When a patient experiences 70 percent or greater stenosis in the carotid artery — a condition that can cause lack of cerebral blood flow, stroke, and in some cases, death — surgeons perform a procedure known as carotid endarterectomy (CEA) to remove the plaque causing the artery stenosis.1,2 The procedure consists of a longitudinal incision made from the common to the internal carotid artery, allowing for removal of the plaque that deposits in the bifurcation.

A synthetic, resorbable scaffold can physically support the damaged tissue during the reparative process while minimizing inflammation and promoting endogenous regeneration without the use of biologics. (Credit: Secant Group)

Once surgeons remove the plaque deposits from the carotid bifurcation, they typically close the surgical site with a patch.3 This technique minimizes the effect of neointimal hyperplasia, or thickening of the arterial walls, and reduces the incidence of scarring.4 The patch also allows for a larger lumen diameter compared to a primary closure, which results in a lower risk of restenosis or occlusion.5

Today’s most commonly marketed prosthetic patches are constructed from nonresorbable expanded polytetrafluoroethylene (ePTFE) and polyester.4 Designed to permanently replace damaged carotid tissue, these synthetic patches can cause inflammatory responses in the body due to the persistent nature of the patch.4 With approximately 100,000 CEAs performed in the United States annually, healthcare professionals need an alternative arterial patch — ideally, one that supports the healing of the damaged tissue and ultimately resorbs into the patient’s body, reducing the risk of a chronic inflammatory response.6

Researchers at Secant Group, an innovator in the development and transformation of next-generation biomaterials, structures, and medical textile designs for restoration of the human body, aim to meet that need. The goal is to provide a synthetic, resorbable scaffold that can physically support the damaged tissue during the reparative process while minimizing inflammation and promoting endogenous regeneration without the use of biologics.

Design

Secant Group’s research team considered several criteria when designing the carotid patch. The patch needed to be compliant, impermeable, and exhibit high suture retention. It was also necessary for the patch to be constructed from resorbable materials while being non-thrombogenic and nonimmunologic, which gave the team the opportunity to utilize its deep expertise of bioresorbable materials into the design.

Adhering to the chosen criteria, the team designed a composite patch consisting of a polyglycolide-woven textile infused with a glycerol ester elastomer. To create the textile base, poly(glycolic acid) (PGA) was melt-extruded into fibers (see Figure 1a) to be used in yarns for the textile scaffold base structure (see Figure 1b). PGA offers a degradation profile similar to that of the arterial regeneration timeline.

Fig. 1 - The bioresorbable patch was constructed by melt extruding the PGA fibers (a) that were used to create the scaffold textile base structure (b). The scaffold was spray-coated to infuse PGS into the structure, then cured to create an impermeable patch (c).

The team characterized many different weave iterations before selecting one that met specific criteria. The final textile possessed a thin profile, demonstrated high flexibility, and exhibited high suture retention. The weave pattern, yarn size, and porosity had to be fine-tuned, as each element specifically contributed to the physical properties and behavior of the structure.

The textile was then infused with a poly(glycerol sebacate) (PGS) solution using a spray-coating procedure and thermally cured in a vacuum oven to functionally improve the device. PGS offers many advantages, including the creation of a blood-tight structure, while providing the desired physical strength and degradation properties. PGS is also inherently immunomodulatory and antimicrobial in nature. The degradation products of PGS consist of natural metabolites, making it safe for resorption.

Optimization Through Benchtop Testing

The researchers achieved design optimization through several testing mechanisms adopted by ASTM International and ISO standards. Permeability, suture retention, and probe burst were measured using methods adopted by ISO 7918:2016, while patch flexibility was measured according to ASTM D1338. Researchers also used a novel method and apparatus to characterize the patch’s resistance to keyholing, a common concern with arterial patches that can cause blood effusion from the suture site. The team used scanning electron microscopy to view and evaluate the coating distribution along with thermal gravimetric analysis to quantify the amount of coating. Finally, cytotoxicity was evaluated using the ISO 1099 MEM extraction method resulting in scores of 0 at the neat concentration.

Large-Animal Study

With a final iteration of the patch in hand, the researchers launched a large-animal study. The patch was cut into 4 × 1.5 cm football shapes and implanted into six crossbred domestic Yorkshire pigs, one of which received two implants — one in each carotid artery. The terminal time point for the study was three months.

