Discussion:
Presented with the challenges and complications associated with
subcutaneous device implantations, this study demonstrated the ability
of CanGaroo ECM Envelopes to secure clinically relevant CIEDs and
mitigate fibrotic tissue capsule thickness in a pre-clinical animal
model. The rabbit model that was used was highly susceptible to device
movement in the pocket due to the range of motion of the animals and
ability to directly aggravate the surgical site through rolling or
rubbing. Devices also did not have leads attached, which usually limit
the mobility of CIEDs. Despite these vulnerabilities, SIS ECM envelopes
securing the CIEDs substantially reduced the incidence of device
flipping by 5 times compared to the group containing CIEDs without
envelopes. Device flipping could cause lead dislodgement in clinical
patients [30]. This type of movement also creates friction and
abrasion, which in more long term models or clinical cases could develop
into CIED erosions and infections or the devices migrating outside of
the subcutaneous pocket [8]. It should be noted that no erosions
were observed in the study, as compared to a previous study utilizing a
thin-skinned mouse model and customized biotelemetry devices [31].
In addition to stabilizing CIEDs in the study, use of SIS ECM envelopes
correlated with a general reduction in thickness of the fibrotic
capsule. However, capsule thickness varied greatly between different
animals leading to high standard deviation in the data. Future studies
could draw out significance by increasing animal numbers or screening
animals to better standardize the immune system being challenged. SIS
ECM envelopes mitigate the foreign body response to reduce fibrosis and
promote a favorable environment for constructive tissue remodeling.
CanGaroo is composed of non-crosslinked SIS ECM that elicits M2
macrophage polarization and production of IL-10 and other
anti-inflammatory cytokines [24, 26, 28, 29, 32-34]. This ability is
in direct contrast to synthetic scaffolds, which often favor a
pro-inflammatory M1 macrophage phenotype, especially when the implanted
material is non-degradable [24, 26].
SIS scaffolds contain a natural three-dimensional architecture that
allows cells to migrate throughout the matrix. Fibronectin, laminin, and
proteoglycans supply attachment sites to enable cells to remodel and
organize new tissue [18]. GAGs of the proteoglycans also bind and
protect important growth factors that are utilized in a controlled, time
dependent manner by cells. Several of these growth factors in SIS
promote scarless healing at the site of application, especially bFGF.
bFGF accelerates wound healing and regulates organized collagen
deposition by fibroblasts [35]. SIS recruits a variety of other
cells types important for sustained tissue remodeling including
endothelial cells, epithelial cells, and mesenchymal stem cells
[36]. Cells recruited and signaled during the natural remodeling of
the scaffold promote tissue regeneration, compared to cases of synthetic
materials that often stimulate excess fibrosis or formation of poorly
organized connective tissue [18].
Besides mitigating fibrosis, treatment with SIS ECM envelopes also
improved angiogenesis and neovascularization. Using a 0 to 4 scoring
criteria where a greater score represented more capillary proliferation,
subcutaneous tissue surrounding CIEDs with CanGaroo Envelopes scored
significantly higher than tissue adjacent to CIEDs without envelopes.
This result is at least partially due to SIS’s growth factor milieu of
angiogenic growth factors such as TGF-β, bFGF, and VEGF. These proteins
are not only anti-inflammatory but promote angiogenesis by upregulating
endothelial cell migration and proliferation [18, 21, 37, 38]. Cells
also mediate the proteolytic cleavage and release of matricryptic
peptides from the scaffold’s ECM, which have similar angiogenic effects
on both endothelial cells and perivascular stem cells [39, 40]. The
natural porosity of SIS ECM scaffolds supports cell infiltration and
ultimately allows for fast and efficient vessel and capillary growth
[18]. Generating healthy, vascularized tissue around the device
facilitates easier and successful CIED change-outs and lowers the
incidence of infection, which may be particularly important in a younger
patient who will likely experience multiple change-outs [11, 12].
These angiogenic advantages also translate to positive surgical outcomes
in a variety of other clinical cardiovascular applications of SIS such
as pericardial closure and cardiac and vascular reconstruction [41,
42].
Properly vascularized tissue grants the body’s immune and regenerative
cells direct access into the CIED pocket to aid in the steady resorption
and remodeling of the CanGaroo Envelope. This process not only releases
peptides from the SIS ECM with angiogenic potential, but the peptides
also contain inherent antimicrobial properties, thereby assisting in the
prevention of bacterial infections of the subcutaneous pocket [18, 38,
43-45]. Many synthetic or crosslinked scaffolds are non-degradable or
can take years or more to fully resorb [24, 26]. In this rabbit
study, CanGaroo Envelopes showed steady resorption and remodeling over
time with about 26.8% of the starting material remaining after 26
weeks. The subcutaneous space in rabbits is slower to remodel
biomaterials than humans, but full turnover of the remaining ECM would
have been achieved soon thereafter. Although this timetable may be
different from clinical cases, the ability of the host tissue to utilize
and remodel the SIS ECM envelope into native tissue is conserved.