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J Am Coll Cardiol, 2006; 48:161-169, doi:10.1016/j.jacc.2006.02.057
(Published online 7 June 2006). © 2006 by the American College of Cardiology Foundation |
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* Departments of Pediatric Cardiology and Pediatric Intensive Care Medicine, Georg-August University, Goettingen, Germany
Hannover Medical School, Hannover, Germany
Institute of Pathology, School of Veterinary Medicine, Hannover, Germany.
Manuscript received October 17, 2005; revised manuscript received February 9, 2006, accepted February 14, 2006.
* Reprint requests and correspondence: Dr. Christian Jux, Department of Pediatric Cardiology and Pediatric Intensive Care Medicine, Georg-August University, Robert Koch Strasse 40, D-37099 Goettingen, Germany. (Email: Dr.C.Jux{at}medizin.uni-goettingen.de).
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Abstract |
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BACKGROUND: The ideal septal occluder scaffold should promote the healthiest and most complete healing response while eventually facilitating the full resorption of the material and leaving "native" tissue behind, thus minimizing the potential for future complications from chronic foreign body and maintaining the possibility for later unobstructed transseptal access to the left atrium.
METHODS: The STARFlex occluders (NMT Medical Inc., Boston, Massachusetts) were modified by substituting the conventional polyester fabric for a bioengineered, acellular type-I collagen matrix derived from porcine submucosa with a heparin-coated surface (BioSTAR occluder, NMT Medical Inc.). Comparative transcatheter closure of ASDs was performed in young sheep (n = 36). Gross pathology and histopathology were obtained after follow-up periods ranging from 7 days to 2 years.
RESULTS: The STARFlex (control) devices were encapsulated time-dependently by ingrown fibrous tissue. Histology showed a mild but chronically persisting foreign body reaction. By contrast, BioSTAR devices exhibited a mild-to-moderate transient cellular immune response. Heparin coating of the BioSTAR surface improved the biocompatibility of the device by reducing surface thrombogencity. A remodeling process of the collagen scaffold, starting after 30 days in vivo, resulted in the full replacement of the matrix by host tissue after 2 years of follow-up.
CONCLUSIONS: The BioSTAR device is the first septal occluder with a totally bioresorbable matrix that is fully replaced by host tissue during the healing process. The promising results of this study support testing of the BioSTAR device in clinical trials.
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Despite considerable differences between the designs of the various septal occluder implants, all current commercially available devices consist of a metal framework and a synthetic fabric. Studies in experimental animals have characterized the histologic features and time course of the healing response and tissue ingrowth onto the device after implantation (1–7).
Although potential short- and mid-term complications such as residual shunts, thromboembolism, friction lesions, perforations, metal fractures, and rhythm disturbances have been well described (8–11), the long-term potential for adverse effects over several decades remains to be determined. At the same time, technologies are just now evolving for the treatment of left-sided heart disease, including percutaneous heart valve repair or replacement, arrhythmia studies, and therapies (e.g., pulmonary vein exclusion and left atrial appendage closure). An increasing proportion of the young population is likely to benefit from these technologies in the future. The maintenance of an unobstructed trans-septal access to the left atrium is of paramount importance for these interventional procedures, which may be hampered by metal-rich devices and synthetic fabrics.
The aim of this preclinical feasibility study was to provide a proof of the concept of biodegradable interventional ASD closure devices and to assess the efficacy and safety of a degradable occluder matrix in an experimental animal model.
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Methods |
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Following trans-septal puncture, a defect within the interatrial septum (Fig. 2A) was created by subsequent balloon dilation of the interatrial septum using balloons with diameters of 6, 10, and 15 mm, respectively (Opta Pro, Cordis Europe N.V., Roden, the Netherlands; and Balt CBV, Montmorency, France) over a guidewire inserted into the left atrium or a pulmonary vein. Heparin (200 U/kg after trans-septal puncture) and antibiotics (flucloxacillin 1.5 g at the start of the procedure) were administered intravenously.
