Bioengineering Strategies for Treating Neointimal Hyperplasia in Peripheral Vasculature: Innovations and Challenges

Figures

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  Figure 1. Overview of bioengineering approaches for neointimal hyperplasia treatment within peripheral vasculature. Various therapeutics including living cells, cellular products, and bioactive molecules are delivered through innovative modalities to target specific mechanisms involved in neointimal hyperplasia. These mechanisms include promoting re‐endothelialization, inhibiting vascular smooth muscle cell proliferation, reducing inflammation, and scavenging reactive oxygen species. MSC: mesenchymal stem cell; EPC: endothelial progenitor cell; VSMC: vascular smooth muscle cell; ROS: reactive oxygen species. Created in Biorender.

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  Figure 2. An overview of the cell types involved in neointimal hyperplasia progression, and a summary of existing clinical therapies for the condition. Healthy arteries possess three layers: the intima, a thin, single layer of ECs supported by the internal elastic lamina, the media, formed by VSMCs and ECM components and the adventitia, which is composed primarily of ECM components, supported by external elastic lamina. Endothelial dysfunction or denudation resulting from vascular manipulation causes immune cell recruitment and platelet adhesion and activation at the site. This also induces a phenotypic switch in VSMCs from a contractile to a synthetic and proliferative state. These proliferative VSMCs migrate from the intimal and internal elastic lamina, proliferate rapidly, and begin secreting ECM proteins. This creates the neointima, and when left unchecked, leads to luminal narrowing and eventual restenosis of the treated artery. Current clinical treatments for neointimal hyperplasia include drug‐eluting stents and drug‐coated balloons, along with systemic administration of drug therapies such as antiplatelet therapy.

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  Figure 3. Microneedling as a method of targeted drug delivery. A) Diagram of microneedle patterned balloon designed by Lee et al.[ 63 ] for improved endovascular drug delivery compared to traditional drug eluting balloons. B) Masson's staining of injured, non‐injured, drug eluting balloon‐treated (DEB), and microneedle‐pattern drug eluting balloon‐treated (MNDEB) iliac arteries in rabbits. The area stenosis, diameter stenosis, and plaque area were all quantified. MNDEB significantly lowered area stenosis, diameter stenosis, and plaque area compared to DEB. Reproduced (Adapted) with permission.[ 63 ] 2020, Elsevier. C) Fabrication and application of the microneedle cuff by Lee et al.,[ 65 ] and its hypothesized effect. D) Surgical application of the cuff in the rabbit abdominal aorta. E) Histological sections of the abdominal aorta. (a) and (b) represent the control and microneedle‐treated aortas after two weeks, respectively. (c) and (d) represent the control and microneedle‐treated aortas after four weeks, respectively. Reproduced (Adapted) with permission.[ 65 ] 2014, Elsevier.

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  Figure 4. Electrical stimulation as a potential therapy for neointimal hyperplasia. A) Deployment of the external conducting stent in vivo in rabbit jugular vein graft model, with comparison to non‐stented vein graft. B) Analysis of intimal area in electro‐stimulated stented vein grafts, non‐electro‐stimulated stented vein grafts, and non‐stented vein grafts. Adding the conductive stent showed a significant decrease in the intimal area compared to the non‐stented vein graft. C) H&E staining of explanted vein grafts 1 week post implantation. Vein grafts with the conductive stent had thinner intimas compared to the non‐stented graft. D–F) Images of explanted electronic blood vessels from the rabbit carotid interposition model. (D) shows a cross sectional view, (E) shows the anastomosis site between the electronic vessel and native carotid, and (F) shows a lateral view. G) H&E staining of electronic and native blood vessels. The electronic blood vessel stayed patent, with red arrows indicating the successful migration of host cells into the vessel. A–C: Reproduced (Adapted) with permission.[ 70 ] 2020, American Chemical Society. D–G: Reproduced (Adapted) with permission.[ 71 ] 2020, Matter.