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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Postoperative peritoneal adhesion (PPA) is a prevalent incidence that generally happens during the healing process of traumatized tissues. It causes multiple severe complications such as intestinal ...obstruction, chronic abdominal pain, and female infertility. To prevent PPA, several antiadhesion materials and drug delivery systems composed of biomaterials are used clinically, and clinical antiadhesive is one of the important applications nowadays. In addition to several commercially available materials, like film, spray, injectable hydrogel, powder, or solution type have been energetically studied based on natural and synthetic biomaterials such as alginate, hyaluronan, cellulose, starch, chondroitin sulfate, polyethylene glycol, polylactic acid, etc. Moreover, many kinds of animal adhesion models, such as cecum abrasion models and unitary horn models, are developed to evaluate new materials’ efficacy. A new animal adhesion model based on hepatectomy and conventional animal adhesion models is recently developed and a new adhesion barrier by this new model is also developed. In summary, many kinds of materials and animal models are studied; thus, it is quite important to overview this field's current progress. Here, PPA is reviewed in terms of the species of biomaterials and animal models and several problems to be solved to develop better antiadhesion materials in the future are discussed.
Postoperative peritoneal adhesion (PPA) is a prevalent and severe pathological condition. Different preventive strategies based on natural polysaccharides and their derivatives with synthetic polymers are available in the injectable hydrogel, solid sheet, sponge, and solutions. The antiadhesion efficacy of materials evaluates using different animal models. The effectiveness of antiadhesion barriers with better handling is expected in clinical application.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Various natural and synthetic polymers, such as hyaluronan and functionalized polyethylene glycol (PEG), have been used to fabricate biodegradable membranes. They can potentially be used for local ...drug release in the body because of their biodegradability. However, this biodegradability causes to difficulties in sustained drug release, and an insufficient ability to control drug permeability can lead to adverse effects. In this study, we developed biodegradable lyophilized PEG membranes from highly crosslinked PEG hydrogels to control drug permeation. Three-arm thiol-modified PEG (PEG-SH, molecular weight Mw = 1300) and four-arm acrylate-modified PEG (PEG-AC, Mw = 1892) were used to fabricate the PEG hydrogels, which were then lyophilized to obtain PEG membranes. The degradation time of these PEG membranes was 25 days under physiological conditions. Despite their biodegradability, the membranes allowed the permeation of model drugs constantly until complete degradation around physiological pH. The normalized diffusion coefficients (lnD/D0) for vitamin B12 and lysozyme (Lys) were −2.6 and −4.8, respectively. In addition, the membranes showed biodegradability and biocompatibility in the abdominal cavity of mice. These results indicate that PEG membranes can be used for sustained drug release in the body due to their biodegradability and drug permeability.
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•Highly crosslinked, lyophilized polyethylene glycol (PEG) membranes were developed.•Permeability of several model drugs through the PEG membranes was analyzed.•The measured permeability of the drugs depended on their molecular weight.•PEG membranes indicated pH-dependent degradability and release kinetics.•PEG membranes showed excellent biocompatibility and biodegradability in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We have developed a new hydrogel hemostat composed of hyaluronan (HA) conjugated with inorganic polyphosphate (PolyP). A hemostatic hydrogel, HAX-PolyP, was formed rapidly by mixing aldehyde-modified ...HA and hydrazide-modified HA conjugated with PolyP (HA-PolyP). Although the gelation rate decreased with increasing PolyP content, the gelation time was below 5 min. In addition, the hydrogel swelling volume decreased with increasing PolyP content, but the degradation rate did not depend on PolyP content and the hydrogel underwent complete degradation through hydrolysis over 3 weeks in phosphate buffered saline. HAX-PolyP showed similar biocompatibility with the HA hydrogel without PolyP conjugation in vitro and in vivo. Intraperitoneal administration of HAX-PolyP did not induce any adhesion in the peritoneum and clot formation in the lungs. Finally, HA-PolyP accelerated the coagulation rate of human plasma ex vivo, and HAX-PolyP showed as strong a hemostatic effect as fibrin glue in a mouse liver bleeding model in vivo.
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IJS, KILJ, NUK, PNG, UL, UM
We have developed microsized perfluorocarbon (PFC) emulsions with different sizes as artificial oxygen carriers (OCs) via Shirasu porous glass membrane emulsification. Monodispersed PFC emulsions ...with narrow size distribution were obtained. By changing the membrane pore size, we were able to precisely control the size of emulsions and fabricate emulsions similar in size to human red blood cells. Behaviors of Pluronics with different physiochemical properties (F127, F68, P85, and P103) as surfactants were also investigated, which evidenced that the type and concentration of Pluronics have a major impact on the size of emulsions and the response to different thermal conditions. The F127-stabilized microsized PFC emulsions were stable even during autoclave sterilization. The emulsions were loaded with Ru(ddp)an oxygen-sensitive probeon their surfaces to indicate oxygen concentration. Finally, incubations with HeLa cells that show fluorescence in response to hypoxia cultured in 2D and 3D suggested promising potential of our emulsions for OCs.
