Shigemitsu Iwai

In situ tissue regeneration using a novel tissue-engineered, small-caliber vascular graft without cell seeding

OBJECTIVE Various types of natural and synthetic scaffolds with arterial tissue cells or differentiated stem cells have recently attracted interest as potential small-caliber vascular grafts. It was thought that the synthetic graft with the potential to promote autologous tissue regeneration without any seeding would be more practical than a seeded graft. In this study, we investigated in situ tissue regeneration in small-diameter arteries using a novel tissue-engineered biodegradable vascular graft that did not require ex vivo cell seeding. METHODS Small-caliber vascular grafts (4 mm in diameter) were fabricated by compounding a collagen microsponge with a biodegradable woven polymer tube that was constructed in a plain weave pattern with a double layer of polyglycolic acid (core) and poly-L-lactic acid (sheath) fibers. We implanted these tissue-engineered vascular grafts bilaterally into the carotid arteries of mongrel dogs (body weight, 20-25 kg). No anticoagulation regimen was used after implantation. We sacrificed the dogs 2, 4, 6, and 12 months (n = 4 in each group) after implantation and evaluated the explants histologically and biochemically. RESULTS All of the tissue-engineered vascular grafts were patent with no signs of thrombosis or aneurysm at any time. Histologic and biochemical examinations showed excellent in situ tissue regeneration with an endothelial cell monolayer, smooth muscle cells, and a reconstructed vessel wall with elastin and collagen fibers. CONCLUSION Our study indicated that this novel tissue-engineered vascular graft promoted in situ tissue regeneration and did not require ex vivo cell seeding, thereby conferring better patency on small-caliber vascular prostheses.

A self-renewing, tissue-engineered vascular graft for arterial reconstruction

OBJECTIVE Various tissue-engineered vascular grafts have been studied to overcome the clinical disadvantages of conventional prostheses. Previous tissue-engineered vascular grafts have generally required preoperative cellular manipulation or use of bioreactors to improve performance, and their mechanical properties have been insufficient. We focused on the concept of in situ cellularization and developed a tissue-engineered vascular graft for arterial reconstruction that would facilitate renewal of autologous tissue without any pretreatment. METHODS The graft comprised an interior of knitted polyglycolic acid compounded with collagen to supply a scaffold for tissue growth and an exterior of woven poly-L-lactic acid for reinforcement. All components were biocompatible and biodegradable, with excellent cellular affinity. The grafts, measuring 10 mm in internal diameter and 30 mm in length, were implanted into porcine aortas, and their utility was evaluated to 12 months after grafting. RESULTS All explants were patent throughout the observation period, with no sign of thrombus formation or aneurysmal change. Presence in the neomedia of endothelialization with proper integrity and parallel accumulation of functioning smooth muscle cells, which responded to vasoreactive agents, was confirmed in an early phase after implantation. Sufficient collagen synthesis and lack of elastin were quantitatively demonstrated. Dynamic assessment and long-term results of the in vivo study indicated adequate durability of the implants. CONCLUSION The graft showed morphologic evidence of good in situ cellularization, satisfactory durability to withstand arterial pressure for 12 postoperative months, and the potential to acquire physiologic vasomotor responsiveness. These results suggest that our tissue-engineered vascular graft shows promise as an arterial conduit prosthesis.

Effect of a Polymorphonuclear Elastase Inhibitor (Sivelestat Sodium) on Acute Lung Injury After Cardiopulmonary Bypass: Findings of a Double-Blind Randomized Study

PurposeWe evaluated the effect of sivelestat sodium (SiV), a novel synthesized polymorphonuclear (PMN) elastase inhibitor, on acute lung injury (ALI) caused by cardiopulmonary bypass (CPB).MethodsFourteen patients who underwent cardiopulmonary surgery using CPB, followed by the development of both systemic inflammatory response syndrome (SIRS) and ALI, were treated with either 0.2 mg/kg per hour SiV (SiV group, n = 7) or saline (control group, n = 7) for 4 days from the time of arrival in the intensive care unit.ResultsThe SiV group had a significantly lower ratio of serum PMN elastase and interleukin (IL)-8, a significantly lower ratio of the respiratory index, and a significantly higher ratio of PaO2/FiO2 after 24 h of treatment than the control group.ConclusionSivelestat sodium suppressed the production of PMN elastase and IL-8, resulting in improved respiratory function in patients with ALI caused by CPB.

