RESUMEN
Pancreatic islet transplantation is an effective treatment for type I diabetes mellitus. However, many problems associated with pancreatic islet engraftment remain unresolved. In this study, we developed a hydrogel microwell device for islet implantation, fabricated by crosslinking gelatin-methacryloyl (GelMA) and 2-hydroxyethyl methacrylate (HEMA) in appropriate proportions. The fabricated hydrogel microwell device could be freeze-dried and restored by immersion in the culture medium at any time, allowing long-term storage and transport of the device for ready-to-use applications. In addition, due to its non-swelling properties, the shape of the wells of the device was maintained. Thus, the device allowed pancreatic ß cell lines to form spheroids and increase insulin secretion. Intraperitoneal implantation of the ß cell line-seeded GelMA/HEMA hydrogel microwell device reduced blood glucose levels in diabetic mice. In addition, they were easy to handle during transplantation and were removed from the transplant site without peritoneal adhesions or infiltration by inflammatory cells. These results suggest that the GelMA/HEMA hydrogel microwell device can go from spheroid and/or organoid fabrication to transplantation in a single step.
Asunto(s)
Gelatina , Hidrogeles , Células Secretoras de Insulina , Metacrilatos , Animales , Ratones , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citología , Metacrilatos/química , Hidrogeles/química , Gelatina/química , Esferoides Celulares , Diabetes Mellitus Experimental/terapia , Trasplante de Islotes Pancreáticos , Glucemia/metabolismo , Glucemia/análisis , Insulina/metabolismo , Polihidroxietil Metacrilato/química , Diabetes Mellitus Tipo 1/terapiaRESUMEN
Nanoparticles (NPs) are anticipated to be used for various biomedical applications in which their aggregation has been an important issue. However, concerns regarding slightly aggregated but apparently monodispersed NPs have been difficult to address because of a lack of appropriate evaluation methods. Here, we report centrifugal field-flow fractionation (CF3) as a powerful method for analyzing the slight aggregation of NPs, using antibody-modified gold NPs (Ab-AuNPs) prepared by a conventional protocol with centrifugal purification as a model. While common evaluation methods such as dynamic light scattering cannot detect significant signs of aggregation, CF3 successfully detects distinct peaks of slightly aggregated NPs, including dimers and trimers. Their impact on biological interactions was also demonstrated by a cellular uptake study: slightly aggregated Ab-AuNPs exhibited 1.8 times higher cellular uptake than monodispersed Ab-AuNPs. These results suggest the importance of aggregate evaluation via CF3 as well as the need for careful attention to the bioconjugation procedures for NPs.
Asunto(s)
Fraccionamiento de Campo-Flujo , Nanopartículas del Metal , Oro , Dispersión Dinámica de Luz , Transporte Biológico , Fraccionamiento de Campo-Flujo/métodosRESUMEN
Biomedical applications of nanoparticles (NPs) have attracted much attention. With the advancement of personalized medicine, researchers are now proposing the concept that the design of NPs needs to be optimized according to the individual patient. To realize this concept, an important question is how precisely we can tailor the physicochemical properties of NPs, such as size, shape, and surface chemistry, using current technology. This review discusses recent advances and challenges in the precise control of the size, shape, and surface chemistry of NPs. While control methods have advanced significantly over the past 20 years, the size, shape, and surface chemistry of currently available NPs vary by type, requiring careful selection based on the targeted disease, organ, and patient.
Asunto(s)
Nanopartículas , Medicina de Precisión , Medicina de Precisión/métodos , Nanopartículas/química , Humanos , Propiedades de Superficie , Tamaño de la PartículaRESUMEN
In the present study, we report the first synthesis of diazirine-modified hyaluronic acid (HA-DAZ). In addition, we also produced a precursor polymer solution composed of HA-DAZ and dendritic polyethyleneimine (DPI) that showed strong shear-thinning properties. Furthermore, its viscosity was strongly reduced (i.e., from 5 × 105 mPa s at 10-3 s-1 to 6 × 101 mPa s at 103 s-1), substantially, which enhanced solution injectability using a 21 G needle. After ultraviolet irradiation at 365 nm and 6 mW cm-2, the HA-DAZ/DPI solution achieved rapid gelation, as measured using the stirring method, and its gelation time decreased from 200 s to 9 s as the total concentrations of HA-DAZ and DPI increased. Following UV irradiation, the storage modulus increased from 40 to 200 Pa. In addition, reversible sol-gel transition and self-healing properties were observed even after UV irradiation. This suggests that the HA-DAZ/DPI hydrogel was crosslinked in multiple ways, i.e., via covalent bonding between the diazirine and amine groups and via intermolecular interactions, including hydrogen bonding, electrostatic interactions, and hydrophobic interactions. A lap shear test showed that the HA-DAZ/DPI hydrogel exhibited strong adhesiveness as a fibrin glue following UV irradiation. Finally, the HA-DAZ/DPI hydrogel showed higher tissue reinforcement than fibrin glue in an ex vivo burst pressure test of the porcine esophageal mucosa.
