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Interact CardioVasc Thorac Surg 2009;8:402-407. doi:10.1510/icvts.2008.192831
© 2009 European Association of Cardio-Thoracic Surgery
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Institutional report - Congenital

Development of novel drug-eluting biodegradable nano-fiber for prevention of postoperative pulmonary venous obstruction{star}, ,{star}{star}

Masato Mutsugaa, Yuji Naritaa,b,*, Aika Yamawakib, Makoto Satakec, Hiroaki Kanekoc, Akihiko Usuia and Yuichi Uedaa

a Department of Cardiac Surgery, Nagoya University, Graduate School of Medicine, Nagoya, Aichi, Japan
b Department of Clinical Cell Therapy and Tissue Engineering, Nagoya University School of Medicine, 65 Tsurumaicho Showa-ku, Nagoya, Aichi, 466-8550, Japan
c Department of Tissue Engineering Development, Technology Innovation Center, Teijin Limited, Hino, Tokyo, Japan

Received 1 September 2008; received in revised form 15 December 2008; accepted 16 December 2008

{star} Presented at the 22nd Annual Meeting of the European Association for Cardio-thoracic Surgery, Lisbon, Portugal, September 14–17, 2008. Back

{star}{star} The study was funded in part by the Miyata Cardiac Research Promotion Foundation.

*Corresponding author. Tel.: +81-52-744-2424; fax: +81-52-744-1978.

E-mail address: ynarita{at}med.nagoya-u.ac.jp (Y. Narita).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Conference discussion
 Acknowledgements
 References
 
Pulmonary venous obstruction (PVO) after correction of total anomalous pulmonary venous connection (TAPVC) frequently occurs due to intimal-hyperplasia and the required re-operation. We have developed a novel sustained-release drug delivery system, using Tacrolimus-eluting biodegradable nano-fiber (TEBN). It consists of nano-scale fiber composed of biodegradable polymer and Tacrolimus. This study evaluated the effects of TEBN for prevention of venous anastomotic stricture in a rat model to apply to PVO operation. Tacrolimus was incorporated into poly (L-lactide-co-glycolide). The venous stricture model was made by rat inferior vena cava anastomosis. The IVC anastomosis was covered with TEBN with 1.0 wt% Tacrolimus (n=12) or without TEBN as a control (n=12), and evaluated histologically at 1, 2, and 4 weeks after operation. The ratio of intimal area was significantly reduced in the TEBN group compared with the control group (ratio; 1 week: 0.43±0.26 vs. 0.07±0.04, P=0.04, 2 weeks: 0.39±0.19 vs. 0.05±0.02, P=0.01, 4 weeks: 0.31±0.15 vs. 0.09±0.04, P=0.03, control vs. TEBN, respectively). Histological findings showed endothelialization along the inner surface of the vein even in TEBN. The TEBN reduced intimal hyperplasia and preserved endothelialization even in a venous stricture. These results suggested that this strategy might be useful for prevention of recurrent PVO after TAPVC correction.

Key Words: Pulmonary venous obstruction; Total anomalous pulmonary venous connection; Tacrolimus; Nano-fiber; Intimal hyperplasia


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Conference discussion
 Acknowledgements
 References
 
PVO develops as a progressive and usually lethal complication after surgical repair of any type of TAPVC [1]. The mechanisms and causes of PVO are still unclear, but neointimal hyperplasia apparently has some kind of involvement with PVO progression. The relief of PVO with conventional procedures has revealed a high risk of failure and the need for re-operation [2–5]. A sutureless procedure for relief of PVO using the in situ pericardium was the only one procedure to have the efficacy and good outcome [6]. However, a primary procedure or technology to prevent PVO for any types of TAPVC, including the high-risk group such as heterotaxy, remains an urgent issue.

We used an electrospinning method to develop a nano-scaled ‘cotton-wool’ configuration fiber to continuously release an anti-scarring agent to prevent anastomotic stricture. This fiber is composed of biodegradable polymer and tacrolimus, called Tacrolimus-eluting biodegradable nano-fiber (TEBN), to achieve the sustained release of tacrolimus. We previously reported that TEBN inhibited neointimal hyperplasia of the arterial anastomotic stricture in a rat model [7]. The technology behind TEBN is based on the preventive effect against neointimal overgrowth by sustained release of an anti-scarring agent. The mechanism of sustained release is achieved by continuous and gradual degradation of biodegradable polymer due to hydrolysis over time. Tacrolimus has been evaluated in many previous studies as a preventative drug for neointimal hyperplasia in terms of its release kinetics, effective dosage, safety in clinical practice, and benefit [8, 9]. TEBN is characterized by its cotton-wool-like texture, which can flexibly fit any type of anastomosis. Therefore, this new product will be welcomed in pediatric cardiac surgery departments, which have limited storage space.

