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PURPOSE: The purpose of this study was to evaluate the safety and efficacy of intralesional injection of chitosan hydrogel (CH) combined with sodium tetradecyl sulfate (STS) to sclerose and embolize venous malformations (VMs) by comparison with 3% STS foam and placebo in a mouse model. MATERIALS AND METHODS: Subcutaneous VMs were created by injecting HUVEC_TIE2-L914F cells, mixed with matrigel, into the back of athymic mice (Day [D] 0). After VM-like lesions were established at D10, 70 lesions were randomly assigned to one of six treatment groups (untreated, saline, 3% STS-foam, CH, 1% STS-CH, 3% STS-CH). For 3% STS-foam, the standard Tessari technique was performed. VMs were regularly evaluated every 2-3 days to measure lesion size until the time of collection at D30 (primary endpoint). At D30, VM lesions including the matrigel plugs were culled and evaluated by histological analysis to assess vessel size, chitosan distribution and endothelial expression. One-way analysis of variance (ANOVA) test was performed to compare quantitative variables with normal distribution, otherwise Kruskal-Wallis test followed by pairwise comparisons by a Wilcoxon rank sum test was performed. RESULTS: All VMs were successfully punctured and injected. Six VMs injected with 3% STS-CH showed early skin ulceration with an extrusion of the matrigel plug and were excluded from final analysis. In the remaining 64 VMs, skin ulceration occurred on 26 plugs, resulting in the loss of three 3% STS-foam and one 1% STS-CH plugs. Both chitosan formulations effectively controlled growth of VMs by the end of follow-up compared to untreated or 3% STS-foam groups (P < 0.05). Vessel sizes were smaller with both CH formulations compared to untreated and saline groups (P < 0.05). Additionally, there were smaller vascular channels within the 1% STS-CH group compared to the 3% STS-foam group (P < 0.05). CONCLUSION: Chitosan's ability to control the growth of VMs suggests a promising therapeutic effect that outperforms the gold standard (STS-foam) on several variables.
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The viscosity of gelatin methacryloyl (GelMA)-based bioinks generates shear stresses throughout the printing process that can affect cell integrity, reduce cell viability, cause morphological changes, and alter cell functionality. This study systematically investigated the impact of the viscosity of GelMA-gelatin bioinks on osteoblast-like cells in 2D and 3D culture conditions. Three bioinks with low, medium, and high viscosity prepared by supplementing a 5% GelMA solution with different concentrations of gelatin were evaluated. Cell responses were studied in a 2D environment after printing and incubation in non-cross-linked bioinks that caused the gelatin and GelMA to dissolve and release cells for attachment to tissue culture plates. The increased viscosity of the bioinks significantly affected cell area and aspect ratio. Cells printed using the bioink with medium viscosity exhibited greater metabolic activity and proliferation rate than those printed using the high viscosity bioink and even the unprinted control cells. Additionally, cells printed using the bioink with high viscosity demonstrated notably elevated expression levels of alkaline phosphatase (ALP) and bone morphogenetic protein-2 (BMP-2) genes. In the 3D condition, the printed cell-laden hydrogels were photo-cross-linked prior to incubation. The medium viscosity bioink supported greater cell proliferation compared to the high viscosity bioink. However, there were no significant differences in the expression of osteogenic markers between the medium and high viscosity bioinks. Therefore, the choice between medium and high viscosity bioinks should be based on the desired outcomes and objectives of the bone tissue engineering application. Furthermore, the bioprinting procedure with the medium viscosity bioink was used as an automated technique for efficiently seeding cells onto 3D printed porous titanium scaffolds for bone tissue engineering purposes.
