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Biomedical subjects

Y Ikada

Publications and source records attributed to Y Ikada.

At least 37 records · Page 2Linked to original sources
PubMed2000

Biodegradable scleral implant for controlled intraocular delivery of betamethasone phosphate.

We evaluated nail-like, biodegradable scleral implants as a controlled intraocular delivery system of betamethasone phosphate (BP) for the treatment of chronic uveitis using pigmented rabbits. The scleral implants, which contained 10% and 25% of BP (weight 8.5 mg; length 5 mm), were made of poly (D,L-lactide-co-glycolide) (PLGA). In vivo release and retinal toxicity after implantation were also studied in pigmented rabbits. The in vitro release studies demonstrated the 10% and 25% BP-loaded scleral implants released BP in a biphasic release pattern for at least 1 month. The BP concentrations in the vitreous and the retina/choroid after application of scleral implants in pigmented rabbit eyes stayed within the concentration range capable of suppressing inflammatory responses for over 1 month. The BP concentration was greater in the retina/choroid than in the vitreous throughout the study. No substantial toxic reactions in the retina were observed by electroretinography. Our findings suggest that the BP-loaded scleral implant may be a promising device for treatment of chronic uveitis.

Animals↗
PubMed2000

Long-term sustained release of ganciclovir from biodegradable scleral implant for the treatment of cytomegalovirus retinitis.

The previous scleral implant composed of poly(D, L-lactide-co-glycolide) with ganciclovir (GCV) had some disadvantages such as the second burst in the late phase of release. In this study, the GCV release rate from scleral implants was modified by blending poly(D,L-lactide) (PLA) of two different molecular weights. The scleral implants were prepared by blending PLA-70000 (molecular weight: 70000) and PLA-5000 (molecular weight: 5000) or PLA-130000 (molecular weight: 130000) and PLA-5000 at weight ratios of 100/0, 95/5, 90/10, 80/20, and 0/100. In vitro release tests were performed in 0.1 M phosphate-buffered solution (pH 7.4) at 37 degrees C. An increase in the blended amount of PLA-5000 clearly accelerated the GCV release and the onset of the second burst in the late phase of release tended to delay. The two implants both prepared at a blend ratio of 80/20 successfully prevented the second burst and the GCV release profiles followed the pseudozero-order kinetics after the initial burst as resulting from a diffusional mechanism following Higuchi's equation. Duration of the sustained GCV release could be controlled by changing the blending ratio of high and low molecular weight PLA. The 25% GCV-loaded scleral implants composed of PLA-70000 and PLA-5000 with a blending ratio of 80/20 were implanted in pigmented rabbit eyes. The GCV concentrations in the vitreous after implantation of PLA-70000/PLA-5000 scleral implant with a blending ratio of 80/20 were maintained in the range of effective level for 6 months without a significant burst. Our results suggest that the blended implants are promising for the intraocular controlled drug delivery over a period of several months to one year to treat cytomegalovirus retinitis.

Animals↗
PubMed2000

Bone regeneration by transforming growth factor beta1 released from a biodegradable hydrogel.

This paper describes the sustained release of transforming growth factor beta1 (TGF-beta1) from a biodegradable hydrogel based on polyion complexation for the enhancement of bone regeneration activity. Basic TGF-beta1 was adsorbed onto the biodegradable hydrogel of acidic gelatin with an isoelectric point of 5.0 by an electrostatic interaction. The TGF-beta1 could not be adsorbed onto basic gelatin. When acidic gelatin hydrogels incorporating 125I-labeled TGF-beta1 were implanted into the back subcutis of mice, the radioactivity decreased with time and the in vivo retention of TGF-beta1 was prolonged with a decrease in the water content of hydrogels. The higher the water content of hydrogels, the faster their biodegradation. The in vivo retention of TGF-beta1 correlated well with that of gelatin hydrogels, indicating that TGF-beta1 was released from the gelatin hydrogel as a result of hydrogel biodegradation. The ability of TGF-beta1-incorporated into acidic gelatin hydrogels to induce bone regeneration was evaluated in a rabbit calvarial defect model. Eight weeks after treatment, the gelatin hydrogels with water contents of 90 and 95 wt% induced significantly high bone regeneration compared with those with lower and higher water contents and free TGF-beta1. This indicates that the sustained release of TGF-beta1 from the hydrogel with suitable in vivo degradability is necessary to effectively enhance its osteoinductive function. Rapid hydrogel degradation will result in a retention time of TGF-beta1 which is too short to induce bone regeneration. It is possible that the slow degradation of the hydrogel physically blocked TGF-beta1-induced bone regeneration at the skull defect. It can be concluded that the gelatin hydrogel is a promising matrix of TGF-beta1 release to induce skull bone regeneration.