Minimally immunogenic decellularized porcine valve provides in situ recellularization as a stentless bioprosthetic valve

Currently used bioprosthetic valves have several limitations such as calcification and functional deterioration, and revitalization through cellular ingrowth is impossible. To overcome these obstacles, we have developed a minimally immunogenic tissue-engineered valve that consists of an unfixed, decellularized porcine valve scaffold capable of being spontaneously revitalized in vivo after implantation. Porcine aortic root tissue was decellularized using detergents such as sodium lauryl sulfate and Triton X-100. The porcine valve was treated very gently and plenty of time was allowed for constituents to diffuse in and out of the matrix. In a preliminary study, a piece of decellularized porcine valve tissue was implanted into the rat subdermal space for 14 and 60 days and the structural integrity and calcification were evaluated. As an in vivo valve replacement model, the decellularized porcine valve was implanted in the pulmonary valve position in dogs and functional and histological evaluation was performed after 1, 2, and 6 months. Histological examination showed that the newly developed detergent treatment effectively removed cellular debris from the porcine aortic tissue. Decellularized porcine valve tissue implanted subdermally in rats showed minimal inflammatory cell infiltration and calcification. In the valve replacement model, spontaneous reendothelialization and repopulation of the medial cells were observed within 2 months, and good valve function without regurgitation was observed by echocardiography up to 6 months. The minimally immunogenic decellularized porcine valve proved effective in mitigating postimplant calcification and provided a suitable matrix for revitalizing prostheses through in situ recellularization, cellular ingrowth, and tissue remodeling.

Contractility–Afterload Mismatch in Patients With Protein-Losing Enteropathy After the Fontan Operation

This study aimed to clarify the relationship between onset of protein-losing enteropathy (PLE) and Fontan circulation, with special reference to the development of contractility–afterload mismatch. The PLE group comprised 9 patients who experienced PLE after undergoing the Fontan operation, and the control group consisted of 32 patients had did not experienced PLE more than 10 years after the Fontan operation. The study compared the pre- and postoperative values of arterial elastance (Ea), end-systolic elastance (Ees), and contractility–afterload mismatch (Ea/Ees). Furthermore, the variations in the values were examined during the preoperative, postoperative, and midterm postoperative periods in seven PLE patients who underwent cardiac catheterization at the onset of PLE and during the pre- and postintervention periods in three PLE patients who underwent surgical intervention to improve the Fontan circulation after the onset of PLE. Comparison of the values obtained before and after Fontan operations showed that the Ea values increased significantly in the PLE group. However, the pre- and postoperative Ees values did not differ in the two groups. During the postoperative period, Ea/Ees increased significantly, and the Ea and Ea/Ees values increased continuously until the onset of PLE in the PLE group. In the patients who underwent surgical intervention to improve the Fontan circulation after the onset of PLE, the Ea/Ees decreased significantly, and the serum albumin levels improved after the intervention. Contractility–afterload mismatch, mainly caused by the increase in the afterload of the systemic ventricle, may have an important role in the development of PLE after the Fontan operation.

Antigen clearing from porcine heart valves with preservation of structural integrity

Bioprostheses currently used for replacement of diseased cardiovascular tissue are preserved and partially protected from immune rejection through chemical fixation. However, after implantation, chemically preserved (fixed) material has limited durability and lacks the ability to revitalize through cellular ingrowth and remodeling. As an alternative to fixation, we aimed at thoroughly removing antigens from tissue, leaving an intact scaffold, suitable for integration and revitalization in the host. Extensive washing of porcine heart valves with a mixture of two detergents (SDS and Triton X-100) yielded an intact matrix devoid of cells and depleted of soluble proteins that was minimally immunogenic in rabbits. A detailed characterization of the biomechanics and durability of the tissue is under way. If the lack of immunogenicity is confirmed in primates, our results would suggest that a detergent-washed, unfixed porcine heart valve can be an attractive non-inflammatory scaffold for heart valve regeneration in humans.

