Letter to the Editor

Fever after BioSTAR® Implantation: Is It a Systemic Reaction to the Collagen Matrix? “The BioSTAR® septal repair implant for patent foramen ovale (PFO) closure is an exciting development, as it uses a bioabsorbable collagen matrix layer, which is thought to induce low host immune response and is absorbed and replaced by healthy host tissue. In the BEST study (first human trial with the implant), no major adverse events were reported and no evidence of a systematic inflammatory response was recorded. We report 2 patients who developed fever within 24-hours of receiving a BioSTAR implant for a PFO. All tests were negative for any evidence of infection and the patients became apyrexial within 24 hours of starting oral steroids. We are concerned that this may be a hitherto unknown complication of this device. Colleagues around the world should be aware of this and may have similar experiences to share.” _________________________________ Dear Editor, We wish to highlight a potential side effect of the septal repair implant BioSTAR® (NMT Medical, Boston, Massachusetts), which is a novel bioabsorbable device specifically designed for the closure of PFOs in children and adults.1 BioSTAR received its CE mark in 2007. BioSTAR uses an acellular purified porcine intestinal collagen layer (ICL) matrix (Organogenesis, Canton, Massachusetts) mounted on an MP35N STARFlex (NMT Medical) “double-umbrella” metal framework. Gradual remodeling occurs over a period of 2 years, during which the collagen is absorbed and replaced by healthy host tissue. Preclinical experiments have demonstrated a low immune response during gradual absorption and replacement by host tissue.2 A key advantage of this acellular Type I collagen matrix is thought to be its unique ability to induce a host connective tissue response that results in site-specific tissue regeneration as opposed to scar tissue formation.3,4 It is thought to be only mildly immunoreactive, as the collagen is acellular and RNA, DNA and pyrogen-free.5 The BioSTAR Evaluation STudy (BEST) reported no major adverse events during the study period and identified no major safety issues.1 It found no evidence of a systematic inflammatory response to the collagen. One patient in the study developed urticaria after implant that resolved spontaneously, with no rise in inflammatory markers. We report two patients who developed a fever after BioSTAR 28 mm implants for PFO closure. Patient 1, a 55-year-old male, developed a fever 24 hours after the implant. His inflammatory markers were normal. There was no clinical focus of infection. All laboratory blood culture results came back negative after 7 days. Serological testing for common viral infections was also negative. The echocardiogram did not reveal any pericardial effusion. The predischarge echocardiogram showed good ventricular function, no pericardial effusion and no shunt across the device. The patient was started on oral steroids after which the fever subsided. At 1-month follow up, the patient was doing well and was apyrexial and off steroids. The immunological tests revealed no abnormalities. Patient 2, a 68-year-old female, developed a fever 24 hours after the implant. Her inflammatory markers were normal. There was no clinical focus of infection. All laboratory blood culture results came back negative after 7 days. Serological testing for common viral infections was also negative. The predischarge echocardiogram showed good ventricular function, no pericardial effusion and no shunt across the device. The patient was started on oral steroids and the fever subsided within 24 hours. She was discharged 5 days after implant on a tapered-dose regimen of steroids. At the follow-up visit 1 month after discharge, the patient was doing well and was off steroids. We hypothesize that this unexplained fever could be a systemic reaction to the “acellular” collagen matrix. If this is so, then it raises some interesting and potentially serious issues with this device. It would be interesting and educational to know if other practitioners have had similar experiences with this device. Sincerely, *Dr. Jaspal S. Dua, *Dr Massimo Chessa, §Dr. Norman Jones, *Dr. Diana Negura, *Dr. Angelo Micheletti,*Dr. Mario Carminati *Department of Pediatric Cardiology and Adults with Congenital Heart Defect IRCCS-Policlinico San Donato, via Morandi 30, San Donato Milanese, 20097, Milan, Italy. E-mail: jaspaldua@yahoo.com §Centro di Riabilitazione Cardiologica, Ospedale Civile Di Vimercate, via Verdi Giuseppe 2, 20038, Seregno Milanese, Milan, Italy.

1. Mullen MJ, Hildick-Smith D, De Giovanni JV, et al. BioSTAR Evaluation STudy (BEST): A prospective, multicenter, phase I clinical trial to evaluate the feasibility, efficacy, and safety of the BioSTAR bioabsorbable septal repair implant for the closure of atrial-level shunts. Circulation 2006;31;114:1962–1967.

2. Jux C, Bertram H, Wohlsein P, et al. Interventional atrial septal defect closure using a totally bioresorbable occluder matrix: Development and preclinical evaluation of the BioSTAR device. J Am Coll Cardiol 2006;48:161–169.

3. Badylak SF. Xenogeneic extracellular matrix as a scaffold for tissue reconstruction. Transpl Immunol 2004;12:367–377.

4. Huynh T, Abraham G, Murray J, et al. Remodeling of an acellular collagen graft into a physiologically responsive neovessel. Nat Biotechnol 1999;17:1083–1086.

5. Hardin-Young J, Carr R, Downing G, et al. Modification of native collagen reduces antigenicity but preserves cell compatibility. Biotechnol Bioeng 1996;49:675– 682.