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Device implantation/defect closure. After allowing for healing of the created ASD edges for two to three weeks, animals were divided randomly into two groups. Defect closure was performed using either conventional 23-mm STARFlex devices (control group, total n = 10) or 23-mm BioSTAR devices (total n = 26), respectively. Animals were anesthetized as described earlier. Before defect occlusion, heparin (200 units/kg intravenously) and antibiotics (flucloxacillin 1.5 g intravenously) were administered and balloon sizing of the defect was performed (Arrow, Reading, Pennsylvania) by ICE using color Doppler to assess for stop of flow. All devices were deployed transvenously through a 10-F–long Mullins-type transseptal sheath (Cook Inc., Bjaeverskov, Denmark) under fluoroscopy and ICE control as described previously (14). Color Doppler was used to assess potential residual shunting. Animals did not receive any anticoagulation during follow-up.
Device explantation/macroscopic and histologic examination. One day before sacrifice of animals with more than seven days of follow-up, device position was confirmed by both fluoroscopy and ICE control under general anesthesia as described earlier. A color Doppler examination was performed to assess residual shunting. The degree of residual shunts was quantified according to the protocol published by Boutin et al. (15). Animals from both groups were sacrificed 7 days, 30 days, 90 days, 180 days, 1 year, and 2 years, respectively, after defect closure (2 STARFlex control devices and 4 BioSTAR devices per time point). The 2-year follow-up group consisted of 4 BioSTAR devices only; in the 7-day group 2 BioSTAR devices without heparin coating were added.
Before sacrifice, each animal received an intravenous dose of heparin (400 U/kg body weight) to prevent postmortem clot formation on the device, followed by a lethal injection of pentobarbital. Complete autopsy was performed in each of the animals by two veterinary pathologists. The hearts and adjacent vessels were inspected for the gross appearance of the implanted device and then fixed in alcoholic formaldehyde (two parts ethanol 95%, one part formaldehyde [40% gas by weight] [vol/vol]) for 48 h. In all animals, sections from 6 to 8 representative locations from the right and left atrial wall including the device (3 or 4 from the distal and 3 or 4 from the proximal umbrella, respectively) and from both ventricular and septal myocardium were taken. Tissue samples were embedded in paraffin wax, serially sectioned, and stained with hematoxylin and eosin (general stain and evaluation of cellularity) or elastica van Gieson (elastic fibers). All gross and microscopic specimens were reviewed by two experienced veterinary pathologists (P. W. and M. B.).
Statistics. A two-tailed unpaired Student t test was used for comparison of the means of defect sizes and device size to defect size ratios between the two device groups. A value of p < 0.05 was considered statistically significant.
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Results |
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In the 30-day follow-up groups, one of the four BioSTAR devices and both STARFlex devices showed trivial residual shunts as assessed by color flow Doppler using ICE. In the 90-day follow-up groups, none of the four BioSTAR devices (but one of the two STARFlex devices) showed a trivial residual shunt. No residual shunting was observed in the 180-day and 1- and 2-year follow-up groups. All except one of the residual shunts (in a 30-day STARFlex explant) were confirmed later at postmortem examination. In all animals with residual leakage, a probe patent shunt was found at the margin of the device where the fabric was not firmly attached to the septum, resulting in space between fabric and septal wall.
Effect of heparin coating. Early thrombogenicity of the surface of the devices was compared after seven days in vivo. Heparin-coated BioSTAR devices showed considerably less deposition of blood-derived material on their surfaces than STARFlex control devices and uncoated BioSTAR devices (Figs. 3A to 3F). Histologic workup of these devices confirmed the presence of less friable material consisting of deposited plasma proteins and blood cells on heparin coated BioSTAR devices (Figs. 3G to 3I). Thus, the defects covered by these devices could still be seen owing to the transparency of the matrix (Figs. 3C and 3F). Very early signs of a beginning neo-endothelialization were observed in the form of a cellular monolayer on the surface of these devices (Fig. 3I).
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Conventional STARFlex devices were almost completely covered, except for the central pin and the metal arms, by a shiny, glistening surface layer through which the polyester fabric could be seen after 30 days in vivo (Fig. 4A). Devices with a longer follow-up in vivo showed a small amount of whitish, dull tissue underneath a complete glistening surface layer. Although the thickness of the tissue layer between surface and polyester fabric increased somewhat after 180 and 360 days compared with 90 days in vivo, the fabric remained visible through this tissue. The metal framework of the device was covered only by a shining film after 90 days. However, after 180 days in vivo, the ingrown tissue covered the straight parts of the metal arms, leaving merely the central pin and shoulder and elbow joint coils unincorporated (Figs. 4E and 4G).