Absorbable Implants↗
PubMed2000

Progenitor endothelial cells on vascular grafts: an ultrastructural study.

The morphology of progenitor endothelial cells on vascular graft surfaces is addressed in this report. Such cells were seen to attach to intima-expressed CD34 and Flk-1 antigen and showed positive 5-bromo-2-deoxyuridine (BrdU) uptake. We examined CD34 and Flk-1 antigen-expressing endothelial progenitor cells three-dimensionally using confocal laser scanning microscopy (CLSM). Under detailed CLSM observation, through an ameboid-form cell, these progenitor endothelial cells changed from a globular to a flattened form. We also investigated these morphological changes using scanning electron microscopy. From these results, progenitor endothelial cells were observed not only near the advancing edge of endothelium, but also around the developing intimal site. Their form also changed from globular to flattened as observed in the CLSM results. These morphological changes were seen more frequently near the advancing edge and around the developing intimal site. They attached directly to vascular prosthesis fibers and likewise covered the graft luminal surface. Progenitor endothelial cells in any form had a common surface structure. We conclude from our results that progenitor endothelial cells can attach to graft fibers directly without clotting and directly cover the graft luminal surfaces.

Animals↗
PubMed2000

Synthetic absorbable film for prevention of air leaks after stapled pulmonary resection.

Staple-line reinforcement buttresses made of bovine pericardium (BP), expanded polytetrafluoroethylene (ePTFE), and so on have been shown to be effective in preventing air leaks after stapled lung volume reduction operations, and some of them have been clinically utilized. However, each buttress suffers at least one disadvantage such as risk of viral infection and chronic inflammation. A new buttress was made using a poly(L-lactic acid-co-epsilon-caprolactone) film (L/C film) and its effectiveness as a staple-line reinforcement was examined by performing lung volume reduction operation on a canine model. Soft tissue responses to the buttress were compared with those to the BP strip and the absorbable behavior was studied. The L/C film buttress was flexible and thin enough to easily cut. Death of dogs, infection, acute and prolonged air leaks, and any complications related to its use were not observed. The tissue responses to the film were more mild and favorable than those to BP. The L/C film was absorbed after the staple line was covered by a connective tissue. The results described above suggest that the buttress made of an L/C film is a promising staple-line reinforcement material.

Absorption↗
PubMed2000

Biodegradable scleral implant for intravitreal controlled release of ganciclovir.

BACKGROUND: The aims of this study were to develop biodegradable scleral implants that could overcome previously reported disadvantages such as an adverse burst in the late phase of release and to investigate the release profile of modified scleral implants in vitro and in vivo. METHODS: The modified scleral implants (weight 8.5 mg, length 5 mm) were made of mixtures of poly(DL-lactide) (PLA) with different molecular weights and contained 25 weight % of ganciclovir (GCV). The release of GCV was evaluated in vitro by spectrophotometry. Intravitreal GCV concentrations in vivo were measured by high-performance liquid chromatography following plug implantation in pigmented rabbits. The biocompatibility of the device was determined by indirect ophthalmoscopy and light microscopy. RESULTS: The in vitro release studies showed stable, long-term sustained and slow release. The in vivo release studies showed that the implants had long-term release in the diffusional phase of the triphasic release pattern and only a minor adverse burst of GCV in the late phase. No significant retinal toxicity was observed by histologic examination. CONCLUSION: Our findings showed that this newly modified scleral implant may provide suitable intravitreal drug delivery for treatment of cytomegalovirus retinitis.

