Introduction:
Cardiac arrhythmias are often treated by use of cardiac implantable electronic devices (CIEDs), which include pacemakers, implantable cardioverter-defibrillators, and devices for cardiac resynchronization therapy. As examined in a variety of studies, these CIEDs evoke a foreign body reaction and prolonged inflammatory response in the subcutaneous tissue that stimulate the formation of a fibrotic tissue capsule surrounding the implanted material [1-5]. In high risk patients, CIED-induced scar tissue formation and incomplete surgical healing often result in complications at the implant sites of CIED generators or leads, such as migration, erosion, dislodgement, or infection, which require additional procedures and dissection of the device pockets [6-9]. In addition, younger patients are receiving CIEDs and surviving long enough to require multiple pulse generator change-outs and lead revisions [10, 11]. Complication rates after generator or lead exchanges and upgrade or revision surgeries are considerable, and complication rates increase with each additional reoperative procedure [7, 11-15]. The thickness of the fibrotic tissue surrounding devices proportionately increases the difficulty of these procedures, while a lack of vascularization in the scar tissue greatly elevates the risks of post-surgery infection [4, 12, 16]. A product that mitigates the local tissue response to CIEDs and promotes healthy, vascularized tissue formation around the devices can improve patient outcomes and reduce complications of the implant or revision surgeries.
To address the difficulties caused by patients’ immune reactions to CIEDs and neurostimulator devices, a natural extracellular matrix (ECM) envelope product called CanGaroo (Aziyo Biologics) was developed to wrap electronic implants. Biologic ECM scaffolds are created from various processes and tissue sources to promote healthy, site-specific tissue remodeling in patients [17]. CanGaroo utilizes non-chemically crosslinked multilaminate sheets of decellularized, lyophilized porcine small intestinal submucosa (SIS) that are strong and supportive in structure, but compliant and porous enough to allow cell infiltration and achieve optimal tissue remodeling outcomes [18-20].
SIS is an ECM biomaterial that has been well-characterized in multiple regenerative medicine applications [18]. SIS ECM is rich in growth factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), as well as glycosaminoglycans (GAGs) and structural proteins, such as heparin sulfate, collagens, and fibronectin [21, 22]. These natural ECM structures and bioactive factors, absent in synthetic scaffolds, effectively reduce dense fibrous scarring by stimulating healthy tissue regeneration and angiogenesis [23-25]. This capacity is at least partially attributed to the fact that SIS promotes macrophages with a pro-remodeling, anti-inflammatory M2 phenotype versus a pro-inflammatory M1 phenotype [26]. When placed around an implanted electronic device, the SIS ECM envelope naturally resorbs over time and releases intrinsic biologic signals which mitigate fibrotic encapsulation normally caused by an inflammatory response to the foreign generator [27]. By supporting host cell infiltration and proliferation and promoting anti-inflammatory immune cell phenotypes such as M2 macrophages, SIS ECM envelopes create a conducive environment for constructive remodeling [28, 29].
In this study using a clinically relevant subcutaneous rabbit model, we tested the ability of CanGaroo ECM Envelopes to mitigate fibrotic tissue and scar formation induced by implantation of CIEDs for up to 26 weeks. The study also analyzed the natural resorption and remodeling of the SIS ECM envelopes over time, while evaluating neovascularization, normal collagen organization, and necrosis. Finally, by using full-size, clinically relevant CIEDs, we observed the ability of CanGaroo Envelopes to stabilize the devices in healthy tissue within the subcutaneous pockets of a model highly susceptible to device movement due to normal rabbit motion and behavior.