Asunto(s)
Adhesivos Tisulares , Animales , Porcinos , Ácido Hialurónico/química , Diazometano , Polietileneimina , Hidrogeles/química , Adhesivo de Tejido de FibrinaRESUMEN
Endoscopic submucosal dissection (ESD) for the treatment of esophageal mucosal lesions often leads to postoperative stenosis, causing difficulty in swallowing, known as dysphagia. In this study, we developed an in situ cross-linkable powder composed of alginate, gelatin, transglutaminase (TG), and calcium chloride ions (Ca2+), which can be administered through a 1.5 m-long and 3.2 mm-diameter endoscopic instrument channel. The powdered mixture of alginate and gelatin quickly formed a hydrogel by absorbing body fluids and was cross-linked by TG and Ca2+, which adhered ex vivo to porcine submucosal layers for over 2 weeks. In addition, we developed a new submucosal exfoliation model in rats that induced severe stenosis, similar to the ESD-induced stenosis models in clinical practice. When administered to the new rat model, the powder system effectively reduced the severity of esophageal stenosis based on body weight change monitoring, anatomical findings, and histological analysis. The body weight of the rats was maintained at the initial weight on postoperative day 14 (POD14), and epithelialization on POD7 and 14 improved to almost 100%. Additionally, collagen accumulation and the number of α-SMA-positive cells decreased due to powder administration. Therefore, these findings indicate that the in situ cross-linkable powder can prevent esophageal stenosis after ESD.
Asunto(s)
Estenosis Esofágica , Ratas , Animales , Porcinos , Estenosis Esofágica/prevención & control , Estenosis Esofágica/etiología , Gelatina , Polvos , Constricción Patológica , Peso CorporalRESUMEN
We developed a new muco-adhesive hydrogel composed of cationic guar gum (CGG) and boric acid (BA). The CGG-BA precursor solution of 0.5-2% w/v concentration exhibited fluidity at low pH (3-5), while gelation occurred within 1 min at physiological pH (7-8) conditions. Scanning electron microscopy and Fourier-transform infrared spectroscopy results confirmed the change in physical and chemical behavior, respectively, with change in pH. The pH-responsive self-healing ability was analyzed through microscopy and rheology. CGG-BA hydrogels showed good self-healing property at pH 7.4. The in vitro biocompatibility test of the hydrogel studied using NIH3T3 and NHEK cells showed that it was non-toxic at concentrations of CGG-BA below 2% w/v. Ex vivo mucoadhesive tests confirmed the hydrogel's potential for use as a muco-adhesive. Burst pressure tests were conducted using pig esophageal mucosa and the results showed that at pH 7.4, 1% w/v CGG-BA self-healable hydrogel resisted about 8 ± 2 kPa pressure, comparable to that of Fibrin glue. This was higher than that at solution (pH 5) and brittle gel (pH 10) conditions. To confirm the good adhesive strength of the self-healable hydrogels, lap shear tests conducted, resulted in adhesive strengths measured in the range of 1.0 ± 0.5-2.0 ± 0.6 kPa, which was also comparable to fibrin glue control 1.8 ± 0.6 kPa. Hydrogel weight measurements showed that 40-80% gel lasted under physiological conditions for 10 h. The results suggest that CGG-BA hydrogel has potential as a pH responsive mucosal protectant biomaterial.
