Tomokazu Mukai

Bioabsorbable device for small-caliber vessel anastomosis.

Although the devices for large‐caliber vessel (>2‐mm diameter) anastomosis are available, there are no devices for performing anastomosis of small‐caliber vessels. We designed a hooked device composed of a bioabsorbable polymer for sutureless anastomosis of small‐caliber vessels. The efficacy of this device was evaluated by in vitro degradation and arterial‐fixation strength tests as well as in vivo transplantation experiments with common carotid arteries of growing SD rats. A nonabsorbable device without hooks served as the control in the fixation strength and animal experiments. The tensile strength of the bioabsorbable device decreased to 27 and 9% of the initial value after 8‐ and 24‐week incubation, respectively. The fixation strength was greater and the anastomotic time was shorter with this device than with the control. The transplantation experiments showed complete endothelial bridging in both devices at 2 weeks after surgery (n = 6). The control device created a considerable protrusion into the arterial lumen at 8 postoperative weeks, whereas the experimental device did not (n = 6). Arterial diameter measurements detected a significant difference between the inner diameters at the respective anastomotic sites (n = 6, P < 0.05) and demonstrated that the control device hindered the vessel growth while the experimental device did not. Therefore, the bioabsorbable hooked device was an effective tool for anastomosis of small‐caliber arteries (ca. 1‐mm diameter).

Development of Watertight and Bioabsorbable Synthetic Dural Substitutes

We have developed novel watertight and bioabsorbable synthetic dural substitutes. The substitutes were designed such that they had a three-layered structure, and each layer comprised a bioabsorbable copolymer prepared from L-lactide, glycolide, and epsilon-caprolactone. Various copolymers were synthesized, and appropriate compositions were selected for preparing the substitutes based on the results of leakage tests. Experimental substitutes that prevented the leakage of saline through the suture lines between the substitutes and dura mater were prepared. An in vitro study was performed in which the substitutes were sutured to porcine dura mater, and the amount of saline leakage was measured. It was demonstrated that leakage through the suture line could be completely suppressed by using the substitutes we developed along with favorable suturing techniques.

Laser perforated accordion nerve conduit of poly(lactide-co-glycolide-co-ɛ-caprolactone).

Accordion nerve conduit of poly(lactide-co-glycolide-co-ε-caprolactone) with perforations was developed by excimer laser processing. We evaluated its in vivo function for nerve repairing and discussed the influence of pore size and density. It was found that perforations help inner nerve regeneration remarkably, which effect is unrelated to pore size or density, and is not parallel with revascularization increment. Inducing of permeability only to allow substance exchange but not vessel ingrowth could facilitate nerve regeneration too. Perforating micropores with the size of 100 μm and the density of 25/cm provides permeability and vessel ingrowth both, therefore promotes the axon extension the best, larger, and more pores do not advance axon regeneration more.

Alternative plasticizer, 4-cyclohexene-1,2-dicarboxylic acid dinonyl ester, for blood containers with protective effects on red blood cells and improved cold resistance

Di (2-ethylhexyl) phthalate (DEHP), a typical plasticizer used for polyvinyl chloride (PVC), is eluted from PVC-made blood containers and protects against red blood cell (RBC) hemolysis. However, concerns have arisen regarding the reproductive and developmental risks of DEHP in humans, and the use of alternative plasticizers for medical devices has been recommended worldwide. In this study, we propose that the use of a novel plasticizer, 4-cyclohexene-1,2-dicarboxylic acid dinonyl ester (DL9TH), could help produce more useful and safe blood containers. PVC sheet containing DL9TH and di (2-ethylhexyl) 4-cyclohexene-1,2-dicarboxylate (DOTH) provides comparable or superior protective effects to RBCs relative to PVC sheet containing DEHP or di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH® , an alternative plasticizer that has been used in PVC sheets for blood containers). The total amount of plasticizer eluted from DOTH/DL9TH-PVC sheets is nearly the same as that eluted from DEHP-PVC sheets. In addition, DOTH/DL9TH-PVC has better cold resistance than DEHP- and DINCH® -PVC sheets. In vitro and in vivo tests for biological safety based on International Organization for Standardization guidelines (10993 series) suggest that the DOTH/DL9TH-PVC sheet can be used safely. Subchronic toxicity testing of DL9TH in male rats in accordance with the principles of Organisation for Economic Co-operation and Development Test Guideline 408 showed that DL9TH did not induce adverse effects up to the highest dose level tested (717 mg/kg body weight/day). There were no effects on testicular histopathology and sperm counts, and no indications of endocrine effects: testosterone, thyroid-stimulating hormone, follicle-stimulating hormone, and 17β-estradiol were unchanged by the treatment, compared with the control group.

Development of Bioabsorbable DURA MATER

Regeneration of dura mater of the brain is one of the most urgent tasks in the fields of regeneration medicine, considering the facts that we have many patients infected with fatal Creutzfeldt-Jakob disease following transplant of dried dura mater in the brain operations. Hence we designed the artificial dura mater made from poly(L-lactic acid-co-glycolic acid-co-ε-caprolactone). The sutured substitutes have the ability to prevent the leakage of cerebral fluid, would be absorbed in several months and the patient might be free from the possible side effects caused by the implanted materials. The leakage-proof tests for the developed substitutes were carried out and it was demonstrated that the sutured substitutes and dura mater support the pressure of saline as large as 400mmAq without leakage. The dural regeneration experiments were carried out with rabbits and successful regenerations of dura mater were observed. No inflammations were observed around the substitutes throughout the experimental period till the complete absorption of the materials.