We hypothesized that TEBN may be applied to prevent stricture of pulmonary venous anastomosis. In the present study, we established a model of venous anastomotic stricture in a rat inferior venous cava (IVC) to evaluate whether TEBN can effectively prevent venous stricture. The structure of a pulmonary vein is histologicaly similar to that of the human inferior vena cava, because systemic vein and PV had a connection in the embryo [10]. Although there are differences of vascular healing between rat and humans, and structural difference between veno-venous and veno-atrial anastomosis, we applied our IVC anastomosis model as a PVO model at least partly. Our definitive goal is to develop a means to prevent PVO in humans.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Conference discussion
 Acknowledgements
 References
 
2.1. Animals

The animals were cared for in accordance with the ‘Guide for the Care and Use of Laboratory Animals’ (NIH Publication 85-23, National Academy Press, Washington, DC, revised in 1996). All procedures involving animals were approved by the Animal Experiment Advisory Committee of the Nagoya University School of Medicine. In this study, we used male Wistar/ST rats 8–10 weeks old, weighing 300–350 g (Chubu Kagaku Shizai Corporation Nagoya, Japan).

2.2. Fabrication of tacrolimus-eluting biodegradable nano-fiber and kinetics

We focused on tacrolimus as an anti-stricture agent. Methods of TEBN fabrication were described previously [7]. In brief, tacrolimus (Fermentel Ltd, Israel) was mixed with biodegradable polymer. We prepared poly (L-lactide-co-glycolide) (PLGA, PLLA:PGA=50:50) for biodegradable polymer. To fabricate nano-scale fiber, we applied an electrospinning procedure. The shape of TEBN looks like a ‘cotton wool’ formation (Fig. 1a). The diameter of the nanofiber ranged from 100 to 800 nm (Fig. 1b,c). It is easy to handle for any type of vascular anastomosis in virtue of its flexible property and characteristic configuration. The maximum tacrolimus content in the TEBN was 1 wt%. In vitro and in vivo release tests revealed that tacrolimus was released from TEBN gradually (Fig. 2). The cell growth curves for inhibition test in cell proliferation showed that TEBN significantly inhibited proliferation of human aortic smooth muscle cell (HASMC) (Fig. 3). Meanwhile, 5 mg TEBN-placed rats survived for at least more than eight weeks, and no marrow suppression, renal dysfunction, liver dysfunction or pancreatic dysfunction were observed. In addition, the tacrolimus did not flow out in blood.


Figure 1
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  		Fig. 1. Photograph and scanning electron microscopic (SEM) image of tacrolimus-eluting biodegradable nano-fiber (TEBN). (a) Overall appearance of TEBN was shaped in a ‘cotton wool’ like formation. (b) SEM (original magnification, x200) of TEBN showed that it looks like non-woven fabric. Scale bar is 100 µm. (c) SEM (original magnification, x2000) of TEBN revealed that fiber diameter of the polymer was 100–800 nm. Scale bar is 10 µm.

 

Figure 2
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  		Fig. 2. In vitro and in vivo tacrolimus releasing test from tacrolimus-eluting biodegradable nano-fiber (TEBN). (a) In vitro tacrolimus releasing test was evaluated by measurement of the remaining tacrolimus concentration in the TEBN, which was incubated in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Longitudinal axis of the graph indicates remaining percentage of tacrolimus in the TEBN (%). The releasing curve seems to be logarithmic curve. (b) In vivo tacrolimus releasing test from TEBN was performed by implanting TEBN into the subcutaneous space of the rat and evaluated by measurement of the remaining tacrolimus concentration in the back of TEBN. This graph shows that tacrolimus was revealed at fast initial burst phase during the first few days followed by a slow sustained phase over the following four weeks.

 

Figure 3
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  		Fig. 3. Inhibition of cell proliferation by tacrolimus-eluting biodegradable nano-fiber (TEBN). The examination was performed by co-culture with TEBN and human aortic smooth muscle cell (HASMC). The cell growth curves showed that 25 mg TEBN added group was significantly inhibited proliferation of HASMC.