RESUMEN
Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. Although the first-line treatment, R-CHOP treatment, shows efficacy in approximately 80% of patients with DLBCL, some patients have refractory disease or relapse after the initial response to therapy, resulting in a significantly poorer prognosis. In this study, we developed a microRNA (miRNA) signature-based companion diagnostic model to predict the response of patients with DLBCL to R-CHOP treatment by integrating two clinical study datasets. To select the optimum miRNA combination as a panel, we examined three feature selection methods (p-value-based ranking, stepwise method, and Boruta), together with 11 types of classifiers systematically. Boruta selection enabled a higher area under the curve (AUC) with a lower number of miRNAs compared with other feature selection methods, leading to an AUC of 0.751 via the random forest classifier using 36 miRNAs. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that Boruta avoided multiple selection of miRNAs with similar functions, thereby preventing the decrease in diagnostic ability via collinearity. The AUC value first increased with an increasing number of miRNAs and then became almost constant at approximately 30 miRNAs, suggesting the existence of the optimum number of miRNAs as a panel for future clinical translation of multiple miRNA-based diagnostics.
Asunto(s)
Linfoma de Células B Grandes Difuso , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Rituximab/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Ciclofosfamida/uso terapéutico , Vincristina/uso terapéutico , Doxorrubicina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
The focus of this brief review is to describe the application of nanoparticles, including endogenous nanoparticles (e.g., extracellular vesicles, EVs, and virus capsids) and exogenous nanoparticles (e.g., organic and inorganic materials) in cancer therapy and diagnostics. In this review, we mainly focused on EVs, where a recent study demonstrated that EVs secreted from cancer cells are associated with malignant alterations in cancer. EVs are expected to be used for cancer diagnostics by analyzing their informative cargo. Exogenous nanoparticles are also used in cancer diagnostics as imaging probes because they can be easily functionalized. Nanoparticles are promising targets for drug delivery system (DDS) development and have recently been actively studied. In this review, we introduce nanoparticles as a powerful tool in the field of cancer therapy and diagnostics and discuss issues and future prospects.
Asunto(s)
Vesículas Extracelulares , Nanopartículas , Neoplasias , Humanos , Sistemas de Liberación de Medicamentos/métodos , Comunicación CelularRESUMEN
Stimuli-responsive star polymers are promising functional materials whose aggregation, adhesion, and interaction with cells can be altered by applying suitable stimuli. Among several stimuli assessed, the potassium ion (K+), which is known to be captured by crown ethers, is of considerable interest because of the role it plays in the body. In this study, a K+-responsive star copolymer was developed using a polyglycerol (PG) core and grafted copolymer arms consisting of a thermo-responsive poly(N-isopropylacrylamide) unit, a metal ion-recognizing benzo-18-crown-6-acrylamide unit, and a photoluminescent fluorescein O-methacrylate unit. Via optimization of grafting density and copolymerization ratio of grafted arms, along with the use of hydrophilic hyperbranched core, microsized aggregates with a diameter of 5.5 µm were successfully formed in the absence of K+ ions without inducing severe sedimentation (the lower critical solution temperature (LCST) was 35.6 °C). In the presence of K+ ions, these aggregates dispersed due to the shift in LCST (47.2 °C at 160 mM K+), which further induced the activation of fluorescence that was quenched in the aggregated state. Furthermore, macrophage targeting based on the micron-sized aggregation state and subsequent fluorescence activation of the developed star copolymers in response to an increase in intracellular K+ concentration were performed as a potential K+ probe or K+-responsive drug delivery vehicle.
RESUMEN
In surgery, both antiperitoneal adhesion barriers and hemostats with high efficiency and excellent handling are necessary. However, antiadhesion and hemostasis have been examined separately. In this study, six different ultrapure alginate bilayer sponges with thicknesses of 10, 50, 100, 200, 300, and 500 µm were fabricated via lyophilization and subsequent mechanical compression. Compression significantly enhanced mechanical strength and improved handling. Furthermore, it had a complex effect on dissolution time and contact angle. Therefore, the 100 µm compressed sponge showed the highest hemostatic activity in the liver bleeding model in mice, whereas the 200 µm sponge demonstrated the highest antiadhesion efficacy among the compressed sponges in a Pean crush hepatectomy-induced adhesion model in rats. For the first time, we systematically evaluated the effect of sponge compression on foldability, fluid absorption, mechanical strength, hemostatic effect, and antiadhesion properties. The optimum thickness of an alginate bilayer sponge by compression balances antiperitoneal adhesion and hemostasis simultaneously.
