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.