 
2.3. Operative procedures

The experiments were carried out on 24 Wistar/ST rats. General anesthesia was induced with etherization, maintained with 25–50 mg/kg of pentobarbital sodium (Kyoritsu Seiyaku Corp, Tokyo, Japan) and 0.01 mg/kg of atropine sulfate (Mitsubishi Tanabe Pharma Corp, Osaka, Japan) was injected into the peritoneal cavity. An abdominal midline incision was made to enter the peritoneal cavity. Then, the infra-renal inferior vena cava (IVC) was simply clamped and the anterior half was divided. The IVC was anastomosed by a continuous running suture with 9-0 nylon (CROWNJUN, Kono Seisakusho, Co, Ltd, Chiba, Japan) (Fig. 4). Neither anticoagulant nor antiplatelet agents were administered throughout the procedure.


Figure 4
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  		Fig. 4. The scheme of operative procedure. (a) Division half part of inferior vena cava and (b) continuous running suture by 9-0 nylon. The mechanical anastomotic stricture was designed to make a turbulent flow through anastomosis.

 
Rats were randomly divided into two groups (n=12 in each group) using a table of random numbers: (1) without TEBN (as a control), or (2) with 1.0 wt% of tacrolimus, respectively. Rats were sacrificed at 1, 2 and 4 weeks after operation, and evaluated with the following procedures (n=4 in each time point).

2.4. Histological analysis and ratio of intima/vessel wall (Intima+Media) area

For the histological analysis, the anastomotic sites were resected beyond the suture lines, fixed with 7.5% buffered formaldehyde (Sigma Aldrich Japan, Tokyo, Japan), and embedded in paraffin. Short axial consecutive 5 µm serial sections were obtained just around the suture anastomosis. Three individual and random sections from the anastomosis site were evaluated. The sections were stained with hematoxylin and eosin (HE) for morphometric analysis. The area of the intima (including neointima) and media at the anastomosis site was measured on the sections stained with HE. To achieve a reproducible result, the mean value of this area (intima and media) from three sections was adopted. To characterize neointimal hyperplasia, the ratio of intimal area was calculated with the following formula: Ratio of Intimal Area=Intimal Area/(Intimal+Median Area)

This morphometric analysis was performed by a specialized technician using Image J for Mac OS X (Wane Rasband, NIH) with masking.

2.5. Immunohistochemical analysis for neointimal hyperplasia and endothelial cells

Immunohistochemical staining was performed to identify the cells which composed the intimal hyperplasia, and to evaluate re-endothelialization at the injured anastomotic site. {alpha}-Smooth muscle actin antibody (1:3000) (ASMA; Sigma), SMemb (1:3000) (Sigma) and factor VIII antibody (ready-to-use) (NeoMarker, CA) were used as primary antibodies. Biotinylated secondary antibody (1:400) (anti-mouse IgG; Vector Laboratories, CA) was applied, and avidin–biotin complex Vecstain ABC kit (Vector Laboratories) was used for visualization. Finally, slides were developed in diaminobenzidine solution and counterstained with hematoxylin.

2.6. Statistical analysis

Statistical analysis was performed using software Statview for Mac (Version 5.0, SAS Institute Inc, Cary, NC). These data were analyzed by unpaired t-test for comparison between both groups in each time point of ‘Ratio of Intimal Area’. And one-way analysis of variance (ANOVA) with post hoc multiple comparisons of Scheffe procedure was performed for time course change in both groups. Experimental results were expressed as mean±S.D. A difference with a P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Conference discussion
 Acknowledgements
 References
 
All the animals survived to the end of our protocol and no sign of infection was detected.

3.1. Ratios of neointimal-hyperplasia and histological findings

The ratio of intimal area in the control without TEBN and with 5 mg of TEBN (tacrolimus containing 1.0 wt%) were 0.43±0.26 and 0.07±0.04 at 1 week, 0.39±0.19 and 0.05±0.05 at 2 weeks, and 0.31±0.15 and 0.09±0.04 at 4 weeks, respectively (Fig. 5). TEBN inhibited neointimal hyperplasia significantly at each time point (1, 2 and 4 weeks).


Figure 5
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  		Fig. 5. Ratio of intimal area. The area of neointimal hyperplasia was significantly decreased in each time point of TEBN group compared with control group. The ratio of intima did not have significant change with a time course among the same group.