Asunto(s)
Alginatos , Hemostáticos , Alginatos/farmacología , Animales , Vendajes , Hemostasis , Hemostáticos/farmacología , Ratones , Ratas , Adherencias Tisulares/prevención & controlRESUMEN
Conjugated polymer nanoparticles (Pdots) are expected to be novel bioimaging and sensing probes. However, the size tuning required to control biological interactions has not been well established. Herein, we achieved a size-tunable synthesis of Pdots ranging from 30 to 200 nm by controlling the hydrolysis rate of the stabilising agent and evaluated their cellular imaging properties.
RESUMEN
The industrial use of living organisms for bioproduction of valued substances has been accomplished mostly using microorganisms. To produce high-value bioproducts such as antibodies that require glycosylation modification for better performance, animal cells have been recently gaining attention in bioengineering because microorganisms are unsuitable for producing such substances. Furthermore, animal cells are now classified as products because a large number of cells are required for use in regenerative medicine. In this article, we review animal cell technologies and the use of animal cells, focusing on useable cell generation and large-scale production of animal cells. We review recent advance in mammalian cell line development because this is the first step in the production of recombinant proteins, and it largely affects the efficacy of the production. We next review genetic engineering technology focusing on CRISPR-Cas system as well as surrounding technologies as these methods have been gaining increasing attention in areas that use animal cells. We further review technologies relating to bioreactors used in the context of animal cells because they are essential for the mass production of target products. We also review tissue engineering technology because tissue engineering is one of the main exits for mass-produced cells; in combination with genetic engineering technology, it can prove to be a promising treatment for patients with genetic diseases after the establishment of induced pluripotent stem cell technology. The technologies highlighted in this review cover brief outline of the recent animal cell technologies related to industrial and medical applications.
Asunto(s)
Sistemas CRISPR-Cas , Ingeniería Genética , Animales , Reactores Biológicos , Línea Celular , Edición Génica/métodos , Humanos , Mamíferos/genética , Medicina RegenerativaRESUMEN
Carboxymethyl cellulose (CMC) is a promising material for moist wound healing, and silver loading onto CMC has been examined for anti-bacterial activity. In this study, we developed silver-loaded CMC nonwoven sheets with different counterions, namely sodium CMC (CMC-Na/Ag) and partially protonated CMC (CMC-H/Ag), to examine their anti-bacterial and wound-healing properties. Owing to the presence of counter protons, CMC-H/Ag showed slower water adsorption, dissolution, and Ag release than CMC-Na/Ag. In addition, CMC-H/Ag and CMC-Na/Ag exhibited differences in anti-bacterial activities in shake-flask and inhibition zone tests in vitro. An in vivo experiment using a pressure ulcer mouse model with Pseudomonas aeruginosa infection showed that CMC-Na/Ag significantly accelerated wound healing compared to CMC-H/Ag and a commercially available Ag-loaded CMC nonwoven sheet, Aquacel Ag. These results suggest the importance of controlling CMC counterions and the therapeutic potential of the developed product as a wound dressing.
Asunto(s)
Plata , Infección de Heridas , Animales , Vendajes , Carboximetilcelulosa de Sodio/farmacología , Ratones , Plata/farmacología , Plata/uso terapéutico , Cicatrización de Heridas , Infección de Heridas/tratamiento farmacológicoRESUMEN
Malignant pleural mesothelioma (MPM) is one of the intractable cancers that require a more effective therapeutic strategy for clinical practice. Hyaluronic acid (HA) nanogels were prepared by the chelation of cisplatin (CDDP) with different molecular weights of iminodiacetic acid-conjugated hyaluronic acid (HA-IDA). The sizes of the 100, 850, and 2000 kDa HA nanogels were 33, 43, and 44 nm, respectively. MSTO-211H, a human MPM cell line, was more effective in taking up all three HA nanogels compared to AB22, a mouse MPM cell line. In addition, the 850 kDa HA nanogel showed higher anticancer activity against AB22 and MSTO-211H than 100 and 2000 kDa HA nanogels. Furthermore, all the HA nanogels showed a milder cytotoxic effect on normal Met-5A mesothelial cells compared to that exhibited by free CDDP. Finally, the 850 kDa HA nanogel was administrated intrapleurally into both the MSTO-211H xenograft and AB22 allograft mouse models of MPM using an injectable HA-based hydrogel. HA nanogels showed a significant therapeutic effect in both the xenograft and allograft models.
