to many diseases in various tissues. MN research is ongoing to solve this issue. AREAS COVERED: Most recent MNs developed by combining various biomaterials with appropriate fabrication processes are detachable MNs (DeMNs). Because of advances in biomaterials and fabrication techniques, various DeMNs have been rapidly developed. In this review, we discuss four types of DeMN: substrate-separable, multi-layered, crack-inducing, and shell DeMN. These DeMNs deliver various therapeutic agents ranging from small- and large-molecular-weight drugs to proteins and even stem cells for regeneration therapy. Furthermore, DeMNs are applied to skin as well as non-transdermal tissues. EXPERT OPINION: It has become increasingly evident that novel MN technologies can be expected in terms of designs, fabrication methods, materials, and even possible application sites given the recent advances in DeMNs.
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Sistemas de Liberação de Medicamentos , Agulhas , Administração Cutânea , Materiais Biocompatíveis , Sistemas de Liberação de Medicamentos/métodos , Humanos , Microinjeções , Preparações FarmacêuticasRESUMO
We propose a new centrality incorporating two classical node-level centralities, the degree centrality and the information centrality, which are considered as local and global centralities, respectively. These two centralities have expressions in terms of the graph Laplacian L, which motivates us to exploit its fractional analog L^{γ} with a fractional parameter γ. As γ varies from 0 to 1, the proposed fractional version of the information centrality makes intriguing changes in the node centrality rankings. These changes could not be generated by the fractional degree centrality since it is mostly influenced by the local aspect. We prove that these two fractional centralities behave similarly when γ is close to 0. This result provides its complete understanding of the boundary of the interval in which γ lies since the fractional information centrality with γ=1 is the usual information centrality. Moreover, our computation for the correlation coefficients between the fractional information centrality and the degree centrality reveals that the fractional information centrality is transformed from a local centrality into being a global one as γ changes from 0 to 1.
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A hyaluronic acid (HA)-based one-pot hydrogel reactor with single syringe injection and immediate gelation was developed for starvation therapy (ST), chemodynamic therapy (CDT), ferroptosis, and photothermal therapy (PTT) against breast cancer. A rheologically tuned hydrogel network, composed of HA-phenylboronic acid (HP) and HA-dopamine (HD), was designed by introducing a boronate ester linkage (phenylboronic acid-dopamine interaction) and polydopamine bond (pH control). Ferrocene (Fc)-conjugated HP (Fc-HP) was synthesized to achieve ferroptosis, Fenton reaction-involved toxic hydroxyl radical (â¢OH) generation, and photothermal ablation in cancer therapy. Glucose oxidase (GOx) was entrapped in the pH-modulated Fc-HP (Fc-HP°)/HD hydrogel network for converting intracellular glucose to H2O2 to enable its own supply. The GOx/Fc combination-installed hydrogel reactor system can provide sustained ST/CDT/PTT functions along with ferroptosis. Injection of Fc-HP°/HD/GOx hydrogel with single-syringe injectability, shear-thinning feature, and self-healing capability offered a slow biodegradation rate and high safety profiles. Peritumorally injected Fc-HP°/HD/GOx hydrogel also efficiently suppressed the growth of breast cancer based on multifunctional therapeutic approaches with reduced dosing frequency. Hyperthermia induced by near-infrared (NIR) laser absorption may amplify the therapeutic effects of free radicals. It is expected that this Fc-HP°/HD/GOx hydrogel system can be applied to local cancer therapy with high efficacy and safety profiles.
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Neoplasias da Mama , Hipertermia Induzida , Neoplasias , Ácidos Borônicos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Dopamina/uso terapêutico , Ésteres/uso terapêutico , Feminino , Compostos Ferrosos , Glucose/metabolismo , Glucose Oxidase/química , Glucose Oxidase/uso terapêutico , Humanos , Ácido Hialurônico/química , Hidrogéis/química , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/uso terapêutico , Metalocenos/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
Intravitreal injection (IVI) is a common technology which is used to treat ophthalmic diseases inside eyeballs by delivering various drugs into the vitreous cavity using hypodermic needles. However, in some cases, there are possible side effects such as ocular tissue damage due to repeated injection or eyeball infection through the hole created during the needle retraction process. The best scenario of IVI is a one-time injection of drugs without needle retraction, keeping the system of the eyeball closed. Microneedles (MNs) have been applied to ocular tissues over 10 years, and no serious side effects on ocular tissue due to MN injection have been reported. Therefore, a self-plugging MN (SPM) is developed to perform intraocular drug delivery and to seal the scleral puncture simultaneously. The SPMs are fabricated by a thermal drawing process and then coated with a polymeric carrier of drugs and a hydrogel-based scleral plugging component. Each coated functional layer is characterized and demonstrated by in vitro and ex vivo experiments. Finally, in vivo tests using a porcine model confirms prompt sealing of SPM and sustained intraocular drug delivery.