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The conventional technique for successful bone grafts, involving the use of a patients own tissue (autografts), is challenged by limited availability and donor site morbidity. While allografts and xenografts offer alternatives, they come with the risk of rejection. This underscores the pressing need for tailor-made artificial bone graft materials. In this context, injectable hydrogels are emerging as a promising solution for bone regeneration, especially in complex maxillofacial reconstruction cases. These hydrogels can seamlessly adapt to irregular shapes and conservatively fill defects. Our study introduces a shear-thinning biomaterial by blending silicate nanoplatelets (SNs) enriched with human blood-derived plasma rich in growth factors (PRGF) for personalized applications. Notably, our investigations unveil that injectable hydrogel formulations comprising 7.5% PRGF yield sustained protein and growth factor release, affording precise control over critical growth factors essential for tissue regeneration. Moreover, our hydrogel exhibits exceptional biocompatibility in vitro and in vivo and demonstrates hemostatic properties. The hydrogel also presents a robust angiogenic potential and an inherent capacity to promote bone differentiation, proven through Alizarin Red staining, gene expression, and immunostaining assessments of bone-related biomarkers. Given these impressive attributes, our hydrogel stands out as a leading candidate for maxillofacial bone regeneration application. Beyond this, our findings hold immense potential in revolutionizing the field of regenerative medicine, offering an influential platform for crafting precise and effective therapeutic strategies.
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In addressing the intricate challenges of enterocutaneous fistula (ECF) treatment, such as internal bleeding, effluent leakage, inflammation, and infection, our research is dedicated to introducing a regenerative adhesive hydrogel that can seal and expedite the healing process. A double syringe setup was utilized, with dopagelatin and platelet-rich plasma (PRP) in one syringe and Laponite and sodium periodate in another. The hydrogel begins to cross-link immediately after passing through a mixing tip and exhibits tissue adhesive properties. Results demonstrated that PRP deposits within the pores of the cross-linked hydrogel and releases sustainably, enhancing its regenerative capabilities. The addition of PRP further improved the mechanical properties and slowed down the degradation of the hydrogel. Furthermore, the hydrogel demonstrated cytocompatibility, hemostatic properties, and time-dependent macrophage M1 to M2 phase transition, suggesting the anti-inflammatory response of the material. In an in vitro bench test simulating high-pressure fistula conditions, the hydrogel effectively occluded pressures up to 300 mmHg. In conclusion, this innovative hydrogel holds promise for ECF treatment and diverse fistula cases, marking a significant advancement in its therapeutic approaches.
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Hidrogeles , Fístula Intestinal , Cicatrización de Heridas , Hidrogeles/química , Hidrogeles/farmacología , Fístula Intestinal/terapia , Animales , Cicatrización de Heridas/efectos de los fármacos , Humanos , Ratones , Plasma Rico en Plaquetas/química , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacología , Silicatos/química , Silicatos/uso terapéutico , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacologíaRESUMEN
Enterocutaneous fistula (ECF) is a severe medical condition where an abnormal connection forms between the gastrointestinal tract and skin. ECFs are, in most cases, a result of surgical complications such as missed enterotomies or anastomotic leaks. The constant leakage of enteric and fecal contents from the fistula site leads to skin breakdown and increases the risk of infection. Despite advances in surgical techniques and postoperative management, ECF accounts for significant mortality rates, estimated between 15-20%, and causes debilitating morbidity. Therefore, there is a critical need for a simple and effective method to seal and heal ECF. Injectable hydrogels with combined properties of robust mechanical properties and cell infiltration/proliferation have the potential to block and heal ECF. Herein, we report the development of an injectable nanoengineered adhesive hydrogel (INAH) composed of a synthetic nanosilicate (Laponite®) and a gelatin-dopamine conjugate for treating ECF. The hydrogel undergoes fast cross-linking using a co-injection method, resulting in a matrix with improved mechanical and adhesive properties. INAH demonstrates appreciable blood clotting abilities and is cytocompatible with fibroblasts. The adhesive properties of the hydrogel are demonstrated in ex vivo adhesion models with skin and arteries, where the volume stability in the hydrated internal environment facilitates maintaining strong adhesion. In vivo assessments reveal that the INAH is biocompatible, supporting cell infiltration and extracellular matrix deposition while not forming fibrotic tissue. These findings suggest that this INAH holds promising translational potential for sealing and healing ECF.
