Controlled-release of various peptides has enabled the local and sustained action of various growth factors at a desired concentration, which is the concept of drug delivery system. Controlled-release is achieved by biodegradable materials such as gelatin, collagen. By using the controlled release system of bFGF (basic fibroblast growth factor) from gelatin hydrogel sheet or microspheres, we induced arteriogenesis in ischemic limb and infarcted heart. Combined with the ornentum including the gastroepiploic artery, bFGF has made it possible to revascularize even an avascular area on ischemic heart. Controlled-release of bFGF enhanced myogenesis of cell therapy including cardiomyocytes or skeletal myoblasts in infracted heart. Some researchers try to regenerate heart tissue by ex vivo cell culture through an approach of tissue engineering. In the field of heart and vessels, clinical application of some of those regeneration therapy is already under way, and the safety and the effectiveness of them are being evaluated discreetly.

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This paper reviews the potential of cell transplantation to restore inner ear hair cells. Histological analysis revealed survival and incorporation of grafted stem cells in various portion of the inner, suggesting the ability of stem cells for differentiation into inner ear hair cells.

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Both gene therapy and cell transplantation are promising approathes for therapeutic angiogenesis. However, some patients are refractory to these therapies. Here, we present a new concept for hybrid cell-gene therapy using a nonviral vector, gelatin hydrogel. Gelatin-mediated gene transfer may enhance the therapeutic potency of cell transplantation. Endothelial progenitor cells (EPCs) play an important role in modulating angiogenesis and vasculogenesis. Genetically-modified EPCs served not only as a tissue-engineering tool to reconstruct the vasculature, but also as a vehicle for gene delivery to injured endothelium. In fact, intravenous administration of vasodilator gene-modified EPCs attenuated monocrotaline-induced pulmonary hypertension and improved survival. Mesenchymal stem cells (MSCs) are pluripotent cells that differentiate into a variety of cells including cardiomyocytes and vascular endothelial cells. A recent study has shown that antiapoptotic gene-transduced MSCs effectively induce myogenesis in rats with myocardial infarction. Thus, hybrid cell-gene therapy may be a new therapeutic strategy for the treatment of intractable cardiovascUlar disease.

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Regenerative medical therapy based on the self-repairing potential of patients has been clinically tried to allow to induce tissue regeneration at a lost or seriously impaired tissue for disease treatment. Recently basic biology and medicine have been developed to manifest the molecular mechanisms of tissue regeneration repairing for chronic fibrosis. Thus, based on the natural potential to induce tissue regeneration, a therapeutic trial for fibrotic diseases with drug delivery system is highly expected. After digested and degraded, a fibrotic tissue is repaired based on the potential of the surrounding healthy tissue to induce tissue regeneration. This paper describes this new concept of regenerative therapy of internal medicine by introducing some concrete examples.

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Endovascular embolization for cerebral aneurysm with platinum coils has become an alternative therapy to surgical clipping. However, recent clinical trials have demonstrated disappointing long-term results for patients treated with the conventional platinum coils. The problem includes recanalization and the rupture of giant and large-neck aneurysm. This is mainly because thrombosis of aneurysm induced by the platinum coil is often unstable. Basic fibroblast growth factor (bFGF) is an ideal growth factor to use for aneurysm healing. We have reported that the controlled release of bFGF with a gelatin hydrogel stimulated the formation of fibrosis in a rabbit aneurysm, resulting in aneurysmal obliteration. The current state of treatment using endovascular surgery for cerebral aneurysm, the problem and the view in the future are described.

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The tissue engineering has been advenced in the field of the veterinary medicine of dog and cat. Regeneration of each organ such as trachea, nerve, spinal cord, bone and skin has been done in the clinical cases in this field.

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The purpose of this study was to examine the pharmacological effects of flunisolide nasal dosage formulations (suspension formulation, hydrogel and white petrolatum ointments) on the increased nasal vascular permeability induced by histamine using non-sensitized rats as an experimental model of allergic rhinitis. The pharmacological evaluation was done 2 and 24 hours after administration of nasal dosage formulations. In addition, the rheological behavior of the ointments was studied to obtain a better understanding of the pharmacological effects. hydrogel and white petrolatum ointments containing flunisolide significantly inhibited nasal vascular permeability at 2 hours after pretreatment, whereas the suspension formulation did not show any pharmacological effects. Additionally, hydrogel ointment containing flunisolide showed a pharmacological effect that continued up to 24 hours, whereas the effect of the white petrolatum ointment was not continuous. The viscosity of white petrolatum ointment was much higher than that of hydrogel ointment, implying that the spreadability of hydrogel ointment in the nasal mucosa was superior to white petrolatum ointment.

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SG-01 is newly developed hydrophilic wound dressing material. To evaluate the safety of SG-01, we performed a primary skin irritation test, a cumulative skin irritation test, an infracutaneous reactivity test, a skin sensitization test, and a pyrogen test. To investigate irritation of SG-01, it was applied to the intact/abraded skin of the rabbit back for 4 hours. Neither intact nor abraded skin showed any reactions. To investigate cumulative irritation, SG-01 was applied to the skin of the rabbit back for 6 hours once a day for 14 days. No dermal reactions were observed. Intracutaneous reactivities on rabbits were examined using the extracted solutions by physiological saline or sesame oil at 37°C for 72 hours. Negative reactions were obtained. A skin sensitization tests were performed by the adjuvant and patch method using guinea pigs. In SG-01 group, there were no dermal reactions, as demonstrated in the control group treated with vehicle (water for injection). A pyrogen test was performed on SG-01 using the extracted in physiological saline at 37°C for 72 hours. The results revealed the absence of pyrogen. The safety of SG-01 was ensured by the results from these studies.

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[in Japanese]

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