Patch Materials for Pulmonary Artery Arterioplasty and Right Ventricular Outflow Tract Augmentation: A Review

Autologous pericardium was the first non-synthetic material to be compared to synthetic materials for use in the reconstruction and repair of the RVOT and pulmonary arteries [17]. In the early 1970s, multiple studies confirmed the superiority of autologous pericardium over a previous clinical standard of formalinized polyvinyl (Ivalon) and indicated similar performance to polytetrafluoroethylene (PTFE) [18, 19]. Autologous pericardium is a logical choice, as it is free of cost, non-immunogenic, and can be sourced directly from the patient during surgery [20‐22]. However, a primary limitation of autologous pericardium is lack of availability. Many CHDs require staged surgical procedures and a lack of available tissue for surgery is not an uncommon occurrence [17]. In its natural, unfixed state, autologous pericardium also tends to shrink or curl, which renders it difficult to handle surgically. Additionally, unfixed autologous pericardium may progressively dilate in situ, predisposing patches to aneurysm [20]. An example of RVOT patch aneurysm formation is shown in Fig. 1. Importantly, the significance of the potential complication of dilatation is not universally agreed upon, and some researchers maintain that the benefits of fresh autologous pericardium outweigh the potential risks [23]. A recently published study by Tatari et al. demonstrated outcomes of fresh autologous pericardium RVOT patches at a mean follow-up interval of 13.48 ± 7.38 years [23]. Of a 72-patient cohort, 53 (73.6%) showed no RVOT dilatation, 17 (23.6%) showed mild RVOT dilatation, and 2 (2.8%) had RVOT aneurysms [23]. In the same study, histologic analysis confirmed the positivity of explanted patches for CD31, CD34, smooth muscle alpha-actin, and von Willebrand factor (VWF) [23]. In a separate study, Hibino et al. showed histologically at three-year post-implant that autologous pericardium used for pulmonary artery arterioplasty differentiates to resemble tissue of the pulmonary artery (Fig. 2) [3]. This suggests that unfixed autologous pericardium has improved potential to differentiate into vascular wall tissue, at the risk of RVOT aneurysm.

Glutaraldehyde fixation is a method of treating autologous pericardium that makes it easier to handle and improves material stiffness, reducing the risk of aneurysm [20]. This tissue processing technique can be performed intraoperatively, resulting in little delay and no need for separate procedures to harvest and implant the material [20]. In a comparison between saline- and glutaraldehyde-treated pericardial patches used in RVOT reconstruction, Messina et al. found reduced RVOT dilatation in the glutaraldehyde group 6 months after the operation [24]. The severity of dilatation (+ 0 to + 4) was assessed relative to the size of the aortic valve annulus [24]. Lee et al. found that longer fixation times in glutaraldehyde resulted in improved extensibility and better fixation compared to saline-treated controls, but a higher risk of long-term calcification [25]. An example of RVOT patch calcification is shown in Fig. 3. Tatari et al. evaluated 72 untreated autologous pericardial RVOT patches histologically, finding 7 (9.72%) were mildly calcified and 7 (9.72%) were moderately calcified at a mean follow-up of 13.48 years [23]. No severe calcification was noted. In terms of overall clinical performance, one study with a median follow-up time of 3.7 years compared a cohort of unprocessed autologous pericardial RVOT patches and glutaraldehyde-fixed autologous pericardial patches to a cohort of alternative patch materials covered later in this review, including homograft pericardium, bovine pericardium, and porcine small intestinal submucosa extracellular matrix (ECM) [26]. Autologous pericardial RVOT patches had a 7.3% reintervention rate, as opposed to a 15.9% rate in the total cohort [26].

Homograft pericardium, sourced from genetically unrelated human donors, is considered inferior to autologous pericardium by performance metrics, but its increased availability makes this material a favorable option [27]. Homografts exhibit handling properties very similar to those of autologous pericardium and are often treated with glutaraldehyde to improve tissue handling characteristics, decrease the likelihood of in situ aneurysm, and reduce antigenicity [27, 28]. Unfortunately, calcification is a common complication associated with homograft pericardium and is usually attributed to inflammatory processes incited by transplant antigens [11]. Gluck et al. reported their institutional experience with cryopreserved homograft pericardium in a study with a mean follow-up time of 5.05 years and range of 3 days to 12.41 years [27]. Twelve patients (8.96%) underwent reoperation and 18 patients (13.4%) underwent catheter interventions at sites of patch implantation [27]. In another study, when compared to multiple other standard patch materials including decellularized porcine small intestine submucosa (CorMatrix™), bovine pericardium, and autologous pericardium, homograft patches were found to have the highest rate of surgical or catheter-based reintervention, 18.5%. This outpaced the study average of 15.9% and the autologous pericardium group rate of 7.3%, although these differences were not statistically significant [26]. Hopkins et al. demonstrated a 20.3% failure rate for cryopreserved homograft patches compared to 0% and 4.9% for decellularized allogeneic pulmonary artery patches (MatrACELL™) and polytetrafluoroethylene (PTFE) patches, respectively, over an approximate three-year follow-up period [11].