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Fístula Intestinal , Adhesivos Tisulares , Humanos , Hidrogeles/farmacología , Adhesivos , Gelatina , Fístula Intestinal/terapiaRESUMEN
Personalized bone-regenerative materials have attracted substantial interest in recent years. Modern clinical settings demand the use of engineered materials incorporating patient-derived cells, cytokines, antibodies, and biomarkers to enhance the process of regeneration. In this work, we formulated short microfiber-reinforced hydrogels with platelet-rich fibrin (PRF) to engineer implantable multi-material core-shell bone grafts. By employing 3D bioprinting technology, we fabricated a core-shell bone graft from a hybrid composite hydroxyapatite-coated poly(lactic acid) (PLA) fiber-reinforced methacryolyl gelatin (GelMA)/alginate hydrogel. The overall concept involves 3D bioprinting of long bone mimic microstructures that resemble a core-shell cancellous-cortical structure, with a stiffer shell and a softer core with our engineered biomaterial. We observed a significantly enhanced stiffness in the hydrogel scaffold incorporated with hydroxyapatite (HA)-coated PLA microfibers compared to the pristine hydrogel construct. Furthermore, HA non-coated PLA microfibers were mixed with PRF and GelMA/alginate hydrogel to introduce a slow release of growth factors which can further enhance cell maturation and differentiation. These patient-specific bone grafts deliver cytokines and growth factors with distinct spatiotemporal release profiles to enhance tissue regeneration. The biocompatible and bio-responsive bone mimetic core-shell multi-material structures enhance osteogenesis and can be customized to have materials at a specific location, geometry, and material combination.
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Hidrogeles , Osteogénesis , Humanos , Hidrogeles/química , Durapatita , Gelatina/química , Alginatos/química , Citocinas , PoliésteresRESUMEN
The field of cancer immunotherapy has shown significant growth, and researchers are now focusing on effective strategies to enhance and prolong local immunomodulation. Injectable hydrogels (IHs) have emerged as versatile platforms for encapsulating and controlling the release of small molecules and cells, drawing significant attention for their potential to enhance antitumor immune responses while inhibiting metastasis and recurrence. IHs delivering natural killer (NK) cells, T cells, and antigen-presenting cells (APCs) offer a viable method for treating cancer. Indeed, it can bypass the extracellular matrix and gradually release small molecules or cells into the tumor microenvironment, thereby boosting immune responses against cancer cells. This review provides an overview of the recent advancements in cancer immunotherapy using IHs for delivering NK cells, T cells, APCs, chemoimmunotherapy, radio-immunotherapy, and photothermal-immunotherapy. First, we introduce IHs as a delivery matrix, then summarize their applications for the local delivery of small molecules and immune cells to elicit robust anticancer immune responses. Additionally, we discuss recent progress in IHs systems used for local combination therapy, including chemoimmunotherapy, radio-immunotherapy, photothermal-immunotherapy, photodynamic-immunotherapy, and gene-immunotherapy. By comprehensively examining the utilization of IHs in cancer immunotherapy, this review aims to highlight the potential of IHs as effective carriers for immunotherapy delivery, facilitating the development of innovative strategies for cancer treatment. In addition, we demonstrate that using hydrogel-based platforms for the targeted delivery of immune cells, such as NK cells, T cells, and dendritic cells (DCs), has remarkable potential in cancer therapy. These innovative approaches have yielded substantial reductions in tumor growth, showcasing the ability of hydrogels to enhance the efficacy of immune-based treatments. STATEMENT OF SIGNIFICANCE: As cancer immunotherapy continues to expand, the mode of therapeutic agent delivery becomes increasingly critical. This review spotlights the forward-looking progress of IHs, emphasizing their potential to revolutionize localized immunotherapy delivery. By efficiently encapsulating and controlling the release of essential immune components such as T cells, NK cells, APCs, and various therapeutic agents, IHs offer a pioneering pathway to amplify immune reactions, moderate metastasis, and reduce recurrence. Their adaptability further shines when considering their role in emerging combination therapies, including chemoimmunotherapy, radio-immunotherapy, and photothermal-immunotherapy. Understanding IHs' significance in cancer therapy is essential, suggesting a shift in cancer treatment dynamics and heralding a novel period of focused, enduring, and powerful therapeutic strategies.