Asunto(s)
Cisplatino , Mesotelioma Maligno , Animales , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Humanos , Ácido Hialurónico , Iminoácidos , Ratones , NanogelesRESUMEN
Intraperitoneal chemotherapy demonstrates potential applicability in the treatment of peritoneally disseminated ovarian cancer because the disseminated tumors can directly receive exposure to high concentrations of anticancer drugs. However, a considerable proportion of drugs, particularly micromolecular and hydrophilic drugs, such as cisplatin (CDDP), are often excreted through glomerular filtration for a short period. To effectively deliver CDDP into peritoneally disseminated ovarian cancer tissues, we developed an alginate (AL)-based hybrid system in which a CDDP-loaded AL nanogel (AL/CDDP-nanogel) was encapsulated in an injectable AL-hydrogel cross-linked with calcium ions. This system enabled the sustained release of CDDP from the AL/CDDP-nanogel/AL-hydrogel hybrid for over a week. Herein, we constructed a peritoneally disseminated ovarian cancer mouse model using ovarian cancer cell lines with KRAS mutations (ID8-KRAS: KRASG12V). The AL/CDDP-nanogel/AL-hydrogel hybrid system showed significant antitumor activity in vivo. This therapy may be considered a novel strategy for the treatment of advanced-stage ovarian cancer with KRAS mutations.
Asunto(s)
Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Sistema de Administración de Fármacos con Nanopartículas/química , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Ácido Algínico/química , Animales , Línea Celular Tumoral , Femenino , Humanos , Hidrogeles/química , Inyecciones Intraperitoneales , Ratones , Nanogeles/química , Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Peritoneo/patología , Polietilenglicoles/química , Polietileneimina/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The blood-brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies. The widening of BBB tight junctions via focused ultrasound (FUS) offers a promising approach for enhancing the delivery of nanoparticles into the brain. However, there is currently an insufficient understanding of how nanoparticles pass through the opened BBB gaps. Here we investigated the size-dependence of nanoparticle delivery into the brain assisted by FUS-induced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. For 3- and 15-nm AuNPs, FUS exposure significantly increased permeation across an in vitro BBB model by up to 9.5 times, and the permeability was higher with smaller diameter. However, in vivo transcranial FUS exposure in mice demonstrated that smaller particles were not necessarily better for delivery into the brain. Medium-sized (15 nm) AuNPs showed the highest delivery efficiency (0.22% ID), compared with 3- and 120-nm particles. A computational model suggested that this optimum size was determined by the competition between their permeation through opened BBB gaps and their excretion from blood. Our results would greatly contribute to designing nanoparticles for their delivery into the brain for the treatment of central nervous system diseases.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Encefalopatías/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de la radiación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas del Metal/administración & dosificación , Ondas Ultrasónicas , Animales , Barrera Hematoencefálica/efectos de la radiación , Encéfalo/metabolismo , Encefalopatías/metabolismo , Encefalopatías/patología , Imagen por Resonancia Magnética/métodos , Masculino , Nanopartículas del Metal/química , Ratones , Ratones Endogámicos ICR , MicroburbujasRESUMEN
Inorganic polyphosphate (PolyP) is a potential hemostatic material. However, the effect of PolyP chain length on the immune response and hemostatic function remains to be established. We have developed PolyP-conjugated hyaluronans (HA-PolyPs) with three different short-chain PolyPs (n = 13, 40, and 100 phosphate units). All short-chain PolyPs showed biocompatibility in the cell viability and inflammatory cytokine secretion test in vitro and in vivo, wherein shorter PolyPs showed milder responses in some cases. We then produced HA-PolyP hydrogels (HAX-PolyPs) with three different short-chain PolyPs as hemostats. Interestingly, the in vivo biocompatibility and hemostatic activity of HAX-PolyP were not significantly affected by the length of conjugated PolyPs. HAX-PolyP with all chain lengths significantly decreased the amount of bleeding in a novel mouse liver bleeding model. These results indicated that the shortest PolyP (n = 13) induced milder acute inflammation and had an efficient hemostatic effect when conjugated to hyaluronic acid. The present study provides key insights into the design of PolyP-based biomaterials and bioconjugates, which are expected to grow in importance for various medical applications.