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Sistemas de Liberação de Medicamentos , Agulhas , Administração Cutânea , Animais , Excipientes , Olho , Hidrogéis/farmacologia , Microinjeções , SuínosRESUMO
Injectable shear-thinning biomaterials (STBs) have attracted significant attention because of their efficient and localized delivery of cells as well as various molecules ranging from growth factors to drugs. Recently, electrostatic interaction-based STBs, including gelatin/LAPONITE® nanocomposites, have been developed through a simple assembly process and show outstanding shear-thinning properties and injectability. However, the ability of different compositions of gelatin and LAPONITE® to modulate doxorubicin (DOX) delivery at different pH values to enhance the effectiveness of topical skin cancer treatment is still unclear. Here, we fabricated injectable STBs using gelatin and LAPONITE® to investigate the influence of LAPONITE®/gelatin ratio on mechanical characteristics, capacity for DOX release in response to different pH values, and cytotoxicity toward malignant melanoma. The release profile analysis of various compositions of DOX-loaded STBs under different pH conditions revealed that lower amounts of LAPONITE® (6NC25) led to higher pH-responsiveness capable of achieving a localized, controlled, and sustained release of DOX in an acidic tumor microenvironment. Moreover, we showed that 6NC25 had a lower storage modulus and required lower injection forces compared to those with higher LAPONITE® ratios. Furthermore, DOX delivery analysis in vitro and in vivo demonstrated that DOX-loaded 6NC25 could efficiently target subcutaneous malignant tumors via DOX-induced cell death and growth restriction.
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Melanoma , Nanopartículas , Materiais Biocompatíveis , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Gelatina , Humanos , Concentração de Íons de Hidrogênio , Melanoma/tratamento farmacológico , Microambiente TumoralRESUMO
Infectious keratitis is mainly treated with topical antibiotics. To achieve and maintain the required therapeutic concentration in the cornea where the tear fluid continuously rinses the surface, the antibiotics must be frequently applied, even while the patient is sleeping, and oral medication is sometimes required. However, the inevitably poor compliance and avascular nature of the cornea decrease drug bioavailability. In this study, a single microneedle (MN) is injected into the cornea to substitute for the repeated application of eyedrops in the treatment of infectious keratitis. After comparing the mechanical integrity and drug release profiles of three different drug-tips, the drug-tip with the "high" drug concentration that releases 12.5 ng drug within 3 days is applied to a cornea to evaluate the transferability and in vivo drug release. In the treatment of infectious keratitis with repeated application of eyedrops for six consecutive days, a single MN injection is substituted for the initial 3 days of eyedrop applications. The progression remains similarly attenuated after 3 days without eyedrops, and comparable efficacy is achieved on day 6 when combined with delayed eyedrop treatment from day 3. Thus, the single administration of a biodegradable MN can substitute for the repeated application of eyedrops in the treatment of infectious keratitis.
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Ceratite , Administração Tópica , Córnea , Humanos , Ceratite/tratamento farmacológico , Agulhas , Soluções Oftálmicas/uso terapêutico , LágrimasRESUMO
Polypseudorotaxane structure and polydopamine bond-based crosslinked hyaluronic acid (HA) hydrogels including donepezil-loaded microspheres were developed for subcutaneous injection. Both dopamine and polyethylene glycol (PEG) were covalently bonded to the HA polymer for catechol polymerization and inclusion complexation with alpha-cyclodextrin (α-CD), respectively. A PEG chain of HA-dopamine-PEG (HD-PEG) conjugate was threaded with α-CD to make a polypseudorotaxane structure and its pH was adjusted to 8.5 for dopamine polymerization. Poly(lactic-co-glycolic acid) (PLGA)/donepezil microsphere (PDM) was embedded into the HD-PEG network for its sustained release. The HD-PEG/α-CD/PDM 8.5 hydrogel system exhibited an immediate gelation pattern, injectability through single syringe, self-healing ability, and shear-thinning behavior. Donepezil was released from the HD-PEG/α-CD/PDM 8.5 hydrogel in a sustained pattern. Following subcutaneous injection, the weight of excised HD-PEG/α-CD/PDM 8.5 hydrogel was higher than the other groups on day 14. These findings support the clinical feasibility of the HD-PEG/α-CD/PDM 8.5 hydrogel for subcutaneous injection.