Absorbable Implants↗
PubMed2000

Bioabsorbable thread for tight tying of bones.

The purpose of this research was to develop a bioabsorbable thread for tight fixation of fractured bones and to examine its mechanical performance in an in-vitro simulation study. The thread is a blend of bioabsorbable poly(L-lactic acid); (PLLA) and poly(epsilon-caprolactone); (PCL) fibers and can be tightly connected by fusion welding of the PCL fibers. The tying strength of the PLLA-PCL blend thread was 39.7 N, which was comparable to that of stainless steel wire. A testing machine was fabricated to measure the fatigue strength of the tying by simulating bone fixation. The results showed that metal wires always failed because of breakage within 25,000 loading cycles, whereas the blend threads did not fail until 50,000 loading cycles. The looseness of tying for simulated bone fixation by the blend thread was within 1mm even after 50 000 loading cycles. In-vivo testing using rats revealed that the blend thread did not cause any severe inflammatory reaction.

Animals↗
PubMed2000

Accelerated tissue regeneration through incorporation of basic fibroblast growth factor-impregnated gelatin microspheres into artificial dermis.

The objective of this study was to evaluate the effect of incorporation of basic fibroblast growth factor (bFGF)-impregnated gelatin microspheres into an artificial dermis on the regeneration of dermis-like tissues. When used in the free form in vivo, bFGF cannot induce sufficient wound healing activity, because of its short half-life. Therefore, sustained release of bFGF was achieved by impregnation into biodegradable gelatin microspheres. A radioisotope study revealed that incorporation of bFGF-impregnated gelatin microspheres significantly prolonged in vivo retention of bFGF in the artificial dermis. Artificial dermis with incorporated bFGF-impregnated gelatin microspheres or bFGF in solution was implanted into full-thickness skin defects on the back of guinea pigs (1.5 cm x 1.5 cm) (n = 4). Incorporation of bFGF into the artificial dermis accelerated fibroblast proliferation and capillary formation in a dose-dependent manner. However, the accelerated effects were more significant with the incorporation of bFGF-impregnated gelatin microspheres than with free bFGF at doses of 50 microg or higher. We conclude that the gelatin microsphere is a promising tool to accelerate bFGF-induced tissue regeneration in artificial dermis.

Animals↗
PubMed2000

Non-adhesive cyanoacrylate as an embolic material for endovascular neurosurgery.

Endovascular neurosurgery is now becoming available as one of strategies for the treatment of cerebro-spinal arterio-venous malformations and aneurysms. For this treatment, a microcatheter is advanced into or close to a lesion and then an embolic material is administered through it to obliterate the lesion. N-butyl-2-cyanoacrylate (NBCA) has preferentially been used as an embolic material in Europe and America. However, its exceptionally strong adhesive force sometimes causes adhesion between the tip of the microcatheter and the artery. In this study, a new non-adhesive cyanoacrylate, isostearyl-2-cyanoacrylate (ISCA), was developed. It carries a long hydrophobic side isostearyl group with lower reactivity and adhesion than other cyanoacrylates. Its polymerization rate is, however, too low to obliterate a vascular lesion with a rapid blood flow. To increase the polymerization rate. ISCA was mixed with NBCA. As a result, the adhesive force of the mixture became extremely low, compared with that of NBCA. The viscosity of the mixture was low enough to allow its' use as an embolic material. Tissue reactions against the mixture was milder than those against NBCA. Radio-angiography became possible by mixing further with Lipiodol. The evaluation of this new embolic material with a rabbit renal artery showed that the obliteration effect of the mixture of ISCA and NBCA was excellent to use as an embolic material for clinical applications.

Animals↗
PubMed2000

Surface modification of polyethylene balloon catheters for local drug delivery.