Autologous ECM constructs have been created, harvested, and applied for RVOT and pulmonary artery reconstructive surgeries using an in situ tissue engineering approach to develop tissue-engineered vascular grafts (TEVG) [5, 17, 45, 46]. Cylindrical 19-French silicone molds were embedded into the upper abdominal subcutaneous space and grown for 4 weeks to 4 months. TEVGs were harvested during the reconstructive surgery and cut open to be used as patch materials [5, 17, 46]. Histologic analysis prior to implantation characterized TEVGs as having smooth luminal surfaces and walls mainly composed of collagen fibers and some fibroblasts (Fig. 5) [5, 45].

This patch design was first clinically tested by Kato et al. who found no aneurysm formation or stenotic change of the patch after nine months in a single patient [17]. In another clinical study, researchers treated the TEVG patch with 70% ethanol to improve mechanical and surgical handling properties, similar to approaches tested with autologous, homograft, and xenograft pericardium [45]. Ethanol treatment dehydrates tissue and destroys cells ultimately “killing” the graft, but it is believed that tissue regeneration is enabled by the unique ECM structure that remains, even after such tissue preparation [45]. An analysis of the suture retention strength and burst pressure of this patch material indicated that it is safe to use for pulmonary arterioplasty [45]. Treatment of the TEVG material with 70% ethanol prior to implantation has continued in all subsequent studies thus far [5, 45, 46]. In a four-patient study, Nakatsuji et al. reported no mortality and satisfactory pulmonary dilation in all patients with an average follow-up period of 18.3 (range, 4–48) months [5]. One patient required right pulmonary artery augmentation due to bronchus compression-induced restenosis. In a separate manuscript reporting results from the same study, two additional patients underwent pulmonary artery augmentation via TEVG patches without complications noted [46]. Fibroblast invasion and collagen deposition, indicators of tissue remodeling, have been seen on histologic examination of TEVG patches without elastic fibers or smooth muscle cells in animal models, but no such clinical data exist, since no human patches have required explantation [5, 46]. The potential of TEVGs to enable neotissue development is a major driver behind this technology, but histologic analyses of patches post-explant from clinical studies are not available to evaluate this possibility further.

In future studies, several points are of interest that can improve the assessment of patch efficacy. A uniform evaluation and consistent criteria for intervention need to be applied across all patch types. While angiographic metrics are necessary for evaluating the degree of stenosis, assessment of angiographic measurements is challenging due to a lack of normative data regarding pulmonary artery size with no accepted z-scores. Additionally, there is no clear pressure gradient defined for intervention for RVOT stenosis or branch pulmonary arteries. In general, “significant stenosis is obvious when there are measurable gradients of > 20 to 30 mmHg across the stenotic area, when there is elevation of the right ventricular or proximal main pulmonary artery pressure to greater than one half to two-thirds of systemic pressure secondary to the more distal obstruction, or when there is relative flow discrepancy between the 2 lungs of 35%/65% or worse [47].” Differences in the mammalian regenerative capacity of the cardiovascular system have been shown to vary with age. Examples include the marked improvement in ventricular function that may occur after surgical correction of an anomalous left coronary artery arising from the pulmonary artery or in children with univentricular hearts who present enormous morphological changes after volume unloading [48]. The correlation of increased regenerative potential with age may be of critical importance when considering the possible regenerative capability of future patch materials. Differences in the mechanical cues imparted by the material and sensed by the resident cells may have a profound effect on patch remodeling and remodeling of the surrounding native vasculature. One such example is the variability of calcification of ePTFE patches depending on their location of implantation in patients with CHD [1]. Quantification of the differences in hemodynamics and mechanical stresses between patch materials applied to treat various congenital lesions will likely be of importance to better understand differences in outcomes. Although patches derived from human cells have a logical advantage in biocompatibility, it is difficult to test this possibility in preclinical studies. Uniform histologic analysis of explanted tissue for assessment of inflammation, fibrosis, necrosis, degenerative changes, eosinophil response, presence of foreign body giant cells, neovascularization, and calcification is key toward defining the immunologic response and capacity of patches to enable the regeneration of native vascular architecture [2].