 
There were no significant differences in the ratio among 1, 2, and 4 weeks in each group. Representative photographs of anastomotic sections stained with HE are shown in Fig. 6.


Figure 6
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  		Fig. 6. Histological findings in the anastomotic site at one week after operation. HE staining of normal group (a) x40 (b) x200, control group (c) x40 (d) x200 and TEBN group (e) x40 (f) x200. The neointimal hyperplasia occurred at around the surgical suture (d). The neointimal hyperplasia is clearly decreased in TEBN group (f). Scale bar in (a), (c) and (e) is 500 µm and in (b), (d) and (f) is 100 µm.

 
3.2. Immunohistochemical analysis

Immunohistochemical staining for mesenchymal cells revealed that the cells constituting the intimal hyperplasia were positive for ASMA and SMemb (Fig. 7a,b,d,e). These findings meant that the cells that constituted neointimal hyperplasia consisted of dedifferentiated smooth muscle cells, myofibroblasts, and/or bone marrow-derived mesenchymal stem/progenitor cells. Endothelial cells (EC), which were stained with factor VIII immunohistochemically, covered the surface of the venous lumen in both groups and at each time point (Fig. 7c,f). There was endothelialization even at the site of inhibited neointimal hyperplasia in the TEBN group.


Figure 7
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  		Fig. 7. Immunohistochemical staining the anastomotic site at one week after operation. (a–c) x200 are control group, (d–f) x200 are the TEBN group. (a) and (d) were stained with ASMA. ASMA positive cells are shown in smooth muscle layer and neointimal hyperplasia. (b) and (e) were stained with SMemb (smooth muscle myosin heavy chain embryo type). The cells of neointimal hyperplasia were positive for SMemb. (c) and (f) were stained with Factor VIII. Factor VIII positive cells covered the surface of the inner lumen. Scale bar in each is 100 µm.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Conference discussion
 Acknowledgements
 References
 
The main finding of this study was that gradual sustained release of tacrolimus from TEBN was applied to perivascularly inhibited neointimal hyperplasia and preserved endothelialization after veno-venous anastomotic stricture of the IVC in a rat model.

Recurrent PVO can be localized at the site of the PV anastomosis or endocardial thickening of the PV ostia frequently resulting in diffuse PV sclerosis. The cause of PVO could be that the abnormal architecture of the pulmonary vasculature typically observed in patients with TAPVC could render these vessels more vulnerable to developing intimal hyperplasia, and ultimately obstruction, in response to distal anastomotic stenosis [11, 12]. After all, focal injury from the suture line, suture material, or handling of the vein tissue can also serve as a focal point of acute injury [5].

In the present study, we proposed a novel strategy to prevent PVO using an anti-scarring drug which was processed into controlled release. The drug selected for use is a major issue. Steroid is a major medicine for internal (oral or intravenous) systemic administration to prevent PVO conventionally. However, discontinuation of steroid can require re-operation and steroid therapy can induce serious side effects such as adrenal insufficiency or infection [3, 13]. On the other hand, our device may be able to reduce side effects, because our strategy is local administration of a drug. Sirolimus and paclitaxel are famous drugs for drug eluting stent (DES) in the field of coronary disease. These drugs are also a candidate for anti-scarring agent. However, we did not choose these drugs for our material, because paclitaxel is an anti-cancer drug (not appropriate for neonates), and sirolimus has a possibility of late thrombosis which is reported after DES treatment.

Our results of the previous report revealed that 5 mg of 1.0 wt% of TEBN in which tacrolimus amounted to 50 µg, prevented neointimal hyperplasia but did not affect reendothelialization after arterial anastomotic stricture [7]. There was no blood concentration of tacrolimus and no remarkable side effects in our rat models weighing from 300 to 350 g that was smaller than neonates. Thus, tacrolimus with its potent anti-inflammatory and less prothromobotic effects may be a promising compound for use in drug-eluting material or clinically applicable mode of treatment even in a field of neonates and pediatric cardiac surgery.

In conclusion, we have developed a novel sustained drug delivery device called TEBN. And we proposed novel strategy for preventing PVO after TAPVC repair. This cotton-wool shaped TEBN reduced neointimal hyperplasia and preserved endothelialization in a rat venous anastomotic model, suggesting that it will be a very promising material for vascular anastomotic stricture to prevent PVO.