Local drug delivery is an attractive approach to the associated problems of percutaneous transluminal coronary angioplasty (PTCA), including arterial injury. The objective of the present research was to deliver a high concentration of a potent anti-thrombin agent, argatroban (ARG), to the vessel wall in order to reduce arterial injury. Local delivery was accomplished by the ionic attachment of drug particles to a modified balloon surface. Surface graft polymerization of ionic monomers to a high-density poly(ethylene) (PE) substrate was performed utilizing ultra-violet (UV) methods. Acrylic acid (AAc) and 2(dimethylamino) ethyl methacrylate (DMAEMA) were successfully grafted onto PE surfaces. Surface grafting was verified by contact angle, X-ray photoelectron spectroscopy, and zeta potential measurements. The amount of ARG adsorbed onto the modified PE surface was highly dependent on the pH of the drug media for both anionic and cationic grafted monomers. The efficacy of local drug delivery to the arterial wall was analyzed using drug-immobilized PE balloon catheters in the rabbit common carotid artery model. High concentrations of ARG (280 nmol/g tissue) were found within the ballooned arterial segment immediately after angioplasty, followed by a decrease after blood flow was restored.

Acrylates↗
PubMed2000

Promotion of fibrovascular tissue ingrowth into porous sponges by basic fibroblast growth factor.

Fibrovascular tissue ingrowth into poly(vinyl alcohol) (PVA) sponges of different pore sizes was investigated by incorporating basic fibroblast growth factor (bFGF) into the sponges. The average pore size of PVA sponges used in this study was 30, 60, 110, 250, 350, and 700 microm and gelatin microspheres were employed as release carrier of bFGF. The sponges were subcutaneously implanted into the back of mice after incorporating free bFGF or gelatin microspheres containing bFGF into the sponges. Fibrovascular tissue infiltrated with time into the sponge pores and the extent of fibrous tissue ingrowth showed a maximum at a pore size around 250 microm 1 and 6 weeks after implantation. Significant promotion of the growth of fibrous tissue by bFGF was observed only at 3 weeks post-implantation (p < 0.05). New capillaries were formed in the tissue at any time, as long as bFGF was given to the sponges. Both empty gelatin microspheres and phosphate buffered solution neither promoted tissue ingrowth nor induced capillary formation in the sponges. It was concluded that bFGF was essential to induce the fibrovascular tissue ingrowth into the pores of PVA sponges.

Journal Article↗
PubMed2000

Long-term follow-up study of artificial dermis composed of outer silicone layer and inner collagen sponge.

In the oriental population including the Japanese, donor-site hypertrophy is more pronounced than in Caucasians. To solve the problem of donor-site morbidity and to ensure graft 'take', we started the second-stage procedure of a thin split thickness skin graft (STSG) onto acellular 'bilayer artificial skin', or 'artificial dermis'. Since reporting the original version of the material (OV), a revised version (RV) and the present version (PV, Pelnac) have been developed in stages to eliminate inconveniences associated with its use and to reduce the primary cost of manufacture. We have now used our materials, consisting of OV, RV and PV, on 52 skin defects in 41 patients. STSG took almost perfectly in all patients. The long-term results of these three materials were investigated in 20 patients who had been followed up for more than 2 years, excluding three patients whose donor sites had been directly closed. The longest and the mean follow-up periods of these patients were 12 years 5 months and 6 years 10 months, respectively. At the grafted sites, wrinkles caused by shrinkage, partial depigmentation and hypertrophy were observed in five (25%), one (5%) and one (5%) of the 20 patients, respectively. At the donor sites, slight unsightliness was observed in five (25%) of the 20 patients. Excellent or good results were obtained in 18 (90%) of the 20 patients in comprehensive evaluation. There were no significant differences in the long-term follow-up evaluations among these materials. In conclusion, the long-term postoperative appearance of the STSG site was good though a very thin (approximately 0.2mm) STSG is used; scarring of the donor site was minimal and it was possible to take repeated skin grafts from the same donor site.

Adolescent↗
PubMed2000

Active drug targeting with immunoconjugates to choroidal neovascularization.