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At gross pathology, BioSTAR devices showed a complete shining, glistening coverage on the device after 30 days in vivo (Fig. 4B). Compared to STARFlex control devices, BioSTAR occluders showed a significantly more thorough coverage of the device by grayish-white tissue at any time of follow-up during the entire study (Fig. 4).
Infolding ("scalloping") of the edges was not observed in the BioSTAR explants. Rather, in comparison to control devices, the BioSTAR devices exhibited a smoother interface toward the adjacent atrial tissue. However, in some occluders there was a tendency for contraction in the middle of the edges of the ICL matrix. Again, none of the devices showed any evidence of thrombus formation.
Histology of healing response and bioresorption of the occluder matrix. The histologic examination of STARFlex devices after 30 days in vivo revealed a low amount of loosely arranged and poorly vascularized young granulation tissue covered by neo-endothelium (Fig. 5A). At later stages during follow-up, the ingrown tissue on the polyester surface was found to be organized in a longitudinal orientation parallel to the surface of the device (Figs. 5B and 5C). After 180 days in vivo, encapsulation of the polyester was observed. The typical histologic finding consisted of a bilayered texture: dense avascular connective tissue was observed immediately underneath the neo-endothelium, whereas more loosely arranged fibers containing capillaries and small vessels were found in deeper segments of the ingrown tissue (Fig. 5C). The amount of newly formed collagen and elastic fibers increased over time.
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At later stages during follow-up, after 6 to 12 months in vivo, the ICL matrix had lost its structural continuity (Figs. 6G and 6I), although with some inter- and intraindividual variability; many sections exhibited only collagen fragments. In some sections, focal lymphocytic infiltration was found in the vicinity of the matrix (Fig. 6H). However, these lymphocytic infiltrations were always circumscribed and not seen in any area where the collagen had undergone full degradation.
After two years in vivo, the implanted collagen matrix was completely resorbed and fully replaced by autologous host tissue in 63% of all specimen locations (i.e., all serially cut sections in these locations were free of previously implanted collagen). In the remaining locations, only a few sections showed small remnants or tiny spots of the previously implanted ICL material. On the basis of these findings, it was calculated that approximately 90% of all implanted ICL material had been resorbed after two years in vivo. In comparison to the histology of earlier stages, the autologous repair tissue appeared relatively poor in fibroblastic cells but richer in connective fiber content. Especially the amount of newly formed elastic fibers increased over time (elastica van Gieson staining) (Figs. 6K and 6L). However, no fibrous capsule formation was found.
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Discussion |
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Healing response to control and BioSTAR devices. The healing response to STARFlex control devices described in this study was uncomplicated and resembled that described previously by others both in experimental animals (1,2) and humans (16). Complete neo-endothelialization in all sections was observed after three months in vivo. Ingrowth of granulation tissue started in the device periphery and proceeded preferably along the framework arms toward the central parts of the device. The thickness of the tissue layer on the device surface increased over time, finally reaching a steady state after one year where only some arm joints remained unburied by tissue. A mild to moderate but persistent foreign-body reaction was noted in our study as well as in previously reported studies close to the polyester fabric (2,16).
Intestinal collagen layer, which has been used as the occluder scaffold on BioSTAR devices, is a highly purified acellular bioengineered type I collagen derived from porcine submucosa. It is gradually resorbed by the host organism and subsequently replaced by host tissue (12,17). Following extensive experimental investigations, porcine small intestinal submucosa has been successfully used clinically in various fields of soft tissue augmentation, to treat hernias and in tendon repair (18–20), stress urinary incontinence (21), leg ulcers (22), plastic surgery (23), and vascular surgery (24).