4.1. Study limitations

This study was based on the rat veno-venous anastomosis model. The vascular healing process of the rat may be quite different from that of other animals including human. And there is a structural difference between veno-venous anastomosis and veno-atrial anastomosis. Further study is necessary to investigate whether the same effect is observed in a large animal model and veno-atrial anastomosis model.

There is study limitation in the measurement method of intimal area. We tried to make the sections carefully to avoid oblique, however, it could not be denied completely by our procedure. However, we believe that over and under estimation of the intimal area are offset by adopting three points of average.


   Conference discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Conference discussion
Acknowledgements
 References
 
Dr. A. Corno (Liverpool, UK): As the authors presented very well in the introduction, the pulmonary venous obstruction following surgery for total anomalous pulmonary venous connection is accompanied by substantial mortality/morbidity. The only approach accompanied by acceptable result is the one proposed by Francois Lacour-Gayet in '96 using the sutureless technique with in situ pericardium. And now this technique is followed by other institutions with quite good success.

The authors of this study devised a very interesting experimental protocol to study the possibility of preventing the pulmonary venous obstruction following surgery for total anomalous pulmonary venous connection. And they used a tacrolimus-eluting biodegradable nano-fiber — a very clever idea, I have to say — implanted in this experimental model of surgical stenosis in inferior vena cava in rats. The aim of the treatment was to avoid or prevent obstruction considering the neointimal hyperplasia as the main mechanism.

The histological results provided are quite encouraging. Furthermore, and first of all, the authors demonstrate the feasibility of their technique. The question remaining open mainly relates to the safety of the approach before any potential move into the clinical use in patients.

My questions are related to three main topics. First is the choice of the model. The authors used a rat as a model creating a surgical stenosis in inferior vena cava. The rat model is well known to have a very low complication rate in terms of thrombosis, compared to experimental models of other species of large size, particularly pigs and so forth. In addition to that, the authors didn't use any antiplatelet or anticoagulant treatment in the period of this study. Therefore, the first question is: are you considering now to move this same type of protocol to large-size animals with thrombogenesis more similar to the one of human beings, like pigs, or are you considering the potential increased risk of thrombosis when you move to another model?

Second topic is the size of the stent in correspondence of the created stenosis of the inferior vena cava. In the paper and in your presentation I didn't find any information regarding the size of the inferior vena cava after creating the obstruction. Could you please give us this type of information, because it's very important as a potential correlation with the size of the obstructed pulmonary veins in infants?

And final question is the species-to-species relationship. Do you have any information about the neointima formation and the relationship with the biodegradable stent when you move to another species, or do you have any correlation between rat model and human beings in terms of development of neointima?

Anyway, the authors are to be encouraged to continue their experimental studies in order to find all the answers before moving with this technique to the potential clinical application.

Dr. Mutsuga: With regard to your first question, I didn't show the thrombosis rate in this series. In the one-week series, there is significant difference between the control group and the TEBN group. Control group is 75% thrombosis rate and TEBN group was 25%. However, 2 weeks and 4 weeks, we have only 25% in both groups.

And the size of this material is about 5 mm, but this shape resembles a cotton-wool appearance. We can change the shape, divide 2 piece and 3 pieces, and it is easy to fit any types of surgical anastomosis which is real along the PV in neonates.

And with regard to your third question, the vascular healing process of the rat may be quite different from that of other animals, including human, and it is also different from venoatrial anastomosis. Further study is necessary to investigate whether the same effect is observed in a large animal model or venoatrial anastomosis model.

Dr. S. Sano (Okayama, Japan): I have a couple of questions to you.

First question is that is your drug-eluting stent with sirolimus different from usual stent used in coronary artery disease?

The second question is that the most difficult patient with recurrent PVO occurs distal to the suture line. Does your material prevent the neointimal proliferation along this stent or just inside the stent?

Dr. Mutsuga: The famous drug for using drug-eluting stent is sirolimus and paclitaxel. Paclitaxel is an anticancer drug. And we did not choose for our material because we think this material for neonates. And sirolimus is a famous drug also, but sirolimus effect is strong. The tacrolimus is 100 times less potential than sirolimus.

Dr. Sano: Did you compare the two? Did you compare the intimal proliferation between two?

Dr. Mutsuga: No, we have no data.