Use of the Damus-Kaye-Stansel procedure prevents increased ventricular strain in Fontan candidates

OBJECTIVES In Fontan candidates, we have recently been aggressively performing the Damus-Kaye-Stansel procedure (DKS) to prevent increased afterload on the systemic ventricle. The present study investigated the efficacy of the DKS procedure in terms of the ventricular function following a Fontan operation. METHODS Patients undergoing a Fontan operation were divided into three groups: DKS performed at the time of the bidirectional Glenn or Fontan operation (DKS group, n = 25); DKS not performed at any stage due to mild pulmonary stenosis (PS) (PS group, n = 23) and DKS not performed due to pulmonary atresia (PA) or severe PS (PA group, n = 24). Ventricular function, afterload on the systemic ventricle and atrioventricular valve regurgitation were compared between groups. RESULTS Cardiac catheterization before a Glenn or Fontan operation and at 1-year following the Fontan revealed significantly decreased ventricular end-diastolic pressure in the DKS group. The ventricular ejection fraction was significantly deteriorated in the PS group. Effective arterial elastance, as an index of total ventricular afterload, was increased after a Fontan in all groups, with a substantial increase in the PS group. As an index of ventricular mechanical efficiency, ventriculoarterial coupling was significantly increased only in the PS group. Cardiac ultrasonography revealed atrioventricular valve regurgitation above grade 3 persisting in many patients from the PS group. Semilunar valve function after DKS operation did not progress to moderate or worse in any patients. CONCLUSIONS The proactive performance of the DKS procedure prevents increased ventricular afterload, avoiding deterioration of cardiac function and contributing to improved long-term results following a Fontan operation.

Modified aortic root remodeling for annuloaortic ectasia with abnormal coronary take-off

The abnormality of coronary arterial take-off is a limiting factor for a successful aortic valve sparing procedure. We present a 13-year-old boy, with Marfan syndrome and annuloaortic ectasia, whose coronary take-off was found to be abnormal during surgery. Two adjacent coronary orifices were located in the left coronary sinus and very close to the right-left commissure. A modified aortic remodeling procedure was successfully performed without translocation of the coronary artery.

Risk Factors for Semilunar Valve Insufficiency After the Damus-Kaye-Stansel Procedure

BACKGROUND Cardiac function and survival after the Damus-Kaye-Stansel (DKS) procedure are encouraging, but only limited data exist related to postprocedural semilunar valve function. We investigated postprocedural midterm to long-term outcomes and changes in semilunar valve function and identified risk factors of semilunar valve function deterioration. METHODS Between 1996 and 2012, 63 patients with a single functional ventricle underwent the DKS procedure. Of them, 50 had previously undergone pulmonary artery banding. Cardiac function was measured by catheter examination 5.3 months (interquartile range, 2.6 to 9.7) preoperatively and 1.2 years (interquartile range, 1.0 to 1.4) postoperatively. Echocardiographic examination of the semilunar valve was performed concurrently with the catheter examination and at the last follow-up (5.3 years [interquartile range, 3.1 to 9.2] postoperatively). RESULTS The overall survival rate at 1, 5, and 10 years postoperatively was 0.97, 0.92, and 0.89, respectively. Aortic and pulmonary valve regurgitation grade 1 year postoperatively and at the last follow-up increased compared with the preoperative grade. There was no significant difference between regurgitation at 1 year and the last follow-up. The duration from pulmonary artery banding to the DKS procedure was longer in the group with at least mild regurgitation (n = 6) than in the group with less than mild regurgitation (n = 54). CONCLUSIONS Although the duration from pulmonary artery banding to the DKS procedure was associated with postoperative regurgitation, neither postprocedural aortic nor pulmonary valve regurgitation increased over time, and there were no deleterious effects on the clinical conditions.

Prognosis in tetralogy of Fallot with absent pulmonary valve

Tetralogy of Fallot with absent pulmonary valve (TF/APV) is a rare and severe congenital heart disease with high mortality. The aim of this study was to assess whether TF/APV prognosis is related to fetal and postnatal clinical course and pulmonary artery (PA) configuration.