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Hidrogeles , Neoplasias , Humanos , Hidrogeles/uso terapéutico , Inmunoterapia/métodos , Neoplasias/patología , Linfocitos T , Terapia Combinada , Microambiente TumoralRESUMEN
Developing theranostic devices to detect bleeding and effectively control hemorrhage in the prehospital setting is an unmet medical need. Herein, an all-in-one theranostic platform is presented, which is constructed by sandwiching silk fibroin (SF) between two silver nanowire (AgNW) based conductive electrodes to non-enzymatically diagnose local bleeding and stop the hemorrhage at the wound site. Taking advantage of the hemostatic property of natural SF, the device is composed of a shape-memory SF sponge, facilitating blood clotting, with ≈82% reduction in hemostatic time in vitro as compared with untreated blood. Furthermore, this sandwiched platform serves as a capacitive sensor that can detect bleeding and differentiate between blood and other body fluids (i.e., serum and water) via capacitance change. In addition, the AgNW electrode endows anti-infection efficiency against Escherichia coli and Staphylococcus aureus. Also, the device shows excellent biocompatibility and gradually biodegrades in vivo with no major local or systemic inflammatory responses. More importantly, the theranostic platform presents considerable hemostatic efficacy comparable with a commercial hemostat, Dengen, in rat liver bleeding models. The theranostic platform provides an unexplored strategy for the intelligent management of hemorrhage, with the potential to significantly improve patients' well-being through the integration of diagnostic and therapeutic capabilities.
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Fibroínas , Hemostáticos , Nanocables , Ratas , Animales , Medicina de Precisión , Plata/uso terapéutico , Hemorragia/tratamiento farmacológico , Hemostáticos/uso terapéutico , Hemostáticos/metabolismoRESUMEN
Shear-thinning biomaterials (STBs) based on gelatin-silicate nanoplatelets (SNs) are emerging as an alternative to conventional coiling and clipping techniques in the treatment of vascular anomalies. Improvements in the cohesion of STB hydrogels pave the way toward their translational application in minimally invasive therapies such as endovascular embolization repair. In the present study, sodium phytate (Phyt) additives are used to tune the electrostatic network of SNs-gelatin STBs, thereby promoting their mechanical integrity and facilitating injectability through standard catheters. We show that an optimized amount of Phyt enhances storage modulus by approximately one order of magnitude and reduces injection force by ≈58% without compromising biocompatibility and hydrogel wet stability. The Phyt additives are found to decrease the immune responses induced by SNs. In vitro embolization experiments suggest a significantly lower rate of failure in Phyt-incorporated STBs than in control groups. Furthermore, the addition of Phyt leads to accelerated blood coagulation (reduces clotting time by ≈45% compared to controls) due to the contributions of negatively charged phosphate groups, which aid in the prolonged durability of STB in coagulopathic patients. Therefore, the proposed approach is an effective method for the design of robust and injectable STBs for minimally invasive treatment of vascular malformations.