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Portadores de Fármacos/química , Ácido Hialurônico/análogos & derivados , Hidrogéis/química , Indóis/química , Polímeros/química , Animais , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/toxicidade , Ciclodextrinas/síntese química , Ciclodextrinas/química , Ciclodextrinas/toxicidade , Donepezila/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Ácido Hialurônico/toxicidade , Hidrogéis/síntese química , Hidrogéis/toxicidade , Indóis/síntese química , Indóis/toxicidade , Masculino , Camundongos Endogâmicos ICR , Microesferas , Poloxâmero/síntese química , Poloxâmero/química , Poloxâmero/toxicidade , Polímeros/síntese química , Polímeros/toxicidade , Rotaxanos/síntese química , Rotaxanos/química , Rotaxanos/toxicidade , Substâncias Viscoelásticas/síntese química , Substâncias Viscoelásticas/química , Substâncias Viscoelásticas/toxicidadeRESUMO
Increasing evidence from cancer cell fusion with different cell types in the tumor microenvironment has suggested a probable mechanism for how metastasis-initiating cells could be generated in tumors. Although human mesenchymal stem cells (hMSCs) have been known as promising candidates to create hybrid cells with cancer cells, the role of hMSCs in fusion with cancer cells is still controversial. Here, we fabricated a liver-on-a-chip platform to monitor the fusion of liver hepatocellular cells (HepG2) with hMSCs and study their invasive potential. We demonstrated that hMSCs might play dual roles in HepG2 spheroids. The analysis of tumor growth with different fractions of hMSCs in HepG2 spheroids revealed hMSCs' role in preventing HepG2 growth and proliferation, while the hMSCs presented in the HepG2 spheroids led to the generation of HepG2-hMSC hybrid cells with much higher invasiveness compared to HepG2. These invasive HepG2-hMSC hybrid cells expressed high levels of markers associated with stemness, proliferation, epithelial to mesenchymal transition, and matrix deposition, which corresponded to the expression of these markers for hMSCs escaping from hMSC spheroids. In addition, these fused cells were responsible for collective invasion following HepG2 by depositing Collagen I and Fibronectin in their surrounding microenvironment. Furthermore, we showed that hepatic stellate cells (HSCs) could also be fused with HepG2, and the HepG2-HSC hybrid cells possessed similar features to those from HepG2-hMSC fusion. This fusion of HepG2 with liver-resident HSCs may propose a new potential mechanism of hepatic cancer metastasis.
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Neoplasias Hepáticas , Células-Tronco Mesenquimais , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Hepáticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Microambiente TumoralRESUMO
Various perivascular drug delivery techniques have been demonstrated for localized post-treatment of intimal hyperplasia: a vascular inflammatory response caused by endothelial damages. Although most perivascular devices have focused on controlling the delivery duration of anti-proliferation drug, the confined and unidirectional delivery of the drug to the target tissue has become increasingly important. In addition, careful attention should also be paid to the luminal stability and the adequate exchange of vascular protein or cell between the blood vessel and extravascular tissue to avoid any side effect from the long-term application of any perivascular device. Here, a highly flexible and porous silk fibroin microneedle wrap (Silk MN wrap) is proposed to directly inject antiproliferative drug to the anastomosis sites while ensuring sufficient vascular exchanges. Drug-embedded silk MNs were transfer-molded on a highly flexible and porous silk wrap. The enhanced cell compatibility, molecular permeability, and flexibility of silk MN wrap guaranteed the structural integrity of blood vessels. Silk wrap successfully supported the silk MNs and induced multiple MN penetration to the target tissue. Over 28 days, silk MN wrap significantly inhibited intimal hyperplasia with a 62.1% reduction in neointimal formation.