Objectives of this study included 1) evaluating the handling characteristics of the patch; 2) evaluating changes in artery diameter over time using angiography; 3) evaluating patency of the patch at two weeks, one month, and three months using angiography; and 4) evaluating neovessel formation and biocompatibility of the patch at three months via histopathology.

Fig. 2 - Cross sections of the repaired carotid artery at three months, stained with Movat’s pentachrome (a) and for smooth muscle actin (b), demonstrating endogenous regeneration of the repair site.

The team identified some areas for improvement during the study. It was noted that the football shape of the patch had directionality due to a difference in flexibility. The suture retention along the edges of the patch was adequate but experienced some tear-outs at the ends (the surgeon noted that this is routine with other materials). At day 0, the angiographies (six out of seven patches) showed slight narrowing at the proximal and distal ends. However, most of the narrowing (five out of six) resolved in the two-week angiographies. One patch needed to be explanted due to blood leakage at the two-week time point. At four weeks, the angiographies showed kinks in four out of six arteries. Researchers believe the kinks may be due to the transition of the mechanical load from the degrading patch to the newly formed vascular tissue, which had yet to fully mature. At three months, the angiographies showed fully patent arteries where it was difficult to distinguish the location of the implant site.

The animals were sacrificed at the three-month time point and histology was performed on the implantation site. Cross sections of the carotid artery were taken at various locations along the patch site and stained with Movat’s pentachrome. Complete resorption of the patch material and remodeling of the vascular wall with reendothelialization of the treated artery was observed. Staining for smooth muscle actin showed widespread smooth muscle cell infiltration, which is indicative of healing toward a fully muscularized tissue. There were no adverse effects on the vascular lumen, such as neointimal formation or thrombosis.

Conclusion

Overall, the patch was effective in the carotid endarterectomy procedure, and the material was fully resorbed, supporting endogenous regeneration of the carotid artery. Unlike other biodegradable systems, arterial neotissue formation was achieved despite the absence of any biologics. Although promising results were obtained, the patch design was further improved by altering the textile scaffold to be isotropic and more flexible, which enables easier utilization of the patch. The PGS formulation was also optimized to increase the elasticity of the polymer coating. In addition, reduction in cure time increased the coating’s flexibility and increased the crystallinity of the PGA yarn to slow the degradation rate to better match the arterial regeneration.

References

  1. Marsman MS, Wetterslev J, Jahrome AK, et al. Carotid endarterectomy with primary closure versus patch angioplasty in patients with symptomatic and significant stenosis: protocol for a systematic review with metaanalyses and trial sequential analysis of randomised clinical trials. BMJ Open 2019;9:e026419. doi:10.1136/ bmjopen-2018-026419.
  2. Collaborators∗ N. A. S. C. E. T. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. New England Journal of Medicine. 1991;325(7):445–453. doi: 10.1056/nejm199108153250701.
  3. Paraskevas KI, Robertson V, Saratzis AN, Naylor AR. An updated systematic review and meta-analysis of outcomes following eversion vs. conventional carotid endarterectomy in randomised controlled trials and observational studies. European Journal of Vascular and Endovascular Surgery. 2018;67(5):p. 1632. doi: 10.1016/ j.jvs.2018.03.400.
  4. Muto, Akihito et al. “Patches for carotid artery endarterectomy: current materials and prospects.” Journal of vascular surgery, Vol. 50,1 (2009): 206-13. doi:10.1016/ j.jvs.2009.01.062
  5. Ho, Karen J. et al. Intermediate-term outcome of carotid endarterectomy with bovine pericardial patch closure compared with Dacron patch and primary closure. Society for Vascular Surgery. 2012; Volume 55, Issue 3, 708–71.
  6. Lichtman JH, Jones MR, Leifheit EC, et al. Carotid endarterectomy and carotid artery stenting in the US Medicare population, 1999-2014. JAMA. 2017;318(11):1035–1046. doi: 10.1001/jama.2017.12882.

This article was written by Ryan Smalley, Associate Scientist – Research, Secant Group, Telford, PA. For more information, visit here .


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This article first appeared in the December, 2019 issue of Medical Design Briefs Magazine.

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