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Materiales Biocompatibles , Hemostáticos , Humanos , Materiales Biocompatibles/farmacología , Gelatina/farmacología , Ácido Fítico , Silicatos/farmacología , Hidrogeles/farmacologíaRESUMEN
Sac embolization of abdominal aortic aneurysms (AAAs) remains clinically limited by endoleak recurrences. These recurrences are correlated with recanalization due to the presence of endothelial lining and matrix metalloproteinases (MMPs)-mediated aneurysm progression. This study incorporated doxycycline (DOX), a well-known sclerosant and MMPs inhibitor, into a shear-thinning biomaterial (STB)-based vascular embolizing hydrogel. The addition of DOX was expected to improve embolizing efficacy while preventing endoleaks by inhibiting MMP activity and promoting endothelial removal. The results showed that STBs containing 4.5% w/w silicate nanoplatelet and 0.3% w/v of DOX were injectable and had a 2-fold increase in storage modulus compared to those without DOX. STB-DOX hydrogels also reduced clotting time by 33% compared to untreated blood. The burst release of DOX from the hydrogels showed sclerosing effects after 6 h in an ex vivo pig aorta model. Sustained release of DOX from hydrogels on endothelial cells showed MMP inhibition (ca. an order of magnitude larger than control groups) after 7 days. The hydrogels successfully occluded a patient-derived abdominal aneurysm model at physiological blood pressures and flow rates. The sclerosing and MMP inhibition characteristics in the engineered multifunctional STB-DOX hydrogels may provide promising opportunities for the efficient embolization of aneurysms in blood vessels.
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Hemorrhage is the leading cause of trauma-related deaths, in hospital and prehospital settings. Hemostasis is a complex mechanism that involves a cascade of clotting factors and proteins that result in the formation of a strong clot. In certain surgical and emergency situations, hemostatic agents are needed to achieve faster blood coagulation to prevent the patient from experiencing a severe hemorrhagic shock. Therefore, it is critical to consider appropriate materials and designs for hemostatic agents. Many materials have been fabricated as hemostatic agents, including synthetic and naturally derived polymers. Compared to synthetic polymers, natural polymers or biopolymers, which include polysaccharides and polypeptides, have greater biocompatibility, biodegradability and processibility. Thus, in this review, we focus on biopolymer-based hemostatic agents of different forms, such as powder, particles, sponges and hydrogels. Finally, we discuss biopolymer-based hemostatic materials currently in clinical trials and offer insight into next-generation hemostats for clinical translation.
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PURPOSE: To compare the mechanical properties of aneurysm content after endoleak embolization with a chitosan hydrogel (CH) with that with a chitosan hydrogel with sodium tetradecyl sulfate (CH-STS) using strain ultrasound elastography (SUE). MATERIALS AND METHODS: Bilateral common iliac artery type Ia endoleaks were created in 9 dogs. Per animal, 1 endoleak was randomized to blinded embolization with CH, and the other, with CH-STS. Brightness-mode ultrasound, Doppler ultrasound, SUE radiofrequency ultrasound, and computed tomography were performed for up to 6 months until sacrifice. Radiologic and histopathologic studies were coregistered to identify 3 regions of interest: the embolic agent, intraluminal thrombus (ILT), and aneurysm sac. SUE segmentations were performed by 2 blinded independent observers. The maximum axial strain (MAS) was the primary outcome. Statistical analysis was performed using the Fisher exact test, multivariable linear mixed-effects models, and intraclass correlation coefficients (ICCs). RESULTS: Residual endoleaks were identified in 7 of 9 (78%) and 4 of 9 (44%) aneurysms embolized with CH and CH-STS, respectively (P = .3348). CH-STS had a 66% lower MAS (P < .001) than CH. The ILT had a 37% lower MAS (P = .01) than CH and a 77% greater MAS (P = .079) than CH-STS. There was no significant difference in ILT between treatments. The aneurysm sacs embolized with CH-STS had a 29% lower MAS (P < .001) than those embolized with CH. Residual endoleak was associated with a 53% greater MAS (P < .001). The ICC for MAS was 0.807 (95% confidence interval: 0.754-0.849) between segmentations. CONCLUSIONS: CH-STS confers stiffer intraluminal properties to embolized aneurysms. Persistent endoleaks are associated with increased sac strain, an observation that may help guide management.