And with regard to the second question, we think and we believe this material is usual for the distal side of neointimal hyperplasia point.

Dr. V. Hraska (Sankt Augustin, Germany): I have just a comment. I wish it works, of course.

But I think it's a big difference between the native pulmonary venous stenosis and the secondary pulmonary venous stenosis. Recently we had a patient with a native pulmonary venous stenosis involving all veins. He was successfully operated on, sent home without obstruction. Now he is coming back on a regular basis because of recurrent obstruction. In this patient we have used drug-eluted stents with no effect.

So probably the mechanism is completely different between these two lesions. On the top of that usually surgery is successful in the secondary pulmonary venous stenosis. Nevertheless it sounds promising that something might be available on the market in the future.


   Acknowledgements
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Conference discussion
 Acknowledgements
References
 
We are grateful to Ms Ayuko Kimura for her technical assistance with the cell culture and histology.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Conference discussion
 Acknowledgements
 References
 

  1. Caldarone CA, Najm HK, Kadletz M, Smallhorn JF, Freedom RM, Williams WG, Coles JG. Surgical management of total anomalous pulmonary venous drainage: impact of coexisting anomalies. Ann Thorac Surg 1998;66:1521–1526.[Abstract/Free Full Text]
  2. Devaney EJ, Chang AC, Ohye RG, Bove EL. Maagement of congenital and acquired pulmonary vein stenosis. Ann Thorac Surg 2006;81:992–996.[Abstract/Free Full Text]
  3. Lacour-Gayet F, Zoghbi J, Serraf AE, Belli E, Pilot D, Rey C, Marcon F, Bruniaux J, Planche C. Surgical management of progressive pulmonary venous obstruction after repair of total anomalous pulmonary venous connection. J Thorac Cardiovasc Surg 1999;117:679–687.[Abstract/Free Full Text]
  4. Ricci M, Elliot M, Cohen GA, Catalan G, Stark J, de Leval MR, Tsang VT. Management of pulmonary venous obstruction after correction of TAPVC: risk factors for adverse outcome. Eur J Cardiothorac Surg 2003;24:28–36.[Abstract/Free Full Text]
  5. Caldarone CA, Najm HK, Kadletz M, Smallhorn JF, Freedom RM, Williams WG, Coles JG. Surgical management of total anomalous pulmonary venous drainage: impact of coexisting anomalies. Ann Thorac Surg 1998;66:1514–1520.[Abstract/Free Full Text]
  6. Lacour-Gayet F, Rey C, Planche C. Pulmonary vein stenosis. Description of a sutureless surgical procedure using the pericardium in situ. Arch Mal Coeur Vaiss 1996;89:633–636.[Medline]
  7. Mutsuga M, Narita Y, Yamawaki A, Satake M, Kaneko H, Suematsu Y, Usui A, Ueda Y. A new strategy for prevention of anastomotic stricture using tacrolimus eluting biodegradable nanofiber. J Thorac Cardiovasc Surg, in press.
  8. Bartorelli AL, Trabattoni D, Fabbiocchi F, Montorsi P, de Martini S, Calligaris G, Teruzzi G, Galli S, Ravagnani P. Synergy of passive coating and targeted drug delivery: the tacrolimus-eluting Janus CarboStent. J Interv Cardiol 2003;16:499–505.[CrossRef][Medline]
  9. Wallemacq PE, Reding R. FK506 (tacrolimus), a novel immunosuppressant in organ transplantation: clinical, biomedical, and analytical aspects. Clinical Chemistry 1993;39:2219–2228.[Abstract]
  10. Herlong JR, Jaggers JJ, Ungerleider RM. Congenital heart surgery nomenclature and database project: pulmonary venous anomalies. Ann Thorac Surg 2000;69:56–69.[Abstract/Free Full Text]
  11. Van Son JAM, Danielson GK, Puga FJ, Edwards WD, Dricolli DJ. Repair of congenital and acquired pulmonary vein stenosis. Ann Thorac Surg 1995;60:144–150.[Abstract/Free Full Text]
  12. Haworth SG, Reid L. Structural study of pulmonary circulation and of heart in total anomalous pulmonary venous return in early infancy. Br Heart J 1977;39:80–92.[Abstract/Free Full Text]
  13. Sands A, Craig B, Casey F. A possible role for steroid therapy in preventing postoperative stenosis in TAPVC. Cardiol Young 1998;8:240–242.




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