Asunto(s)
Hemostáticos , Polifosfatos , Animales , Ácido Hialurónico , Hidrogeles , Inmunidad , RatonesRESUMEN
Pemetrexed (PMX) is a multi-targeted antifolate drug used for the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer. Hyaluronan (HA) in blood is well known as a disease marker of MPM. We synthesized PMX-conjugated hyaluronan (HA-ADH-PMX) for the first time to develop a novel anticancer chemotherapeutic agent. HAs with different molecular weights (76 and 130â¯kDa) were first derivatized with adipic dihydrazide (ADH) and then conjugated to PMX. The obtained HA-ADH-PMX retained inhibitory activity against folate metabolism enzymes; thymidylate synthase was inhibited to the same extent as native PMX, whereas the inhibition constant against dihydrofolate reductase was 3.3% for 76â¯kDa HA-ADH-PMX and 12% for 130â¯kDa HA-ADH-PMX when compared with that of native PMX. The in vitro cytotoxicity of HA-ADH-PMX from both molecular weights against MPM cell lines was lower than that of native PMX. On the other hand, intrapleural administration of 76â¯kDa HA-ADH-PMX resulted in a survival rate of MPM model mice comparable to that with native PMX, suggesting the potential for future MPM therapy.
Asunto(s)
Antineoplásicos/farmacología , Ácido Hialurónico/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Pemetrexed/envenenamiento , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Mesotelioma Maligno , Ratones , Ratones Endogámicos BALB C , Timidilato Sintasa/metabolismoRESUMEN
Thermoreversible gelation and liquid-liquid phase separation are theoretically studied for the gels of polyfunctional molecules (polymers) whose network junctions are formed by complexation of functional groups on the polymer chains with added metal ions. Phase diagrams on the polymer/ion/solvent concentration plane, including both sol-gel transition lines and liquid-liquid phase separation lines (spinodals), are derived as functions of the polymer functionality, molecular weight, maximum coordination number of ions, and temperature. Binding isotherms of ions are also calculated as functions of the ion concentration. Results of the calculated sol-gel transition lines are compared with our recent experimental data on gelation of star block and telechelic, acrylic copolymers cross-linked by iron ions. It is shown that, owing to reaction stoichiometry, there is an optimal ion concentration at which the solution gels for the lowest polymer concentration and also that a re-entrant sol phase appears in the ion concentrations higher than the optimal one. The effect of stepwise complex formation constants on the re-entrant phase is studied in detail.
RESUMEN
BACKGROUND: Adhesion formation is a critical issue in surgery, particularly in hepatectomy. The present study aimed to develop a bilayer adhesion barrier comprising alginate (Alg) of different molecular weight (Mw). It was expected that a slowly dissolving layer remains on the cut surface, functioning as a physical barrier, whereas a rapidly dissolving layer widely distributes in the peritoneal cavity to prevent de novo adhesions. METHODS: Bilayer Alg sponges were fabricated using low Mw Alg for the upper layer and high Mw Alg for the bottom layer. The dissolution behavior of each layer was evaluated in vitro in peritoneum-like environments. We constructed a Pean crush hepatectomy-induced adhesion model in rats. The effects of the bilayer sponge on cut surface and de novo adhesions were separately evaluated in terms of their extent and grade. RESULTS: The Alg sponge layer with low Mw dissolved faster than that with high Mw in vitro. One week after the hepatectomy, although no significant decrease in adhesion extent on the cut surface was observed in rats that received Seprafilm and Interceed, treatment with Alg bilayer sponge significantly decreased the adhesion extent to 38% of that without treatment. Moreover, a significant decrease in de novo adhesion extent was observed in the Alg bilayer sponge compared with the Interceed group. CONCLUSIONS: The Alg bilayer sponge was effective for preventing both cut surface and de novo adhesions in the rat Pean crush hepatectomy model. The simple yet functional design of the Alg bilayer sponge can facilitate its use in future clinical practice.