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Embolización Terapéutica , Endofuga , Animales , Quitosano , Perros , Diagnóstico por Imagen de Elasticidad , Embolización Terapéutica/efectos adversos , Embolización Terapéutica/métodos , Endofuga/diagnóstico por imagen , Endofuga/terapia , Hidrogeles , Estudios Retrospectivos , Tetradecil Sulfato de Sodio , Trombosis/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: To evaluate residual endoleak and thrombus organisation with shear wave imaging (SWI) after endoleak embolisation through an animal study. METHODS: This prospective experimental study involved eight dogs with creation of 16 iliac aneurysms and type I endoleak after endovascular aneurysm repair (EVAR). Embolisation agents were injected into the sac to seal endoleak. SWI and colour flow Doppler ultrasound (DUS) were performed at implantation, one week, and one and three months after implantation; for three dogs, SWI and DUS were also performed six months after implantation. Digital subtraction angiography and contrast-enhanced computed tomography were performed at sacrifice. Macroscopic and histopathological analyses were processed to identify regions of interest (ROIs) for endoleak, fresh thrombus, organised thrombus and embolisation agent, where SWI elasticity moduli were compared. RESULTS: At sacrifice, nine aneurysms had residual endoleak, while seven were sealed. Ten had a fresh and 15 had an organised thrombus. SWI was able to detect all endoleaks, including two cases undetected with DUS. Elasticity moduli of 0.2 kPa ± 0.1 kPa (mean ± SD), 9.5 kPa ± 3.3 kPa, 48.1 kPa ± 21.3 kPa and 44.9 kPa ± 23.7 kPa were found in the ROIs positioned in endoleaks, fresh thrombi, organised thrombi and embolisation agent, respectively. Elasticity values of endoleak and fresh thrombus were lower than those of organised thrombi and embolisation agent (p < 0.001). Stiffness of fresh thrombus at one week (8.7 kPa ± 3.6 kPa) increased at three months (30.2 kPa ± 13.8 kPa), indicating thrombus maturation (p < 0.001). CONCLUSIONS: In a dog model of iliac EVAR, SWI was able to identify endoleak, thrombus maturation and embolising agents after endoleak embolisation.
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Chitosan (CH) hydrogels with remarkable mechanical properties and rapid gelation rate were recently synthesized by combining sodium hydrogen carbonate (SHC) with another weak base, such as beta-glycerophosphate (BGP). To improve their biological responses, in the present study, chondroitin sulfate (CS) was added to these CH hydrogels. Hydrogel characteristics in terms of pH and osmolarity, as well as rheological, mechanical, morphological and swelling properties, were studied in the absence and presence of CS. Effect of CS addition on cytocompatibility of hydrogels was also assessed by evaluating the viability and metabolic activity of encapsulated L929 fibroblasts. New CH hydrogels containing CS were thermosensitive and injectable with pH and osmolality close to physiological levels and enhanced swelling capacity. Encapsulated cells were able to maintain their viability and proliferative capacity up to 7â¯days and CS addition improved the viability of the cells, particularly in serum-free conditions. Addition of CS showed a reducing and dose-dependent effect on the mechanical strength of the hydrogels after complete gelation. This work provides evidence that CH-CS hydrogels prepared with a combination of SHC and BGP as a gelling agent have a promising potential to be used as thermosensitive, injectable and biocompatible matrices with tunable mechanical properties for cell therapy applications.