PURPOSE: Active drug targeting with monoclonal antibody to neovascular vessels may be a potential treatment for choroidal neovascularization (CNV) in age-related macular degeneration (AMD). Endoglin (CD105) is a proliferating endothelial cell marker with excellent potential for targeting. The goals of this study were to investigate the expression of CD105 in CNV membranes surgically excised from patients with AMD and CNV lesions induced by intense laser photocoagulation in a cynomolgus monkey and to evaluate the in vitro effect of immunoconjugates on endothelial cells. METHODS: CNV membranes were surgically excised from 10 patients with AMD. Experimental CNV was induced by intense laser photocoagulation in a cynomolgus monkey. Immunolocalization of CD105 on frozen sections of CNV lesions was studied by immunohistochemical evaluation. Anti-von Willebrand's factor antibody was used as an endothelial cell marker. The cytotoxic effect of immunoconjugates of anti-CD105 monoclonal antibody and dextran binding mitomycin C on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro. RESULTS: Endothelial cells demonstrated strong immunoreactivity of CD105 in all surgically excised CNV membranes. In the monkey eye, CD105-positive cells were detected only in CNV lesions but not in normal chorioretinal tissues. Immunoconjugates with anti-CD105 monoclonal antibody showed a specific inhibitory effect on proliferating HU-VECs. CONCLUSIONS: These results suggest that anti-CD105 monoclonal antibody-mediated drug targeting has a potential to treat CNV in AMD.

Aged↗
PubMed2000

Promoted bone healing at a rabbit skull gap between autologous bone fragment and the surrounding intact bone with biodegradable microspheres containing transforming growth factor-beta1.

This study is a trial to promote repairing of the rabbit skull bone gap between an autologous bone flap and the intact bone with biodegradable gelatin microspheres containing transforming growth factor-beta1 (TGF-beta1). A 10-mm diameter bone defect was prepared in rabbit skulls by drilling out a bone flap of 6 mm in diameter. After a surrounding gap defect of 2 mm was created and treated with 0.5 microg of free TGF-beta1 and gelatin microspheres containing 0.5 microg of free TGF-beta1, the circular autologous bone flap was placed in the center. Significant bone healing at the gap defect was observed 3 weeks after implantation of the TGF-beta1-containing gelatin microspheres. The bone mineral density (BMD) was significantly higher than that of other experimental groups. On the contrary, when applied with free TGF-beta1, a fibrous tissue initially infiltrated into the gap defect, resulting in impairing bone healing. The tissue response was similar to that at the defect implanted with empty gelatin microspheres and TGF-beta1-free phosphate-buffered saline solution alone. There was more space in the gap-filling bone in the 16-week view than the 3-week view. It is possible that this was an intermediate step along the way toward normal healing and formation of cancellous bone. We conclude that gelatin microspheres containing TGF-beta1 show promise as an agent to promote bone regeneration of subcritical size defects between surgically positioned autologous bone flaps and surrounding host bone.

Animals↗
PubMed2000

De novo formation of adipose tissue by controlled release of basic fibroblast growth factor.

De novo adipogenesis at the implanted site of a basement membrane extract (Matrigel) was induced through controlled release of basic fibroblast growth factor (bFGF). bFGF was incorporated into biodegradable gelatin microspheres for its controlled release. When the mixture of Matrigel and bFGF-incorporated gelatin microspheres was implanted subcutaneously into the back of mice, a clearly visible fat pad was formed at the implanted site 6 weeks later. Histologic examination revealed that the de novo formation of adipose tissue accompanied with angiogenesis was observed in the implanted Matrigel at bFGF doses of 0.01, 0.1, and 1 microg/site, the lower and higher doses being less effective. The de novo formation induced by the bFGF-incorporated microspheres was significantly higher than that induced by free bFGF of the same dose. The mRNA of a lipogenesis marker protein, glycerophosphate dehydrogenase, was detected in the formed adipose tissues, biochemically indicating de novo adipogenesis. Free bFGF, the bFGF-incorporated gelatin microspheres, or Marigel alone and bFGF-free gelatin microspheres with or without Matrigel did not induce formation of adipose tissue. This de novo adipogenesis by mixture of Matrigel and the bFGF-incorporated gelatin microspheres will provide a new idea for tissue engineering of adipose tissue.

Adipocytes↗