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IJS, KILJ, NUK, PNG, UL, UM
Supplementing sufficient oxygen to cells is always challenging in biomedical engineering fields such as tissue engineering. Originating from the concept of a 'blood substitute', nano-sized artificial ...oxygen carriers (AOCs) have been studied for a long time for the optimization of the oxygen supplementation and improvement of hypoxia environments in vitro and in vivo. When circulating in our bodies, micro-sized human red blood cells (hRBCs) feature a high oxygen capacity, a unique biconcave shape, biomechanical and rheological properties, and low frictional surfaces, making them efficient natural oxygen carriers. Inspired by hRBCs, recent studies have focused on evolving different AOCs into microparticles more feasibly able to achieve desired architectures and morphologies and to obtain the corresponding advantages. Recent micro-sized AOCs have been developed into additional categories based on their principal oxygen-carrying or oxygen-releasing materials. Various biomaterials such as lipids, proteins, and polymers have also been used to prepare oxygen carriers owing to their rapid oxygen transfer, high oxygen capacity, excellent colloidal stability, biocompatibility, suitable biodegradability, and long storage. In this review, we concentrated on the fabrication techniques, applied biomaterials, and design considerations of micro-sized AOCs to illustrate the advances in their performances. We also compared certain recent micro-sized AOCs with hRBCs where applicable and appropriate. Furthermore, we discussed existing and potential applications of different types of micro-sized AOCs.
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•Calcium phosphate-loaded carboxymethyl cellulose non-woven sheets (CMC/CaP sheet) were fabricated.•The combined effect of CMC and CaP promoted osteoblast differentiation of human ...mesenchymal stromal cells in vitro.•In vivo bone regeneration by the CMC/CaP sheet was demonstrated in a mouse calvarial defect model.
Calcium phosphate-loaded carboxymethyl cellulose non-woven sheets (CMC/CaP sheet) were fabricated and their potential to induce in vitro osteoblast differentiation and in vivo bone regeneration were investigated. The CMC/CaP sheets were prepared by alternately soaking protonated-CMC non-woven sheets in CaCl2 and Na2HPO4 aqueous solutions. Because of its slow water uptake rate, the protonated-CMC was successfully loaded with a mixed phase of brushite and hydroxyapatite. In vitro, the CMC/CaP sheet induced osteoblast differentiation of human mesenchymal stromal cells (hMSCs), as shown by calcification and the upregulation of osteoblast marker genes. In absence of CaP, hMSCs on the CMC sheet had enhanced expression of alkaline phosphatase (ALP) only, indicative of early osteoblast differentiation. Finally, bone regeneration by the CMC/CaP sheet was demonstrated in a mouse calvarial defect model, based on micro-computed tomography (micro-CT), Masson’s trichrome staining, and immunostaining for osteoblast markers. Cells expressing the transcription factor Sp7/Osterix, which is essential for osteoblast differentiation, were detected around the new bone. The combined effect of CMC and CaP enhanced osteoblast differentiation and the CMC/CaP non-woven sheet was found to be an easy-to-handle and flexible scaffold for bone regeneration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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IJS, KILJ, NUK, PNG, UL, UM
Extracellular environments significantly affect cell proliferation, differentiation, and functions. The extracellular environment changes during many physiological and pathological processes such as ...embryo development, wound healing, and tumor growth. To mimic these changes, we developed novel thiol–maleimide clickable alginate microcapsules, which can introduce thiol-containing peptides by “in situ conjugation” with maleimide-modified alginate, even in serum-containing cell culture media. Additive peptides were rapidly concentrated into microcapsules by a diffusion-reaction process in the capsule. The proliferation of encapsulated fibroblasts was accelerated by in situ conjugation of CRGDS, while free RGDS showed no effect. Moreover, encapsulated preosteoblastic cells started osteogenic differentiation via in situ conjugation of BMP-2 mimetic peptides such as CDWIVA and CG-BMP-2 knuckle epitope peptide, while BMP-2 did not induce differentiation of the encapsulated cells. Especially in tissue engineering, accurate and inexpensive methods for inducing cell differentiation are required. We believe that this in situ conjugation approach employing various functional peptides will be useful in biomedical, bioindustrial, and biochemical fields in the future.
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IJS, KILJ, NUK, PNG, UL, UM
Novel hemoglobin-based artificial oxygen carriers are necessary in tissue engineering. We developed human hemoglobin (hHb) and albumin (HSA)-based microspheres using Shirasu porous glass (SPG) ...membrane emulsification. The obtained microspheres had a uniform size with an average diameter of 15.1 μm measured by optical microscope, which is similar to the diameter of human red blood cells (7–8 μm). The loading amount of hHb in the microspheres was 20 wt%, which is similar to that of red blood cells (33 wt%). The hHb–HSA microspheres showed similar oxygen dissociation behavior and methemoglobin formation resistance to native hHb. Incubation with genetically engineered HeLa cells that shows hypoxia-responsive EGFP expression demonstrated efficient oxygen supply from the microspheres. Our study suggests the utility of hHb–HSA microspheres as oxygen carriers for tissue engineering with a low risk of infectious disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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