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Materiales Biocompatibles/química , Tratamiento Basado en Trasplante de Células y Tejidos , Quitosano/química , Sulfatos de Condroitina/química , Hidrogeles/química , Fenómenos Mecánicos , Ingeniería de Tejidos , Animales , Materiales Biocompatibles/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Concentración de Iones de Hidrógeno , Inyecciones , Ratones , Concentración Osmolar , PorosidadRESUMEN
The success of endovascular repair of abdominal aortic aneurysms remains limited due to the development of endoleaks. Sac embolization has been proposed to manage endoleaks, but current embolizing materials are associated with frequent recurrence. An injectable agent that combines vascular occlusion and sclerosing properties has demonstrated promise for the treatment of endoleaks. Moreover, the inhibition of aneurysmal wall degradation via matrix metalloproteinases (MMPs) may further prevent aneurysm progression. Thus, an embolization agent that promotes occlusion, MMP inhibition and endothelial ablation was hypothesized to provide a multi-faceted approach for endoleak treatment. In this study, an injectable, occlusive chitosan (CH) hydrogel containing doxycycline (DOX)-a sclerosant and MMP inhibitor-was developed. Several CH-DOX hydrogel formulations were characterized for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo. All formulations were injectable and gelled rapidly at body temperature. Only hydrogels prepared with 0.075M sodium bicarbonate and 0.08M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel was in a two-stage pattern: a burst release followed by a slow continuous release. Released DOX was bioactive and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appear to be promising new multifunctional embolic agents for the treatment of endoleaks. STATEMENT OF SIGNIFICANCE: An injectable embolizing chitosan hydrogel releasing doxycycline (DOX) was developed as the first multi-faceted approach for the occlusion of blood vessels. It combines occlusive properties with DOX sclerosing and MMP inhibition properties, respectively known to prevent recanalization process and to counteract the underlying pathophysiology of vessel wall degradation and aneurysm progression. After drug release, the biocompatible scaffold can be invaded by cells and slowly degrade. Local DOX delivery requires lower drug amount and decreases risks of side effects compared to systemic administration. This new gel could be used for the prevention or treatment of endoleaks after endovascular aneurysm repair, but also for the embolization of other blood vessels such as venous or vascular malformations.
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Aneurisma de la Aorta Abdominal/terapia , Quitosano , Doxiciclina , Endofuga/prevención & control , Inhibidores de Proteasas , Soluciones Esclerosantes , Animales , Línea Celular Tumoral , Quitosano/química , Quitosano/farmacología , Perros , Doxiciclina/química , Doxiciclina/farmacología , Gelatinasas/antagonistas & inhibidores , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Soluciones Esclerosantes/química , Soluciones Esclerosantes/farmacologíaRESUMEN
INTRODUCTION: Onyx and ethanol are well-known embolic and sclerotic agents that are frequently used in embolization. These agents present advantages and disadvantages regarding visibility, injection control and penetration depth. Mixing both products might yield a new product with different characteristics. The aim of this study is to evaluate the injectability, radiopacity, and mechanical and occlusive properties of different mixtures of Onyx 18 and ethanol in vitro and in vivo (in a swine model). MATERIALS AND METHODS: Various Onyx 18 and ethanol formulations were prepared and tested in vitro for their injectability, solidification rate and shrinkage, cohesion and occlusive properties. In vivo tests were performed using 3 swine. Ease of injection, radiopacity, cohesiveness and penetration were analyzed using fluoroscopy and high-resolution CT. RESULTS: All mixtures were easy to inject through a microcatheter with no resistance or blockage in vitro and in vivo. The 50%-ethanol mixture showed delayed copolymerization with fragmentation and proximal occlusion. The 75%-ethanol mixture showed poor radiopacity in vivo and was not tested in vitro. The 25%-ethanol mixture showed good occlusive properties and accepted penetration and radiopacity. CONCLUSION: Mixing Onyx and ethanol is feasible. The mixture of 25% of ethanol and 75% of Onyx 18 could be a new sclero-embolic agent. Further research is needed to study the chemical changes of the mixture, to confirm the significance of the added sclerotic effect and to find out the ideal mixture percentages.