The BioSTAR devices showed an accelerated healing response compared with the control implants. First signs of a single-layer neo-endothelium were observed already after 7 days in vivo (Fig. 3I). A state of complete neo-endothelialization was observed after 30 days (Figs. 6A and 6B). This early neo-endothelialization argues in favor of the biocompatibility of the BioSTAR device. A layer of ingrown young granulation tissue that was in smooth continuity with the adjacent atrial tissue was found on the BioSTAR devices. The BioSTAR device showed an excellent efficacy in ASD closure. Although animal numbers involved in this study are too low to reach statistical power, the observed lower incidence of early residual leakage with the BioSTAR device is potentially attributable to the better alignment of the device to the surface of the atrium. Furthermore, the fact that the BioSTAR matrix is a foil rather than a knitted mesh may also decrease early residual shunting as observed as "foaming" through the polyester. However, larger scale clinical studies will be needed to verify this hypothesis.
Thrombogenicity of control and BioSTAR devices. Contact between blood and a foreign material is known to activate the coagulation and complement systems. Thrombus formation and thromboembolism due to the thrombogenicity of the implanted occluder surface are rare but clinically well-described potential complications. The vast majority of thrombi formations on ASD occluder devices occur in the early vulnerable phase before a protective complete neo-endothelialization on the device surface has developed (8,25). The BioSTAR devices as used in this study were heparin-coated, which led to a reduced thrombogenicity of their surface. The amount of blood cells and deposited plasma protein on the surface after seven days in vivo was significantly lower compared with both the uncoated BioSTAR devices and the polyester matrix of conventional STARFlex devices. Heparin surface coatings have been shown to reduce blood activation upon contact with various artificial surfaces, such as bypass tubings, intravascular catheters, stents, and Nitinol devices (26–28). The surface-bound heparin triggers a cascade of effects, including the initial interaction between heparin and antithrombin, reducing fibronectin deposition, inhibition of complement and platelet activation, and reduction of an initial inflammatory response (29–31).
Immunogenicity of control and BioSTAR devices. The ICL collagen matrix exhibited a surprisingly low immune response, given its xenogenic origin. Whereas the polyester fabric showed a mild but chronically persisting foreign body reaction, the BioSTAR matrix led to a transient, focally circumscribed mild-to-moderate lymphocytic immune response. Cellular infiltration was not observed once the implanted collagen matrix had undergone full degradation. The low immunogenicity may be explained by various facts. First, type I collagen, as the most abundant protein component of the extracellular matrix, is a highly preserved protein in evolution (32,33). Second, the particular cleaning process of the porcine submucosa removes cells and cellular debris, to which most of the immunogenicity is attributed, without damaging the native collagen structure (12,34,35). Finally, molecular studies showed that porcine small intestinal submucosa elicits a predominantly TH2-restricted immune response, consistent with a bioresorbable remodeling reaction rather than a graft rejection (36).
Biodegradability of the BioSTAR matrix. The unique feature of the ICL matrix, however, is its biodegradability. Remodeling of the collagen matrix started after 30 days in vivo with host cell infiltration. Autologous fibroblasts were observed to infiltrate the collagen implant, leading to the deposition and rearrangement of new host collagen. After 180 days in vivo, a significant degree of degradation of the matrix was obvious. Resorption of the material occurred by phagocytosis. In addition, collagen is known to be metabolized by various endopeptidases such as matrix metalloproteinases, serine, cysteine, and aspartic proteases (37). Through its ability to interact with the host, the purified collagen first acts as a scaffold for new tissue ingrowth. The matrix assimilates with host tissue as it is initially augmented by host tissue before it is resorbed, finally leaving nothing but autologous tissue behind.
Conclusions. This study proves the feasibility of the concept of biodegradable interventional ASD closure devices. The BioSTAR device is the first septal occluder device with a totally biodegradable matrix. It is, therefore, a step away from a mere mechanical septal defect occluder toward a septal repair device. Although the BioSTAR device only leaves a minimal amount of foreign material (i.e. the framework) behind, thus minimizing the potential risk for future complications from chronic foreign body and facilitating future trans-septal access to the left atrium, work is currently underway to develop a resorbable and fully retrievable occluder framework. This research may eventually result in various totally bioresorbable cardiovascular devices.
Because of the promising results of this experimental study, the BEST (Biostar Evaluation STudy) trial, the first in human investigation of this new technology, has been scheduled.
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Acknowledgments |
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Footnotes |
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