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.