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Embolización Terapéutica/métodos , Etanol/administración & dosificación , Polivinilos/administración & dosificación , Tantalio/administración & dosificación , Animales , Combinación de Medicamentos , Quimioterapia Combinada , Estudios de Factibilidad , Fluoroscopía , Humanos , Técnicas In Vitro , Inyecciones , Modelos Animales , Arteria Renal/diagnóstico por imagen , Reología , Porcinos , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: To compare the efficacy of an embolization agent with sclerosing properties (made of chitosan and sodium tetradecyl sulfate, CH-STS) with a similar embolization agent but without sclerosing properties (made of chitosan, CH) in treating endoleaks in a canine endovascular aneurysm repair model. METHODS: Two chitosan-based radiopaque hydrogels were prepared, one with STS and one without STS. Their rheological, injectability, and embolizing properties were assessed in vitro; afterwards, their efficacy in occluding endoleaks was compared in a canine bilateral aneurysm model reproducing type I endoleaks (n = 9 each). The primary endpoint was endoleak persistence at 3 or 6 months, assessed on a CT scan and macroscopic examination. Secondary endpoints were the occurrence of stent-graft (SG) thrombosis, the evolution of the aneurysm mean diameter, as well as aneurysm healing and inflammation scores in pathology examinations. RESULTS: In vitro experiments showed that both products gelled rapidly and presented initial storage moduli greater than 800 Pa, which increased with time. Both gels were compatible with microcatheter injection and occlude flow up to physiological pressure in vitro. In a type I endoleak model, the injection of CH-STS sclerosing gel tended to reduce the risk of occurrence of endoleaks, compared to CH non-sclerosing agent (2/9 vs. 6/9, p = 0.069). No case of SG thrombosis was observed. Moderate inflammation was found around both gels, with a comparable intensity score in both CH and CH-STS groups (2.6 ± 0.9 and 2.7 ± 0.9, respectively; p = 0.789). CONCLUSIONS: Flow occlusion combined with chemical endothelial denudation appears promising for the treatment of endoleaks. LEVEL OF EVIDENCE: N/A.
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Quitosano/administración & dosificación , Embolización Terapéutica/métodos , Endofuga/terapia , Hidrogeles/administración & dosificación , Soluciones Esclerosantes/administración & dosificación , Tetradecil Sulfato de Sodio/administración & dosificación , Animales , Modelos Animales de Enfermedad , Perros , Procedimientos Endovasculares/métodosRESUMEN
Chitosan-thermosensitive hydrogels present interesting features for the embolization of blood vessels, but need to be better characterized and optimized. Chitosan polymer (degree of deacetylation (DDA) of 94%) was purified and combined with Visipaque (VIS), a nonionic isotonic contrast agent composed of iodixanol. A beta-glycerolphosphate (ßGP) solution was then added to induce gelation at body temperature. The gelation process was monitored by rheometry, measuring the evolution of the sample storage (G') and loss (Gâ³) moduli as a function of VIS and ßGP concentration. Adding VIS significantly slowed down gelation kinetics, but a 12% and higher ßGP concentration provided a radiopaque solution, which at 37°C, gels immediately. A custom-made in vitro embolization bench test was developed to assess the gel's occlusive properties, and its injectability through a small diameter catheter was verified. Results show that the short-term occlusive properties of the gel were insufficient when using a ßGP concentration of 12% w/v (about 0.4M), but that increasing the ßGP to 20% (0.6M) allowed an acceleration of the gelation and the immediate blocking of flow above physiological pressure. The contrast agent was rapidly released in solution, such that it would not interfere with future follow-up imaging. In accordance with the literature data, the cytotoxicity of gel extracts increased with ßGP concentration and to a lesser extent with VIS concentration. Preliminary in vivo testing showed easy injection by catheter and good visibility under fluoroscopy. These results suggest that radiopaque CH/ßGP20%/VIS hydrogels present significant potential as embolizing agents for blood vessels and aneurysms. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1551-1562, 2016.